Clinical trial NCT03266172
Conditions: Autoimmune Diseases
Keywords: immediate release tablet GSK2982772 Modified release minitablet
Sponsor: GlaxoSmithKline
Start date: 2017-09-27; Completion date: 2018-11-21
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
GSK2982772 is a first-in-class, highly selective, receptor-interacting protein-1 (RIP1) kinase inhibitor being developed for the treatment of inflammatory bowel disease, plaque psoriasis (PsO), rheumatoid arthritis (RA) and other disease conditions. PK data from the first time in human (FTIH) study for GSK2982772 showed that the half life of GSK2982772 was short (approximately 2 to 3 hours). A once daily (QD) formulation would be more convenient from a subject perspective and could offer the advantage of providing a flatter GSK2982772 concentration time profile. Following completion of Parts A and B, it was determined that the slowest minitab formulation provided a PK profile suitable for QD dosing but this formulation was susceptible to a food effect. This study will evaluate the pharmacokinetics of GSK2982772 following administration of different minitab MR formulations in a capsule relative to an IR reference tablet formulation, the pharmacokinetics of selected MR formulation in capsule following repeat doses for 3 days and to compare the pharmacokinetics of GSK2982772 following administration of MR tablet formulations in the fed and fasted state relative to an IR tablet formulation. The study is divided into three parts: Part A will be a non-randomized 6 periods, sequential, 6-way fixed sequence design in which up to 4 MR minitab formulations in a capsule will be evaluated. Periods 1, 2, and 3 will evaluate a slow MR release duration (nominally 24 hours), a fast MR release duration (nominally 10 hours), and IR tablet respectively. Periods 4, 5 and 6 will have flexible dose regimen and it will depend on the outcomes of Period 1 to 3. Subjects will be admitted to the clinic the previous day before dosing. Each in-patient period will consist of 3 days and 2 nights followed by a minimum washout period of 7 days between doses, for both Part A and C. In Part A and C, 16 healthy subjects will be enrolled such that at least 12 evaluable subjects complete the study. Part B will be an open-label, repeat dose study in which the selected MR minitab formulation in capsule will be evaluated. Each in-patient period will consist of 5 days and 4 nights. There will be a minimum of 7 days washout period between the last morning dose of one period and the first dose of the next period. In Part B, 10 healthy subjects will be enrolled such that at least 6 evaluable subjects complete the study. Part C of the study will be a non-randomised 6 period, sequential, fixed sequence crossover design in which MR tablet formulations will be evaluated. Periods 1 and 2 will evaluate single dose administration of a 240 milligram (mg) MR tablet and the 240 mg IR tablet (reference), respectively. Periods 3, 4, 5 and 6 will be flexible and the dosing regimen will be dependent on the outcome of Periods 1 and 2.

Detailed description:

Arms: arm 1: Subjects in Part A will receive GSK2982772 MR (Period 1, 2, 4, 5 and 6) and GSK2982772 IR (Period 3) arm 2: Subjects in Part B will receive GSK2982772 MR arm 3: Subjects in Part C will receive GSK2982772 MR (Period 1, 3, 4, 5 and 6) and GSK2982772 IR (Period 2)
Interventions: intervention 1: GSK2982772 Modified Release intervention 2: GSK2982772 Immediate Release
Intervention descriptions: intervention 1: GSK2982772 MR will be available as prototype MR minitablet in capsules with unit dose strength of 60 mg in Part A. In Part B, GSK2982772 MR minitablet in capsules with unit dose strength of 15, 30 or 60 mg will be administered by subjects for Days 1 to 3. In Part C, GSK2982772 MR tablet with unit dose strength of 240, 360 or 480 mg will be administered by subjects. GSK2982772 MR will be administered orally with 240 mL of water. intervention 2: In part A, GSK2982772 IR tablet will be available with unit dose strength of 30 mg and the total dose administered by subjects will be 120 mg (4 tablets of dose strength 30 mg) orally with 240 mL of water. In part C, GSK2982772 IR tablet will be available with unit dose strength of 30 mg and the total dose administered by subjects will be 240 mg (8 tablets of dose strength 30 mg) orally with 240 mL of water.

Protocol documents:
Prot_001.pdf: 
2017N315344_02
CONFIDENTIAL
GlaxoSmithKline group of companies
205017
1
TITLE PAGE
Protocol Title: A three part, non-randomised, open label study designed to assess the 
pharmacokinetics of GSK2982772 following administration of minitab modified release 
formulations in a capsule relative to an immediate release reference tablet formulation 
(Part A),  the pharmacokinetics of escalating, repeat doses of a selected minitab modified 
release prototype (Part B), and the pharmacokinetics of GSK2982772 following 
administration of modified release tablet formulations in the fed and fasted state (Part C)
in healthy participants
Protocol Number: 205017/02
Short Title: A study to compare the pharmacokinetics of GSK2982772 following 
administration of different minitab modified release formulations in capsule relative to an 
immediate release tablet formulation, to investigate the pharmacokinetics of a selected 
minitab modified release formulation in capsule following repeat doses for 3 days, and to 
compare the pharmacokinetics of GSK2982772 following administration of modified 
release tablet formulations in the fed and fasted state relative to an immediate release 
tablet formulation.
Compound Number:
GSK2982772
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Communication 
Plan
Regulatory Agency Identifying Number(s): EudraCT Number 2017-000652-25
Approval Date: 14-JUN-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


2017N315344_02
CONFIDENTIAL
205017
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 02
14-Jun-2018
Amendment 01
18-Sep-2017
Original Protocol
07-Jul-2017
Amendment 02 14-Jun-2018
Overall Rationale for the Amendment:
Section # 
and Name
Description of Change
Brief Rationale
Sections 
throughout 
protocol
Addition of Part C
Part C has been included to investigate a 
MR tablet formulation as the minitab 
capsule formulations were susceptible to a 
food effect
Sections 
throughout 
protocol and 
title
Term “Subject” has been replaced 
by “Participant”.
Terminology updated within GSK.
In addition, the protocol has been updated with NSA02, dated 11 Oct 2017 and NSA05, dated 
23 Feb 2018


2017N315344_02
CONFIDENTIAL
205017
4
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
3.
INTRODUCTION....................................................................................................21
3.1.
Study Rationale ..........................................................................................21
3.2.
Background ................................................................................................22
3.3.
Benefit/Risk Assessment ............................................................................23
3.3.1.
Risk Assessment .........................................................................25
3.3.2.
Benefit Assessment.....................................................................30
3.3.3.
Overall Benefit:Risk Conclusion...................................................30
4.
OBJECTIVES AND ENDPOINTS...........................................................................30
5.
STUDY DESIGN ....................................................................................................31
5.1.
Overall Design ............................................................................................31
5.1.1.
Criteria for Interim Decisions........................................................33
5.2.
Number of Participants ...............................................................................34
5.3.
Participant and Study Completion...............................................................35
5.4.
Scientific Rationale for Study Design ..........................................................36
5.5.
Dose Justification........................................................................................37
6.
STUDY POPULATION...........................................................................................38
6.1.
Inclusion Criteria.........................................................................................38
6.2.
Exclusion Criteria........................................................................................39
6.3.
Lifestyle Restrictions...................................................................................41
6.3.1.
Meals and Dietary Restrictions ....................................................41
6.3.2.
Activity .........................................................................................43
6.4.
Screen Failures...........................................................................................43
7.
TREATMENTS.......................................................................................................43
7.1.
Treatments Administered............................................................................44
7.1.1.
Treatments Administered - Part A................................................44
7.1.2.
Treatments Administered - Part B................................................46
7.1.3.
Treatments Administered - Part C................................................47
7.2.
Dose Modification .......................................................................................48
7.3.
Method of Treatment Assignment ...............................................................48
7.4.
Blinding.......................................................................................................48
7.5.
Preparation/Handling/Storage/Accountability..............................................48
7.6.
Treatment Compliance................................................................................49
7.7.
Concomitant Therapy..................................................................................49
7.8.
Treatment after the End of the Study ..........................................................50
8.
DISCONTINUATION CRITERIA.............................................................................50
8.1.
Discontinuation of Study Treatment ............................................................50
8.1.1.
Liver Chemistry Stopping Criteria ................................................50


2017N315344_02
CONFIDENTIAL
205017
5
8.1.2.
QTc Stopping Criteria ..................................................................51
8.1.3.
Individual Safety Stopping Criteria ...............................................51
8.1.4.
Temporary Discontinuation ..........................................................51
8.1.5.
Rechallenge.................................................................................52
8.1.5.1.
Study Treatment Restart or Rechallenge....................52
8.2.
Withdrawal from the Study..........................................................................52
8.3.
Lost to Follow Up........................................................................................52
8.4.
Study Stopping Criteria...............................................................................53
8.5.
Study Termination.......................................................................................53
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................54
9.1.
Efficacy Assessments.................................................................................55
9.2.
Adverse Events...........................................................................................55
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................55
9.2.2.
Method of Detecting AEs and SAEs.............................................55
9.2.3.
Follow-up of AEs and SAEs.........................................................55
9.2.4.
Regulatory Reporting Requirements for SAEs .............................56
9.2.5.
Pregnancy ...................................................................................56
9.3.
Treatment of Overdose...............................................................................56
9.4.
Safety Assessments ...................................................................................57
9.4.1.
Physical Examinations.................................................................57
9.4.2.
Vital Signs....................................................................................57
9.4.3.
Electrocardiograms......................................................................58
9.4.4.
Clinical Safety Laboratory Assessments ......................................58
9.4.5.
Suicidal Risk Monitoring...............................................................59
9.5.
Pharmacokinetics .......................................................................................60
9.6.
Pharmacodynamics ....................................................................................60
9.7.
Genetics .....................................................................................................60
9.8.
Biomarkers .................................................................................................61
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................61
10. STATISTICAL CONSIDERATIONS........................................................................61
10.1.
Hypotheses.................................................................................................61
10.2.
Sample Size Determination ........................................................................61
10.2.1.
Sample Size Determination - Part A.............................................61
Sample Size Sensitivity – Part A.................................................................61
10.2.2.
Sample Size Determination - Part B.............................................62
Sample Size Sensitivity – Part B.................................................................62
10.2.3.
Sample Size Determination - Part C ............................................63
Sample Size Sensitivity – Part C.................................................................63
10.3.
Populations for Analyses ............................................................................64
10.4.
Statistical Analyses.....................................................................................64
10.4.1.
Pharmacokinetic Analyses...........................................................64
10.4.2.
Safety Analyses...........................................................................67
10.4.3.
Interim Analyses ..........................................................................67
10.4.4.
Stopping Criteria..........................................................................67
11. REFERENCES.......................................................................................................69
12. APPENDICES........................................................................................................70


2017N315344_02
CONFIDENTIAL
205017
6
12.1.
Appendix 1: Abbreviations and Trademarks................................................70
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................73
12.3.
Appendix 3: Study Governance Considerations..........................................75
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting to GSK...........................80
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................86
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................90
12.7.
Appendix 7: Safety Reporting to Ethics Committee and Regulatory 
Authorities...................................................................................................92
12.8.
Appendix 8: Protocol Amendment History...................................................94


2017N315344_02
CONFIDENTIAL
205017
7
1.
SYNOPSIS
Protocol Title: A three part, non-randomised, open label study designed to assess the 
pharmacokinetics of GSK2982772 following administration of minitab modified release 
formulations in a capsule relative to an immediate release reference tablet formulation 
(Part A), the pharmacokinetics of escalating, repeat doses of a selected minitab modified 
release prototype (Part B), and the pharmacokinetics of GSK2982772 following 
administration of modified release tablet formulations in the fed and fasted state (Part C) 
in healthy participants.
Short Title: A study to compare the pharmacokinetics of GSK2982772 following 
administration of different minitab modified release formulations in capsule relative to an 
immediate release tablet formulation, to investigate the pharmacokinetics of a selected 
minitab modified release formulation in capsule following repeat doses for 3 days, and to 
compare the pharmacokinetics of GSK2982772 following administration of modified 
release tablet formulations in the fed and fasted state relative to an immediate release 
tablet formulation.
Rationale: The purpose of this study is to evaluate a modified release (MR) formulation 
of GSK2982772 using a minitab approach filled into a capsule in order to develop a more 
convenient once daily (QD) dosing formulation.  Each minitab will contain 5 mg 
GSK2982772 and the amount of polymer can be adjusted to achieve the desired in-vitro 
release profile. Initially, the pharmacokinetic (PK) profiles of slow (approximately 
24 hours) and fast (approximately 10 hours) release rates of MR minitab will be 
compared to the PK profile of the immediate release (IR) tablet.  In subsequent arms of 
the study, the release rate may be adapted to achieve the target PK profile.  The effect of 
a high fat meal on the absorption of GSK2982772 when co-administered with the 
selected minitab MR formulation will be evaluated to ensure that dose dumping does not 
occur.  In addition, the PK profile of repeat doses at 3 dose levels will be evaluated to 
ensure that the MR formulation can achieve a sufficient GSK2982772 systemic exposure 
range to support the Phase IIb dose ranging (DR) studies.  Part C of the study has been 
included to evaluate the PK profile of single doses of MR tablet formulations of 
GSK2982772. The formulations will be evaluated at up to 4 dose levels and compared to 
the PK profile of the IR tablet.  The 240 mg MR tablet will have a fixed composition; 
however, for the 360 mg and 480 mg tablets polymer compositions may be adjusted as 
part of a ‘design space concept’ to try to optimize the in vivo performance of 360 mg and 
/or 480 mg tablets based on the PK of the 240 mg MR tablet formulation, if required.  
This adjustment will be done ahead of dosing to select a formulation at each dose unit to 
achieve an adjusted in vivo profile based on the PK of the 240 mg MR tablet formulation.  
The effect of a standard meal on the PK profile of GSK2982772 will also be investigated.  
The effect of a high fat meal, a delayed standard meal, twice daily dosing (BID) or dosing 
of multiple dose units may also be investigated, if required. 


2017N315344_02
CONFIDENTIAL
205017
8
Objectives and Endpoints:
Objective
Endpoint
Primary

To evaluate the single dose PK profile of 
GSK2982772 from each test minitab MR 
formulation in a capsule (120 mg) compared
to the IR formulation (120 mg)

GSK2982772 area under the curve from 
time zero to infinity (AUC(0-inf)), area under 
the curve from time zero to the last 
measurable concentration (AUC(0-t)), area 
under the curve from time zero to 24 hours 
(AUC(0-24)), area under the curve from time 
zero to 12 hours (AUC(0-12)), maximum 
observed concentration (Cmax), 
Concentration at 12 hours post-dose (C12h), 
Concentration at 24 hours post-dose (C24h) 
and ratio of Cmax : C12h and Cmax : C24h, 
relative bioavailability (Frelformulation) based 
on AUC and Cmax

To evaluate the single dose PK profile of 
GSK2982772 from a MR tablet (240 mg) 
compared to the IR formulation (240 mg)

GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), 
AUC(0-12), Cmax, C12h, C24h and ratio of Cmax : 
C12h and Cmax : C24h, Frelformulation based on 
AUC and Cmax
Secondary

To assess the impact of high fat meal on 
the PK of GSK2982772 following single 
dose administration of the selected minitab 
MR formulation in a capsule (120 mg) 

GSK2982772 AUC(0-inf), AUC(0-t), Cmax and 
time to Cmax (Tmax), FrelFE based on AUC 
and Cmax

To determine if there are any dose 
dependant changes in the absorption of 
GSK2982772 following repeat dose 
administration of the selected minitab MR 
formulation in a capsule at target daily 
doses of 30, 60 and 240 mg

GSK2982772 AUC(0-24), Cmax and Tmaxif 
once daily (QD) dosing, on Day 1 and Day 3

GSK2982772 AUC(0-12), AUC(12-24),, Cmax
and Tmax after morning dose, Cmax and Tmax
after evening dose if BID dosing, on Day 1 
and Day 3


2017N315344_02
CONFIDENTIAL
205017
9
Objective
Endpoint

To assess the impact of food on the PK of 
GSK2982772 following single dose 
administration of the MR tablet (dose 
corrected, as appropriate)

GSK2982772 AUC(0-inf), AUC(0-t)or AUC(0-24), 
Cmax and time to Cmax (Tmax), FrelFE based 
on AUC and Cmax(dose corrected, as 
appropriate)

To determine if there are any dose 
dependent changes in the absorption of 
GSK2982772 following single dose 
administration or BID dose administration of 
the MR tablet

GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), 
Cmax, C24h and ratio of Cmax : C24h, and Tmax

GSK2982772 AUC(0-12), C12h, and ratio of 
Cmax : C12 if BID dosing

To assess the safety and tolerability of 
single doses of GSK2982772 IR formulation 
and single and repeat doses of the MR 
formulation in a capsule, and single doses
or BID dose of the MR tablet

Adverse events (AEs)

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature)

12-Lead electrocardiogram (ECG)
monitoring
Exploratory

To assess the impact of a standard meal on 
the PK of GSK2982772 following 
administration of the selected minitab MR 
formulation in a capsule

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, Tmax
and FrelFE based on AUC and Cmax (dose 
corrected as appropriate)
Overall Design:
This is an open label, single centre, three part, single and repeat dose study in healthy 
male and female participants to assess MR minitab formulations of GSK2982772 in a 
capsule.  Assuming a suitable MR minitab formulation in a capsule is identified, the 
impact of food (high-fat meal) on the rate and extent of absorption will be evaluated as 
well as an assessment of the relationship between dose and systemic exposure to 
GSK2982772 following repeat dosing for 3 days. MR tablet formulations of 
GSK2982772 will also be investigated, along with the impact of food on the rate and 
extent of absorption.
Part A of the study is a non-randomised 6 period, sequential, 6-way fixed sequence
design in which up to 4 MR minitab formulations in a capsule may be evaluated 
following single dose administration in the fasted state (120 mg).  Periods 1, 2 and 3 will 
evaluate a slow MR release duration (nominally 24 hours), a fast MR release duration 
(nominally 10 hours), and IR tablet, respectively.  Periods 4, 5 and 6 will be flexible and 
the dosing regimen will be dependent on the outcome of Periods 1 to 3.  In Periods 4 to 6, 


2017N315344_02
CONFIDENTIAL
205017
10
there will be the option to optimise the MR release duration and/or to evaluate the impact 
of food (high-fat meal) on the selected MR minitab formulation in a capsule.  There will 
also be the option to cancel Periods 5 and 6 if an optimal formulation is determined in 
Periods 1 or 2.
Part B of the study will be an open-label, repeat dose study in which the selected MR 
minitab formulation in a capsule will be evaluated following 3 days repeat dosing of 
GSK2982772 at target daily doses of 30, 60 and 240 mg.  In Part B, administration of the 
MR minitab formulation in a capsule will either be in the fasted state or with a standard 
meal (non-high fat), depending on the results of the food effect assessment in Part A.  
The prandial state for each dosing period may be selected as fasted or fed (standard meal) 
but within each dosing period, all doses will be administered in the same prandial state.  
The frequency of dosing in Part B will either be QD or BID depending on the PK profile 
in Part A.  Whether dosing is QD or BID, the total daily doses will remain the same.
Part C of the study is a non-randomised 6 period, sequential, fixed sequence crossover
design in which MR tablet formulations will be evaluated.  Periods 1 and 2 will evaluate 
single dose administration of a 240 mg MR tablet and the 240 mg IR tablet (reference), 
respectively.  Periods 3, 4, 5 and 6 will be flexible and the dosing regimen will be 
dependent on the outcome of Periods 1 and 2.  In Periods 3 to 6, there will be the option 
to evaluate higher doses, the impact of a high-fat meal and/or standard meal after dosing 
or BID dosing. 
Number of Participants:
Sixteen participants will be enrolled into Part A of the study to allow for the completion 
of at least 12 evaluable participants. An evaluable participant will have completed the 
planned safety and PK assessments up to 32 hours after dosing (or 24 hours after dosing 
for Period 3; IR regimen).  An evaluable participant must also have received the relevant 
test and reference formulations for the comparisons of interest e.g. an MR formulation 
and the IR reference and/or the selected MR formulation in both the fed and fasted states.
Ten participants will be enrolled into Part B of the study to allow for the completion of at 
least 6 evaluable participants. An evaluable participant will have received all 3 doses and 
completed the planned safety and PK assessments up to 24 hours after the last dose.  
In Part C, 16 participants will be enrolled such that at least 12 evaluable participants 
complete the study.  An evaluable participant will have completed the planned safety and 
PK assessments up to 32 hours after dosing (or 24 hours after dosing for Period 2; IR 
regimen).  An evaluable participant must also have received the relevant test and 
reference formulations for the comparisons of interest e.g. the MR tablet and the IR 
reference at 240 mg.
Treatment Groups and Duration:
In Part A, each participant will be enrolled in the study for approximately 8 to 13 weeks, 
dependent on screening and washout duration between periods.  Participation will include 
a screening evaluation within 28 days of study treatment administration and up to 
6 separate inpatient periods.  Participants will be admitted to the clinic in the morning of 
the day before dosing (i.e. Day -1) of each inpatient period.  Each inpatient period will 
consist of 3 days and 2 nights followed by a minimum washout of 7 days between doses.  


2017N315344_02
CONFIDENTIAL
205017
11
A follow-up visit will occur at least 7 days after the last study treatment.  Participants will 
receive a single oral dose of study treatment during each inpatient period.
In Part B, each participant will be enrolled in the study for approximately 9 weeks.  
Participation will include a screening evaluation within 28 days of study treatment 
administration and 3 separate periods. Participants will be admitted to the clinic in the 
morning of the day before dosing (i.e. Day -1) of each inpatient period.  Each inpatient 
period will consist of a 5 day, 4-night inpatient period with a minimum of 7 days washout 
between the last morning dose of one period and the first dose of the next period.  A 
follow-up visit will occur at least 7 days after the last study treatment. 
In Part C, each participant will be enrolled in the study for approximately 8 to 13 weeks, 
dependent on screening and washout duration between periods.  Participation will include 
a screening evaluation within 28 days of study treatment administration and up to 
6 separate inpatient periods.  Participants will be admitted to the clinic in the morning of 
the day before dosing (i.e. Day -1) of each inpatient period.  Each inpatient period will 
consist of 3 days and 2 nights followed by a minimum washout of 7 days between doses.  
A follow-up visit will occur at least 7 days after the last study treatment.  Participants will 
receive a single oral dose of study treatment during each inpatient period (if BID dosing 
is selected for Period 6, participants will receive 2 doses of study treatment in this 
inpatient period).
2.
SCHEDULE OF ACTIVITIES (SOA)
The schedules of activities for Parts A and C are presented in Table 1, and are presented 
in Table 3 for Part B.  The time points for the PK blood sample collection in Parts A and
Care presented in Table 2, and are presented in Table 4 for Part B, respectively.
The timing and number of planned study assessments, including safety or 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. 
Any changes in the timing or addition of time points for any planned study assessments 
as a result of emerging pharmacokinetic data must be documented and approved by the 
relevant study team member and then archived in the sponsor and site study files. The 
competent authority (CA) and ethics committee (EC) will be informed of any safety 
issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the informed consent form (ICF). The changes will 
be approved by the CA and the EC before implementation.
There are times where the protocol requires more than one procedure to be completed at 
the same time point. In these instances the following will apply to post-dose time points:
PK samples should take priority over other procedures scheduled at the same time point. 
As guidance, the preferred order of assessments is:


2017N315344_02
CONFIDENTIAL
205017
12
ECGs
Vital 
Signs
PK blood 
sampling
(nominal time)
Other assessments eg 
physical exams, 
Electrocardiograms (ECGs) should be taken prior to vital signs when both measurements 
are scheduled at the same time point. Other assessments, e.g. physical examinations etc, 
will be performed within the required time windows. All safety assessments will be 
timed and performed relative to the start of dosing.


2017N315344_02
CONFIDENTIAL
205017
13
Table 1
Schedule of Activities for Parts A and C
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3, 4, 5, 6
Day
Follow-up/Study 
Discontinuation
(7 days post last dose)
Notesa
–1
1
2
Informed consent
X
Inclusion and exclusion criteria1
X
1.
Recheck clinical status 
before 1st dose of study 
medication.
Demography
X
Demonstrate ability to swallow size 0-00 
capsules
X
Full physical examination including height 
and weight
X
Brief physical examination
X
X2
X
2.
Discharge
(32 h post-dose for 
Treatment Period 1, 2, 4, 
5 and 6 in Part A and 
Treatment Period 1, 3, 4, 
5 and 6 in Part C
24 h post-dose for 
Treatment Period 3 in 
Part A and Treatment 
Period 2 Part C)
Medical history (includes substance 
usage)3
X
3.
Substances: Drugs, 
Alcohol, tobacco and 
caffeine
Past and current medical conditions  
X


2017N315344_02
CONFIDENTIAL
205017
14
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3, 4, 5, 6
Day
Follow-up/Study 
Discontinuation
(7 days post last dose)
Notesa
–1
1
2
Follicle Stimulating Hormone (FSH) (as 
needed in women of non-childbearing 
potential only)
X
Serum pregnancy test (WOCBP only)
X
X
Urine pregnancy test (WOCBP only)
X
Human Immunodefeciency Virus (HIV), 
Hepatitis B and C screening4
X
4.
If test otherwise 
performed within 3 
months prior to first dose 
of study treatment, testing 
at screening is not 
required
Tuberculosis (TB) Test
X
Urine drug screen
X
X
Alcohol breath test
X
X
Carbon monoxide breath test
X
X
Laboratory assessments (haematology, 
clinical chemistry and urinalysis)
X
X
X5
X5
X
5.
Pre-dose (Treatment 
Period 1 only) and 24 h 
post-dose
Allowable windows in 
Section 9.4.4
Glomerular filtration rate
X
C-reactive protein (CRP)
X


2017N315344_02
CONFIDENTIAL
205017
15
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3, 4, 5, 6
Day
Follow-up/Study 
Discontinuation
(7 days post last dose)
Notesa
–1
1
2
12-lead ECG
X6
X
X7
X8
X
6.
In triplicate
7.
Pre-dose and 2 and 12 h 
post-dose
8.
24 h post-dose
Allowable windows in 
Section 9.4.3
Vital signs
X
X
X9
X10
X
9.
Pre-dose and 2 and 12 h 
post-dose
10. 24 h post-dose
Allowable windows in 
Section 9.4.2
Study treatment
X
AE review
============================
X
Serious AE (SAE) review
X
============================
X
Concomitant medication review
============================
X
PK blood sample collection
X11
X11
11. Time points in Table 2
a The timing of assessments may be amended in Part C if BID dosing is selected for any of the regimens.


2017N315344_02
CONFIDENTIAL
205017
16
Table 2
Pharmacokinetic Blood Sample Collection Times – Parts A and C
Part A Treatment Periods 1, 2, 4, 5 and 6 (MR Formulations)
Part C Treatment Periods 1, 3, 4, 5 and 6 (MR Formulations)
Time (h)
Pre-
dose
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
Dosing
X
PK sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Part A: Treatment Period 3 (IR Formulation)
Part C: Treatment Period 2 (IR Formulation)
Time (h)
Pre-
dose
0
0.33
0.66
1
1.5
2
3
4
6
8
10
12
24
Dosing
X
PK sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
a PK sampling schedule may be amended in Part C if BID dosing is selected for any of the regimens. If BID dosing is employed the 
number of PK samples may be reduced i.e. some of the samples between 14 and 24 h may not be required.  In addition, the 12 h sample 
will be taken prior to administering the second daily dose.


2017N315344_02
CONFIDENTIAL
205017
17
Table 3
Schedule of Activities for Part B
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
Informed consent
X
Inclusion and exclusion criteria1
X
1.
Recheck clinical status before 
1st dose of study medication.
Demography
X
Demonstrate ability to swallow size 
0-00 capsules
X
Full physical examination including 
height and weight
X
Brief physical examination
X
X2
X
2.
Discharge (24 h after the last 
dose)
Medical history (includes substance 
usage)3
X
3.
Substances: Drugs, Alcohol, 
tobacco and caffeine
Past and current medical conditions  
X
FSH (as needed in women of non-
childbearing potential only)
X
Serum pregnancy test (WOCBP only)
X
X
Urine pregnancy test (WOCBP only)
X


2017N315344_02
CONFIDENTIAL
205017
18
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
HIV, Hepatitis B and C screening4
X
4.
If test otherwise performed 
within 3 months prior to first 
dose of study treatment, 
testing at screening is not 
required
Tuberculosis Test
X
Urine drug screen
X
X
Alcohol breath test
X
X
Carbon monoxide breath test
X
X
Laboratory assessments 
(haematology, clinical chemistry and 
urinalysis)
X
X
X5
X6
X
5.
Pre-dose 
6.
24 h after the last dose
Allowable windows in Section 
9.4.4
Glomerular filtration rate
X
CRP 
X
ANA
X
X7
7.
24 h after the last dose


2017N315344_02
CONFIDENTIAL
205017
19
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
12-lead ECG 
X8
X
X9
X10
X9
X11
X
8.
In triplicate
9.
Pre-dose and 2 and 12 h 
post-dose
10. Pre-dose
11. 24 h after the last dose
Allowable windows in Section 
9.4.3
Time points may be subject to 
change depending on results
from Part A
Vital signs 
X
X
X12
X13
X12
X14
X
12. Pre-dose and 2 and 12 h 
post-dose
13. Pre-dose 
14. 24 h after the last dose
Allowable windows in Section 
9.4.2
Time points may be subject to 
change depending on results 
from Part A
Columbia Suicide Risk questionnaire
X
X15
X16
15. Pre-dose
16. 24 h after last dose of each 
period
Study treatment
X
X
X
AE review
============================
X
SAE review
X
============================
X
Concomitant medication review
============================
X


2017N315344_02
CONFIDENTIAL
205017
20
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
PK blood sample collection
X17
X17
X17
X17
17. Time points in Table 4
Table 4
Pharmacokinetic Blood Sample Collection Times – Part B
Periods 1, 2 and 3
Days 1 and 3
Time (h)
Pre-
dose
0
2
4
6
8
10
12
14
16
18
20
22
24
Dosinga
X
PK samplingb
X
X
X
X
X
X
X
X
X
X
X
X
Xc
a Participants will be dosed on Days 1, 2 and 3; however, no PK samples will be taken post-dose on Day 2
b PK sampling schedule may be amended based upon the PK data from Part A and/or if BID dosing is selected for Part B. If BID dosing is 
employed the number of PK samples may be reduced i.e. some of the samples between 14 and 24 h may not be required.  In addition, the 
12 h sample will be taken prior to administering the second daily dose. 
c Day 1 24 h post-dose sample should be taken prior to dosing on Day 2.


2017N315344_02
CONFIDENTIAL
205017
21
3.
INTRODUCTION
GSK2982772 is a first-in-class, highly selective, receptor-interacting protein-1 (RIP1)
kinase inhibitor being developed for the treatment of inflammatory bowel disease, plaque 
psoriasis (PsO), rheumatoid arthritis (RA) and other disease conditions.
3.1.
Study Rationale
Pharmacokinetic data from the first time in human (FTIH) study for GSK2982772 
(200975) [GlaxoSmithKline Document Number 2014N204126_03] showed that the 
half-life of GSK2982772 was short (~2 to 3 hours).  As a result, BID and three times 
daily (TID) dosing regimens are being evaluated in three ongoing proof of mechanism 
studies.  A QD formulation would be more convenient from a patient perspective and 
could offer the advantage of providing a flatter GSK2982772 concentration time profile.  
This current study is being conducted to evaluate the feasibility of developing an MR 
formulation using a minitab approach filled into a capsule.  Each minitab will contain 
5 mg GSK2982772 and the amount of polymer can be adjusted to achieve the desired 
in-vitro release profile. In addition, the number of minitabs included in the capsule can be 
varied to adjust the dose.
The Clinical Trial Authorisation application for this study describes a flexible protocol 
design using the concept of formulation design space to allow decision-making in 
response to interim PK observations. The principles of a flexible protocol were discussed 
and agreed with the Medicines and Healthcare products Regulatory Agency (MHRA) at a 
Scientific Advice Meeting between the MHRA and Quotient Sciences (formerly 
Pharmaceutical Profiles).
Based upon the concept of formulation design space, specific Investigational Medicinal 
Products (IMPs) are not detailed within the Investigational Medicinal Product Dossier but 
rather a defined range of formulation inputs and corresponding performance outputs are 
described and justified based on in vitro studies.
There will be the option to test a range of formulations based on a 2-dimensional design 
space describing the dose level and release rate of the IMP (Figure 1).


2017N315344_02
CONFIDENTIAL
205017
22
Figure 1
Two-Dimensional Design Space for the Modified Release 
Formulation of Capsules Filled with Minitabs
Following completion of Parts A and B, it was determined that the slowest minitab 
formulation provided a PK profile suitable for QD dosing but this formulation was
susceptible to a food effect. Therefore, Part C of the study will investigate MR tablet
formulations at up to 4 different dose levels in the fasted state. The 240 mg tablet will 
have a fixed composition which will have a dissolution profile similar to the slowest 
minitab; however, for the 360 mg and 480 mg tablets polymer compositions may be 
adjusted as part of a ‘design space’ concept to try to optimize the in vivo performance of 
360 mg and /or 480 mg tablets based on the PK of the 240 mg MR tablet formulation.  
This adjustment will be done ahead of dosing to select a formulation at each dose unit to 
achieve an adjusted in vivo profile based on the PK of the 240 mg MR tablet formulation.  
The effect of food (standard meal) will then be investigated at either the 240 mg, 360 mg 
or 480 mg dose level with the option to evaluate the effect of a high fat or a delayed 
standard meal, to determine whether GSK2982772 can be administered with or without a 
food restriction in the planned proof of concept study.  Although the target dosing 
regimen is QD, if a food effect is observed or the single dose exposure profile is not 
appropriate for QD dosing, BID dosing may be investigated.  Dosing of multiple dose 
units may also be investigated.
3.2.
Background
RIP1 is a member of the receptor-interacting Serine/Threonine kinase family containing 
an amino-terminal kinase domain, an intermediate domain and a carboxy-terminal death 
domain. RIP1 is a key signalling node which plays an essential role in inflammation and 
cell death in response to signals including tumour necrosis factor (TNF) family cytokines, 
ligands for toll like receptor (TLR)3/TLR4, sensors of viral infection, and interferons 
[Ofengeim, 2013]. Through tight regulation by ubiquitylation, deubiquitylation and 
interaction with its receptors, RIP1 has dual roles as a kinase and a scaffolding protein, 
Release Rate 


2017N315344_02
CONFIDENTIAL
205017
23
and serves as an upstream checkpoint for both cell death and survival [Ofengeim, 2013]. 
Detailed understanding of RIP1 kinase function has not been fully elucidated, but it is 
known that RIP1 exerts it signalling functions through both its catalytic kinase activity 
and by acting as a scaffolding protein for signalling complexes. Recent work has 
demonstrated that RIP1 catalytic kinase activity can regulate TNF-mediated necroptosis 
[Ofengeim, 2013] and noncanonical apoptosis [Wang, 2008; Dondelinger, 2013]. In 
addition, the production of certain inflammatory cytokines can be regulated by RIP1 
kinase activity. In contrast, RIP1’s scaffolding function acts to facilitate other immune 
processes including TNF mediated classical apoptosis and Nuclear factor-kappaB-
signalling [Ofengeim, 2013; Humphries, 2015]. With this, an inhibitor of RIP1 kinase 
activity with GSK2982772 may fill a unique niche in the treatment of inflammatory 
conditions, such as ulcerative colitis, chronic PsO and RA, through multiple mechanisms, 
including inhibition of inflammation-induced cell death (necroptosis and apoptosis) and 
inhibition of the production of certain pro-inflammatory cytokines.
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK2982772 is provided in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2014N204126_03].
3.3.
Benefit/Risk Assessment
As of 10 November 2017, approximately 159 participants have been enrolled in 6 clinical 
studies with GSK2982772. In completed Study 200975, GSK2982772 was administered 
up to 120 mg BID for 14 days.  A total of 67 participants received GSK2982772 and 26 
participants received placebo (including crossover) in that study, of whom 31 participants 
received a single dose of GSK2982772.  
In ongoing Phase 1 studies (high dose PK Study [205184] and MR formulation Study 
[205017]), a total of approximately 9 and 19 participants have been randomised to single 
doses of GSK2982772 up to 720 mg/day and repeat doses up to 300 mg/day for 3 days, 
respectively.  
In the ongoing Phase 2a studies in PsO Study (203167), RA (Study 203168) and 
Ulcerative Colitis (Study 202152), a total of approximately 64 participants have been 
randomised to GSK2982772 60 mg BID or 60 mg TID. . No safety concerns have been 
identified in the GSK2982772 development program. In Study 203167, there was a death 
of a 19-year-old male participant receiving GSK2982772 due to an accidental overdose 
with 3,4-methylenedioxy-methamphetamine (MDMA) that was not considered drug 
related by the Principal Investigator (PI). 
There is currently limited information available about the relationship of adverse events 
(AEs) to administration of GSK2982772 in human participants. Therefore, all SAEs are 
considered unexpected. Any SAE deemed related to the IMP will be reported as a 
Suspected Unexpected Serious Adverse Reaction (SUSAR), in compliance with local 
health authority safety reporting requirements (see Appendix 7).
Limited reproductive toxicity studies have been conducted with GSK2982772 to date.
The compound must not be administered to pregnant women or nursing mothers. 
Women of childbearing potential must use highly effective methods of contraception 


2017N315344_02
CONFIDENTIAL
205017
24
(<1% failure rate; Appendix 5) for 30 days prior to exposure to GSK2982772 until 
30 days after the last dose.
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of GSK2982772 may be found in the Investigator’s Brochure.


2017N315344_02
CONFIDENTIAL
205017
25
3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2982772
Central Nervous System (CNS) effects
Non-clinical data: 
In the 4-week Good Laboratory Practice (GLP) toxicology study, 
CNS findings were observed in 4/12 monkeys which were 
administered 100 or 300 mg/kg/day.  CNS findings included 
uncoordination, irregular gait, trembling, hunched appearance, and 
decreased activity. The clinical relevance of these findings in 
humans is not known.  The no observed adverse effect level 
(NOAEL) for this study was determined at 10 mg/kg/day.
In the 13-week GLP toxicology study, there were no CNS findings 
observed in monkeys administered 10, 30 or 100 mg/kg/day.  The 
NOAEL for this study was determined at 30 mg/kg/day.
In the 39-week GLP toxicology study, there were no CNS findings 
observed in monkeys administered 6, 20 or 60 mg/kg/day.  The 
NOAEL for this study was determined at 60 mg/kg/day.  
Clinical data:
A FTIH study with single ascending and multiple ascending dose 
study has been performed in 67 healthy male volunteers to date.  
See Investigator’s Brochure (IB) [GlaxoSmithKline Document 
Number 2014N204126_03].  No drug-associated CNS AEs were 
identified and no SAEs were reported.
In the Phase 2a psoriasis study (203167), there was one SAE of 
death via accidental overdose of Ecstasy/MDMA in a  subject
receiving GSK2982772 60 mg BID.  There was no evidence 
reported to suggest that this event was a suicide.
Subject Selection:

Participants with known history of significant 
neurologic disorders including but not limited to 
progressive multiple sclerosis (MS), Amyotrophic 
lateral sclerosis (ALS), Alzheimer’s and dementia will 
be excluded.

Individuals with potentially increased susceptibility for 
neurologic effects will be excluded based on medical 
history at screening.
Subject Monitoring:

Participants will be monitored for standard CNS-
related AEs.
Immunosuppression
The possibility of immunosuppression, including an increase in the 
frequency and/or severity of infection, may result from the intended 
Subject Selection:

Participants with recurrent, chronic or active infections 


2017N315344_02
CONFIDENTIAL
205017
26
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
pharmacologic effect of GSK2982772.  This may be enhanced in 
participants taking other immunomodulating drugs or 
corticosteroids.
Clinical data:
In the FTiH study, no SAEs were reported. 
One subject in the FTiH study was diagnosed with herpes zoster 
42 days after receiving GSK2982772 80 mg (Treatment Period 2).  
The blinded investigator considered the AE to be potentially 
drug-related.
One subject from the PsO study experienced an AE of herpes 
zoster on Study Day 9 (GSK2982772 60 mg BID ).  The blinded 
investigator considered the AE to be of moderate severity and not 
related to study drug.
will be excluded from the study.

Participants will be screened for TB, HIV, Hepatitis B 
and C, and excluded from the study if positive.
Subject Monitoring:

Participants will be monitored for signs of infection.

See Individual Stopping Criteria for atypical or 
opportunistic infections (Section 8.1.3).
Vaccinations
No preclinical data.
There is a theoretical risk that GSK2982772 could decrease an 
individual’s immune response to vaccines or allow symptoms to 
develop following vaccination with a live vaccine when 
administered while on therapy.
Subject Selection:

Attenuated or live vaccines should not be 
administered to participants from 30 days prior to the 
first dose of GSK2982772, during the study and for 5 
half-lives plus 30 days (total 32 days) after 
GSK2982772 is discontinued.

If indicated, non-live vaccines (eg, inactivated 
influenza vaccines) may be administered while 
receiving GSK2982772 based on a treating physician 
assessment of the benefit:risk (eg, risk of theoretical 
decreased responsiveness). 

Investigators will be expected to have followed local 
and/or national guidelines with respect to 
vaccinations, including against influenza and 
pneumococcus.


2017N315344_02
CONFIDENTIAL
205017
27
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Respiratory
Non-clinical data:
In the single dose Safety Cardiovascular (CV) and Respiratory 
Study in monkeys, a decrease in minute volume and respiratory 
rate was observed at all doses (10, 100, and 300 mg/kg).  These 
findings were noted to be reversible and mild in severity
In a 14-day repeat dose Safety Respiratory Study in monkeys, no 
respiratory effects on total pulmonary ventilation (minute volume) 
or respiratory rate were observed at doses of 1 or 10 mg/kg/day. 
See Investigtor’s Brochure for GSK2982772 [GlaxoSmithKline 
Document Number 2014N204126_03].
Clinical data:
In the FTIH study, repeat doses of GSK2982772 were 
administered x 14 days in 36 healthy male volunteers. Extensive 
respiratory monitoring with end-tidal CO2, oxygen saturation and 
nocturnal respiratory rate monitoring was performed.  No SAEs 
occurred, and no drug-associated respiratory-related AEs were 
identified.
Subject Monitoring:

Participants should be monitored for standard 
respiratory-related AEs.

Vital signs will be monitored during study visits.
Suicidality
GSK2982772 is considered to be a CNS-active drug based upon 
pre-clinical studies.
Clinical data:
In the FTIH study, there have been some reports of lethargy, 
abnormal dreams, and depressed mood.  
In the Phase 2a psoriasis study, one subject reported suicidal 
ideation at Day 43 via the Columbia Suicide Severity Rating Scale. 
Per the investigator, this subject was questioned at the next visit 
and reported that he had had these thoughts on and off prior to 
joining the study and did not plan to take action on these feelings. 
The investigator kept the subject on study.
Subject Selection:

Participants with a current history of suicidal ideation 
and behaviour (SIB) as measured using the Columbia 
Suicide Severity Rating Scale (C-SSRS)  or a history 
of attempted suicide will be excluded from the study.
Subject Monitoring:

Participants receiving multiple doses should be 
monitored appropriately and observed closely for 
suicidal ideation and behaviour or any other unusual 
changes in behaviour.

Baseline and treatment emergent assessment of 
suicidality will be conducted by trained site personnel 


2017N315344_02
CONFIDENTIAL
205017
28
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
using the C-SSRS in all participants receiving multiple 
doses.  See Section 9.4.5.
Reproductive toxicity
Non-clinical data:
There was no maternal or developmental toxicity at doses 
200 mg/kg/day in rats and no developmental toxicity was evident 
at doses up to 300 mg/kg/day in rabbits (AUC of 1270 µg.h/mL 
and Cmax of 153 µg/mL). 
Subject Selection:

Male and female participants of childbearing potential 
will be included in this study only if they agree to use 
highly effective methods of contraception and avoid 
conception for 30 days before first administration of 
study drug until 30 days (females) and 90 days 
(males) after the last administration of study drug 
(Appendix 5). 

Females of childbearing potential will undergo serum 
pregnancy test at screening and follow-up and then 
urine pregnancy testing at regular intervals during the 
study. 

Pregnant and lactating females are not eligible for 
inclusion in the study.
Withdrawal Criteria:

If a female subject should become pregnant during 
the study, study medication should be discontinued.  
The subject will be followed to determine the outcome 
of the pregnancy.  Any pregnancy complication or 
elective termination of a pregnancy will be reported as 
an AE or SAE.
Drug Interaction
Non-clinical data:
In vitro studies with GSK2982772 assessing potential drug-drug 
interactions with Cytochrome P450 3A4 (CYP3A4) substrates, 
P-glycoprotein (Pgp) inhibitors and OAT3 substrates were 
completed.  To date, formal drug interaction studies in humans 
have not been performed with GSK2982772. 
There is a low risk that GSK2982772 could be a perpetrator of 
OAT3 substrates.  
Subject Selection:

No concomitant medications will be permitted in this 
study 
with 
the 
exception 
of 
paracetamol/acetaminophen, hormonal contraception, 
hormone replacement therapy and other treatments 
required for AEs.


2017N315344_02
CONFIDENTIAL
205017
29
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
There is a low risk that GSK2982772 could be an inducer of 
CYP3A4 and therefore may lower circulating levels of concomitant 
medications that are metabolised by CYP3A4 when co 
administered with GSK2982772.
GSK2982772 is a Pgp substrate and therefore co administration 
with concomitant medications that are Pgp inhibitors could 
increase circulating levels of GSK2982772.
See Section 4.3.6 of the GSK2982772 Investigators Brochure 
[GlaxoSmithKline Document Number 2014N204126_03].
Subject Monitoring:

Caution is advised when dosing GSK292772 with 
CYP3A4 NTI substrates, OAT3 substrates or Pgp 
inhibitors.
Study Procedures
Cannulation 
During cannulation, more than one attempt may be needed to 
insert the cannula in a vein of a participant and it is possible that 
bruising and/or inflammation may be experienced at the site of 
cannulation.

A vein assessment will be conducted at screening to 
ensure only volunteers with veins suitable for multiple 
venepuncture and cannulation are enrolled.  
Cannulation and venepuncture will only be performed 
by staff who are trained in these procedures.
Electrocardiograms
Electrocardiogram stickers on the participants' chests and limbs 
may cause some local irritation and may be uncomfortable to 
remove. 

Participants will be closely monitored to ensure any 
local irritation does not persist.


2017N315344_02
CONFIDENTIAL
205017
30
3.3.2.
Benefit Assessment
There is no intended direct health benefit to the participants in this study.  The benefit to 
participants include contributing to the process of developing new therapies in an area of 
unmet need and the medical evaluations/assessments associated with study procedures 
(eg, physical exam, ECG, Labs, etc).
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to healthy participants
participating in this study, the potential risks identified in association with GSK2982772
are justified by the anticipated benefits that may be afforded to patients with 
inflammatory conditions such as ulcerative colitis, PsO and RA.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the single dose PK profile of 
GSK2982772 from each test minitab MR 
formulation in a capsule (120 mg) compared
to the IR formulation (120 mg)

GSK2982772 area under the curve from 
time zero to infinity (AUC(0-inf)), area under 
the curve from time zero to the last 
measurable concentration (AUC(0-t)), area 
under the curve from time zero to 24 hours 
(AUC(0-24)), area under the curve from time 
zero to 12 hours (AUC(0-12)), maximum 
observed concentration (Cmax), 
Concentration at 12 hours post-dose (C12h), 
Concentration at 24 hours post-dose (C24h) 
and ratio of Cmax : C12h and Cmax : C24h, 
relative bioavailability (Frelformulation) based 
on AUC and Cmax

To evaluate the single dose PK profile of 
GSK2982772 from the MR tablet (240 mg) 
compared to the IR formulation (240 mg)

GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), 
AUC(0-12), Cmax, C12h, C24h and ratio of Cmax : 
C12h and Cmax : C24h, Frelformulation based on 
AUC and Cmax
Secondary

To assess the impact of high fat meal on 
the PK of GSK2982772 following single 
dose administration of the selected minitab
MR formulation in a capsule (120 mg)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax and 
time to Cmax (Tmax), FrelFE based on AUC 
and Cmax

To determine if there are any dose 
dependant changes in the absorption of 
GSK2982772 following repeat dose 

GSK2982772 AUC(0-24), Cmax and Tmax if 
once daily (QD) dosing, on Day 1 and Day 3

GSK2982772 AUC(0-12), AUC(12-24),, Cmax


2017N315344_02
CONFIDENTIAL
205017
31
Objectives
Endpoints
administration of the selected minitab MR 
formulation in a capsule at target daily 
doses of 30, 60 and 240 mg
and Tmax after morning dose, Cmax and Tmax
after evening dose if twice daily (BID) 
dosing, on Day 1 and Day 3

To assess the impact of food on the PK of 
GSK2982772 following single dose 
administration of the MR tablet (dose 
corrected, as appropriate)

GSK2982772 AUC(0-inf), AUC(0-t), or 
AUC(0-24), Cmax and time to Cmax (Tmax), 
FrelFE based on AUC and Cmax(dose 
corrected, as appropriate)

To determine if there are any dose 
dependent changes in the absorption of 
GSK2982772 following single dose 
administration or BID dose administration of 
the MR tablet

GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), 
Cmax, C24h and ratio of Cmax : C24h, and Tmax

GSK2982772 AUC(0-12), C12h, and ratio of 
Cmax : C12h if BID dosing

To assess the safety and tolerability of 
single doses of GSK2982772 IR formulation 
and single and repeat doses of the MR 
formulation in a capsule, and single doses 
or BID doses of the MR tablet

Adverse events (AEs)

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature)

12-Lead electrocardiogram (ECG) 
monitoring
Exploratory

To assess the impact of a standard meal on 
the PK of GSK2982772 following 
administration of the selected minitab MR 
formulation in a capsule

GSK2982772 AUC(0-∞), AUC(0-t), Cmax, Tmax
and FrelFE based on AUC and Cmax (dose 
corrected as appropriate)
5.
STUDY DESIGN
5.1.
Overall Design
This is an open label, single centre, three part, single and repeat dose study in healthy 
male and female participants to assess MR minitab formulations of GSK2982772 in a 
capsule.  Assuming a suitable MR minitab formulation in a capsule is identified, the 
impact of food (high-fat meal) on the rate and extent of absorption will be evaluated as 
well as an assessment of the relationship between dose and systemic exposure to 
GSK2982772 following repeat dosing for 3 days. MR tablet formulations of 
GSK2982772 will also be investigated, along with the impact of food on the rate and 
extent of absorption.


2017N315344_02
CONFIDENTIAL
205017
32
Part A of the study is a non-randomised 6 period, sequential, 6-way fixed sequence 
design in which up to 4 MR minitab formulations in a capsule may be evaluated 
following single dose administration in the fasted state (120 mg) (Figure 2).  Periods 1, 2 
and 3 will evaluate a slow MR release duration (nominally 24 hours), a fast MR release 
duration (nominally 10 hours), and IR tablet, respectively.  Periods 4, 5 and 6 will be 
flexible and the dosing regimen will be dependent on the outcome of Periods 1 to 3.  In 
Periods 4 to 6, there will be the option to optimise the MR release duration and/or to 
evaluate the impact of food (high-fat meal) on the selected MR minitab formulation in a 
capsule.  There will also be the option to cancel Periods 5 and 6 if an optimal formulation 
is determined in Periods 1 to 2.
Participants will be admitted to the clinic in the morning of the day before dosing (i.e. 
Day -1) of each inpatient period.  Each inpatient period will consist of 3 days and 2 nights 
followed by a minimum washout of 7 days between doses.  A follow-up visit will occur 
at least 7 days after the last study treatment.  Participants will receive a single oral dose of 
study treatment during each inpatient period.
Figure 2
Part A Study Design – Formulation Optimisation and Food Effect
Period 1:
120 mg MR 
capsule
Fasted
(24 h release 
rate)
Period 2:
120 mg MR 
capsule
Fasted
(10 h release 
rate)
Period 3:
4 x 30 mg 
IR tablet
Fasted
Period 4:
120 mg MR 
capsule
Fasted or Fed
(release rate 
tbc)
Optional
Period 5:
120 mg MR 
capsule
Fasted or Fed
(release rate 
tbc)
Optional
Period 6:
120 mg MR 
capsule
Fasted or Fed
(release rate 
tbc)
Min 7 day 
washout
Min 7 day 
washout
Min 7 day 
washout
Min 7 day 
washout
Min 7 day 
washout
Part B of the study will be an open-label, repeat dose study in which the selected MR 
minitab formulation in a capsule will be evaluated following 3 days repeat dosing of 
GSK2982772 at target daily doses of 30, 60 and 240 mg (Figure 3).  The target dose may 
be subject to change based upon evaluation of the emerging data from Part A, e.g. if the 
bioavailability of 120 mg MR formulation in a capsule is less than the 120 mg IR tablet 
(reference) formulation.  In Part B, administration of the MR minitab formulation in a 
capsule will either be in the fasted state or with a standard meal (non-high fat), depending 
on the results of the food effect assessment in Part A.  The prandial state for each dosing 
period may be selected as fasted or fed (standard meal) but within each dosing period, all 
doses will be administered in the same prandial state.  The frequency of dosing in Part B
will either be QD or BID depending on the PK profile in Part A.  Whether dosing is QD 
or BID, the total daily doses will remain the same.  If BID dosing is selected the final 
dose will be the evening dose of Day 3. Participants will be admitted to the clinic in the 
morning of the day before dosing (i.e. Day -1) of each inpatient period.  Each inpatient 
period will consist of 5 days and 4 nights.  There will be a minimum of 7 days washout 
between the last morning dose of one period and the first dose of the next period.  A 
follow-up visit will occur at least 7 days after the last study treatment.  
Interim decisions based on PK and safety data. Periods 4, 5 and 6 are flexible and the dosing regimen will be 
dependent on the outcome of the preceding periods.


2017N315344_02
CONFIDENTIAL
205017
33
Figure 3
Part B Study Design – Dose Ranging
Part C of the study is a non-randomised 6 period, sequential, fixed sequence crossover
design in which MR tablet formulations will be evaluated (Figure 4).  Periods 1 and 2 
will evaluate single dose administration of a 240 mg MR tablet in the fasted state and the 
240 mg IR tablet (reference), respectively.  Periods 3, 4, 5 and 6 will be flexible and the 
dosing regimen will be dependent on the outcome of Periods 1 and 2.  In Periods 3 to 6, 
there will be the option to evaluate higher doses, the impact of a high-fat meal and/or 
standard meal after dosing or BID dosing.
Participants will be admitted to the clinic in the morning of the day before dosing (i.e. 
Day -1) of each inpatient period.  Each inpatient period will consist of 3 days and 2 nights 
followed by a minimum washout of 7 days between doses.  A follow-up visit will occur 
at least 7 days after the last study treatment.  Participants will receive a single oral dose of 
study treatment during each inpatient period (if BID dosing is selected for Period 6, 
participants will receive 2 doses of study treatment in this inpatient period).
Figure 4
Part C Study Design –Modified Release Tablet Formulations and 
Food Effect
Period 1:
240 mg 
MR tablet
Fasted
Period 2:
240 mg
IR tablet 
Fasted
Period 3:
360 or 480 mg
MR tablet
Fasted
Period 4:
360 or 480 mg
MR tablet
Fed (standard 
breakfast)
Period 5:
360 or 480 mg
MR tablets
Delayed Fed 
(dose before a 
standard 
breakfast)
or 
Fed (high fat 
breakfast)
Period 6:
Dose tbc
MR tablets
QD or BID
Prandial 
status tbc
Interim decisions based on PK and safety data. Periods 3 to 6 are flexible and the dosing regimen will 
be dependent on the outcome of the preceding periods.
The doses in Periods 3 to 6 may be adjusted based on results from Periods 1 and 2.  The 
dose will not exceed the exposure observed in the high dose PK study (205184) following 
IR dosing of 240 mg TID.
5.1.1.
Criteria for Interim Decisions
In Part A there will be an interim review following completion of Periods 1 to 3 to 
determine the formulation and the prandial state for Period 4. Similarly, there will be an 


2017N315344_02
CONFIDENTIAL
205017
34
interim review following Periods 4 and 5.  Following the final period of Part A, the 
formulation, doses, dosing frequency (QD or BID) and prandial state for each dosing 
period of Part B will be determined. However, the highest dosing regimen will be 
selected to ensure that the maximum daily dose will not exceed the equivalent of an IR 
dose of 240 mg, taking into account the bioavailability of MR relative to IR (i.e. if the 
bioavailability of MR is 50% that of IR, the maximum daily dose of MR to be 
administered would be 480 mg).  In Part C, there will be an interim review following 
completion of Periods 1 and 2 to determine the dose for Periods 3 and 4 (360 mg or 
480 mg). Similarly, there will be an interim review following Periods 4 and 5 to 
determine dose, prandial state and and dosing regimen (QD or BID).
Interim decisions will only be made after a complete review of all relevant data collected 
from the previous dose group. Data must be available from a minimum of 12 participants
who have completed the planned safety and PK assessments up to 32 hours after dosing
(or 24 hours after dosing for Period 3 Part A and Period 2 Part C; IR regimen [Regimen C
and Regimen K]). An evaluable participant must also have received the relevant test and 
reference formulations for the comparisons of interest e.g. an MR formulation and the IR 
reference and/or the selected MR formulation in both the fed and fasted states. If full 
data, as described below, are not available for 12 participants, the principal investigator 
(PI), scientific lead and sponsor will take a decision as to whether the data available are 
sufficient to support the formulation selection decision. If data in fewer than 16 
participants are used in the decision process, additional participants will not be dosed to 
increase the number of participants in the completed regimen.
The following data will be provided to the sponsor by Quotient Sciences:

AEs, vital signs, ECGs, safety laboratory data and physical examinations.

Plasma concentrations of GSK2982772.

PK parameter estimates GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), AUC(0-12), Tmax,
Cmax, C12h, C24h and ratio of Cmax : C12h and Cmax : C24h, Frel based on AUC and Cmax
for test vs reference formulations and fed vs fasted, where relevant.  

Protocol deviations will be reviewed to ensure they have had no significant impact on 
the above data
The decision on formulation and prandial state selection or stopping the study will be 
made by the Quotient study team (i.e., PI, scientific lead and pharmacokineticist) and 
sponsor study team (as a minimum the sponsor’s medical monitor, Clinical 
Pharmacokinetics Modelling and Simulation [CPMS] and Global Clinical Safety and 
Pharmacovigilance [GCSP]). The decision will be documented and signed by the PI as 
per Quotient Sciences current standard operating procedure (SOP). Evidence of the 
decision will be retained in the Investigator Site File (ISF) and GSK Trial Master File.
5.2.
Number of Participants
In Part A, 16 healthy participants will be enrolled such that at least 12 evaluable 
participants complete the study.  An evaluable participant will have completed the 


2017N315344_02
CONFIDENTIAL
205017
35
planned safety and PK assessments up to 32 hours after dosing (or 24 hours after dosing 
for Period 3; IR regimen [Regimen C]).  An evaluable participant must also have 
received the relevant test and reference formulations for the comparisons of interest e.g. 
an MR formulation and the IR reference and/or the selected MR formulation in both the 
fed and fasted states. 
In Part B, 10 healthy participants will be enrolled such that at least 6 evaluable 
participants complete the study. An evaluable participant will have received all 3 days of 
dosing at 2 or more dose levels and completed the planned PK assessments up to 24 
hours after the first dose on Day 3.
In Part C, 16 participants will be enrolled such that at least 12 evaluable participants
complete the study.  An evaluable participant will have completed the planned safety and 
PK assessments up to 32 hours after dosing (or 24 hours after dosing for Period 2; IR 
regimen).  An evaluable participant must also have received the relevant test and 
reference formulations for the comparisons of interest e.g. the MR tablet and the IR 
reference at 240 mg.
Participants withdrawn due to an IMP-related AE or termination of the study will not be 
replaced.  If participants prematurely discontinue the study for other reasons, additional 
replacement participants may be recruited at the discretion of the Sponsor in consultation 
with the investigator.
Up to 8 replacement participants may be enrolled in Part A.  The maximum number of 
participants that may be dosed in Part A is 24. 
Up to 5 replacement participants may be enrolled in Part B.  The maximum number of 
participants that may be dosed in Part B is 15.
Up to 8 replacement participants may be enrolled in Part C.  The maximum number of 
participants that may be dosed in Part C is 24. 
Replacement participants enrolled will be dosed with the next planned treatment of the 
withdrawn subject, and they will not receive any treatment that the withdrawn subject has 
already received with the exception of the need to increase subject numbers to obtain the 
minimum number of evaluable participants required for interim decisions, and to obtain 
data in any other treatment that is required for a valid comparison. Replacement 
participants will receive the required treatments in the same order as planned for the 
original subject and the minimum washout period will be respected with regard to the 
timing of dosing of the IR formulation.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure shown in the SoA i.e. the 
follow-up visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.


2017N315344_02
CONFIDENTIAL
205017
36
5.4.
Scientific Rationale for Study Design
Pharmacokinetic data from the FTIH study for GSK2982772 [GlaxoSmithKline 
Document Number 2014N204126_03] showed that the half-life of GSK2982772 was 
shorter than predicted (~2 to 3 hours).  As a result, BID and TID dosing regimens are 
being evaluated in three ongoing Phase 2a studies in psoriasis, ulcerative colitis and RA.  
A QD formulation would be more convenient from a patient perspective and could offer 
the advantage of providing a flatter GSK2982772 concentration time profile.  Therefore,
switching to a QD formulation for the Phase 2b DR studies and subsequent Phase 3 
studies would be advantageous.  
This current study is being conducted to evaluate the feasibility of developing an MR
formulation using a minitab approach filled into a capsule.  Each minitab will contain 
5 mg GSK2982772 and the amount of polymer can be adjusted to achieve the desired 
in-vitro release profile. The total weight of the minitab will be 20 mg and between 3 and
12 minitabs can be loaded into a capsule for oral administration.  Initially the PK profiles 
of slow (approximately 24 hours) and fast (approximately 10 hours) release rates of MR 
minitab will be compared to the PK profile of the IR tablet.  In subsequent arms of the 
study, the release rate may be adapted to achieve the target PK profile.  The effect of a 
high fat meal on the absorption of GSK2982772 when co-administered with the selected 
minitab MR formulation in a capsule will be evaluated to ensure that dose dumping does 
not occur.  In addition, a range of repeat doses will be evaluated to ensure that the MR 
formulation in a capsule can achieve a sufficient GSK2982772 systemic exposure range 
to support the Phase IIb DR studies.
Part C of this study is being conducted to evaluate a MR tablet formulation of 
GSK2982772 that is expected to give a similar in vivo PK profile to that of the slowest
minitab MR formulation from Part A. Initially, a dose of 240 mg of the MR tablet with a 
fixed polymer composition and similar dissolution profile to the slowest mintab 
formulation will be compared with the IR tablet formulation. The PK profiles of the 
minitab MR formulations were affected by food; therefore, the effect of a standard meal 
on the PK profile of GSK2982772 will also be investigated to determine if the MR tablet
can be administered with or without food restrictions. Higher doses (as higher tablet 
strength [360 mg or 480 mg] and/or multiple dose units and/or BID dosing) will also be 
investigated to determine if there are any dose dependent changes in absorption. The
polymer compositions of 360 mg and 480 mg tablets will be adjusted as part of a ‘design 
space’ concept to try to optimize the in vivo performance of 360 mg and /or 480 mg 
tablets based on the PK of the 240 mg MR tablet formulation.  This adjustment will be 
done ahead of dosing to select a formulation at each dose unit to achieve an improved in 
vivo profile based on the PK of the 240 mg MR tablet formulation.
The results from the first two periods will determine the dose levels of Periods 3 and 4. In 
Periods 5 and 6 of the study, the dose level may be changed , the dose may be given BID, 
and participants may be dosed in the fasted state, following a high fat meal or before a 
standard meal.
As this is a Phase 1 study, the most relevant population is healthy participants which
allows characterisation of safety, tolerability and PK in a homogenous population without 


2017N315344_02
CONFIDENTIAL
205017
37
potential biases from a patient population. The European Medicines Agency (EMA)
recommends including participants aged 18 years and older with normal weight, who are 
non-smokers, without a history of alcohol or drug abuse. The latter criteria are proposed 
to avoid interaction on drug metabolism and to avoid non-compliance. Therefore, this 
study will enrol healthy male and female participants aged between 18 to 65 years of age.
5.5.
Dose Justification
In Part A, a single dose of 120 mg will be used for the MR minitab formulations in a 
capsule and for the IR tablet.  In Part B, it is planned to evaluate target daily doses of 30, 
60 and 240 mg for 3 days.  The selection of these dose levels are based on the doses 
being used in the ongoing Phase 2a studies (IR 60 mg BID) and the safety and PK data 
from the GSK2982772 FTIH study, where doses up to IR 120 mg BID for 14 days were 
administered.
In Part A, a single dose of 120 mg MR has been selected since this dose is anticipated to 
provide systemic exposure similar to the 60 mg BID regimen being used in the ongoing 
Phase 2a studies (assuming a relative bioavailability of 100%).  In the GSK2982772 
FTIH study, 120 mg of the IR formulation was well tolerated when administered as 
single and repeated doses (BID for 14 days).  A single 120 mg dose of the MR 
formulation in a capsule is expected to result in lower Cmax than for the 120 mg IR tablet, 
and overall systemic exposure (AUC) is expected to be similar or lower than a single 
120 mg IR tablet dose.
The administration of 120 mg MR with food is expected to maintain AUC and Cmax
values within the range of values observed following 120 mg dose in the FTIH study. In 
the worst case scenario of dose dumping with food, 120 mg MR would have a PK profile 
similar to a single dose of 120 mg IR.
In Part B, the target daily MR doses of 30, 60, 240 mg reflect the approximate dose range 
that is planned to be taken forward into the Phase 2b DR studies.  The actual dose level 
may be increased (by adding additional minitabs to the capsule or by giving multiple 
capsules) if the relative bioavailability of the selected MR at 120 mg is less than 100% 
compared to a 120 mg dose of the IR tablet.  Taking into account the bioavailability of 
MR relative to IR, it is planned that the highest dose of MR to be administered will be not
exceed a total daily dose equivalent to 240 mg IR (e.g. if the bioavailability of MR is 
50% that of IR, the maximum daily dose of MR to be administered would be 480 mg).
In Part C, the target doses are higher than previously evaluated in Parts A and B to reflect 
a revised estimate of the upper limit of the dose range to be taken forward in the Phase 2b 
DR studies which for the IR formulation equates to 240 mg TID (720 mg/day).  This IR 
dose regimen has been evaluated following 1 day of dosing in healthy participants in 
Study 205184 and was shown to be well tolerated.  The highest target dose is currently 
960 mg which was predicted assuming the bioavailabilty of MR tablet relative to IR is 
the same as observed for the slowest minitab formulation in the fasted state (Frel = 74%).  
The highest dose level may be adjusted based on observed relative bioavailability of the 
MR tablet but will not exceed the GSK2982772 systemic exposure associated with the 


2017N315344_02
CONFIDENTIAL
205017
38
single day administration of 240 mg IR TID (i.e. mean AUC of 45.0 µg.h/mL and mean 
Cmax of 4.3 µg/mL).
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Quotient Sciences must have a full medical history from each participant’s general 
practitioner within the last 12 months, prior to enrolment in the study. Participants will be 
recruited from the Quotient Sciences panel or by direct advertising to the public.
Before participants are admitted to the clinic, The Over Volunteering Prevention System 
will be checked to ensure that each participant has not participated in a study at another 
site within at least 3 months of the dosing date.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
Weight
3.
Body weight ≥50 kg and body mass index within the range 19.0 to 32.0 kg/m2
(inclusive).
Sex
4.
Male or female
a. Male participants:
A male participant must agree to use a highly effective contraception as detailed in 
Appendix 5 of this protocol during the treatment period and for at least 90 days after 
the last dose of study treatment and refrain from donating sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR


2017N315344_02
CONFIDENTIAL
205017
39
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 30 days before and 30 days after 
the last dose of study treatment.
Informed Consent
5.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal (GI), 
endocrine, haematological, or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs; constituting a risk when taking 
the study treatment; or interfering with the interpretation of data.
2.
Parts A and C only: Any history of suicidal behaviour within the past 6 months or 
any history of attempted suicide in a participant’s lifetime. 
3.
Part B only: Participants with current history of Suicidal Ideation Behaviour as 
measured using the C-SSRS or a history of attempted suicide.
4.
History of clinically significant psychiatric disorders as judged by the investigator.  
Depression requiring treatment in the last 2 years.
5.
History of herpes zoster (shingles) reactivation.
6.
History or diagnosis of obstructive sleep apnoea.
7.
History of a significant respiratory disorder. Childhood asthma that has fully 
resolved is permitted.
8.
History or current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions.
9.
A positive diagnostic tuberculosis (TB) test at screening defined as a positive 
QuantiFERON-TB Gold test or T-spot test.  In cases where the QuantiFERON or 
T-spot test is indeterminate, the participant may have the test repeated once, but they 
will not be eligible for the study unless the second test is negative.
10. History of GI surgery (with exception of appendectomy).
11. History of cholecystectomy or gall stones.
12. Presence or history of clinically significant allergy requiring treatment, as judged by 
the investigator. Hayfever is allowed unless it is active.
13. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
14. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35% of total).


2017N315344_02
CONFIDENTIAL
205017
40
15. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome).
16. Corrected QT interval (QTc) >450 milliseconds (msec).
Notes: 
The QTc is the QT interval corrected for heart rate according to either Bazett’s 
formula (QTcB), QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF), or another method, machine or manual over read.
The specific formula that will be used to determine eligibility and discontinuation 
for an individual participant should be determined prior to initiation of the study.  
In other words, several different formulae cannot be used to calculate the QTc for 
an individual participant and the lowest QTc value used to include or discontinue 
the participant from the trial.
For purposes of data analysis, QTcB, QTcF, another QTc correction formula or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan.
Prior/Concomitant Therapy
17. Past or intended use of over-the-counter or prescription medication including herbal 
medications within 7 days prior to dosing (paracetamol/acetaminophen [up to 2 g per 
day], hormone replacement therapy and hormonal contraception are permitted).
18. Live or attenuated vaccine(s) within 30 days of enrolment, or plans to receive such 
vaccines during the study or plans to receive a vaccine within 30 days + 5 half-lives 
of the last dose of study medication.
Prior/Concurrent Clinical Study Experience
19. Participation in the study would result in loss of blood or blood products in excess of
500 mL within a 56 day period; therefore donation or loss of greater than 400 mL of 
blood within the previous 3 months.
20. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
21. Current enrolment or past participation within the last 3 months before signing of 
consent in this or any other clinical study involving an investigational study 
treatment or any other type of medical research.
22. Participants who have previously been enrolled in this study. Participants in Part A
of this study are not permitted to participate in Part B.  Participants in Parts A or B of 
this study are not permitted to participate in Part C.
Diagnostic assessments
23. Current or history of renal disease or estimated glomerular filtration rate (GFR) by 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
calculation <60 mL/min/1.73m2 at screening.
24. Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C 
antibody test result at screening or within 3 months prior to first dose.  As potential 


2017N315344_02
CONFIDENTIAL
205017
41
for and magnitude of immunosuppression with this compound is unknown, 
participants with presence of hepatitis B core antibody (HBcAb) should be excluded.
Participants positive for HBsAg and/or positive for anti-HBc antibody (regardless of 
anti-HBs antibody status) are excluded.
25. An elevated C-reactive protein (CRP) outside the normal reference range.
26. Part B only: A positive anti-nuclear antibody (ANA) outside the normal reference 
range.
27. Confirmed positive pre-study drug/alcohol screen.
28. Positive human immunodeficiency virus (HIV) antibody test.
29. Regular use of known drugs of abuse, or history of drug or alcohol abuse in the past 
5 years.
Other Exclusions
30. Regular alcohol consumption within 6 months prior to the study 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.
31. Current use or history of regular use of tobacco- or nicotine-containing products 
within 6 months prior to screening.  A carbon monoxide breath test reading of 
greater than 10 parts per million (ppm).
32. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study.
33. Unwilling or unable to swallow multiple size 0-00 capsules as part of study 
participation.
34. Participants who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator at screening.
35. Total cholesterol 300 mg/dL (7.77 millimole [mmol]/Liter [L]) or triglycerides 
250 mg/dL (2.82 mmol/L).
36. Participants who are study site employees, or immediate family members of a study 
site or sponsor employee.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from Seville 
oranges and grapefruit derivatives for 24 hours before admission to each study 
period until after collection of the final PK sample in that period.

Refrain from consumption of poppy seeds for 48 hours before screening, and from 
48 hours before admission to each study period until after collection of the final PK
sample in that period.


2017N315344_02
CONFIDENTIAL
205017
42

For fasted dosing, no water is allowed from 1 hour before dosing until 1 hour after 
dosing with the exception of the 240 mL water provided with each dose. Water is 
allowed ad libitum at all other times.

For fasted dosing, participants will be provided with a light snack on the evening 
before dosing and will be required to fast from all food and drink (except water) for a 
minimum of 10 hours before dosing until approximately 4 hours after dosing. Lunch 
will be provided approximately 4 hours after dosing, an evening meal will be 
provided approximately 10 hours after dosing and an evening snack will be provided 
approximately 14 hours after dosing.
If BID dosing in the fasted state is selected for Part B or Part C Period 6, participants
will be dosed in the evening approximately 12 hours after the morning dose. Meals 
will be provide as described above (i.e., no food will be permitted 2 hours before and 
2 hours after dosing).

For dosing after a high fat breakfast (Part A and optionally Part C) or a standard
breakfast (Parts B and C), participants will be provided with a light snack and will 
fast from all food and drink (except water) until the following morning, when they 
will be provided with the appropriate breakfast. The breakfast should be consumed 
over a maximum period of 25 min, with dosing occurring 30 min after the start of 
breakfast. Participants should be encouraged to eat their meal evenly over the 25 
min period. It is acknowledged that some participants will take less time to eat, but 
dosing should still occur 30 min after the start of breakfast.  Lunch will be provided 
approximately 4 hours after dosing, an evening meal will be provided approximately 
10 hours after dosing and an evening snack will be provided approximately 14 hours 
after dosing.
If BID dosing administered with food is selected for Part B or Part C Period 6, 
participants will be dosed in the evening following a standard evening meal. Meals 
will be provided as described above (with evening dosing approximately 30 minutes 
after the start of the evening meal).

If dosing before a standard meal is selected in Part C, participants will be provided 
with a light snack on the evening before dosing and will be required to fast from all 
food and drink (except water) for a minimum of 10 hours before dosing. No water is 
allowed from 1 hour before dosing until 1 hour after dosing, with the exception of the 
240 mL water provided with each dose.  Water will be allowed ad libitum after 
dosing or after administration of the standard breakfast, whichever is sooner.  A 
standard breakfast will be provided either 30 or 60 minutes after dosing. Lunch will 
be provided approximately 4 hours after dosing, an evening meal will be provided 
approximately 10 hours after dosing and an evening snack will be provided 
approximately 14 hours after dosing.

If drug administration in Part B is in the fasted stated, then on Day 2 when PK 
samples are not being collected, meals will be provided at appropriate times, i.e., a 
standard breakfast at approximately 2 hours post-morning dose, lunch at 
approximately 4 hours post-morning dose, dinner at approximately 10 hours 
post-morning dose and an evening snack at approximately 14 hours post-morning 
dose.


2017N315344_02
CONFIDENTIAL
205017
43

If drug administration in Part B is in the fed state, then on Day 2 when PK samples 
are not being collected, meals will be provided at appropriate times, i.e., a standard 
breakfast 30 mins prior to the morning dose, lunch at approximately 4 hours
post-morning dose, dinner at approximately 10 hours post-morning dose and an 
evening snack at approximately 14 hours post-morning dose.

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 
24 hours before admission until after collection of the final PK sample in that period.

Participants will abstain from alcohol for 24 hours before screening. During each 
dosing session, participants will abstain from alcohol from 24 hours before 
admission until after collection of the final PK sample in that period.

Current smokers or users of other tobacco products will not be enrolled in this study.
6.3.2.
Activity

Participants will abstain from strenuous exercise for 72 hours before screening and 
then from 72 hours before admission until discharge from the study. Participants 
may participate in light recreational activities during studies (eg, watching television, 
reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened at the discretion of the investigator if the reasons for the screening 
failure are expected to be temporary. Rescreened participants will be assigned a new 
screening number and will be re-consented.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


2017N315344_02
CONFIDENTIAL
205017
44
7.1.
Treatments Administered
7.1.1.
Treatments Administered - Part A
Regimen
A
B
C
D
E (Optional)
F (Optional)
Study Treatment 
Name:
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
Dosage formulation:
Prototype MR 
Minitablet in 
Capsule
Formulation A
Prototype MR
Minitablet in 
Capsule
Formulation B
IR Tablet
Reference
Prototype MR
Minitablet in Capsule
Formulation A, B or C
Prototype MR
Minitablet in Capsule
Formulation A, B, C or 
D
Prototype MR
Minitablet in 
Capsule
Formulation A, 
B, C or D
Unit dose strength(s)/
Dosage level(s):
60 mg / 
120 mg
60 mg / 
120 mg
30 mg /
120 mg
60 mg / 
120 mg
60 mg / 
120 mg
60 mg / 
120 mg
Route of 
Administration 
Oral with 240 mL water
Dosing instructions:
2 capsules, on 
the morning of 
Day 1 following 
an overnight 
fast
2 capsules, on 
the morning of 
Day 1 following 
an overnight fast
4 tablets in the 
morning of 
Day 1 
following an 
overnight fast
2 capsules, on the 
morning of Day 1 
following an overnight 
fast (if Formulation C) 
or following a high fat 
breakfast (if 
Formulation A or B)
2 capsules, on the 
morning of Day 1 
following an overnight 
fast (if Formulation D) 
or following a high fat
breakfast (if 
Formulation A, B or C)
2 capsules, on 
the morning of 
Day 1 following 
a high fat 
breakfast


2017N315344_02
CONFIDENTIAL
205017
45
Regimen
A
B
C
D
E (Optional)
F (Optional)
Packaging and 
Labelling
85 cc HDPE 
white bottle
85 cc HDPE white 
bottle
45 cc HDPE 
white bottle
85 cc HDPE white 
bottle
85 cc HDPE white
bottle
85 cc HDPE 
white bottle
Each HDPE bottle will be labelled as required per country requirement. 
Manufacturer
Quotient
Quotient
Quotient
Quotient
Quotient
Quotient


2017N315344_02
CONFIDENTIAL
205017
46
7.1.2.
Treatments Administered - Part B
Regimen
G
H
I
Study Treatment 
Name:
GSK2982772
GSK2982772
GSK2982772
Dosage formulation:
Prototype MR Minitablet in Capsule
Formulation X
Prototype MR Minitablet in Capsule
Formulation X
Prototype MR Minitablet in Capsule
Formulation X
Unit dose strength(s)/
Daily Dosage level(s)a:
15 or 30 mg / 
30 mg
30 or 60 mg / 
60 mg
60 mg / 
240 mg
Route of 
Administration 
Oral with 240 mL water
Dosing instructions:
1 x 30 mg capsule in the morning of 
Days 1 to 3
or
1 x 15 mg capsule in the morning and 
evening of Days 1 to 3; dosing will be 
12 hours apart
Fasted or Fed (non-high fat meal)
1 x 60 mg capsule in the morning of 
Days 1 to 3
or
1 x 30 mg capsule in the morning and 
evening of Days 1 to 3; dosing will be 
12 hours apart
Fasted or Fed (non-high fat meal)
4 x 60 mg capsule in the morning of Days 
1 to 3
or
2 x 60 mg capsule in the morning and 
evening of Days 1 to 3; dosing will be 12 
hours apart
Fasted or Fed (non-high fat meal)
Packaging and 
Labelling
Study Treatment will be provided in a 85 cc HDPE white bottle. Each HDPE bottle will be labelled as required per country 
requirement. 
Manufacturer
Quotient
Formulation X is the formulation selected from Part A
a Daily dosage levels are the anticipated dose levels for Part B; but may be subject to change depending on the results from Part A.


2017N315344_02
CONFIDENTIAL
205017
47
7.1.3.
Treatments Administered - Part C
Regimen
J
K
L
M
N
O
Study Treatment Name:
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
Dosage formulation:
MR Tablet 
IR Tablet
Reference
MR Tablet
MR Tablet
MR Tablet
MR Tablet
Unit dose strength(s)/
Dosage level(s):
240 mg / 240 mg
30 mg / 240 mg
360 mg / 360 mg 
or
480 mg / 480 mg
360 mg / 360 mg 
or
480 mg / 480 mg
360 mg / 360 mg or
480 mg / 480 mg
240 mg / xxx mg or 
360 mg / xxx mg or
480 mg / xxx mg
Route of 
Administration 
Oral with 240 mL water
Dosing instructions:
1 tablet, on the 
morning of Day 
1 following an 
overnight fast
8 tablets in the 
morning of 
Day 1 following 
an overnight fast
1 tablet, on the 
morning of 
Day 1 following 
an overnight fast
1 tablet, on the 
morning of 
Day 1 following 
a standard 
breakfast
1 tablet, on the 
morning of Day 1 
following a high fat 
breakfast or following 
an overnight fast, then 
a standard breakfast
0.5 or 1 hour post-dose
X tablets, on the 
morning of Day 1, or 
X tablets on the 
morning and evening 
of Day 1
prandial status tbc  
Packaging and 
Labelling
85 cc HDPE 
white bottle
45 cc HDPE 
white bottle
85 cc HDPE 
white bottle
85 cc HDPE 
white bottle
85 cc HDPE white 
bottle
85 cc HDPE white 
bottle
Each HDPE bottle will be labelled as required per country requirement. 
Manufacturer
Quotient
GSK
Quotient
Quotient
Quotient
Quotient


2017N315344_02
CONFIDENTIAL
205017
48
7.2.
Dose Modification
This protocol allows some alteration from the currently outlined dosing schedule (see 
Section 5.1 and Section 5.5). The dosing regimens in Part B will be selected based on PK 
and safety data from a minimum of 12 participants in Part A, and the maximum daily 
dose will not exceed a total daily dose equivalent to 240 mg IR taking into account the 
bioavailability of MR relative to IR (i.e. if the bioavailability of MR is 50% that of IR, 
the maximum daily dose of MR to be administered would be 480 mg).
In Part C, the maximum daily dose will not exceed a total daily dose equivalent to the 
systemic exposure for IR 240 mg TID (i.e. mean AUC of 45.0 µg.h/mL and mean Cmax of 
4.3 µg/mL) taking into account the bioavailability of MR relative to IR (i.e. if the 
bioavailability of MR is 50% that of IR, the maximum daily dose of MR to be 
administered would be 1440 mg).
The decision to proceed to the next dose level of GSK2982772 (either an increase or a 
decrease) will be made by the sponsor and investigator based on safety, tolerability, and 
PK data obtained in at least 12 participants at the prior dose level, as described in 
Section 5.1.1.
7.3.
Method of Treatment Assignment
This is an open-label, non-randomised study. A treatment allocation list will take the 
place of the randomisation schedule, which will be developed by the sponsor. 
At screening, a unique Subject Number will be assigned to any subject who has at least 
one screening procedure performed, other than informed consent. The unique Subject 
Number will be used to identify individual participants during the course of the study, 
and will start with 
A treatment allocation list will be produced by GSK Clinical Statistics prior to the start of 
the study, using the validated internal software, which will dictate the treatments that 
should be administered to each participant in each period. The master treatment 
allocation list will be sent to the site and retained in the ISF.
Participant numbers will be allocated on the morning of dosing of Period 1 according to 
the code 
to 
for Part A,
to 
for Part B, and 
 to 
 for Part C, using the 
lowest number available. Replacement participants will be assigned Subject Numbers 
 to 
 for Part A,
 to 
 for Part B, and 
 to 
 for Part C.
7.4.
Blinding
This is an open-label study.
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2017N315344_02
CONFIDENTIAL
205017
49
2.
Only participants 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 labeled storage conditions with access 
limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the technical agreement. 

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.
7.6.
Treatment Compliance

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment and study 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.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded in the source workbook and 
electronic Case Report Form (eCRF) along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or nonprescription 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) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. 


2017N315344_02
CONFIDENTIAL
205017
50
Paracetamol/Acetaminophen, at doses of 2 grams/day, is permitted for use any time 
during the study. Use of hormonal contraception and hormone replacement therapy is 
permitted provided use is stable during the study.  Other concomitant medication may be 
considered on a case-by-case basis by the investigator in consultation with the Medical 
Monitor if required to treat AEs.
7.8.
Treatment after the End of the Study
There is no treatment after the end of the study. 
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
See the SoA for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. Discontinuation of study 
treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm below or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes that study treatment discontinuation is in the 
best interest of the participant.
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*


2017N315344_02
CONFIDENTIAL
205017
51
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
8.1.2.
QTc Stopping Criteria
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the participant has been enrolled.
For example, if a participant is eligible for the protocol based on QTcB, then QTcB must 
be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception. 

The QTc should be based on averaged QTc values of triplicate ECGs obtained 
over a brief (e.g., 5-10 minute) recording period.  
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  

QTc >500 msec

Change from baseline (pre-dose Day 1) of QTc >60 msec
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.3.
Individual Safety Stopping Criteria

If a participant experiences a serious or severe clinically significant AE that in the
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The participant becomes pregnant.

The participant initiates treatment with any prohibited medications.

The participant develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria or QTc stopping criteria are met.

The participant experiences any signs of suicidal ideation or behaviour.
8.1.4.
Temporary Discontinuation
If a participant is not dosed when planned in a particular period (eg in case of unexpected 
personal circumstances or AEs that occur between treatment periods), they may be dosed 
at a later date (if a subject cannot re-attend within 28 days, they should be considered 
withdrawn), provided the following criteria are met: 

The AE has resolved or stabilised.

The AE preventing dosing was not considered related to the IMP.


2017N315344_02
CONFIDENTIAL
205017
52

The participant has not met any individual stopping criteria.

It is considered safe to continue to dose in the opinion of the investigator.
8.1.5.
Rechallenge
8.1.5.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons.  If a participant withdraws 
from the study, he/she may request destruction of any samples taken, and the 
Investigator must document this in the site study records.  The reason for 
withdrawal should be documented in the Case Report Form (CRF).

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

The Sponsor’s request, for reasons such as significant protocol deviations or 
participant safety concern (and after discussion with the Investigator).

If a participant is withdrawn from study treatment, this participant is also 
considered to be withdrawn from the study following completion of follow-up 
assessments.

Study is terminated by the Sponsor.

Refer to the SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 


2017N315344_02
CONFIDENTIAL
205017
53
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s source workbook.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
8.4.
Study Stopping Criteria
The study will be halted, and the risk to other participants evaluated, prior to a decision as 
to whether to terminate the study if any of the following criteria are met: 

The occurrence of an SAE, considered at least possibly related to the IMP 
administration in one participant. 

The occurrence of severe non-serious AEs considered as, at least, possibly 
related to the IMP administration in 2 participants at the same dose level
Relatedness will be determined by the investigator. If the study is halted, a temporary halt 
will be submitted to the MHRA and EC in the form of a substantial amendment. The 
study will not be resumed until a further substantial amendment to resume the study is 
submitted and approved by MHRA and EC.
8.5.
Study Termination
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the sponsor and investigator without consultation with the MHRA 
and EC. The end of the trial must be notified to the MHRA and EC immediately and at 
the latest within 15 days after the study is halted, clearly explaining the reasons. A 
description of follow up measures taken for safety reasons if applicable, should also be 
provided.
If the study is abandoned prior to commencement of any protocol activities, the PI or 
sponsor must notify the EC and MHRA by letter outlining the reasons for abandonment 
of the trial.
Once exposure to GSK2982772 has begun, the study will be completed as planned unless 
the following criteria are satisfied that require temporary suspension or early termination 
of the study.

The occurrence of serious or severe AE(s), as defined in Appendix 4, if 
considered to be related to the IMP.

New information regarding the safety of the IMP that indicates a change in the 
risk/benefit profile for the compound, such that the risk/benefit is no longer 
acceptable for participants in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the 
ability to achieve the primary study objectives or compromises participant
safety.
If any of the above occurs, the study may be terminated if careful review of the overall 
risk/benefit analysis described in Section 3.3 demonstrates that the assumptions have 


2017N315344_02
CONFIDENTIAL
205017
54
changed and that the overall balance is no longer acceptable. In these circumstances 
termination can only take place with the agreement of the investigator and sponsor. The 
MHRA and EC will be informed of study termination.
If it becomes necessary to consider termination of the study after dosing has begun, 
dosing may be suspended pending discussion between the investigator and sponsor. 
Dosing will be stopped immediately on safety grounds.
The study may be terminated or suspended at the request of the MHRA or EC.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management or by 
generic screening (e.g., blood count) and obtained before signing of ICF may be 
utilized for screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
550 mL in a 56-day period.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

A participant will be allowed to leave the premises following completion of 
study-specific procedures at 32 hours post-dose (Part A, Treatment Periods 1, 2, 4, 5, 
6 and Part C, Treatment Periods 1, 3, 4, 5, 6) or 24 hours post-dose (Part A, 
Treatment Period 3 and Part C, Treatment Period 2) or 24 hours after the last dose 
(Part B Treatment Periods 1, 2 and 3; if BID dosing selected this will be after the last 
evening dose) providing that:
−
No AEs have been reported during the study visit
−
The participant responds positively when asked “How are you feeling?”
If any of these conditions are not met, then the participant may only be allowed to 
leave the clinical unit with the authorisation of the investigator or appropriately 
qualified delegate.


2017N315344_02
CONFIDENTIAL
205017
55
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit
at the time points specified in the SoA (Section 2).

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 
24 hours, as indicated in Appendix 4. 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 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 


2017N315344_02
CONFIDENTIAL
205017
56
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and sponsor policy and forwarded to investigators as 
necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.

Further details can be found in Appendix 7.
9.2.5.
Pregnancy

Details of all pregnancies in female participants and, female partners of male 
participants will be collected after the start of study treatment and until 30 days after 
the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of GSK2982772 greater than that intended in this study will be 
considered an overdose.
There is no specific antidote for overdose with GSK2982772.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.


2017N315344_02
CONFIDENTIAL
205017
57
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 48 hours following the last 
dose of GSK2982772).
3.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, GI and neurological systems. Height and 
weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, heart rate and 
respiratory rate.

The acceptable deviations from the nominal vital signs measurement time points 
are:
−
The pre-dose vital signs measurements will be taken ≤2 hours before 
dosing.
−
Post-dose vital signs measurements will be taken ± 15 minutes from the 
nominal post-dose time points.
−
Discharge vital signs measurements will be taken ± 1 hour from the 
nominal time point.

If a participant shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution if 
required. Additional measurements may be taken as deemed necessary by the 
investigator.

Any clinically significant abnormality, including changes from baseline
(pre-dose Day 1), must be reported as an AE.


2017N315344_02
CONFIDENTIAL
205017
58
9.4.3.
Electrocardiograms

Triplicate 12-lead ECGs will be obtained at screening and single 12-lead ECGs 
will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc
intervals. If a single ECG shows a QTc increase of ≥ 60 msec from baseline
(pre-dose Day 1), two further ECGs should be performed over a brief period 
(e.g. 5 to 10 minutes) and the assessment made on the mean QTc of the triplicate 
ECGs.  Refer to Section 8.1.2 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.

The QTc should be based on averaged QTc values of triplicate ECGs obtained 
over a brief (e.g. 5 to 10 minutes) recording period.

The acceptable deviations from the nominal ECG measurement time points are:
−
The pre-dose ECG measurements will be taken ≤2 hours before dosing
−
Post-dose ECG measurements will be taken ± 15 minutes from the 
nominal post-dose time point.
−
Discharge ECG measurements will be taken ± 1 hour from the nominal 
time point.

ECGs are to be measured after participant has been in a semi-supine or supine 
position after approximately 5 minutes rest.

If a participant shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution if 
required. Additional measurements may be taken as deemed necessary by the 
investigator.

Any clinically significant abnormality, including changes from baseline
(pre-dose Day 1), will be reported as an AE.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

Blood samples for scheduled laboratory assessments will be taken following an 
overnight fast.

The acceptable deviations from the nominal blood sampling time points for 
laboratory assessments are:
−
The pre-dose blood sample will be taken ≤2 hours before dosing
−
Post-dose blood samples will be taken ± 1 hour from the nominal blood 
sampling time except when the time point coincides with the PK blood 
sampling time. In this situation, the time window for the PK sample applies.

The acceptable deviations from the nominal urine sampling time points for 
urinalysis are:
−
The pre-dose urine sample will be taken ≤3 hours before dosing or the first 
void of the day


2017N315344_02
CONFIDENTIAL
205017
59
−
Post-dose urine samples will be taken ± 2 hour from the nominal urine 
sampling time.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

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 (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.4.5.
Suicidal Risk Monitoring
GSK2982772 is considered to be a CNS-active drug.  There has been some concern that 
some CNS-active drugs may be associated with an increased risk of suicidal thinking or 
behaviour when given to some patients with disease.  Although this drug has not been 
shown to be associated with an increased risk of suicidal thinking or behaviour when 
given to healthy volunteers, GSK considers it important to monitor for such events before 
or during clinical studies with compounds such as this.   
Participants being treated with GSK2982772 should be monitored appropriately for 
suicidal ideation and behaviour or any other unusual changes in behaviour. Study 
medication must be immediately discontinued in all participants who experience signs of 
suicidal ideation or behaviour.
Families and caregivers of patients being treated with GSK2982772 should be alerted 
about the need to monitor participants for the emergence of unusual changes in 
behaviour, as well as the emergence of suicidal ideation and behaviour and to report such 
symptoms immediately to the study Investigator.
At Screening, the ‘Baseline/Screening C-SSRS’ will be completed in Part B only.  
Assessments done at pre-dose Day 1 and Day 4, the ‘Since Last Visit C-SSRS’ will be 
completed in Part B only.  GSK Version 4.1 of both rating scales will be used.


2017N315344_02
CONFIDENTIAL
205017
60
Participant s who answer ‘yes’ to any suicidal behaviour or ‘yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their General Practitioner or appropriate psychiatric 
care and be discontinued from study medication.  The Medical Monitor will be notified.  
If appropriate, an AE or SAE should be reported (see Section 9.2).  In addition, the 
Investigator should complete a Possible Suicidality Related Adverse Event (PSRAE) 
form to collect detailed information on the circumstances of the reported AEs which, in 
the Investigator’s opinion, are possibly suicidality-related.  These may include, but are 
not limited to, an event involving suicidal ideation, a preparatory act toward imminent 
suicidal behaviour, a suicide attempt, or a completed suicide.
9.5.
Pharmacokinetics

Blood samples of approximately 2 mL will be collected for measurement of 
plasma concentrations of GSK2982772 as specified in the SoA (see Section 2).
Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded.

Processing, storage and shipping procedures are provided in the Study Reference 
Manual (SRM) or equivalent.

The acceptable deviations from the nominal post-dose blood sampling times are 
as follows:
−
The pre-dose blood sample will be taken ≤1 hour before dosing. 
−
Post-dose samples will be taken within ± 10 minutes of the nominal post-
dose sampling time 

Samples will be used to evaluate the PK of GSK2982772. Samples collected for 
analyses of GSK2982772 plasma concentration may also be used to evaluate 
safety aspects related to concerns arising during or after the study.

Genetic analyses will not be performed on these plasma samples. Participant 
confidentiality will be maintained. 
Plasma analysis will be performed under the control of Platform Technology & Science 
(PTS), In Vitro/In Vivo Translation (IVIVT) and Third Party Resourcing (TPR), GSK.  
Concentrations of GSK2982772 will be determined in plasma using the current approved 
bioanalytical methodology.  Raw data will be archived at the Bioanalytical site as 
detailed in the SRM or equivalent.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Genetics are not evaluated in this study.


2017N315344_02
CONFIDENTIAL
205017
61
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
No formal hypothesis will be tested. However, point estimates and corresponding 90% 
confidence intervals will be derived for Cmax, AUC(0- inf), C12 and C24 and peak to trough 
concentration ratio for each test minitab MR formulation in a capsule (120 mg) relative to 
the IR formulation (120 mg).
10.2.
Sample Size Determination
10.2.1.
Sample Size Determination - Part A
To date, there are no MR formulation variability data available. The maximum between-
subject coefficient of variation (CVb) for the PK parameters observed in Study 200975 
following GSK2982772 capsule formulation were used for precision estimates; CVb (%) 
for AUC(0-inf) and Cmax for 120 mg GSK2982772 IR capsule formulation were 29.0 and 
31.5 respectively.  Therefore, the estimates of within subject coefficient of variation 
(CVw [%]) are 20.3% and 18.8% for AUC(0-inf) and Cmax, respectively. Based on these 
estimates of variability and a sample size of 12 completers, it is estimated that the lower 
and upper bounds of the 90% confidence interval (CI) for the geometric mean ratio 
(MR/IR) of AUC and Cmax will be within approximately 15.3% and 14.2% of the point 
estimate respectively. 
Since it is expected that the MR formulation is to reduce the Cmax by 50% whilst 
maintaining the AUC, a sample size of 12 ensures that the 90% CI is within the region 
0.8-1.25 for AUC and 0.4-0.625 for Cmax, if the observed geometric ratio is 0.93-1.08 for 
AUC and 0.47-0.54 for Cmax. 
Sample Size Sensitivity – Part A
Using estimates of parameter (this can be any PK parameter AUC, Cmax) variability
observed in Study 200975, the precision of these estimates calculated as half width of a 
90% confidence interval for the mean ratio (MR/IR) and expressed as distance from 
mean to limits for 10, 12, 14 and 16 participants has been calculated (Table 5).


2017N315344_02
CONFIDENTIAL
205017
62
Table 5
Precision Estimate of Mean – Part A
CVw (%)
Precision of Mean (%)
N=10
N=12
N=14
N=16
15
12.70
11.30
10.30
9.50
18.8
16.00
14.20
12.90
11.90
20
17.30
15.30
13.90
12.90
For example, based upon the estimate of variability (CVw%) of 20 and a sample size of 
14, it is estimated that the lower and upper bounds of the 90% confidence interval for the 
means of the PK parameter (eg, AUC, Cmax) will be within approximately 13.9% of the 
point estimate.
10.2.2.
Sample Size Determination - Part B
No repeat dose MR formulation variability data are currently available. Therefore, the 
maximum CVb for the PK parameters were observed in the study 200972 following 
repeat dose of GSK2982772 capsule formulation; CVb (%) for AUC(0-τ) and Cmax for 
20mg QD GSK2982772 IR capsule formulation on Day 1 is 36.1 and 27.1 respectively. 
Therefore, the estimates of equivalent CVw (%) are 23.2 and 17.6 for Cmax and AUC(0-τ)
respectively. Based on these estimates of variability and a sample size of 8 completers, it 
is estimated that the lower and upper bounds of the 90% confidence interval for the 
means of AUC(0-τ) and Cmax will be within approximately 12.1% and 16.7% of the point 
estimate respectively.
Sample Size Sensitivity – Part B
Using estimates of parameter (this can be any PK parameter AUC, Cmax) variability, the 
precision of these estimates calculated as half width of a 90% confidence interval for the 
mean and expressed as distance from mean to limits for  4, 6, 8 and 10 participants has 
been calculated (Table 6).
Table 6
Precision Estimate of Mean – Part B
CVb (%)
Precision of Mean (%)
N=4
N=6
N=8
N=10
18.4%
23.6
16.0
12.8
11.0
19.3%
25.1
16.9
13.6
11.6
24.4%
32.6
21.8
17.4
14.9
25.5%
34.2
22.8
18.2
15.6


2017N315344_02
CONFIDENTIAL
205017
63
For example, based upon the estimate of variability (CVb%) of 19.3 and a sample size of 
4, it is estimated that the lower and upper bounds of the 90% confidence interval for the 
means of the PK parameter (eg, AUC, Cmax) will be within approximately 25.1% of the 
point estimate.
10.2.3.
Sample Size Determination - Part C
The maximum between-subject coefficient of variation (CVb) for the PK parameters 
observed in Part A of Study 205017 were used for precision estimates; CVb (%) for 
AUC(0-inf) and Cmax were 48.7% and 58.5%, respectively. Therefore, the estimates of 
within-subject coefficient of variation (CVw [%]) are 30.9% and 36.7% for AUC(0-inf) and 
Cmax, respectively. Based on these estimates of variability and a sample size of 12 
completers, it is estimated that the lower and upper bounds of the 90% CI for the 
geometric mean ratio (MR/IR) of AUC and Cmax will be within approximately 24.3% and 
29.2% of the point estimate, respectively. 
Since it is expected that the MR tablet formulation is to reduce the Cmax by 50% whilst 
maintaining the AUC, a sample size of 12 ensures that the 90% CI is within the region 
0.748-1.342 for AUC and 0.364-0.698 for Cmax, if the observed geometric ratio is 
0.93-1.08 for AUC and 0.47-0.54 for Cmax. 
Sample Size Sensitivity – Part C
Using estimates of parameter (this can be any PK parameter AUC, Cmax) variability 
observed in Part A of Study 205017, the precision of these estimates calculated as half 
width of a 90% CI for the mean ratio (MR/IR) and expressed as distance from mean to 
limits for 10, 12, 14 and 16 participants has been calculated (Table 7).
Table 7
Precision Estimate of Mean – Part C
CVw (%)
Precision of Mean (%)
N=10
N=12
N=14
N=16
30.9
27.5
24.3
22.0
20.3
36.7
33.1
29.2
26.4
24.3
For example, based upon the estimate of variability (CVw%) of 30.9 and a sample size of 
14, it is estimated that the lower and upper bounds of the 90% CI for the means of the PK 
parameter (eg, AUC, Cmax) will be within approximately 22.0% of the point estimate.


2017N315344_02
CONFIDENTIAL
205017
64
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Participants
All participants who receive at least 1 dose of study treatment and 
will be the population for reporting of safety and study population 
data. Participants will be analyzed according to the treatment they 
actually received.
PK
Participants in the ‘All Participants Population’ for whom a PK 
sample was obtained and analysed and will be the population for 
reporting of PK data.
10.4.
Statistical Analyses
10.4.1.
Pharmacokinetic Analyses
All PK analyses will be performed on the PK Population. 
For all parts of the study, plasma GSK2982772 concentration-time data will be analysed 
by non-compartmental methods.  
In Parts A and C, from the plasma concentration-time data for each of the regimens, the 
following PK parameters will be determined, as data permit: 

maximum observed plasma concentration (Cmax).

time to Cmax (Tmax).

the elapsed time from dosing at which GSK2982772 was first quantifiable in a 
concentration vs time profile (Tlag).

observed concentration at 12 hours and 24 hours post-dose (C12h and C24h).

area under the plasma concentration vs time curve (AUC(0-t), AUC(0-24), AUC(0-12)
and AUC(0-inf)).  

the percentage of AUC extrapolated beyond the last measured time point 
(AUC%extrap).

terminal half-life (t1/2).

Cmax to C12h and Cmax to C24h ratios.

relative bioavailability (Frelformulation) of test formulations vs reference formulation 
based on AUC(0-24) and AUC(0-inf) (or AUC(0-t) if AUC(0-inf) can’t be derived) and 
Cmax.

relative bioavailability (FrelFE) of fed vs fasted based on AUC and Cmax.


2017N315344_02
CONFIDENTIAL
205017
65
In Part B, from the plasma concentration-time data for each of the regimens, the 
following PK parameters will be determined, for Day 1 and Day 3, as data permit: 

maximum observed plasma concentration (Cmax) for QD dosing.  If BID dosing, Cmax
after morning dose and evening dose.

time to Cmax (Tmax) for QD dosing.  If BID dosing, Tmax after morning dose and 
evening dose.

observed concentration at 12 hours and 24 hours post-dose (C12h and C24h).

area under the plasma concentration-time curve (AUC(0-24)) for QD dosing.  If BID 
dosing, AUC(0-12) and AUC(12-24).

Cmax to C12 and Cmax to C24 ratios.

Dose normalised Cmax, C12h, C24h, AUC(0-tau) (for BID dosing), AUC(0-24) and 
AUC(0-inf).

Relative bioavailability (FrelFE) of fed (non-high fat meal) vs fasted based on AUC 
and Cmax (dose corrected as appropriate)
Descriptive statistics (n, arithmetic mean, standard deviation [SD], 95% CI, minimum, 
median and maximum,) will be calculated by treatment for all PK concentrations over 
time and for the derived PK parameters. In addition, for loge-transformed PK parameter 
variables geometric mean, 95% CI and %CVb (100 * √ (exp(SD2) -1)) will be provided, 
where the SD is the standard deviation of log-transformed data.


2017N315344_02
CONFIDENTIAL
205017
66
Endpoint
Statistical Analysis Methods
Primary
The primary PK endpoints to compare MR formulations with IR formulations will 
be summarised descriptively. Ratio of AUC(0-inf) , AUC(0-24), (AUC(0-t), if AUC(0-inf)
cannot be derived), Cmax, C12 and C24 for MR formulation to IR formulation will be 
computed with 90% CI. Cmax to C12h and Cmax to C24h ratio for each MR 
formulation (120 mg or 240 mg) and the corresponding total dose of IR 
formulation (120 mg or 240 mg) will be computed with 90% CI.  
Secondary
The secondary endpoints for food effect will be summarised descriptively. In 
addition, log-transformed AUC(0-inf)(AUC(0-t), if AUC(0-inf) cannot be derived), C12h, 
C24h, and Cmax will be analysed using a mixed effects model with regimen as a 
fixed effect and subject within sequence as a random effect.  Point estimates and
corresponding 90% CI will be computed for the differences for each GSK2982772 
MR formulation (120 mg, 240 mg, 360 mg or 480 mg) taken in the fed state (test) 
vs the same dose in the fasted state (reference) using the residual error from the 
model (MSE). The point and interval estimates on the log-scale will then be 
exponentially back transformed to give estimates of the ratios of geometric 
means and 90% CI.
Within-subject coefficients of variation for AUC(0-inf)and Cmax will be calculated 
based on the loge-Normal distribution: CVw (%) = sqrt[exp(mse) - 1] x 100, where 
MSE is the residual error from the model.
Statistical analysis of the PK endpoint Tmax of each GSK2982772 MR formulation
administered under both fed and fasted conditions will be separately analysed 
non-parametrically [Hauschke, 1990]. The point estimates for the medians for 
each treatment, the median difference and 90% CI for the median difference will 
be calculated for the contrast (test-reference).
Secondary
Part B, the secondary PK endpoints for the selected MR formulation at target 
daily doses of 30, 60 and 240 mg will be summarised descriptively. 
Part C, the secondary PK endpoints MR at target daily doses of 240 mg, 360 mg, 
480 mg and high dose selected in Period 6 will be summarised descriptively.
For Part B and Part C, plots of dose vs dose normalised AUC(0-24), AUC(0-12) 
(AUC(12-24) BID dosing), C12h, C24h and Cmax (after morning and evening doses if 
BID dosing) will be generated to determine if there are any dose dependent 
changes in the absorption of GSK2982772 following repeat dose administration 
of the selected minitab MR formulation.
Exploratory
Part B, the exploratory endpoints for non-high fat meal food effect will be 
summarised descriptively and modelled as specified for the secondary food effect 
endpoints.
The Reporting and Analysis Plan will describe the planned PK analyses in greater detail.


2017N315344_02
CONFIDENTIAL
205017
67
10.4.2.
Safety Analyses
All safety analyses will be performed on the All Participants Population. 
Endpoint
Statistical Analysis Methods
Secondary
The safety endpoints will be summarised descriptively. 
The Reporting and Analysis Plan will describe the planned safety analyses in greater 
detail.
10.4.3.
Interim Analyses
No formal statistical analyses are planned. However, after Periods 1 to 3 of Part A are 
complete, the PK data will be analysed which will guide Periods 4, 5 and 6. Periods 4, 5 
and 6 will be flexible and the dosing regimen will be dependent on the outcome of 
preceding periods.  There will be the option to either optimise the MR release duration 
and/or to evaluate the impact of food on the selected MR minitab formulation in a 
capsule.  There will also be the option to cancel Periods 5 and 6 if an optimal formulation 
is determined in Periods 1 or 2.
There will be an interim review following final period of Part A to determine the 
formulation, doses, dosing frequency (QD or BID) and prandial state for each dosing 
period of Part B.  The data will be sent to the sponsor by Quotient, from which the 
decision on formulation and prandial state selection or stopping the study will be made by 
the Quotient study team (i.e., PI, scientific lead and pharmacokineticist) and sponsor 
study team (as a minimum the sponsor’s medical monitor, CPMS and GCSP).  The 
decision will be documented and signed by the PI as per Quotient Sciences current SOP.  
Evidence of the decision will be retained in the ISF and GSK Trial Master File.
There will be no interim analysis during Part B of the study. 
In Part C, there will be an interim review following completion of Periods 1 and 2 to 
determine the dose to be used in Periods 3 and 4. A further interim analysis after 
Period 4 will be used to determine if dosing should be before a standard meal (i.e.,
delayed standard meal) or after high fat meal in Period 5. There will be a final interim 
review after Period 5 to determine the dose and food status for Period 6. 
See Section 5.1.1 for full details on the criteria for interim decisions.
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
10.4.4.
Stopping Criteria
After data is available and analysed for Period 1, 2 and 3 in Part A, a decision to stop the 
study could be triggered if:


2017N315344_02
CONFIDENTIAL
205017
68

The PK profile of IR and MR are similar , based on visual judgement of 
concentration-time curves or if the PK profiles indicate that a QD or BID dosing 
regimen isn’t feasible.  Consideration of PK parameters, AUC(0-inf) and Cmax will 
assist with this judgement but no formal quantitative no-go will be defined due to 
the exploratory and flexible nature of the study.

Administration of MR with a high-fat meal shows dose dumping 


2017N315344_02
CONFIDENTIAL
205017
69
11.
REFERENCES
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E et al. 
RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions 
of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death & Differ, 2013;20:1381-92.
GlaxoSmithKline Document Number 2014N204126_03.  GSK2982772 Investigator 
Brochure.  Effective Date 25-JAN-2018 
Hauschke D1, Steinijans VW, Diletti E. A distribution-free procedure for the statistical 
analysis of bioequivalence studies. Int J Clin Pharmacol Ther Toxicol, 1990;28(2):72-8.
Humphries F, Yang S, Wang B, Moynagh P N. RIP kinases: key decision makers in cell 
death and innate immunity. Cell Death & Differ, 2015;22:225-236.
Ofengeim D and Yuan J. Regulation of RIP1 kinase signaling at the crossroads of 
inflammation and cell death. Nature Reviews Molecular Cell Biology, 2013;14:727-36.
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. 
Cell, 2008; 133(4):693-703.


2017N315344_02
CONFIDENTIAL
205017
70
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
List of Abbreviations
Abbreviation
Definition
AE
Adverse event
ALT
Alanine transaminase
ANA
Anti-nuclear antibody
AST
Aspartate Aminotransferase
AUC
Area under the concentration vs time curve
AUC(0-12),
Area under the curve from time zero to 12 hours
AUC(0-24)
Area under the curve from time zero to 24 hours
AUC(0-t)
Area under the curve from time zero to the last measurable concentration
BID
Twice daily
BUN
Blood Urea Nitrogen
C12
Concentration at 12 h post-dose
C24
Concentration at 24 h post-dose
CA
Competent Authority
CI 
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacokinetics Modelling and Simulation
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
CRP
C-reactive protein
C-SSRS
Columbia Suicide Severity Rating Scale
CV
Cardiovascular
CVb
Between subject coefficient of variation
CVw
Within subject coefficient of variation
DR
Dose ranging
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
FTIH
First time in human
Frel
Relative bioavailability
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GFR
Glomerular filtration rate
GI
Gastrointestinal
GLP
Good Laboratory Practice


2017N315344_02
CONFIDENTIAL
205017
71
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
hCG
Human Chorioninc Gonadotropin
HIV
Human immunodeficiency virus
HIPPA
Health Insurance Portability and Accountability Act
HRT
Hormonal Replacement Therapy
ICF
Informed consent form
IEC
Independent Ethics Committees
IMP
Investigational medicinal product
INR
International normalized ratio
IR
Immediate release
IRB
Institutional Review Board
ISF
Investigator site file
IVIVT
In Vitro/In Vivo Translation
L
Litre
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
mg
milligrams
MHRA
Medicines and Healthcare products Regulatory Agency
mins
Minutes
mL
Millilitres
mmol
Millimole
MR
Modified release
MSDS
Material Safety Data Sheet
msec
Milliseconds
NOAEL
No observed adverse effect level
Pgp
P-glycoprotein
PI
Principal investigator
PIS
Participant Information Sheet
PK
Pharmacokinetic(s)
ppm
Parts per million
PsO
Plaque psoriasis
PSRAE
Possible Suicidality Related Adverse Event
PTS
Platform Technology & Science
QD
Once daily
QTc
Corrected QT interval
QTcB
QT interval corrected for heart rate according to Bazett’s formula
QTcF
QT interval corrected for heart rate according to Fridericia’s formula
RA
Rheumatoid arthritis
RBC
Red blood cells
RIP1
Receptor-interacting protein-1
SAE
Serious adverse event
SD
Standard deviation
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SoA
Schedule of activities


2017N315344_02
CONFIDENTIAL
205017
72
SRM
Study Reference Manual
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TB
Tuberculosis
TID
Three times daily
TLR
Toll like receptor
Tmax
Time to Cmax
TNF
Tumour necrosis factor
TPR
Third Party Resourcing
ULN
Upper limit of normal
WBC
White blood cells
WOCBP
Woman of childbearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Chiron RIBA
SAS
WinNonlin


2017N315344_02
CONFIDENTIAL
205017
73
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 8 will be performed by The Doctors Laboratory, with 
the exception of routine urinalysis, urine pregnancy test, urine drug screen, 
alcohol and carbon monoxide breath tests. These tests will be performed on-site.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

All laboratory tests with values that are considered clinically significantly 
abnormal during participation in the study should be repeated until the values 
return to normal or baseline.  If such values do not return to normal within a 
period judged reasonable by the Investigator, the etiology should be identified 
and the sponsor notified.
Table 8
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume (MCV)
Mean corpuscular 
haemoglobin (MCH)
Mean corpuscular 
haemoglobin 
concentration (MCHC)
%Reticulocytes
White blood cell (WBC) 
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red Blood Cell (RBC)
Count
Haemoglobin
Haematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin (direct 
only if total is 
elevated)
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Albumin
Chloride
Cholesterol 
(Total)
Triglycerides


2017N315344_02
CONFIDENTIAL
205017
74
Laboratory 
Assessments
Parameters
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocytes by dipstick

Microscopic examination (if blood, protein or leukocytes are abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) at screening only

urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)

alcohol breath test

carbon monoxide breath test

Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)

Serum hCG pregnancy test (as needed for women of childbearing potential)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody) at screening only

Tuberculosis test (QuantiFERON) at screening only

C-reactive protein (CRP) at screening only

Anti-nuclear antibody (ANA) in Part B only
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 6 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE.


2017N315344_02
CONFIDENTIAL
205017
75
12.3.
Appendix 3: Study Governance Considerations
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 GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Prior to the initiation of the study, the Clinical Trial Authorisation application 
must be approved by the MHRA. A copy of this approval and any 
correspondence with the MHRA will be available at the clinical and sponsor 
sites. A copy of the MHRA approval will be provided to the EC.

Any substantial amendments to the protocol will require MHRA and IEC/IRB 
approval before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study participants
(urgent safety measure). 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Protocol Amendments and Deviations
Amendments
After the protocol has been submitted to the MHRA and/or EC, any amendment must be 
agreed by the investigator after discussion with the sponsor and will be formally 
documented.
All substantial amendments will be submitted to the MHRA and/or EC for an opinion as 
required by current regulations. 


2017N315344_02
CONFIDENTIAL
205017
76
If the participant information sheet (PIS) and ICF are updated as a result of an 
amendment, the new versions will be used to re-consent currently enrolled participants
and must be provided to additional participants prior to their entry into the study.
Protocol Deviations
The study must be conducted in accordance with the Clinical Protocol. Should a protocol 
deviation occur, it must be promptly assessed in order to decide whether any of these 
non-compliances should be reported to the MHRA as a serious breach of GCP and the 
Clinical Protocol.
Protocol waivers are not acceptable.
Deviations from the protocol will be recorded in the source workbook as noted by the 
clinical staff. If necessary, the sponsor will be informed of the deviation.
Any protocol deviations assessed as major will be discussed with the sponsor in order to 
determine if the withdrawal criteria stated in Section 8 have been met.
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.
Informed Consent Process

Participants will be provided with a written explanation of the study at least one 
day before the screening visit.

The investigator or his/her representative will explain the nature of the study, its 
purpose, expected duration and the benefits and risks involved in study 
participation to the participant and answer all questions regarding the study. 
Participants will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that 
carry out clinical studies in the local area.

Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study centre. 

The source workbook 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.


2017N315344_02
CONFIDENTIAL
205017
77

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. 

Participants who are rescreened are required to sign a new ICF.
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 IRB/IEC members, and by inspectors from 
regulatory authorities.
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 multicentre studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

Following completion of the study, a clinical study report will be prepared. 

The procedures and timing for public disclosure of the results summary and for
development of a manuscript for publication will be in accordance with GSK 
policy and will be made available to the EC/MHRA within 1 year of the 
declaration of the end of trial.
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 (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.


2017N315344_02
CONFIDENTIAL
205017
78

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/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 from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
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. 
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

A study-specific source documentation list will be finalised by the sponsor 
before the start of the clinical phase of the study. The document will identify 
what data should be considered source data for this study.


2017N315344_02
CONFIDENTIAL
205017
79
Declaration of the End of the Study
The definition of the end of the study is defined as the last visit of the last participant
(eg follow-up assessment). Any changes to this definition will be notified as a substantial
amendment.
The EC and MHRA should be notified in writing of the conclusion of the study within 
90 days of the end of the study, or within 15 days if the study is terminated early, clearly 
explaining the reasons for the termination.
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 
IRB/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


2017N315344_02
CONFIDENTIAL
205017
80
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting to GSK
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 (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, 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 (eg, 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 


2017N315344_02
CONFIDENTIAL
205017
81
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 (eg, 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 fulfils 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, diarrhoea, influenza, 
and accidental trauma (eg, 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 


2017N315344_02
CONFIDENTIAL
205017
82
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.
Definition of an Adverse Drug Reaction (ADR)
An ADR is defined as any untoward medical occurrence that, at any dose:

where a causal relationship with the IMP is at least a reasonable possibility (possibly 
related or related)
Definition of SUSAR
A SUSAR is defined as any untoward medical occurrence that, at any dose:

Is believed to be related to an IMP and is both unexpected (ie the nature or severity is 
not expected from the information provided in the Investigator’s Brochure) and 
serious. SUSARs are subject to expedited reporting to the MHRA, European 
Medicines Agency (EMA), EC (see Appendix 7)
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF (ie the 
date and time of onset, a description of the AE, severity, duration, actions taken, 
outcome and an investigator’s current opinion on the relationship between the study 
treatment and the event).

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 


2017N315344_02
CONFIDENTIAL
205017
83
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; intervention may be needed.

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 
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.


2017N315344_02
CONFIDENTIAL
205017
84
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 via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (eg, check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the Communication Plan.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.


2017N315344_02
CONFIDENTIAL
205017
85

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Communication Plan.


2017N315344_02
CONFIDENTIAL
205017
86
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
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 WOCBP
1. Premenarchal
2. 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.
3. 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 (ie 
≥40 IU/L) 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 enrolment.
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 during the protocol-defined 
time frame in Section 6.1: 

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 Table 9 when having 
penile-vaginal intercourse with a woman of childbearing potential 


2017N315344_02
CONFIDENTIAL
205017
87

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 3 months after study 
completion or from last dose.

As there is a significant risk of drug exposure through the ejaculate (which also 
applies to vasectomised males) that might be harmful to the sexual partners 
(both male and female), including pregnant partners of male participants, a 
condom should be used by all male participants during the protocol-defined time 
frame in Section 6.1.
Female participants
Female participants who are not of childbearing potential do not need to use any methods 
of contraception.
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 9. 
Table 9
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 
ovulationb

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 WOCBP and the absence of sperm has been confirmed. If 


2017N315344_02
CONFIDENTIAL
205017
88
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

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test 

Additional pregnancy testing will be performed at admission to each study period
and at the follow-up visit

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Urine pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using 
the SureScreen Diagnostics test in accordance with instructions provided in its 
package insert at each admission. Serum pregnancy testing, with a sensitivity of
5.8 mIU/mL will be performed and assayed in the certified local laboratory (The 
Doctors Laboratory)  
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 foetal
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 


2017N315344_02
CONFIDENTIAL
205017
89

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of foetal status (presence 
or absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will be withdrawn 
from the study 


2017N315344_02
CONFIDENTIAL
205017
90
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
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 subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor 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 2 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 paracetamol/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:


2017N315344_02
CONFIDENTIAL
205017
91
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

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. NOTE: not required in 
China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
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 
subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM
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.


2017N315344_02
CONFIDENTIAL
205017
92
12.7.
Appendix 7: Safety Reporting to Ethics Committee and 
Regulatory Authorities
Events Requiring Expedited Reporting
SUSARs are subject to expedited reporting to the MHRA, EMA and EC.
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of an IMP or that would be 
sufficient to consider changes in the IMPs administration or in the overall conduct of the 
study, for instance:

an increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important

SAEs that occur after the participant has completed the clinical study where the 
sponsor considers them to be a SUSAR

new events related to the conduct of the study or the development of the IMPs and 
likely to affect the safety of the participants, such as:
−
an SAE which could be associated with the study procedures and which could 
modify the conduct of the study
−
a major safety finding from a newly completed animal study (such as 
carcinogenicity)
−
any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same IMPs in another country by the same sponsor
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible.
Expedited Reporting of Events
It is the responsibility of the sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible.
Where expedited reporting is required, the following procedures should be followed.
Fatal or life-threatening SUSARs
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA and EMA as soon as possible, but no later than 7 calendar days after they first 
became aware of the reaction. This responsibility may be delegated to the
pharmacovigilance provider.
The investigator is required to notify the EC of any SUSAR as soon as possible, but no 
later than 7 calendar days after they first became aware of the reaction.
Any additional relevant information should be sent within 8 days of the report.


2017N315344_02
CONFIDENTIAL
205017
93
Other SUSARs
It is the responsibility of the sponsor to report other SUSARs to the MHRA and EMA as 
soon as possible, but no later than 15 calendar days after they first became aware of the 
reaction. This responsibility may be delegated to the pharmacovigilance provider.
The investigator is required to notify the EC of other SUSARs as soon as possible, but no 
later than 15 calendar days after they first became aware of the reaction.
Any additional relevant information should be sent within 8 days of the report.
Urgent Safety Measures
If Quotient Sciences or any of its staff or contractors becomes aware of an actual or 
potential urgent safety issue, then the sponsor must be immediately contacted so that 
appropriate urgent safety measures can be agreed. An urgent safety issue is defined as: 

An immediate hazard to the health or safety of participants enrolled in a clinical study

A serious risk to human health or potentially a serious risk to human health
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe conduct 
of the study or that pose a risk to study participants.
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, Quotient Sciences may take urgent safety measures before 
informing the sponsor, but the sponsor must be informed immediately after the hazard 
has resolved. 
Quotient Sciences will take responsibility for informing appropriate competent 
authorities, and the EC.
Reporting of Urgent Safety Issues
Quotient Sciences is required to inform the appropriate competent authorities and the EC
within 3 calendar days of the urgent safety issue.
Serious Breaches
It is the responsibility of the sponsor to notify the licensing authority of any serious 
breach, which is likely to affect, to a significant degree, the safety or mental integrity of 
the participants of the study or the scientific value of the study. 
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach.


2017N315344_02
CONFIDENTIAL
205017
94
12.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 01 18-Sep-2017
Overall Rationale for the Amendment: Changes in response to MHRA feedback.
Section # 
and Name
Description of Change
Brief Rationale
2, Schedule 
of Activities
Wording amended in paragraph 3.
MHRA requested clarification that any 
changes in safety monitoring will require 
regulatory approval in the form of a 
substantial amendment.


2017N315344_01
CONFIDENTIAL
GlaxoSmithKline group of companies
205017
1
TITLE PAGE
Protocol Title: A two part, non-randomised, open label study designed to assess the
pharmacokinetics of GSK2982772 following administration of modified release 
formulations in capsule relative to an immediate release reference tablet formulation
(Part A) and the pharmacokinetics of escalating, repeat doses of a selected modified 
release prototype (Part B) in healthy subjects
Protocol Number: 205017/01
Short Title: A study to compare the pharmacokinetics of GSK2982772 following 
administration of different modified release formulations in capsule relative to an 
immediate release tablet formulation and to investigate the pharmacokinetics of a 
selected modified release formulation in capsule following repeat doses for 3 days.
Compound Number:
GSK2982772
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Communication 
Plan
Regulatory Agency Identifying Number(s): EudraCT Number 2017-000652-25
Approval Date: 18-SEP-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


	


		
			

( #$((($(&#(
%"$( '(!(





 	

PPD
PPD


2017N315344_01
CONFIDENTIAL
205017
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 01
18-Sep-2017
Original Protocol
07-Jul-2017
Amendment 01 18-September-2017
Overall Rationale for the Amendment: Changes in response to MHRA feedback.
Section # 
and Name
Description of Change
Brief Rationale
2, Schedule 
of Activities
Wording amended in paragraph 3.
MHRA requested clarification that any 
changes in safety monitoring will require 
regulatory approval in the form of a 
substantial amendment.


2017N315344_01
CONFIDENTIAL
205017
4
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
3.
INTRODUCTION....................................................................................................20
3.1.
Study Rationale ..........................................................................................20
3.2.
Background ................................................................................................21
3.3.
Benefit/Risk Assessment ............................................................................22
3.3.1.
Risk Assessment .........................................................................23
3.3.2.
Benefit Assessment.....................................................................28
3.3.3.
Overall Benefit:Risk Conclusion...................................................28
4.
OBJECTIVES AND ENDPOINTS...........................................................................28
5.
STUDY DESIGN ....................................................................................................29
5.1.
Overall Design ............................................................................................29
5.1.1.
Criteria for Interim Decisions........................................................30
5.2.
Number of Participants ...............................................................................31
5.3.
Participant and Study Completion...............................................................32
5.4.
Scientific Rationale for Study Design ..........................................................32
5.5.
Dose Justification........................................................................................33
6.
STUDY POPULATION...........................................................................................34
6.1.
Inclusion Criteria.........................................................................................34
6.2.
Exclusion Criteria........................................................................................35
6.3.
Lifestyle Restrictions...................................................................................37
6.3.1.
Meals and Dietary Restrictions ....................................................37
6.3.2.
Activity .........................................................................................39
6.4.
Screen Failures...........................................................................................39
7.
TREATMENTS.......................................................................................................39
7.1.
Treatments Administered............................................................................40
7.1.1.
Treatments Administered - Part A................................................40
7.1.2.
Treatments Administered - Part B................................................42
7.2.
Dose Modification .......................................................................................43
7.3.
Method of Treatment Assignment ...............................................................43
7.4.
Blinding.......................................................................................................43
7.5.
Preparation/Handling/Storage/Accountability..............................................43
7.6.
Treatment Compliance................................................................................44
7.7.
Concomitant Therapy..................................................................................44
7.8.
Treatment after the End of the Study ..........................................................45
8.
DISCONTINUATION CRITERIA.............................................................................45
8.1.
Discontinuation of Study Treatment ............................................................45
8.1.1.
Liver Chemistry Stopping Criteria ................................................45
8.1.2.
QTc Stopping Criteria ..................................................................46


2017N315344_01
CONFIDENTIAL
205017
5
8.1.3.
Individual Safety Stopping Criteria ...............................................46
8.1.4.
Temporary Discontinuation ..........................................................46
8.1.5.
Rechallenge.................................................................................47
8.1.5.1.
Study Treatment Restart or Rechallenge....................47
8.2.
Withdrawal from the Study..........................................................................47
8.3.
Lost to Follow Up........................................................................................47
8.4.
Study Stopping Criteria...............................................................................48
8.5.
Study Termination.......................................................................................48
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................49
9.1.
Efficacy Assessments.................................................................................49
9.2.
Adverse Events...........................................................................................50
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................50
9.2.2.
Method of Detecting AEs and SAEs.............................................50
9.2.3.
Follow-up of AEs and SAEs.........................................................50
9.2.4.
Regulatory Reporting Requirements for SAEs .............................51
9.2.5.
Pregnancy ...................................................................................51
9.3.
Treatment of Overdose...............................................................................51
9.4.
Safety Assessments ...................................................................................52
9.4.1.
Physical Examinations.................................................................52
9.4.2.
Vital Signs....................................................................................52
9.4.3.
Electrocardiograms......................................................................52
9.4.4.
Clinical Safety Laboratory Assessments ......................................53
9.4.5.
Suicidal Risk Monitoring...............................................................54
9.5.
Pharmacokinetics .......................................................................................55
9.6.
Pharmacodynamics ....................................................................................55
9.7.
Genetics .....................................................................................................55
9.8.
Biomarkers .................................................................................................55
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................56
10. STATISTICAL CONSIDERATIONS........................................................................56
10.1.
Hypotheses.................................................................................................56
10.2.
Sample Size Determination ........................................................................56
10.2.1.
Sample Size Determination - Part A.............................................56
Sample Size Sensitivity – Part A.................................................................56
10.2.2.
Sample Size Determination - Part B.............................................57
Sample Size Sensitivity – Part B.................................................................57
10.3.
Populations for Analyses ............................................................................58
10.4.
Statistical Analyses.....................................................................................58
10.4.1.
Pharmacokinetic Analyses...........................................................58
10.4.2.
Safety Analyses...........................................................................60
10.4.3.
Interim Analyses ..........................................................................61
10.4.4.
Stopping Criteria..........................................................................61
11. REFERENCES.......................................................................................................62
12. APPENDICES........................................................................................................63
12.1.
Appendix 1: Abbreviations and Trademarks................................................63
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................66
12.3.
Appendix 3: Study Governance Considerations..........................................68


2017N315344_01
CONFIDENTIAL
205017
6
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting to GSK...........................73
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................79
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................83
12.7.
Appendix 7: Safety Reporting to Ethics Committee and Regulatory 
Authorities...................................................................................................85
12.8.
Appendix 8: Protocol Amendment History...................................................87


2017N315344_01
CONFIDENTIAL
205017
7
1.
SYNOPSIS
Protocol Title: A two part, non-randomised, open label study designed to assess the 
pharmacokinetics of GSK2982772 following administration of modified release 
formulations in capsule relative to an immediate release reference tablet formulation (Part 
A) and the pharmacokinetics of escalating, repeat doses of a selected modified release 
prototype (Part B) in healthy subjects.
Short Title: A study to compare the pharmacokinetics of GSK2982772 following 
administration of different modified release formulations in capsule relative to an 
immediate release tablet formulation and to investigate the pharmacokinetics of a 
selected modified release formulation in capsule following repeat doses for 3 days.
Rationale: The purpose of this study is to evaluate a modified release (MR) formulation 
of GSK2982772 using a minitab approach filled into a capsule in order to develop a more 
convenient once daily (QD) dosing formulation.  Each minitab will contain 5 mg 
GSK2982772 and the amount of polymer can be adjusted to achieve the desired in-vitro 
release profile. Initially, the pharmacokinetic (PK) profiles of slow (approximately 
24 hours) and fast (approximately 10 hours) release rates of MR minitab will be 
compared to the PK profile of the immediate release (IR) tablet.  In subsequent arms of 
the study, the release rate may be adapted to achieve the target PK profile.  The effect of 
a high fat meal on the absorption of GSK2982772 when co-administered with the 
selected minitab MR formulation will be evaluated to ensure that dose dumping does not 
occur.  In addition, the PK profile of repeat doses at 3 dose levels will be evaluated to 
ensure that the MR formulation can achieve a sufficient GSK2982772 systemic exposure 
range to support the Phase IIb dose ranging (DR) studies.


2017N315344_01
CONFIDENTIAL
205017
8
Objectives and Endpoints:
Objective
Endpoint
Primary

To evaluate the single dose PK profile of 
GSK2982772 from each test MR 
formulation in a capsule (120 mg) compared
to the IR formulation (120 mg)

GSK2982772 area under the curve from 
time zero to infinity (AUC(0-inf)), area under 
the curve from time zero to the last 
measurable concentration (AUC(0-t)), area 
under the curve from time zero to 24 hours 
(AUC(0-24)), area under the curve from time
zero to 12 hours (AUC(0-12)), maximum 
observed concentration (Cmax), 
Concentration at 12 hours post-dose (C12h), 
Concentration at 24 hours post-dose (C24h) 
and ratio of Cmax : C12h and Cmax : C24h, 
relative bioavailability (Frelformulation) based 
on AUC and Cmax
Secondary

To assess the impact of high fat meal on 
the PK of GSK2982772 following single 
dose administration of the selected MR 
formulation in a capsule (120 mg) 

GSK2982772 AUC(0-inf), AUC(0-t), Cmax and 
time to Cmax (Tmax), FrelFE based on AUC 
and Cmax

To determine if there are any dose 
dependant changes in the absorption of 
GSK2982772 following repeat dose 
administration of the selected MR 
formulation in a capsule at target daily 
doses of 30, 60 and 240 mg

GSK2982772 AUC(0-24), Cmax and Tmaxif 
once daily (QD) dosing, on Day 1 and Day 3

GSK2982772 AUC(0-12), AUC(12-24),, Cmax
and Tmax after morning dose, Cmax and Tmax
after evening dose if twice daily (BID)
dosing, on Day 1 and Day 3

To assess the safety and tolerability of 
single doses of GSK2982772 IR formulation 
and single and repeat doses of the MR 
formulation in a capsule

Adverse events (AEs)

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature)

12-Lead electrocardiogram (ECG)
monitoring


2017N315344_01
CONFIDENTIAL
205017
9
Overall Design:
This is an open label, single centre, two part, single and repeat dose study in healthy male 
and female participants to assess MR minitab formulations of GSK2982772 in a capsule.  
Assuming a suitable MR minitab formulation in a capsule is identified, the impact of 
food (high-fat meal) on the rate and extent of absorption will be evaluated as well as an 
assessment of the relationship between dose and systemic exposure to GSK2982772
following repeat dosing for 3 days. 
Part A of the study is a non-randomised 6 period, sequential, 6-way fixed sequence
design in which up to 4 MR minitab formulations in a capsule may be evaluated 
following single dose administration in the fasted state (120 mg).  Periods 1, 2 and 3 will 
evaluate a slow MR release duration (nominally 24 hours), a fast MR release duration 
(nominally 10 hours), and IR tablet, respectively.  Periods 4, 5 and 6 will be flexible and 
the dosing regimen will be dependent on the outcome of Periods 1 to 3.  In Periods 4 to 6, 
there will be the option to optimise the MR release duration and/or to evaluate the impact 
of food (high-fat meal) on the selected MR minitab formulation in a capsule.  There will 
also be the option to cancel Periods 5 and 6 if an optimal formulation is determined in 
Periods 1 or 2.
Part B of the study will be an open-label, repeat dose study in which the selected MR 
minitab formulation in a capsule will be evaluated following 3 days repeat dosing of 
GSK2982772 at target daily doses of 30, 60 and 240 mg.  In Part B, administration of the 
MR minitab formulation in a capsule will either be in the fasted state or with a standard 
meal (non-high fat), depending on the results of the food effect assessment in Part A.  
The frequency of dosing in Part B will either be QD or BID depending on the PK profile 
in Part A.  Whether dosing is QD or BID, the total daily doses will remain the same.
Number of Participants:
Sixteen participants will be enrolled into Part A of the study to allow for the completion 
of at least 12 evaluable participants. An evaluable participant will have completed the 
planned safety and PK assessments up to 32 hours after dosing (or 24 hours after dosing 
for Period 3; IR regimen).  An evaluable participant must also have received the relevant 
test and reference formulations for the comparisons of interest e.g. an MR formulation 
and the IR reference and/or the selected MR formulation in both the fed and fasted states.
Ten participants will be enrolled into Part B of the study to allow for the completion of at 
least 6 evaluable participants. An evaluable participant will have received all 3 doses and 
completed the planned safety and PK assessments up to 24 hours after the last dose.  
Treatment Groups and Duration:
In Part A, each participant will be enrolled in the study for approximately 8 to 13 weeks, 
dependent on screening and washout duration between periods.  Participation will include 
a screening evaluation within 28 days of study treatment administration and up to 
6 separate inpatient periods.  Subjects will be admitted to the clinic in the morning of the 
day before dosing (i.e. Day -1) of each inpatient period.  Each inpatient period will 
consist of 3 days and 2 nights followed by a minimum washout of 7 days between doses.  


2017N315344_01
CONFIDENTIAL
205017
10
A follow-up visit will occur at least 7 days after the last study treatment.  Participants will 
receive a single oral dose of study treatment during each inpatient period.
In Part B, each participant will be enrolled in the study for approximately 9 weeks.  
Participation will include a screening evaluation within 28 days of study treatment 
administration and 3 separate periods. Subjects will be admitted to the clinic in the 
morning of the day before dosing (i.e. Day -1) of each inpatient period.  Each inpatient 
period will consist of a 5 day, 4-night inpatient period with a minimum of 7 days washout 
between the last morning dose of one period and the first dose of the next period.  A 
follow-up visit will occur at least 7 days after the last study treatment. 


2017N315344_01
CONFIDENTIAL
205017
11
2.
SCHEDULE OF ACTIVITIES (SOA)
The schedules of activities for Part A and Part B are presented in Table 1 and Table 3, 
respectively.  The time points for the PK blood sample collection in Part A and Part B are 
presented in Table 2 and Table 4, respectively.
The timing and number of planned study assessments, including safety or 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. 
Any changes in the timing or addition of time points for any planned study assessments 
as a result of emerging pharmacokinetic data must be documented and approved by the 
relevant study team member and then archived in the sponsor and site study files. The 
competent authority (CA) and ethics committee (EC) will be informed of any safety 
issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the informed consent form (ICF). The changes will 
be approved by the CA and the EC before implementation.
There are times where the protocol requires more than one procedure to be completed at 
the same time point. In these instances the following will apply to post-dose time points:
PK samples should take priority over other procedures scheduled at the same time point. 
As guidance, the preferred order of assessments is:
ECGs
Vital 
Signs
PK blood 
sampling
(nominal time)
Other assessments eg 
physical exams, 
Electrocardiograms (ECGs) should be taken prior to vital signs when both measurements 
are scheduled at the same time point. Other assessments, e.g. physical examinations etc, 
will be performed within the required time windows. All safety assessments will be 
timed and performed relative to the start of dosing.


2017N315344_01
CONFIDENTIAL
205017
12
Table 1
Schedule of Activities for Part A
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3, 4, 5, 6
Day
Follow-up/Study 
Discontinuation
(7 days post last dose)
Notes
–1
1
2
Informed consent
X
Inclusion and exclusion criteria1
X
1.
Recheck clinical status 
before 1st dose of study 
medication.
Demography
X
Demonstrate ability to swallow size 0-00 
capsules
X
Full physical examination including height 
and weight
X
Brief physical examination
X
X2
X
2.
Discharge
(32 h post-dose for 
Treatment Period 1, 2, 4, 
5 and 6
24 h post-dose for 
Treatment Period 3)
Medical history (includes substance 
usage)3
X
3.
Substances: Drugs, 
Alcohol, tobacco and 
caffeine
Past and current medical conditions  
X
Follicle Stimulating Hormone (FSH) (as 
needed in women of non-childbearing 
potential only)
X
Serum pregnancy test (WOCBP only)
X
X


2017N315344_01
CONFIDENTIAL
205017
13
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3, 4, 5, 6
Day
Follow-up/Study 
Discontinuation
(7 days post last dose)
Notes
–1
1
2
Urine pregnancy test (WOCBP only)
X
Human Immunodefeciency Virus (HIV), 
Hepatitis B and C screening4
X
4.
If test otherwise 
performed within 3 
months prior to first dose 
of study treatment, testing 
at screening is not 
required
Tuberculosis (TB) Test
X
Urine drug screen
X
X
Alcohol breath test
X
X
Carbon monoxide breath test
X
X
Laboratory assessments (haematology, 
clinical chemistry and urinalysis)
X
X
X5
X5
X
5.
Pre-dose (Treatment 
Period 1 only) and 24 h 
post-dose
Allowable windows in 
Section 9.4.4
Glomerular filtration rate
X
C-reactive protein (CRP)
X
12-lead ECG
X6
X
X7
X8
X
6.
In triplicate
7.
Pre-dose and 2 and 12 h 
post-dose
8.
24 h post-dose
Allowable windows in 
Section 9.4.3


2017N315344_01
CONFIDENTIAL
205017
14
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3, 4, 5, 6
Day
Follow-up/Study 
Discontinuation
(7 days post last dose)
Notes
–1
1
2
Vital signs
X
X
X9
X10
X
9.
Pre-dose and 2 and 12 h 
post-dose
10. 24 h post-dose
Allowable windows in 
Section 9.4.2
Study treatment
X
AE review
============================
X
Serious AE (SAE) review
X
============================
X
Concomitant medication review
============================
X
PK blood sample collection
X11
X11
11. Time points in Table 2


2017N315344_01
CONFIDENTIAL
205017
15
Table 2
Pharmacokinetic Blood Sample Collection Times – Part A
Treatment Periods 1, 2, 4, 5 and 6 (MR Formulations)
Time (h)
Pre-
dose
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
Dosing
X
PK sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Period 3 (IR Formulation)
Time (h)
Pre-
dose
0
0.33
0.66
1
1.5
2
3
4
6
8
10
12
24
Dosing
X
PK sampling
X
X
X
X
X
X
X
X
X
X
X
X
X


2017N315344_01
CONFIDENTIAL
205017
16
Table 3
Schedule of Activities for Part B
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
Informed consent
X
Inclusion and exclusion criteria1
X
1.
Recheck clinical status before 
1st dose of study medication.
Demography
X
Demonstrate ability to swallow size 
0-00 capsules
X
Full physical examination including 
height and weight
X
Brief physical examination
X
X2
X
2.
Discharge (24 h after the last 
dose)
Medical history (includes substance 
usage)3
X
3.
Substances: Drugs, Alcohol, 
tobacco and caffeine
Past and current medical conditions  
X
FSH (as needed in women of non-
childbearing potential only)
X
Serum pregnancy test (WOCBP only)
X
X
Urine pregnancy test (WOCBP only)
X


2017N315344_01
CONFIDENTIAL
205017
17
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
HIV, Hepatitis B and C screening4
X
4.
If test otherwise performed 
within 3 months prior to first 
dose of study treatment, 
testing at screening is not 
required
Tuberculosis Test
X
Urine drug screen
X
X
Alcohol breath test
X
X
Carbon monoxide breath test
X
X
Laboratory assessments 
(haematology, clinical chemistry and 
urinalysis)
X
X
X5
X6
X
5.
Pre-dose 
6.
24 h after the last dose
Allowable windows in Section 
9.4.4
Glomerular filtration rate
X
CRP 
X
ANA
X
X7
7.
24 h after the last dose


2017N315344_01
CONFIDENTIAL
205017
18
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
12-lead ECG 
X8
X
X9
X10
X9
X11
X
8.
In triplicate
9.
Pre-dose and 2 and 12 h 
post-dose
10. Pre-dose
11. 24 h after the last dose
Allowable windows in Section 
9.4.3
Time points may be subject to 
change depending on results 
from Part A
Vital signs 
X
X
X12
X13
X12
X14
X
12. Pre-dose and 2 and 12 h 
post-dose
13. Pre-dose 
14. 24 h after the last dose
Allowable windows in Section 
9.4.2
Time points may be subject to 
change depending on results 
from Part A
Columbia Suicide Risk questionnaire
X
X15
X16
15. Pre-dose
16. 24 h after last dose of each 
period
Study treatment
X
X
X
AE review
============================
X
SAE review
X
============================
X
Concomitant medication review
============================
X


2017N315344_01
CONFIDENTIAL
205017
19
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
PK blood sample collection
X17
X17
X17
X17
17. Time points in Table 4
Table 4
Pharmacokinetic Blood Sample Collection Times – Part B
Periods 1, 2 and 3
Days 1 and 3
Time (h)
Pre-
dose
0
2
4
6
8
10
12
14
16
18
20
22
24
Dosinga
X
PK samplingb
X
X
X
X
X
X
X
X
X
X
X
X
Xc
a Subjects will be dosed on Days 1, 2 and 3; however, no PK samples will be taken post-dose on Day 2
b PK sampling schedule may be amended based upon the PK data from Part A and/or if BID dosing is selected for Part B. If BID dosing is 
employed the number of PK samples may be reduced i.e. some of the samples between 14 and 24 h may not be required.  In addition, the 
12 h sample will be taken prior to administering the second daily dose. 
c Day 1 24 h post-dose sample should be taken prior to dosing on Day 2.


2017N315344_01
CONFIDENTIAL
205017
20
3.
INTRODUCTION
GSK2982772 is a first-in-class, highly selective, receptor-interacting protein-1 (RIP1)
kinase inhibitor being developed for the treatment of inflammatory bowel disease, plaque 
psoriasis (PsO), rheumatoid arthritis (RA) and other disease conditions.
3.1.
Study Rationale
Pharmacokinetic data from the first time in human (FTIH) study for GSK2982772 
(200975) [GlaxoSmithKline Document Number 2014N204126_02] showed that the 
half-life of GSK2982772 was short (~2 to 3 hours).  As a result, BID and three times 
daily (TID) dosing regimens are being evaluated in three ongoing proof of mechanism 
studies.  A QD formulation would be more convenient from a patient perspective and 
could offer the advantage of providing a flatter GSK2982772 concentration time profile.  
This current study is being conducted to evaluate the feasibility of developing an MR 
formulation using a minitab approach filled into a capsule.  Each minitab will contain 
5 mg GSK2982772 and the amount of polymer can be adjusted to achieve the desired 
in-vitro release profile. In addition, the number of minitabs included in the capsule can be 
varied to adjust the dose.
The Clinical Trial Authorisation application for this study describes a flexible protocol 
design using the concept of formulation design space to allow decision-making in 
response to interim PK observations. The principles of a flexible protocol were discussed 
and agreed with the Medicines and Healthcare products Regulatory Agency (MHRA) at a 
Scientific Advice Meeting between the MHRA and Quotient Clinical (formerly 
Pharmaceutical Profiles).
Based upon the concept of formulation design space, specific Investigational Medicinal 
Products (IMPs) are not detailed within the Investigational Medicinal Product Dossier but 
rather a defined range of formulation inputs and corresponding performance outputs are 
described and justified based on in vitro studies.
There will be the option to test a range of formulations based on a 2-dimensional design 
space describing the dose level and release rate of the IMP (Figure 1).


2017N315344_01
CONFIDENTIAL
205017
21
Figure 1
Two-Dimensional Design Space for the Modified Release 
Formulation
3.2.
Background
RIP1 is a member of the receptor-interacting Serine/Threonine kinase family containing 
an amino-terminal kinase domain, an intermediate domain and a carboxy-terminal death 
domain. RIP1 is a key signalling node which plays an essential role in inflammation and 
cell death in response to signals including tumour necrosis factor (TNF) family cytokines, 
ligands for toll like receptor (TLR)3/TLR4, sensors of viral infection, and interferons 
[Ofengeim, 2013]. Through tight regulation by ubiquitylation, deubiquitylation and 
interaction with its receptors, RIP1 has dual roles as a kinase and a scaffolding protein, 
and serves as an upstream checkpoint for both cell death and survival [Ofengeim, 2013]. 
Detailed understanding of RIP1 kinase function has not been fully elucidated, but it is 
known that RIP1 exerts it signalling functions through both its catalytic kinase activity 
and by acting as a scaffolding protein for signalling complexes. Recent work has 
demonstrated that RIP1 catalytic kinase activity can regulate TNF-mediated necroptosis 
[Ofengeim, 2013] and noncanonical apoptosis [Wang, 2008; Dondelinger, 2013]. In 
addition, the production of certain inflammatory cytokines can be regulated by RIP1 
kinase activity. In contrast, RIP1’s scaffolding function acts to facilitate other immune 
processes including TNF mediated classical apoptosis and Nuclear factor-kappaB-
signalling [Ofengeim, 2013; Humphries, 2015]. With this, an inhibitor of RIP1 kinase 
activity with GSK2982772 may fill a unique niche in the treatment of inflammatory 
conditions, such as ulcerative colitis, chronic PsO and RA, through multiple mechanisms, 
including inhibition of inflammation-induced cell death (necroptosis and apoptosis) and 
inhibition of the production of certain pro-inflammatory cytokines.
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK2982772 is provided in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2014N204126_02].


2017N315344_01
CONFIDENTIAL
205017
22
3.3.
Benefit/Risk Assessment
To date, approximately 124 participants have been enrolled in 4 clinical studies with 
GSK2982772. In Study 200975, GSK2982772 was administered up to 120 mg BID for 
14 days.  A total of 67 participants received GSK2982772 and 26 participants received 
placebo (including crossover) in that study.  In the ongoing Phase 2a studies in PsO Study 
(203167), RA (Study 203168) and Ulcerative Colitis (Study 202152), a total of 
approximately 26 participants have been randomised to GSK2982772 60 mg BID.
Overall, GSK2982772 has been generally well tolerated and no drug-related SAEs have 
been reported.  In Study 203167, there was a death of a 19-year-old male participant due 
to an accidental overdose with 3,4-methylenedioxy-methamphetamine (MDMA) that was 
not considered drug related by the Principal Investigator (PI). 
There is currently limited information available about the relationship of adverse events 
(AEs) to administration of GSK2982772 in human subjects. Therefore, all SAEs are 
considered unexpected. Any SAE deemed related to the IMP will be reported as a 
Suspected Unexpected Serious Adverse Reaction (SUSAR), in compliance with local 
health authority safety reporting requirements (see Appendix 7).
Limited reproductive toxicity studies have been conducted with GSK2982772 to date.
The compound must not be administered to pregnant women or nursing mothers. 
Women of childbearing potential must use highly effective methods of contraception 
(<1% failure rate; Appendix 5) for 30 days prior to exposure to GSK2982772 until 
30 days after the last dose.
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of GSK2982772 may be found in the Investigator’s Brochure.


2017N315344_01
CONFIDENTIAL
205017
23
3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2982772
Central Nervous System (CNS) effects
Non-clinical data: 
In the 4-week Good Laboratory Practice (GLP) toxicology 
study, CNS findings were observed in 4/12 monkeys which 
were administered 100 or 300 mg/kg/day.  CNS findings 
included uncoordination, irregular gait, trembling, hunched 
appearance, and decreased activity. The clinical relevance 
of these findings in humans is not known.  The no 
observed adverse effect level (NOAEL) for this study was 
determined at 10 mg/kg/day.
In the 13-week GLP toxicology study, there were no CNS 
findings observed in monkeys administered 10, 30 or 100 
mg/kg/day.  The NOAEL for this study was determined at 
30 mg/kg/day.  
Clinical data:
A FTIH study with single ascending and multiple ascending 
dose study has been performed in 67 healthy male 
volunteers to date.  See Investigator’s Brochure (IB) 
[GlaxoSmithKline Document Number 2014N204126_02].  
No drug-associated CNS AEs were identified and no SAEs 
were reported.
Subject Selection:

Subjects with known history of significant neurologic 
disorders including but not limited to progressive 
multiple sclerosis (MS), Amyotrophic lateral sclerosis 
(ALS), Alzheimer’s and dementia will be excluded.

Individuals with potentially increased susceptibility for 
neurologic effects will be excluded based on medical 
history at screening.
Subject Monitoring:

Subjects will be monitored for standard CNS-related 
AEs.
Immunosuppression
The possibility of immunosuppression, including an 
increase in the frequency and/or severity of infection, may 
result from the intended pharmacologic effect of 
GSK2982772.  This may be enhanced in subjects taking 
other immunomodulating drugs or corticosteroids.
Subject Selection:

Subjects with recurrent, chronic or active infections 
will be excluded from the study.

Subjects will be screened for TB, HIV, Hepatitis B and 


2017N315344_01
CONFIDENTIAL
205017
24
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical data:
In the FTiH study, no SAEs were reported.  One subject 
experienced an Adverse Effect (AE) herpes zoster 
approximately 27 days after receiving his last dose with 
GSK2982772 or placebo.  The blinded Investigator 
determined this to be potentially drug-related.
C, and excluded from the study if positive.
Subject Monitoring:

Subjects will be monitored for signs of infection.

See Individual Stopping Criteria for atypical or 
opportunistic infections (Section 8.1.3).
Vaccinations
There is a theoretical risk that GSK2982772 could 
decrease an individual’s immune response to vaccines or 
allow symptoms to develop following vaccination with a live 
vaccine when administered while on therapy.
Subject Selection:

Attenuated or live vaccines should not be 
administered to subjects from 30 days prior to the first 
dose of GSK2982772, during the study and for 5 half-
lives plus 30 days (total 32 days) after GSK2982772 
is discontinued.

If indicated, non-live vaccines (eg, inactivated 
influenza vaccines) may be administered while 
receiving GSK2982772 based on a treating physician 
assessment of the benefit:risk (eg, risk of theoretical 
decreased responsiveness). 

Investigators will be expected to have followed local 
and/or national guidelines with respect to 
vaccinations, including against influenza and 
pneumococcus.
Respiratory
Non-clinical data:
In the single dose Safety Cardiovascular (CV) and 
Respiratory Study in monkeys, a decrease in minute 
volume and respiratory rate was observed at all doses (10, 
100, and 300 mg/kg).  These findings were noted to be 
reversible and mild in severity
In a 14-day repeat dose Safety Respiratory Study in 
monkeys, no respiratory effects on total pulmonary 
ventilation (minute volume) or respiratory rate were 
observed at doses of 1 or 10 mg/kg/day. See Investigtor’s 
Subject Monitoring:

Subjects should be monitored for standard 
respiratory-related AEs.

Vital signs will be monitored during study visits.


2017N315344_01
CONFIDENTIAL
205017
25
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Brochure for GSK2982772 [GlaxoSmithKline Document 
Number 2014N204126_02].
Clinical data:
In the FTIH study, repeat doses of GSK2982772 were 
administered x 14 days in 36 healthy male volunteers. 
Extensive respiratory monitoring with end-tidal CO2, 
oxygen saturation and nocturnal respiratory rate monitoring 
was performed.  No SAEs occurred, and no drug-
associated respiratory-related AEs were identified.
Suicidality
GSK2982772 is considered to be a CNS-active drug based 
upon pre-clinical studies.
Clinical data:
In the FTIH study, there have been some reports of 
lethargy, abnormal dreams, and depressed mood.  No 
events of suicidal ideation or behaviour or changes in 
behaviour were reported. 
Subject Selection:

Subjects with a current history of suicidal ideation and 
behaviour (SIB) as measured using the Columbia 
Suicide Severity Rating Scale (C-SSRS)  or a history 
of attempted suicide will be excluded from the study.
Subject Monitoring:

Subjects receiving multiple doses should be 
monitored appropriately and observed closely for 
suicidal ideation and behaviour or any other unusual 
changes in behaviour.

Baseline and treatment emergent assessment of 
suicidality will be conducted by trained site personnel 
using the C-SSRS in all subjects receiving multiple 
doses.  See Section 9.4.5.
Reproductive toxicity
Non-clinical data:
In an early rat embryofoetal development study, there was 
no maternal or developmental toxicity at doses 200 
mg/kg/day.
In a rabbit embryofoetal development study, GSK2982772 
was administered at doses of 0, 10, 100, 300 or 600 
mg/kg/day on gestation day 7 to 19.  No developmental 
toxicity was evident at doses up to 300 mg/kg/day.
Subject Selection:

Male and female subjects of childbearing potential will 
be included in this study only if they agree to use 
highly effective methods of contraception and avoid 
conception for 30 days before first administration of 
study drug until 30 days (females) and 90 days 
(males) after the last administration of study drug 
(Appendix 5). 

Females of childbearing potential will undergo serum 
pregnancy test at screening and follow-up and then 


2017N315344_01
CONFIDENTIAL
205017
26
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
urine pregnancy testing at regular intervals during the 
study. 

Pregnant and lactating females are not eligible for 
inclusion in the study.
Withdrawal Criteria:

If a female subject should become pregnant during 
the study, study medication should be discontinued.  
The subject will be followed to determine the outcome 
of the pregnancy.  Any pregnancy complication or 
elective termination of a pregnancy will be reported as 
an AE or SAE.
Drug Interaction
Non-clinical data:
In vitro studies with GSK2982772 assessing potential drug-
drug interactions with Cytochrome P450 3A4 (CYP3A4) 
substrates, P-glycoprotein (Pgp) inhibitors and OAT3 
substrates were completed.  To date, formal drug 
interaction studies in humans have not been performed 
with GSK2982772. 
There is a low risk that GSK2982772 could be a 
perpetrator of OAT3 substrates.  
There is a low risk that GSK2982772 could be an inducer 
of CYP3A4 and therefore may lower circulating levels of 
concomitant medications that are metabolised by CYP3A4 
when co administered with GSK2982772.
GSK2982772 is a Pgp substrate and therefore co 
administration with concomitant medications that are Pgp 
inhibitors could increase circulating levels of GSK2982772.
See Section 4.3.6 of the GSK2982772 Investigators
Brochure [GlaxoSmithKline Document Number
2014N204126_02].
Subject Selection:

No concomitant medications will be permitted in this 
study 
with 
the 
exception 
of 
paracetamol/acetaminophen, hormonal contraception, 
hormone replacement therapy and other treatments 
required for AEs.
Subject Monitoring:

Caution is advised when dosing GSK292772 with 
CYP3A4 NTI substrates, OAT3 substrates or Pgp 
inhibitors.


2017N315344_01
CONFIDENTIAL
205017
27
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Cannulation 
During cannulation, more than one attempt may be needed 
to insert the cannula in a vein of a participant and it is 
possible that bruising and/or inflammation may be 
experienced at the site of cannulation.

A vein assessment will be conducted at screening to 
ensure only volunteers with veins suitable for multiple 
venepuncture and cannulation are enrolled.  
Cannulation and venepuncture will only be performed 
by staff who are trained in these procedures.
Electrocardiograms
Electrocardiogram stickers on the participants' chests and 
limbs may cause some local irritation and may be 
uncomfortable to remove. 

Participants will be closely monitored to ensure any 
local irritation does not persist.


2017N315344_01
CONFIDENTIAL
205017
28
3.3.2.
Benefit Assessment
There is no intended direct health benefit to the participants in this study.  The benefit to 
participants include contributing to the process of developing new therapies in an area of 
unmet need and the medical evaluations/assessments associated with study procedures 
(eg, physical exam, ECG, Labs, etc).
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to healthy participants
participating in this study, the potential risks identified in association with GSK2982772
are justified by the anticipated benefits that may be afforded to patients with 
inflammatory conditions such as ulcerative colitis, PsO and RA.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the single dose PK profile of 
GSK2982772 from each test MR 
formulation in a capsule (120 mg) compared
to the IR formulation (120 mg)

GSK2982772 area under the curve from 
time zero to infinity (AUC(0-inf)), area under 
the curve from time zero to the last 
measurable concentration (AUC(0-t)), area 
under the curve from time zero to 24 hours 
(AUC(0-24)), area under the curve from time 
zero to 12 hours (AUC(0-12)), maximum 
observed concentration (Cmax), 
Concentration at 12 hours post-dose (C12h), 
Concentration at 24 hours post-dose (C24h) 
and ratio of Cmax : C12h and Cmax : C24h, 
relative bioavailability (Frelformulation) based 
on AUC and Cmax
Secondary

To assess the impact of high fat meal on 
the PK of GSK2982772 following single 
dose administration of the selected MR 
formulation in a capsule (120 mg)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax and 
time to Cmax (Tmax), FrelFE based on AUC 
and Cmax

To determine if there are any dose 
dependant changes in the absorption of 
GSK2982772 following repeat dose 
administration of the selected MR 
formulation in a capsule at target daily 
doses of 30, 60 and 240 mg

GSK2982772 AUC(0-24), Cmax and Tmax if 
once daily (QD) dosing, on Day 1 and Day 3

GSK2982772 AUC(0-12), AUC(12-24),, Cmax
and Tmax after morning dose, Cmax and Tmax
after evening dose if twice daily (BID) 
dosing, on Day 1 and Day 3

To assess the safety and tolerability of 
single doses of GSK2982772 IR formulation 

Adverse events (AEs)


2017N315344_01
CONFIDENTIAL
205017
29
Objectives
Endpoints
and single and repeat doses of the MR 
formulation in a capsule

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature)

12-Lead electrocardiogram (ECG) 
monitoring
5.
STUDY DESIGN
5.1.
Overall Design
This is an open label, single centre, two part, single and repeat dose study in healthy male 
and female participants to assess MR minitab formulations of GSK2982772 in a capsule.  
Assuming a suitable MR minitab formulation in a capsule is identified, the impact of 
food (high-fat meal) on the rate and extent of absorption will be evaluated as well as an 
assessment of the relationship between dose and systemic exposure to GSK2982772
following repeat dosing for 3 days. 
Part A of the study is a non-randomised 6 period, sequential, 6-way fixed sequence 
design in which up to 4 MR minitab formulations in a capsule may be evaluated 
following single dose administration in the fasted state (120 mg) (Figure 2).  Periods 1, 2 
and 3 will evaluate a slow MR release duration (nominally 24 hours), a fast MR release 
duration (nominally 10 hours), and IR tablet, respectively.  Periods 4, 5 and 6 will be 
flexible and the dosing regimen will be dependent on the outcome of Periods 1 to 3.  In 
Periods 4 to 6, there will be the option to optimise the MR release duration and/or to 
evaluate the impact of food (high-fat meal) on the selected MR minitab formulation in a 
capsule.  There will also be the option to cancel Periods 5 and 6 if an optimal formulation 
is determined in Periods 1 to 2.
Subjects will be admitted to the clinic in the morning of the day before dosing (i.e. 
Day -1) of each inpatient period.  Each inpatient period will consist of 3 days and 2 nights 
followed by a minimum washout of 7 days between doses.  A follow-up visit will occur 
at least 7 days after the last study treatment.  Participants will receive a single oral dose of 
study treatment during each inpatient period.


2017N315344_01
CONFIDENTIAL
205017
30
Figure 2
Part A Study Design – Formulation Optimisation and Food Effect
Part B of the study will be an open-label, repeat dose study in which the selected MR 
minitab formulation in a capsule will be evaluated following 3 days repeat dosing of 
GSK2982772 at target daily doses of 30, 60 and 240 mg (Figure 3).  The target dose may 
be subject to change based upon evaluation of the emerging data from Part A, e.g. if the 
bioavailability of 120 mg MR formulation in a capsule is less than the 120 mg IR tablet 
(reference) formulation.  In Part B, administration of the MR minitab formulation in a 
capsule will either be in the fasted state or with a standard meal (non-high fat), depending 
on the results of the food effect assessment in Part A.  The frequency of dosing in Part B
will either be QD or BID depending on the PK profile in Part A.  Whether dosing is QD 
or BID, the total daily doses will remain the same.  If BID dosing is selected the final 
dose will be the evening dose of Day 3. Subjects will be admitted to the clinic in the 
morning of the day before dosing (i.e. Day -1) of each inpatient period.  Each inpatient 
period will consist of 5 days and 4 nights.  There will be a minimum of 7 days washout 
between the last morning dose of one period and the first dose of the next period.  A 
follow-up visit will occur at least 7 days after the last study treatment.  
Figure 3
Part B Study Design – Dose Ranging
5.1.1.
Criteria for Interim Decisions
In Part A there will be an interim review following completion of Periods 1 to 3 to 
determine the formulation and the prandial state for Period 4. Similarly, there will be an 
interim review following Periods 4 and 5.  Following the final period of Part A, the 
formulation, doses, dosing frequency (QD or BID) and prandial state for Part B will be 
determined. However, the highest dosing regimen will be selected to ensure that the 
maximum daily dose will not exceed the equivalent of an IR dose of 240 mg, taking into 
account the bioavailability of MR relative to IR (i.e. if the bioavailability of MR is 50% 
that of IR, the maximum daily dose of MR to be administered would be 480 mg).  Interim 


2017N315344_01
CONFIDENTIAL
205017
31
decisions will only be made after a complete review of all relevant data collected from 
the previous dose group. Data must be available from a minimum of 12 participants who 
have completed the planned safety and PK assessments up to 32 hours after dosing (or 
24 hours after dosing for Period 3; IR regimen [Regimen C]). An evaluable participant 
must also have received the relevant test and reference formulations for the comparisons 
of interest e.g. an MR formulation and the IR reference and/or the selected MR 
formulation in both the fed and fasted states. If full data, as described below, are not 
available for 12 participants, the principal investigator (PI), scientific lead and sponsor 
will take a decision as to whether the data available are sufficient to support the 
formulation selection decision. If data in fewer than 16 participants are used in the 
decision process, additional participants will not be dosed to increase the number of 
participants in the completed regimen.
The following data will be provided to the sponsor by Quotient Clinical:

AEs, vital signs, ECGs, safety laboratory data and physical examinations.

Plasma concentrations of GSK2982772.

PK parameter estimates GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), AUC(0-12), Tmax,
Cmax, C12h, C24h and ratio of Cmax : C12h and Cmax : C24h, Frel based on AUC and Cmax
for test vs reference formulations and fed vs fasted, where relevant.  

Protocol deviations will be reviewed to ensure they have had no significant impact on 
the above data
The decision on formulation and prandial state selection or stopping the study will be 
made by the Quotient study team (i.e., PI, scientific lead and pharmacokineticist) and 
sponsor study team (as a minimum the sponsor’s medical monitor, Clinical 
Pharmacokinetics Modelling and Simulation [CPMS] and Global Clinical Safety and 
Pharmacovigilance [GCSP]). The decision will be documented and signed by the PI as 
per Quotient Clinical current standard operating procedure (SOP). Evidence of the 
decision will be retained in the Investigator Site File (ISF) and GSK Trial Master File.
5.2.
Number of Participants
In Part A, 16 healthy participants will be enrolled such that at least 12 evaluable 
participants complete the study.  An evaluable participant will have completed the 
planned safety and PK assessments up to 32 hours after dosing (or 24 hours after dosing 
for Period 3; IR regimen [Regimen C]).  An evaluable participant must also have 
received the relevant test and reference formulations for the comparisons of interest e.g. 
an MR formulation and the IR reference and/or the selected MR formulation in both the 
fed and fasted states. 
In Part B, 10 healthy participants will be enrolled such that at least 6 evaluable 
participants complete the study. An evaluable participant will have received all 3 days of 
dosing at 2 or more dose levels and completed the planned PK assessments up to 24 
hours after the first dose on Day 3.


2017N315344_01
CONFIDENTIAL
205017
32
Participants withdrawn due to an IMP-related AE or termination of the study will not be 
replaced.  If participants prematurely discontinue the study for other reasons, additional 
replacement participants may be recruited at the discretion of the Sponsor in consultation 
with the investigator.
Up to 8 replacement participants may be enrolled in Part A.  The maximum number of 
participants that may be dosed in Part A is 24. 
Up to 5 replacement participants may be enrolled in Part B.  The maximum number of 
participants that may be dosed in Part B is 15.
Replacement subjects enrolled will be dosed with the next planned treatment of the 
withdrawn subject, and they will not receive any treatment that the withdrawn subject has 
already received with the exception of the need to increase subject numbers to obtain the 
minimum number of evaluable subjects required for interim decisions, and to obtain data 
in any other treatment that is required for a valid comparison. Replacement subjects will 
receive the required treatments in the same order as planned for the original subject and 
the minimum washout period will be respected with regard to the timing of dosing of the 
IR formulation.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure shown in the SoA i.e. the 
follow-up visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
Pharmacokinetic data from the FTIH study for GSK2982772 [GlaxoSmithKline 
Document Number 2014N204126_02] showed that the half-life of GSK2982772 was 
shorter than predicted (~2 to 3 hours).  As a result, BID and TID dosing regimens are 
being evaluated in three ongoing Phase 2a studies in psoriasis, ulcerative colitis and RA.  
A QD formulation would be more convenient from a patient perspective and could offer 
the advantage of providing a flatter GSK2982772 concentration time profile.  Therefore,
switching to a QD formulation for the Phase 2b DR studies and subsequent Phase 3 
studies would be advantageous.  
This current study is being conducted to evaluate the feasibility of developing an MR
formulation using a minitab approach filled into a capsule.  Each minitab will contain 
5 mg GSK2982772 and the amount of polymer can be adjusted to achieve the desired 
in-vitro release profile. The total weight of the minitab will be 20 mg and between 3 and
12 minitabs can be loaded into a capsule for oral administration.  Initially the PK profiles 
of slow (approximately 24 hours) and fast (approximately 10 hours) release rates of MR 
minitab will be compared to the PK profile of the IR tablet.  In subsequent arms of the 
study, the release rate may be adapted to achieve the target PK profile.  The effect of a 
high fat meal on the absorption of GSK2982772 when co-administered with the selected 


2017N315344_01
CONFIDENTIAL
205017
33
minitab MR formulation in a capsule will be evaluated to ensure that dose dumping does 
not occur.  In addition, a range of repeat doses will be evaluated to ensure that the MR 
formulation in a capsule can achieve a sufficient GSK2982772 systemic exposure range 
to support the Phase IIb DR studies.
As this is a Phase 1 study, the most relevant population is healthy participants which
allows characterisation of safety, tolerability and PK in a homogenous population without 
potential biases from a patient population. The European Medicines Agency (EMA)
recommends including participants aged 18 years and older with normal weight, who are 
non-smokers, without a history of alcohol or drug abuse. The latter criteria are proposed 
to avoid interaction on drug metabolism and to avoid non-compliance. Therefore, this 
study will enrol healthy male and female participants aged between 18 to 65 years of age.
5.5.
Dose Justification
In Part A, a single dose of 120 mg will be used for the MR minitab formulations in a 
capsule and for the IR tablet.  In Part B, it is planned to evaluate target daily doses of 30, 
60 and 240 mg for 3 days.  The selection of these dose levels are based on the doses 
being used in the ongoing Phase 2a studies (IR 60 mg BID) and the safety and PK data 
from the GSK2982772 FTIH study, where doses up to IR 120 mg BID for 14 days were 
administered.
In Part A, a single dose of 120 mg MR has been selected since this dose is anticipated to 
provide systemic exposure similar to the 60 mg BID regimen being used in the ongoing 
Phase 2a studies (assuming a relative bioavailability of 100%).  In the GSK2982772 
FTIH study, 120 mg of the IR formulation was well tolerated when administered as 
single and repeated doses (BID for 14 days).  A single 120 mg dose of the MR 
formulation in a capsule is expected to result in lower Cmax than for the 120 mg IR tablet, 
and overall systemic exposure (AUC) is expected to be similar or lower than a single 
120 mg IR tablet dose.
The administration of 120 mg MR with food is expected to maintain AUC and Cmax
values within the range of values observed following 120 mg dose in the FTIH study. In 
the worst case scenario of dose dumping with food, 120 mg MR would have a PK profile 
similar to a single dose of 120 mg IR.
In Part B, the target daily MR doses of 30, 60, 240 mg reflect the approximate dose range 
that is planned to be taken forward into the Phase 2b DR studies.  The actual dose level 
may be increased (by adding additional minitabs to the capsule or by giving multiple 
capsules) if the relative bioavailability of the selected MR at 120 mg is less than 100% 
compared to a 120 mg dose of the IR tablet.  Taking into account the bioavailability of 
MR relative to IR, it is planned that the highest dose of MR to be administered will be not
exceed a total daily dose equivalent to 240 mg IR (e.g. if the bioavailability of MR is 
50% that of IR, the maximum daily dose of MR to be administered would be 480 mg).


2017N315344_01
CONFIDENTIAL
205017
34
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Quotient Clinical must have a full medical history from each participant’s general 
practitioner within the last 12 months, prior to enrolment in the study. Participants will be 
recruited from the Quotient Clinical panel or by direct advertising to the public.
Before participants are admitted to the clinic, The Over Volunteering Prevention System 
will be checked to ensure that each participant has not participated in a study at another 
site within at least 3 months of the dosing date.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
Weight
3.
Body weight ≥50 kg and body mass index within the range 19.0 to 32.0 kg/m2
(inclusive).
Sex
4.
Male or female
a. Male participants:
A male participant must agree to use a highly effective contraception as detailed in 
Appendix 5 of this protocol during the treatment period and for at least 90 days after 
the last dose of study treatment and refrain from donating sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR


2017N315344_01
CONFIDENTIAL
205017
35
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 30 days before and 30 days after 
the last dose of study treatment.
Informed Consent
5.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal (GI), 
endocrine, haematological, or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs; constituting a risk when taking 
the study treatment; or interfering with the interpretation of data.
2.
Part A only: Any history of suicidal behaviour within the past 6 months or any 
history of attempted suicide in a participant’s lifetime. 
3.
Part B only: Participants with current history of Suicidal Ideation Behaviour as 
measured using the C-SSRS or a history of attempted suicide.
4.
History of clinically significant psychiatric disorders as judged by the investigator.  
Depression requiring treatment in the last 2 years.
5.
History of herpes zoster (shingles) reactivation.
6.
History or diagnosis of obstructive sleep apnoea.
7.
History of a significant respiratory disorder. Childhood asthma that has fully 
resolved is permitted.
8.
History or current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions.
9.
A positive diagnostic tuberculosis (TB) test at screening defined as a positive 
QuantiFERON-TB Gold test or T-spot test.  In cases where the QuantiFERON or 
T-spot test is indeterminate, the participant may have the test repeated once, but they 
will not be eligible for the study unless the second test is negative.
10. History of GI surgery (with exception of appendectomy).
11. History of cholecystectomy or gall stones.
12. Presence or history of clinically significant allergy requiring treatment, as judged by 
the investigator. Hayfever is allowed unless it is active.
13. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
14. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35% of total).


2017N315344_01
CONFIDENTIAL
205017
36
15. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome).
16. Corrected QT interval (QTc) >450 milliseconds (msec).
Notes: 
The QTc is the QT interval corrected for heart rate according to either Bazett’s 
formula (QTcB), QT interval corrected for heart rate according to Fridericia’s
formula (QTcF), or another method, machine or manual over read.
The specific formula that will be used to determine eligibility and discontinuation 
for an individual participant should be determined prior to initiation of the study.  
In other words, several different formulae cannot be used to calculate the QTc for 
an individual participant and the lowest QTc value used to include or discontinue 
the participant from the trial.
For purposes of data analysis, QTcB, QTcF, another QTc correction formula or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan.
Prior/Concomitant Therapy
17. Past or intended use of over-the-counter or prescription medication including herbal 
medications within 7 days prior to dosing (paracetamol/acetaminophen [up to 2 g per 
day], hormone replacement therapy and hormonal contraception are permitted).
18. Live or attenuated vaccine(s) within 30 days of enrolment, or plans to receive such 
vaccines during the study or plans to receive a vaccine within 30 days + 5 half-lives 
of the last dose of study medication.
Prior/Concurrent Clinical Study Experience
19. Participation in the study would result in loss of blood or blood products in excess of
500 mL within a 56 day period; therefore donation or loss of greater than 400 mL of 
blood within the previous 3 months.
20. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
21. Current enrolment or past participation within the last 3 months before signing of 
consent in this or any other clinical study involving an investigational study 
treatment or any other type of medical research.
22. Participants who have previously been enrolled in this study. Participants in Part A
of this study are not permitted to participate in Part B.
Diagnostic assessments
23. Current or history of renal disease or estimated glomerular filtration rate (GFR) by 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
calculation <60 mL/min/1.73m2 at screening.
24. Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C 
antibody test result at screening or within 3 months prior to first dose.  As potential 


2017N315344_01
CONFIDENTIAL
205017
37
for and magnitude of immunosuppression with this compound is unknown, 
participants with presence of hepatitis B core antibody (HBcAb) should be excluded.
Participants positive for HBsAg and/or positive for anti-HBc antibody (regardless of 
anti-HBs antibody status) are excluded.
25. An elevated C-reactive protein (CRP) outside the normal reference range.
26. Part B only: A positive anti-nuclear antibody (ANA) outside the normal reference 
range.
27. Confirmed positive pre-study drug/alcohol screen.
28. Positive human immunodeficiency virus (HIV) antibody test.
29. Regular use of known drugs of abuse, or history of drug or alcohol abuse in the past 
5 years.
Other Exclusions
30. Regular alcohol consumption within 6 months prior to the study 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.
31. Current use or history of regular use of tobacco- or nicotine-containing products 
within 6 months prior to screening.  A carbon monoxide breath test reading of 
greater than 10 parts per million (ppm).
32. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study.
33. Unwilling or unable to swallow multiple size 0-00 capsules as part of study 
participation.
34. Participants who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator at screening.
35. Total cholesterol 300 mg/dL (7.77 millimole [mmol]/Liter [L]) or triglycerides 
250 mg/dL (2.82 mmol/L).
36. Participants who are study site employees, or immediate family members of a study 
site or sponsor employee.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from Seville 
oranges and grapefruit derivatives for 24 hours before admission to each study 
period until after collection of the final PK sample in that period.

Refrain from consumption of poppy seeds for 48 hours before screening, and from 
48 hours before admission to each study period until after collection of the final PK
sample in that period.


2017N315344_01
CONFIDENTIAL
205017
38

For fasted dosing, no water is allowed from 1 hour before dosing until 1 hour after 
dosing with the exception of the 240 mL water provided with each dose. Water is 
allowed ad libitum at all other times.

For fasted dosing, participants will be provided with a light snack on the evening 
before dosing and will be required to fast from all food and drink (except water) for a 
minimum of 10 hours before dosing until approximately 4 hours after dosing. Lunch 
will be provided approximately 4 hours after dosing, an evening meal will be 
provided approximately 10 hours after dosing and an evening snack will be provided 
approximately 14 hours after dosing.
If BID dosing in the fasted state is selected for Part B, participants will be dosed in 
the evening approximately 12 hours after the morning dose. Meals will be provide as 
described above (i.e., no food will be permitted 2 hours before and 2 hours after 
dosing).

For dosing after a high fat breakfast (Part A) or a standard breakfast (Part B), 
participants will be provided with a light snack and will fast from all food and drink 
(except water) until the following morning, when they will be provided with the 
appropriate breakfast. The breakfast should be consumed over a maximum period of 
25 min, with dosing occurring 30 min after the start of breakfast. Participants should 
be encouraged to eat their meal evenly over the 25 min period. It is acknowledged 
that some participants will take less time to eat, but dosing should still occur 30 min 
after the start of breakfast.  Lunch will be provided approximately 4 hours after 
dosing, an evening meal will be provided approximately 10 hours after dosing and an 
evening snack will be provided approximately 14 hours after dosing.
If BID dosing administered with food is selected for Part B, participants will be 
dosed in the evening following a standard evening meal. Meals will be provided as 
described above (with evening dosing approximately 30 minutes after the start of the 
evening meal).

If drug administration in Part B is in the fasted stated, then on Day 2 when PK 
samples are not being collected, meals will be provided at appropriate times, i.e., a 
standard breakfast at approximately 2 hours post-morning dose, lunch at 
approximately 4 hours post-morning dose, dinner at approximately 10 hours 
post-morning dose and an evening snack at approximately 14 hours post-morning 
dose.

If drug administration in Part B is in the fed state, then on Day 2 when PK samples 
are not being collected, meals will be provided at appropriate times, i.e., a standard 
breakfast 30 mins prior to the morning dose, lunch at approximately 4 hours
post-morning dose, dinner at approximately 10 hours post-morning dose and an 
evening snack at approximately 14 hours post-morning dose.

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for
24 hours before admission until after collection of the final PK sample in that period.

Participants will abstain from alcohol for 24 hours before screening. During each 
dosing session, participants will abstain from alcohol from 24 hours before 
admission until after collection of the final PK sample in that period.


2017N315344_01
CONFIDENTIAL
205017
39

Current smokers or users of other tobacco products will not be enrolled in this study.
6.3.2.
Activity

Participants will abstain from strenuous exercise for 72 hours before screening and 
then from 72 hours before admission until discharge from the study. Participants 
may participate in light recreational activities during studies (eg, watching television, 
reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened at the discretion of the investigator if the reasons for the screening 
failure are expected to be temporary. Rescreened participants will be assigned a new
screening number and will be re-consented.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


2017N315344_01
CONFIDENTIAL
205017
40
7.1.
Treatments Administered
7.1.1.
Treatments Administered - Part A
Regimen
A
B
C
D
E (Optional)
F (Optional)
Study Treatment 
Name:
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
Dosage formulation:
Prototype MR 
Minitablet in 
Capsule
Formulation A
Prototype MR
Minitablet in 
Capsule
Formulation B
IR Tablet
Reference
Prototype MR
Minitablet in Capsule
Formulation A, B or C
Prototype MR
Minitablet in Capsule
Formulation A, B, C or 
D
Prototype MR
Minitablet in 
Capsule
Formulation A, 
B, C or D
Unit dose strength(s)/
Dosage level(s):
60 mg / 
120 mg
60 mg / 
120 mg
30 mg /
120 mg
60 mg / 
120 mg
60 mg / 
120 mg
60 mg / 
120 mg
Route of 
Administration 
Oral with 240 mL water
Dosing instructions:
2 capsules, on 
the morning of 
Day 1 following 
an overnight 
fast
2 capsules, on 
the morning of 
Day 1 following 
an overnight fast
4 tablets in the 
morning of 
Day 1 
following an 
overnight fast
2 capsules, on the 
morning of Day 1 
following an overnight 
fast (if Formulation C) 
or following a high fat 
breakfast (if 
Formulation A or B)
2 capsules, on the 
morning of Day 1 
following an overnight 
fast (if Formulation D) 
or following a high fat
breakfast (if 
Formulation A, B or C)
2 capsules, on 
the morning of 
Day 1 following 
a high fat 
breakfast


2017N315344_01
CONFIDENTIAL
205017
41
Regimen
A
B
C
D
E (Optional)
F (Optional)
Packaging and 
Labelling
Study Treatment will be provided in 60 mL Duma bottle. Each Duma bottle will be labelled as required per country 
requirement. 
Manufacturer
Quotient
Quotient
Quotient
Quotient
Quotient
Quotient


2017N315344_01
CONFIDENTIAL
205017
42
7.1.2.
Treatments Administered - Part B
Regimen
G
H
I
Study Treatment 
Name:
GSK2982772
GSK2982772
GSK2982772
Dosage formulation:
Prototype MR Minitablet in Capsule
Formulation X
Prototype MR Minitablet in Capsule
Formulation X
Prototype MR Minitablet in Capsule
Formulation X
Unit dose strength(s)/
Daily Dosage level(s)a:
15 or 30 mg / 
30 mg
30 or 60 mg / 
60 mg
60 mg / 
240 mg
Route of 
Administration 
Oral with 240 mL water
Dosing instructions:
1 x 30 mg capsule in the morning of 
Days 1 to 3
or
1 x 15 mg capsule in the morning and 
evening of Days 1 to 3; dosing will be 
12 hours apart
Fasted or Fed (non-high fat meal)
1 x 60 mg capsule in the morning of 
Days 1 to 3
or
1 x 30 mg capsule in the morning and 
evening of Days 1 to 3; dosing will be 
12 hours apart
Fasted or Fed (non-high fat meal)
4 x 60 mg capsule in the morning of Days 
1 to 3
or
2 x 60 mg capsule in the morning and 
evening of Days 1 to 3; dosing will be 12 
hours apart
Fasted or Fed (non-high fat meal)
Packaging and 
Labelling
Study Treatment will be provided in 60 mL Duma bottle. Each Duma bottle will be labelled as required per country 
requirement. 
Manufacturer
Quotient
Formulation X is the formulation selected from Part A
a Daily dosage levels are the anticipated dose levels for Part B; but may be subject to change depending on the results from Part A.


2017N315344_01
CONFIDENTIAL
205017
43
7.2.
Dose Modification
This protocol allows some alteration from the currently outlined dosing schedule (see 
Section 5.1 and Section 5.5). The dosing regimens in Part B will be selected based on PK 
and safety data from a minimum of 12 participants in Part A, and the maximum daily 
dose will not exceed a total daily dose equivalent to 240 mg IR taking into account the 
bioavailability of MR relative to IR (i.e. if the bioavailability of MR is 50% that of IR, 
the maximum daily dose of MR to be administered would be 480 mg).
The decision to proceed to the next dose level of GSK2982772 (either an increase or a 
decrease) will be made by the sponsor and investigator based on safety, tolerability, and 
PK data obtained in at least 12 participants at the prior dose level, as described in 
Section 5.1.1.
7.3.
Method of Treatment Assignment
This is an open-label, non-randomised study. A treatment allocation list will take the 
place of the randomisation schedule, which will be developed by the sponsor.
At screening, a unique Subject Number will be assigned to any subject who has at least 
one screening procedure performed, other than informed consent. The unique Subject 
Number will be used to identify individual subjects during the course of the study, and 
will start with 
A treatment allocation list will be produced by GSK Clinical Statistics prior to the start of 
the study, using the validated internal software, which will dictate the treatments that 
should be administered to each participant in each period. The master treatment 
allocation list will be sent to the site and retained in the ISF.
Participant numbers will be allocated on the morning of dosing of Period 1 according to 
the code 
to 
for Part A and 
to 
for Part B, using the lowest number 
available. Replacement subjects will be assigned Subject Numbers 
 to 
 for Part A 
and 
 to 
 for Part B.
7.4.
Blinding
This is an open-label study.
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants 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 labeled storage conditions with access 
limited to the investigator and authorized site staff.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2017N315344_01
CONFIDENTIAL
205017
44
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the technical agreement. 

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.
7.6.
Treatment Compliance

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment and study 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.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded in the source workbook and 
electronic Case Report Form (eCRF) along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or nonprescription 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) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. 
Paracetamol/Acetaminophen, at doses of 2 grams/day, is permitted for use any time 
during the study. Use of hormonal contraception and hormone replacement therapy is 
permitted provided use is stable during the study.  Other concomitant medication may be 
considered on a case-by-case basis by the investigator in consultation with the Medical 
Monitor if required to treat AEs.


2017N315344_01
CONFIDENTIAL
205017
45
7.8.
Treatment after the End of the Study
There is no treatment after the end of the study. 
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
See the SoA for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. Discontinuation of study 
treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm below or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes that study treatment discontinuation is in the 
best interest of the participant.
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 6.


2017N315344_01
CONFIDENTIAL
205017
46
8.1.2.
QTc Stopping Criteria
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the participant has been enrolled.
For example, if a participant is eligible for the protocol based on QTcB, then QTcB must 
be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception. 

The QTc should be based on averaged QTc values of triplicate ECGs obtained 
over a brief (e.g., 5-10 minute) recording period.  
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  

QTc >500 msec

Change from baseline (pre-dose Day 1) of QTc >60 msec
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.3.
Individual Safety Stopping Criteria

If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The participant becomes pregnant.

The participant initiates treatment with any prohibited medications.

The participant develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria or QTc stopping criteria are met.

The participant experiences any signs of suicidal ideation or behaviour.
8.1.4.
Temporary Discontinuation
If a participant is not dosed when planned in a particular period (eg in case of unexpected 
personal circumstances or AEs that occur between treatment periods), they may be dosed 
at a later date (if a subject cannot re-attend within 28 days, they should be considered 
withdrawn), provided the following criteria are met: 

The AE has resolved or stabilised.

The AE preventing dosing was not considered related to the IMP.

The participant has not met any individual stopping criteria.

It is considered safe to continue to dose in the opinion of the investigator.


2017N315344_01
CONFIDENTIAL
205017
47
8.1.5.
Rechallenge
8.1.5.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons.  If a participant withdraws 
from the study, he/she may request destruction of any samples taken, and the 
Investigator must document this in the site study records.  The reason for 
withdrawal should be documented in the Case Report Form (CRF).

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

The Sponsor’s request, for reasons such as significant protocol deviations or 
participant safety concern (and after discussion with the Investigator).

If a participant is withdrawn from study treatment, this participant is also 
considered to be withdrawn from the study following completion of follow-up 
assessments.

Study is terminated by the Sponsor.

Refer to the SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s source workbook.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 


2017N315344_01
CONFIDENTIAL
205017
48
8.4.
Study Stopping Criteria
The study will be halted, and the risk to other participants evaluated, prior to a decision as 
to whether to terminate the study if any of the following criteria are met: 

The occurrence of an SAE, considered at least possibly related to the IMP 
administration in one participant. 

The occurrence of severe non-serious AEs considered as, at least, possibly 
related to the IMP administration in 2 participants at the same dose level
Relatedness will be determined by the investigator. If the study is halted, a temporary halt 
will be submitted to the MHRA and EC in the form of a substantial amendment. The 
study will not be resumed until a further substantial amendment to resume the study is 
submitted and approved by MHRA and EC.
8.5.
Study Termination
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the sponsor and investigator without consultation with the MHRA 
and EC. The end of the trial must be notified to the MHRA and EC immediately and at 
the latest within 15 days after the study is halted, clearly explaining the reasons. A 
description of follow up measures taken for safety reasons if applicable, should also be 
provided.
If the study is abandoned prior to commencement of any protocol activities, the PI or 
sponsor must notify the EC and MHRA by letter outlining the reasons for abandonment 
of the trial.
Once exposure to GSK2982772 has begun, the study will be completed as planned unless 
the following criteria are satisfied that require temporary suspension or early termination 
of the study.

The occurrence of serious or severe AE(s), as defined in Appendix 4, if 
considered to be related to the IMP.

New information regarding the safety of the IMP that indicates a change in the 
risk/benefit profile for the compound, such that the risk/benefit is no longer 
acceptable for participants in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the 
ability to achieve the primary study objectives or compromises participant
safety.
If any of the above occurs, the study may be terminated if careful review of the overall 
risk/benefit analysis described in Section 3.3 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable. In these circumstances 
termination can only take place with the agreement of the investigator and sponsor. The 
MHRA and EC will be informed of study termination.


2017N315344_01
CONFIDENTIAL
205017
49
If it becomes necessary to consider termination of the study after dosing has begun, 
dosing may be suspended pending discussion between the investigator and sponsor. 
Dosing will be stopped immediately on safety grounds.
The study may be terminated or suspended at the request of the MHRA or EC.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management or by 
generic screening (e.g., blood count) and obtained before signing of ICF may be 
utilized for screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
550 mL in a 56-day period.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

A participant will be allowed to leave the premises following completion of 
study-specific procedures at 32 hours post-dose (Part A, Treatment Periods 1, 2, 4, 5, 
6) or 24 hours post-dose (Part A, Treatment Period 3) or 24 hours after the last dose 
(Part B Treatment Periods 1, 2 and 3; if BID dosing selected this will be after the last 
evening dose) providing that:
−
No AEs have been reported during the study visit
−
The participant responds positively when asked “How are you feeling?”
If any of these conditions are not met, then the participant may only be allowed to 
leave the clinical unit with the authorisation of the investigator or appropriately 
qualified delegate.
9.1.
Efficacy Assessments
Not applicable.


2017N315344_01
CONFIDENTIAL
205017
50
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit
at the time points specified in the SoA (Section 2).

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 
24 hours, as indicated in Appendix 4. 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 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.


2017N315344_01
CONFIDENTIAL
205017
51
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and sponsor policy and forwarded to investigators as 
necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.

Further details can be found in Appendix 7.
9.2.5.
Pregnancy

Details of all pregnancies in female participants and, female partners of male 
participants will be collected after the start of study treatment and until 30 days after 
the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of GSK2982772 greater than that intended in this study will be 
considered an overdose.
There is no specific antidote for overdose with GSK2982772.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 48 hours following the last 
dose of GSK2982772).
3.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).


2017N315344_01
CONFIDENTIAL
205017
52
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, GI and neurological systems. Height and 
weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, heart rate and 
respiratory rate.

The acceptable deviations from the nominal vital signs measurement time points 
are:
−
The pre-dose vital signs measurements will be taken ≤2 hours before 
dosing.
−
Post-dose vital signs measurements will be taken ± 15 minutes from the 
nominal post-dose time points.
−
Discharge vital signs measurements will be taken ± 1 hour from the 
nominal time point.

If a participant shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution if 
required. Additional measurements may be taken as deemed necessary by the 
investigator.

Any clinically significant abnormality, including changes from baseline
(pre-dose Day 1), must be reported as an AE.
9.4.3.
Electrocardiograms

Triplicate 12-lead ECGs will be obtained at screening and single 12-lead ECGs 
will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc
intervals. If a single ECG shows a QTc increase of ≥ 60 msec from baseline


2017N315344_01
CONFIDENTIAL
205017
53
(pre-dose Day 1), two further ECGs should be performed over a brief period 
(e.g. 5 to 10 minutes) and the assessment made on the mean QTc of the triplicate 
ECGs.  Refer to Section 8.1.2 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.

The QTc should be based on averaged QTc values of triplicate ECGs obtained 
over a brief (e.g. 5 to 10 minutes) recording period.

The acceptable deviations from the nominal ECG measurement time points are:
−
The pre-dose ECG measurements will be taken ≤2 hours before dosing
−
Post-dose ECG measurements will be taken ± 15 minutes from the 
nominal post-dose time point.
−
Discharge ECG measurements will be taken ± 1 hour from the nominal 
time point.

ECGs are to be measured after participant has been in a semi-supine or supine 
position after approximately 5 minutes rest.

If a participant shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution if 
required. Additional measurements may be taken as deemed necessary by the 
investigator.

Any clinically significant abnormality, including changes from baseline
(pre-dose Day 1), will be reported as an AE.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

Blood samples for scheduled laboratory assessments will be taken following an 
overnight fast.

The acceptable deviations from the nominal blood sampling time points for 
laboratory assessments are:
−
The pre-dose blood sample will be taken ≤2 hours before dosing
−
Post-dose blood samples will be taken ± 1 hour from the nominal blood 
sampling time except when the time point coincides with the PK blood 
sampling time. In this situation, the time window for the PK sample applies.

The acceptable deviations from the nominal urine sampling time points for 
urinalysis are:
−
The pre-dose urine sample will be taken ≤3 hours before dosing or the first 
void of the day
−
Post-dose urine samples will be taken ± 2 hour from the nominal urine 
sampling time.

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 


2017N315344_01
CONFIDENTIAL
205017
54
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

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 (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.4.5.
Suicidal Risk Monitoring
GSK2982772 is considered to be a CNS-active drug.  There has been some concern that 
some CNS-active drugs may be associated with an increased risk of suicidal thinking or 
behaviour when given to some patients with disease.  Although this drug has not been 
shown to be associated with an increased risk of suicidal thinking or behaviour when 
given to healthy volunteers, GSK considers it important to monitor for such events before 
or during clinical studies with compounds such as this.   
Participants being treated with GSK2982772 should be monitored appropriately for 
suicidal ideation and behaviour or any other unusual changes in behaviour. Study 
medication must be immediately discontinued in all participants who experience signs of 
suicidal ideation or behaviour.
Families and caregivers of patients being treated with GSK2982772 should be alerted 
about the need to monitor participants for the emergence of unusual changes in 
behaviour, as well as the emergence of suicidal ideation and behaviour and to report such 
symptoms immediately to the study Investigator.
At Screening and baseline (pre-dose Day 1), the ‘Baseline/Screening C-SSRS’ will be 
completed in Part B only.  Assessments done at Day 4, the ‘Since Last Visit C-SSRS’ 
will be completed in Part B only.  GSK Version 4.1 of both rating scales will be used.
Participant s who answer ‘yes’ to any suicidal behaviour or ‘yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their General Practitioner or appropriate psychiatric 
care and be discontinued from study medication.  The Medical Monitor will be notified.  
If appropriate, an AE or SAE should be reported (see Section 9.2).  In addition, the 
Investigator should complete a Possible Suicidality Related Adverse Event (PSRAE) 
form to collect detailed information on the circumstances of the reported AEs which, in 


2017N315344_01
CONFIDENTIAL
205017
55
the Investigator’s opinion, are possibly suicidality-related.  These may include, but are 
not limited to, an event involving suicidal ideation, a preparatory act toward imminent 
suicidal behaviour, a suicide attempt, or a completed suicide.
9.5.
Pharmacokinetics

Blood samples of approximately 2 mL will be collected for measurement of 
plasma concentrations of GSK2982772 as specified in the SoA (see Section 2).
Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded.

Processing, storage and shipping procedures are provided in the Study Reference 
Manual (SRM) or equivalent.

The acceptable deviations from the nominal post-dose blood sampling times are 
as follows:
−
The pre-dose blood sample will be taken ≤1 hour before dosing. 
−
Post-dose samples will be taken within ± 10 minutes of the nominal post-
dose sampling time 

Samples will be used to evaluate the PK of GSK2982772. Samples collected for 
analyses of GSK2982772 plasma concentration may also be used to evaluate 
safety aspects related to concerns arising during or after the study.

Genetic analyses will not be performed on these plasma samples. Participant 
confidentiality will be maintained. 
Plasma analysis will be performed under the control of Platform Technology & Science 
(PTS), In Vitro/In Vivo Translation (IVIVT) and Third Party Resourcing (TPR), GSK.  
Concentrations of GSK2982772 will be determined in plasma using the current approved 
bioanalytical methodology.  Raw data will be archived at the Bioanalytical site as 
detailed in the SRM or equivalent.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.


2017N315344_01
CONFIDENTIAL
205017
56
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
No formal hypothesis will be tested. However, point estimates and corresponding 90% 
confidence intervals will be derived for Cmax, AUC(0- inf), C12 and C24 and peak to trough 
concentration ratio for each test minitab MR formulation in a capsule (120 mg) relative to 
the IR formulation (120 mg).
10.2.
Sample Size Determination
10.2.1.
Sample Size Determination - Part A
To date, there are no MR formulation variability data available. The maximum between-
subject coefficient of variation (CVb) for the PK parameters observed in Study 200975 
following GSK2982772 capsule formulation were used for precision estimates; CVb (%) 
for AUC(0-inf) and Cmax for 120 mg GSK2982772 IR capsule formulation were 29.0 and 
31.5 respectively.  Therefore, the estimates of within subject coefficient of variation 
(CVw [%]) are 20.3% and 18.8% for AUC(0-inf) and Cmax, respectively. Based on these 
estimates of variability and a sample size of 12 completers, it is estimated that the lower 
and upper bounds of the 90% confidence interval (CI) for the geometric mean ratio 
(MR/IR) of AUC and Cmax will be within approximately 15.3% and 14.2% of the point 
estimate respectively. 
Since it is expected that the MR formulation is to reduce the Cmax by 50% whilst 
maintaining the AUC, a sample size of 12 ensures that the 90% CI is within the region 
0.8-1.25 for AUC and 0.4-0.625 for Cmax, if the observed geometric ratio is 0.93-1.08 for 
AUC and 0.47-0.54 for Cmax. 
Sample Size Sensitivity – Part A
Using estimates of parameter (this can be any PK parameter AUC, Cmax) variability
observed in Study 200975, the precision of these estimates calculated as half width of a 
90% confidence interval for the mean ratio (MR/IR) and expressed as distance from 
mean to limits for 10, 12, 14 and 16 participants has been calculated (Table 5).


2017N315344_01
CONFIDENTIAL
205017
57
Table 5
Precision Estimate of Mean – Part A
CVw (%)
Precision of Mean (%)
N=10
N=12
N=14
N=16
15
12.70
11.30
10.30
9.50
18.8
16.00
14.20
12.90
11.90
20
17.30
15.30
13.90
12.90
For example, based upon the estimate of variability (CVw%) of 20 and a sample size of 
14, it is estimated that the lower and upper bounds of the 90% confidence interval for the 
means of the PK parameter (eg, AUC, Cmax) will be within approximately 13.9% of the 
point estimate.
10.2.2.
Sample Size Determination - Part B
No repeat dose MR formulation variability data are currently available. Therefore, the 
maximum CVb for the PK parameters were observed in the study 200972 following 
repeat dose of GSK2982772 capsule formulation; CVb (%) for AUC(0-τ) and Cmax for 
20mg QD GSK2982772 IR capsule formulation on Day 1 is 36.1 and 27.1 respectively. 
Therefore, the estimates of equivalent CVw (%) are 23.2 and 17.6 for Cmax and AUC(0-τ)
respectively. Based on these estimates of variability and a sample size of 8 completers, it 
is estimated that the lower and upper bounds of the 90% confidence interval for the 
means of AUC(0-τ) and Cmax will be within approximately 12.1% and 16.7% of the point 
estimate respectively.
Sample Size Sensitivity – Part B
Using estimates of parameter (this can be any PK parameter AUC, Cmax) variability, the 
precision of these estimates calculated as half width of a 90% confidence interval for the 
mean and expressed as distance from mean to limits for  4, 6, 8 and 10 participants has 
been calculated (Table 6).
Table 6
Precision Estimate of Mean – Part B
CVb (%)
Precision of Mean (%)
N=4
N=6
N=8
N=10
18.4%
23.6
16.0
12.8
11.0
19.3%
25.1
16.9
13.6
11.6
24.4%
32.6
21.8
17.4
14.9
25.5%
34.2
22.8
18.2
15.6


2017N315344_01
CONFIDENTIAL
205017
58
For example, based upon the estimate of variability (CVb%) of 19.3 and a sample size of 
4, it is estimated that the lower and upper bounds of the 90% confidence interval for the 
means of the PK parameter (eg, AUC, Cmax) will be within approximately 25.1% of the 
point estimate.
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Subjects
All participants who receive at least 1 dose of study treatment and 
will be the population for reporting of safety and study population 
data. Participants will be analyzed according to the treatment they 
actually received.
PK
Participants in the ‘All Subjects Population’ for whom a PK sample 
was obtained and analysed and will be the population for reporting 
of PK data.
10.4.
Statistical Analyses
10.4.1.
Pharmacokinetic Analyses
All PK analyses will be performed on the PK Population. 
For both parts of the study, plasma GSK2982772 concentration-time data will be 
analysed by non-compartmental methods.  
In Part A, from the plasma concentration-time data for each of the regimens, the 
following PK parameters will be determined, as data permit: 

maximum observed plasma concentration (Cmax).

time to Cmax (Tmax).

the elapsed time from dosing at which GSK2982772 was first quantifiable in a 
concentration vs time profile (Tlag).

observed concentration at 12 hours and 24 hours post-dose (C12h and C24h).

area under the plasma concentration vs time curve (AUC(0-t), AUC(0-24), AUC(0-
12) and AUC(0-inf)).  

the percentage of AUC extrapolated beyond the last measured time point
(AUC%extrap).

terminal half-life (t1/2).

Cmax to C12h and Cmax to C24h ratios.


2017N315344_01
CONFIDENTIAL
205017
59

relative bioavailability (Frelformulation) of test formulations vs reference formulation 
based on AUC(0-24) and AUC(0-inf) (or AUC(0-t) if AUC(0-inf) can’t be derived) and 
Cmax.

relative bioavailability (FrelFE) of fed vs fasted based on AUC and Cmax.
In Part B, from the plasma concentration-time data for each of the regimens, the 
following PK parameters will be determined, for Day 1 and Day 3, as data permit: 

maximum observed plasma concentration (Cmax) for QD dosing.  If BID dosing, Cmax
after morning dose and evening dose.

time to Cmax (Tmax) for QD dosing.  If BID dosing, Tmax after morning dose and 
evening dose.

observed concentration at 12 hours and 24 hours post-dose (C12h and C24h).

area under the plasma concentration-time curve (AUC(0-24)) for QD dosing.  If BID 
dosing, AUC(0-12) and AUC(12-24).

Cmax to C12 and Cmax to C24 ratios.

Dose normalised Cmax, C12h, C24h, AUC(0-tau) (for BID dosing), AUC(0-24) and 
AUC(0-inf).
Descriptive statistics (n, arithmetic mean, standard deviation [SD], 95% CI, minimum, 
median and maximum,) will be calculated by treatment for all PK concentrations over 
time and for the derived PK parameters. In addition, for loge-transformed PK parameter 
variables geometric mean, 95% CI and %CVb (100 * √ (exp(SD2) -1)) will be provided, 
where the SD is the standard deviation of log-transformed data.


2017N315344_01
CONFIDENTIAL
205017
60
Endpoint
Statistical Analysis Methods
Primary
The primary PK endpoints to compare MR formulations with IR formulations will 
be summarised descriptively. Ratio of AUC(0-inf) , AUC(0-24), (AUC(0-t), if AUC(0-inf)
cannot be derived), Cmax, C12 and C24 for MR formulation to IR formulation will be 
computed with 90% CI. Cmax to C12h and Cmax to C24h ratio for each minitab MR 
formulation (120 mg) and the IR formulation (120 mg) will be computed with 90% 
CI.  
Secondary
The secondary endpoints for food effect will be summarised descriptively. In 
addition, log-transformed AUC(0-inf)(AUC(0-t), if AUC(0-inf) cannot be derived), C12h, 
C24h, and Cmax will be analysed using a mixed effects model with regimen as a 
fixed effect and subject within sequence as a random effect.  Point estimates and
corresponding 90% CI will be computed for the differences in GSK2982772 MR 
formulation (120 mg) taken in the fed state (test) vs in the fasted state (reference) 
using the residual error from the model (MSE). The point and interval estimates 
on the log-scale will then be exponentially back transformed to give estimates of 
the ratios of geometric means and 90% CI.
Within-subject coefficients of variation for AUC(0-inf)and Cmax will be calculated 
based on the loge-Normal distribution: CVw (%) = sqrt[exp(mse) - 1] x 100, where 
MSE is the residual error from the model.
Statistical analysis of the PK endpoint Tmax of GSK2982772 of GSK2982772 
(120 mg) administered under both fed and fasted conditions will be separately 
analysed non-parametrically [Hauschke, 1990]. The point estimates for the 
medians for each treatment, the median difference and 90% CI for the median 
difference will be calculated for the contrast (test-reference).
Secondary
The secondary PK endpoints for the selected MR formulation at target daily 
doses of 30, 60 and 240 mg will be summarised descriptively. 
Plots of dose vs dose normalised AUC(0-24), AUC(0-12) (AUC(12-24) BID dosing), C12h, 
C24h and Cmax (after morning and evening doses if BID dosing) will be generated 
to determine if there are any dose dependent changes in the absorption of 
GSK2982772 following repeat dose administration of the selected minitab MR 
formulation.
The Reporting and Analysis Plan will describe the planned PK analyses in greater detail.
10.4.2.
Safety Analyses
All safety analyses will be performed on the All Subjects Population. 
Endpoint
Statistical Analysis Methods
Secondary
The safety endpoints will be summarised descriptively. 


2017N315344_01
CONFIDENTIAL
205017
61
The Reporting and Analysis Plan will describe the planned safety analyses in greater 
detail.
10.4.3.
Interim Analyses
No formal statistical analyses are planned. However, after Periods 1 to 3 are complete, 
the PK data will be analysed which will guide Periods 4, 5 and 6. Periods 4, 5 and 6 will 
be flexible and the dosing regimen will be dependent on the outcome of preceding 
periods.  There will be the option to either optimise the MR release duration and/or to 
evaluate the impact of food on the selected MR minitab formulation in a capsule.  There 
will also be the option to cancel Periods 5 and 6 if an optimal formulation is determined 
in Periods 1 or 2.
There will be an interim review following final period of Part A to determine the 
formulation, doses, dosing frequency (QD or BID) and prandial state for Part B.  The data 
will be sent to the sponsor by Quotient, from which the decision on formulation and 
prandial state selection or stopping the study will be made by the Quotient study team 
(i.e., PI, scientific lead and pharmacokineticist) and sponsor study team (as a minimum 
the sponsor’s medical monitor, CPMS and GCSP).  The decision will be documented and 
signed by the PI as per Quotient Clinical current SOP.  Evidence of the decision will be 
retained in the ISF and GSK Trial Master File.
There will be no interim analysis during Part B of the study. 
See Section 5.1.1 for full details on the criteria for interim decisions.
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
10.4.4.
Stopping Criteria
After data is available and analysed for Period 1, 2 and 3, a decision to stop the study 
could be triggered if:

The PK profile of IR and MR are similar , based on visual judgement of 
concentration-time curves or if the PK profiles indicate that a QD or BID dosing 
regimen isn’t feasible.  Consideration of PK parameters, AUC(0-inf) and Cmax will 
assist with this judgement but no formal quantitative no-go will be defined due to 
the exploratory and flexible nature of the study.

Administration of MR with a high-fat meal shows dose dumping 


2017N315344_01
CONFIDENTIAL
205017
62
11.
REFERENCES
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E et al. 
RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions 
of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death & Differ, 2013;20:1381-92.
GlaxoSmithKline Document Number 2014N204126_02.  GSK2982772 Investigator 
Brochure.  Effective Date 27-JAN-2017 
Hauschke D1, Steinijans VW, Diletti E. A distribution-free procedure for the statistical 
analysis of bioequivalence studies. Int J Clin Pharmacol Ther Toxicol, 1990;28(2):72-8.
Humphries F, Yang S, Wang B, Moynagh P N. RIP kinases: key decision makers in cell 
death and innate immunity. Cell Death & Differ, 2015;22:225-236.
Ofengeim D and Yuan J. Regulation of RIP1 kinase signaling at the crossroads of 
inflammation and cell death. Nature Reviews Molecular Cell Biology, 2013;14:727-36.
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. 
Cell, 2008; 133(4):693-703.


2017N315344_01
CONFIDENTIAL
205017
63
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
List of Abbreviations
Abbreviation
Definition
AE
Adverse event
ALT
Alanine transaminase
ANA
Anti-nuclear antibody
AST
Aspartate Aminotransferase
AUC
Area under the concentration vs time curve
AUC(0-12),
Area under the curve from time zero to 12 hours
AUC(0-24)
Area under the curve from time zero to 24 hours
AUC(0-t)
Area under the curve from time zero to the last measurable concentration
BID
Twice daily
BUN
Blood Urea Nitrogen
C12
Concentration at 12 h post-dose
C24
Concentration at 24 h post-dose
CA
Competent Authority
CI 
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacokinetics Modelling and Simulation
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
CRP
C-reactive protein
C-SSRS
Columbia Suicide Severity Rating Scale
CV
Cardiovascular
CVb
Between subject coefficient of variation
CVw
Within subject coefficient of variation
DR
Dose ranging
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
FTIH
First time in human
Frel
Relative bioavailability
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GFR
Glomerular filtration rate
GI
Gastrointestinal
GLP
Good Laboratory Practice


2017N315344_01
CONFIDENTIAL
205017
64
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
hCG
Human Chorioninc Gonadotropin
HIV
Human immunodeficiency virus
HIPPA
Health Insurance Portability and Accountability Act
HRT
Hormonal Replacement Therapy
ICF
Informed consent form
IEC
Independent Ethics Committees
IMP
Investigational medicinal product
INR
International normalized ratio
IR
Immediate release
IRB
Institutional Review Board
ISF
Investigator site file
IVIVT
In Vitro/In Vivo Translation
L
Litre
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
mg
milligrams
MHRA
Medicines and Healthcare products Regulatory Agency
mins
Minutes
mL
Millilitres
mmol
Millimole
MR
Modified release
MSDS
Material Safety Data Sheet
msec
Milliseconds
NOAEL
No observed adverse effect level
Pgp
P-glycoprotein
PI
Principal investigator
PIS
Participant Information Sheet
PK
Pharmacokinetic(s)
ppm
Parts per million
PsO
Plaque psoriasis
PSRAE
Possible Suicidality Related Adverse Event
PTS
Platform Technology & Science
QD
Once daily
QTc
Corrected QT interval
QTcB
QT interval corrected for heart rate according to Bazett’s formula
QTcF
QT interval corrected for heart rate according to Fridericia’s formula
RA
Rheumatoid arthritis
RBC
Red blood cells
RIP1
Receptor-interacting protein-1
SAE
Serious adverse event
SD
Standard deviation
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SoA
Schedule of activities


2017N315344_01
CONFIDENTIAL
205017
65
SRM
Study Reference Manual
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TB
Tuberculosis
TID
Three times daily
TLR
Toll like receptor
Tmax
Time to Cmax
TNF
Tumour necrosis factor
TPR
Third Party Resourcing
ULN
Upper limit of normal
WBC
White blood cells
WOCBP
Woman of childbearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Chiron RIBA
SAS
WinNonlin


2017N315344_01
CONFIDENTIAL
205017
66
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 7 will be performed by The Doctors Laboratory, with 
the exception of routine urinalysis, urine pregnancy test, urine drug screen, 
alcohol and carbon monoxide breath tests. These tests will be performed on-site. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

All laboratory tests with values that are considered clinically significantly 
abnormal during participation in the study should be repeated until the values 
return to normal or baseline.  If such values do not return to normal within a 
period judged reasonable by the Investigator, the etiology should be identified 
and the sponsor notified.
Table 7
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume (MCV)
Mean corpuscular 
haemoglobin (MCH)
Mean corpuscular 
haemoglobin 
concentration (MCHC)
%Reticulocytes
White blood cell (WBC)
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red Blood Cell (RBC)
Count
Haemoglobin
Haematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin (direct 
only if total is 
elevated)
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Albumin
Chloride
Cholesterol 
(Total)
Triglycerides


2017N315344_01
CONFIDENTIAL
205017
67
Laboratory 
Assessments
Parameters
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocytes by dipstick

Microscopic examination (if blood, protein or leukocytes are abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) at screening only

urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)

alcohol breath test

carbon monoxide breath test

Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)

Serum hCG pregnancy test (as needed for women of childbearing potential)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody) at screening only

Tuberculosis test (QuantiFERON) at screening only

C-reactive protein (CRP) at screening only

Anti-nuclear antibody (ANA) in Part B only
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 6 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE.


2017N315344_01
CONFIDENTIAL
205017
68
12.3.
Appendix 3: Study Governance Considerations
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 GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Prior to the initiation of the study, the Clinical Trial Authorisation application 
must be approved by the MHRA. A copy of this approval and any 
correspondence with the MHRA will be available at the clinical and sponsor 
sites. A copy of the MHRA approval will be provided to the EC.

Any substantial amendments to the protocol will require MHRA and IEC/IRB 
approval before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study participants
(urgent safety measure). 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Protocol Amendments and Deviations
Amendments
After the protocol has been submitted to the MHRA and/or EC, any amendment must be 
agreed by the investigator after discussion with the sponsor and will be formally 
documented.
All substantial amendments will be submitted to the MHRA and/or EC for an opinion as 
required by current regulations. 


2017N315344_01
CONFIDENTIAL
205017
69
If the participant information sheet (PIS) and ICF are updated as a result of an 
amendment, the new versions will be used to re-consent currently enrolled participants
and must be provided to additional participants prior to their entry into the study.
Protocol Deviations
The study must be conducted in accordance with the Clinical Protocol. Should a protocol 
deviation occur, it must be promptly assessed in order to decide whether any of these 
non-compliances should be reported to the MHRA as a serious breach of GCP and the 
Clinical Protocol.
Protocol waivers are not acceptable.
Deviations from the protocol will be recorded in the source workbook as noted by the 
clinical staff. If necessary, the sponsor will be informed of the deviation.
Any protocol deviations assessed as major will be discussed with the sponsor in order to 
determine if the withdrawal criteria stated in Section 8 have been met.
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.
Informed Consent Process

Participants will be provided with a written explanation of the study at least one 
day before the screening visit.

The investigator or his/her representative will explain the nature of the study, its 
purpose, expected duration and the benefits and risks involved in study 
participation to the participant and answer all questions regarding the study. 
Participants will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that 
carry out clinical studies in the local area.

Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study centre. 

The source workbook 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.


2017N315344_01
CONFIDENTIAL
205017
70

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. 

Participants who are rescreened are required to sign a new ICF.
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 IRB/IEC members, and by inspectors from 
regulatory authorities.
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 multicentre studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

Following completion of the study, a clinical study report will be prepared. 

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
policy and will be made available to the EC/MHRA within 1 year of the 
declaration of the end of trial.
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 (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 


2017N315344_01
CONFIDENTIAL
205017
71

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/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 from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
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. 
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

A study-specific source documentation list will be finalised by the sponsor 
before the start of the clinical phase of the study. The document will identify 
what data should be considered source data for this study.


2017N315344_01
CONFIDENTIAL
205017
72
Declaration of the End of the Study
The definition of the end of the study is defined as the last visit of the last participant
(eg follow-up assessment). Any changes to this definition will be notified as a substantial 
amendment.
The EC and MHRA should be notified in writing of the conclusion of the study within 
90 days of the end of the study, or within 15 days if the study is terminated early, clearly 
explaining the reasons for the termination.
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 
IRB/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


2017N315344_01
CONFIDENTIAL
205017
73
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting to GSK
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 (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, 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 (eg, 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 


2017N315344_01
CONFIDENTIAL
205017
74
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 (eg, 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 fulfils 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, diarrhoea, influenza, 
and accidental trauma (eg, 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 


2017N315344_01
CONFIDENTIAL
205017
75
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.
Definition of an Adverse Drug Reaction (ADR)
An ADR is defined as any untoward medical occurrence that, at any dose:

where a causal relationship with the IMP is at least a reasonable possibility (possibly 
related or related)
Definition of SUSAR
A SUSAR is defined as any untoward medical occurrence that, at any dose:

Is believed to be related to an IMP and is both unexpected (ie the nature or severity is 
not expected from the information provided in the Investigator’s Brochure) and 
serious. SUSARs are subject to expedited reporting to the MHRA, European 
Medicines Agency (EMA), EC (see Appendix 7)
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF (ie the 
date and time of onset, a description of the AE, severity, duration, actions taken, 
outcome and an investigator’s current opinion on the relationship between the study 
treatment and the event).

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 


2017N315344_01
CONFIDENTIAL
205017
76
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; intervention may be needed.

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 
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.


2017N315344_01
CONFIDENTIAL
205017
77
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 via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (eg, check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the Communication Plan.


2017N315344_01
CONFIDENTIAL
205017
78
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail 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 in the Communication Plan.


2017N315344_01
CONFIDENTIAL
205017
79
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
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 WOCBP
1. Premenarchal
2. 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.
3. 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 (ie 
≥40 IU/L) 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 enrolment.
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 during the protocol-defined 
time frame in Section 6.1: 

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 Table 8 when having 
penile-vaginal intercourse with a woman of childbearing potential 


2017N315344_01
CONFIDENTIAL
205017
80

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 3 months after study 
completion or from last dose.

As there is a significant risk of drug exposure through the ejaculate (which also 
applies to vasectomised males) that might be harmful to the sexual partners 
(both male and female), including pregnant partners of male participants, a 
condom should be used by all male participants during the protocol-defined time 
frame in Section 6.1.
Female participants
Female participants who are not of childbearing potential do not need to use any methods 
of contraception.
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 8. 
Table 8
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 
ovulationb

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 WOCBP and the absence of sperm has been confirmed. If 


2017N315344_01
CONFIDENTIAL
205017
81
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

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test 

Additional pregnancy testing will be performed at admission to each study period
and at the follow-up visit

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Urine pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using 
the SureScreen Diagnostics test in accordance with instructions provided in its 
package insert at each admission. Serum pregnancy testing, with a sensitivity of
5.8 mIU/mL will be performed and assayed in the certified local laboratory (The 
Doctors Laboratory)  
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 foetal
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 


2017N315344_01
CONFIDENTIAL
205017
82

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of foetal status (presence 
or absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will be withdrawn 
from the study 


2017N315344_01
CONFIDENTIAL
205017
83
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
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 subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
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 2 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 paracetamol/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:


2017N315344_01
CONFIDENTIAL
205017
84
Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. NOTE: not required in 
China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants
3.
Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM
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.


2017N315344_01
CONFIDENTIAL
205017
85
12.7.
Appendix 7: Safety Reporting to Ethics Committee and 
Regulatory Authorities
Events Requiring Expedited Reporting
SUSARs are subject to expedited reporting to the MHRA, EMA and EC.
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of an IMP or that would be 
sufficient to consider changes in the IMPs administration or in the overall conduct of the 
study, for instance:

an increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important

SAEs that occur after the participant has completed the clinical study where the 
sponsor considers them to be a SUSAR

new events related to the conduct of the study or the development of the IMPs and 
likely to affect the safety of the participants, such as:
−
an SAE which could be associated with the study procedures and which could 
modify the conduct of the study
−
a major safety finding from a newly completed animal study (such as 
carcinogenicity)
−
any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same IMPs in another country by the same sponsor
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible.
Expedited Reporting of Events
It is the responsibility of the sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible.
Where expedited reporting is required, the following procedures should be followed.
Fatal or life-threatening SUSARs
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA and EMA as soon as possible, but no later than 7 calendar days after they first 
became aware of the reaction. This responsibility may be delegated to the 
pharmacovigilance provider.
The investigator is required to notify the EC of any SUSAR as soon as possible, but no 
later than 7 calendar days after they first became aware of the reaction.
Any additional relevant information should be sent within 8 days of the report.


2017N315344_01
CONFIDENTIAL
205017
86
Other SUSARs
It is the responsibility of the sponsor to report other SUSARs to the MHRA and EMA as 
soon as possible, but no later than 15 calendar days after they first became aware of the 
reaction. This responsibility may be delegated to the pharmacovigilance provider.
The investigator is required to notify the EC of other SUSARs as soon as possible, but no 
later than 15 calendar days after they first became aware of the reaction.
Any additional relevant information should be sent within 8 days of the report.
Urgent Safety Measures
If Quotient Clinical or any of its staff or contractors becomes aware of an actual or 
potential urgent safety issue, then the sponsor must be immediately contacted so that 
appropriate urgent safety measures can be agreed. An urgent safety issue is defined as: 

An immediate hazard to the health or safety of participants enrolled in a clinical study

A serious risk to human health or potentially a serious risk to human health
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe conduct 
of the study or that pose a risk to study participants.
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, Quotient Clinical may take urgent safety measures before informing 
the sponsor, but the sponsor must be informed immediately after the hazard has resolved. 
Quotient Clinical will take responsibility for informing appropriate competent authorities, 
and the EC.
Reporting of Urgent Safety Issues
Quotient Clinical is required to inform the appropriate competent authorities and the EC
within 3 calendar days of the urgent safety issue.
Serious Breaches
It is the responsibility of the sponsor to notify the licensing authority of any serious 
breach, which is likely to affect, to a significant degree, the safety or mental integrity of 
the participants of the study or the scientific value of the study. 
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach.


2017N315344_01
CONFIDENTIAL
205017
87
12.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).


2017N315344_00
CONFIDENTIAL
GlaxoSmithKline group of companies
205017
1
TITLE PAGE
Protocol Title: A two part, non-randomised, open label study designed to assess the
pharmacokinetics of GSK2982772 following administration of modified release 
formulations in capsule relative to an immediate release reference tablet formulation 
(Part A) and the pharmacokinetics of escalating, repeat doses of a selected modified 
release prototype (Part B) in healthy subjects
Protocol Number: 205017
Short Title: A study to compare the pharmacokinetics of GSK2982772 following 
administration of different modified release formulations in capsule relative to an 
immediate release tablet formulation and to investigate the pharmacokinetics of a 
selected modified release formulation in capsule following repeat doses for 3 days.
Compound Number:
GSK2982772
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Communication 
Plan
Regulatory Agency Identifying Number(s): EudraCT Number 2017-000652-25
Approval Date: 07-JUL-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


2017N315344_00
CONFIDENTIAL
205017
3
TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
3.
INTRODUCTION....................................................................................................19
3.1.
Study Rationale ..........................................................................................19
3.2.
Background ................................................................................................20
3.3.
Benefit/Risk Assessment ............................................................................21
3.3.1.
Risk Assessment .........................................................................22
3.3.2.
Benefit Assessment.....................................................................27
3.3.3.
Overall Benefit:Risk Conclusion...................................................27
4.
OBJECTIVES AND ENDPOINTS...........................................................................27
5.
STUDY DESIGN ....................................................................................................28
5.1.
Overall Design ............................................................................................28
5.1.1.
Criteria for Interim Decisions........................................................29
5.2.
Number of Participants ...............................................................................30
5.3.
Participant and Study Completion...............................................................31
5.4.
Scientific Rationale for Study Design ..........................................................31
5.5.
Dose Justification........................................................................................32
6.
STUDY POPULATION...........................................................................................33
6.1.
Inclusion Criteria.........................................................................................33
6.2.
Exclusion Criteria........................................................................................34
6.3.
Lifestyle Restrictions...................................................................................36
6.3.1.
Meals and Dietary Restrictions ....................................................36
6.3.2.
Activity .........................................................................................38
6.4.
Screen Failures...........................................................................................38
7.
TREATMENTS.......................................................................................................38
7.1.
Treatments Administered............................................................................39
7.1.1.
Treatments Administered - Part A................................................39
7.1.2.
Treatments Administered - Part B................................................41
7.2.
Dose Modification .......................................................................................42
7.3.
Method of Treatment Assignment ...............................................................42
7.4.
Blinding.......................................................................................................42
7.5.
Preparation/Handling/Storage/Accountability..............................................42
7.6.
Treatment Compliance................................................................................43
7.7.
Concomitant Therapy..................................................................................43
7.8.
Treatment after the End of the Study ..........................................................44
8.
DISCONTINUATION CRITERIA.............................................................................44
8.1.
Discontinuation of Study Treatment ............................................................44
8.1.1.
Liver Chemistry Stopping Criteria ................................................44
8.1.2.
QTc Stopping Criteria ..................................................................45
8.1.3.
Individual Safety Stopping Criteria ...............................................45
8.1.4.
Temporary Discontinuation ..........................................................45
8.1.5.
Rechallenge.................................................................................46


2017N315344_00
CONFIDENTIAL
205017
4
8.1.5.1.
Study Treatment Restart or Rechallenge....................46
8.2.
Withdrawal from the Study..........................................................................46
8.3.
Lost to Follow Up........................................................................................46
8.4.
Study Stopping Criteria...............................................................................47
8.5.
Study Termination.......................................................................................47
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................48
9.1.
Efficacy Assessments.................................................................................48
9.2.
Adverse Events...........................................................................................49
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................49
9.2.2.
Method of Detecting AEs and SAEs.............................................49
9.2.3.
Follow-up of AEs and SAEs.........................................................49
9.2.4.
Regulatory Reporting Requirements for SAEs .............................50
9.2.5.
Pregnancy ...................................................................................50
9.3.
Treatment of Overdose...............................................................................50
9.4.
Safety Assessments ...................................................................................51
9.4.1.
Physical Examinations.................................................................51
9.4.2.
Vital Signs....................................................................................51
9.4.3.
Electrocardiograms......................................................................51
9.4.4.
Clinical Safety Laboratory Assessments ......................................52
9.4.5.
Suicidal Risk Monitoring...............................................................53
9.5.
Pharmacokinetics .......................................................................................54
9.6.
Pharmacodynamics ....................................................................................54
9.7.
Genetics .....................................................................................................54
9.8.
Biomarkers .................................................................................................54
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................55
10. STATISTICAL CONSIDERATIONS........................................................................55
10.1.
Hypotheses.................................................................................................55
10.2.
Sample Size Determination ........................................................................55
10.2.1.
Sample Size Determination - Part A.............................................55
Sample Size Sensitivity – Part A.................................................................55
10.2.2.
Sample Size Determination - Part B.............................................56
Sample Size Sensitivity – Part B.................................................................56
10.3.
Populations for Analyses ............................................................................57
10.4.
Statistical Analyses.....................................................................................57
10.4.1.
Pharmacokinetic Analyses...........................................................57
10.4.2.
Safety Analyses...........................................................................59
10.4.3.
Interim Analyses ..........................................................................60
10.4.4.
Stopping Criteria..........................................................................60
11. REFERENCES.......................................................................................................61
12. APPENDICES........................................................................................................62
12.1.
Appendix 1: Abbreviations and Trademarks................................................62
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................65
12.3.
Appendix 3: Study Governance Considerations..........................................67
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting to GSK...........................72


2017N315344_00
CONFIDENTIAL
205017
5
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................78
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................82
12.7.
Appendix 7: Safety Reporting to Ethics Committee and Regulatory 
Authorities...................................................................................................84


2017N315344_00
CONFIDENTIAL
205017
6
1.
SYNOPSIS
Protocol Title: A two part, non-randomised, open label study designed to assess the 
pharmacokinetics of GSK2982772 following administration of modified release 
formulations in capsule relative to an immediate release reference tablet formulation (Part 
A) and the pharmacokinetics of escalating, repeat doses of a selected modified release 
prototype (Part B) in healthy subjects.
Short Title: A study to compare the pharmacokinetics of GSK2982772 following 
administration of different modified release formulations in capsule relative to an 
immediate release tablet formulation and to investigate the pharmacokinetics of a 
selected modified release formulation in capsule following repeat doses for 3 days.
Rationale: The purpose of this study is to evaluate a modified release (MR) formulation 
of GSK2982772 using a minitab approach filled into a capsule in order to develop a more 
convenient once daily (QD) dosing formulation.  Each minitab will contain 5 mg 
GSK2982772 and the amount of polymer can be adjusted to achieve the desired in-vitro 
release profile. Initially, the pharmacokinetic (PK) profiles of slow (approximately 
24 hours) and fast (approximately 10 hours) release rates of MR minitab will be 
compared to the PK profile of the immediate release (IR) tablet.  In subsequent arms of 
the study, the release rate may be adapted to achieve the target PK profile.  The effect of 
a high fat meal on the absorption of GSK2982772 when co-administered with the 
selected minitab MR formulation will be evaluated to ensure that dose dumping does not 
occur.  In addition, the PK profile of repeat doses at 3 dose levels will be evaluated to 
ensure that the MR formulation can achieve a sufficient GSK2982772 systemic exposure 
range to support the Phase IIb dose ranging (DR) studies.


2017N315344_00
CONFIDENTIAL
205017
7
Objectives and Endpoints:
Objective
Endpoint
Primary

To evaluate the single dose PK profile of 
GSK2982772 from each test MR 
formulation in a capsule (120 mg) compared
to the IR formulation (120 mg)

GSK2982772 area under the curve from 
time zero to infinity (AUC(0-inf)), area under 
the curve from time zero to the last 
measurable concentration AUC(0-t), area 
under the curve from time zero to 24 hours 
AUC(0-24), area under the curve from time 
zero to 12 hours AUC(0-12), maximum 
observed concentration (Cmax), 
Concentration at 12 hours post-dose (C12h), 
Concentration at 24 hours post-dose (C24h) 
and ratio of Cmax : C1h2 and Cmax : C24h, 
relative bioavailability (Frelformulation) based 
on AUC and Cmax
Secondary

To assess the impact of high fat meal on 
the PK of GSK2982772 following single 
dose administration of the selected MR 
formulation in a capsule (120 mg) 

GSK2982772 AUC(0-inf), AUC(0-t), Cmax and 
time to Cmax (Tmax), FrelFE based on AUC 
and Cmax

To determine if there are any dose 
dependant changes in the absorption of 
GSK2982772 following repeat dose 
administration of the selected MR 
formulation in a capsule at target daily 
doses of 30, 60 and 240 mg

GSK2982772 AUC(0-24), Cmax and Tmaxif 
once daily (QD) dosing, on Day 1 and Day 3

GSK2982772 AUC(0-12), AUC(12-24),, Cmax
and Tmax after morning dose, Cmax and Tmax
after evening dose if twice daily (BID)
dosing, on Day 1 and Day 3

To assess the safety and tolerability of 
single doses of GSK2982772 IR formulation 
and single and repeat doses of the MR 
formulation in a capsule

Adverse events (AEs)

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature)

12-Lead electrocardiogram (ECG)
monitoring


2017N315344_00
CONFIDENTIAL
205017
8
Overall Design:
This is an open label, single centre, two part, single and repeat dose study in healthy male 
and female participants to assess MR minitab formulations of GSK2982772 in a capsule.  
Assuming a suitable MR minitab formulation in a capsule is identified, the impact of 
food (high-fat meal) on the rate and extent of absorption will be evaluated as well as an 
assessment of the relationship between dose and systemic exposure to GSK2982772
following repeat dosing for 3 days. 
Part A of the study is a non-randomised 6 period, sequential, 6-way fixed sequence
design in which up to 4 MR minitab formulations in a capsule may be evaluated 
following single dose administration in the fasted state (120 mg).  Periods 1, 2 and 3 will 
evaluate a slow MR release duration (nominally 24 hours), a fast MR release duration 
(nominally 10 hours), and IR tablet, respectively.  Periods 4, 5 and 6 will be flexible and 
the dosing regimen will be dependent on the outcome of Periods 1 to 3.  In Periods 4 to 6, 
there will be the option to optimise the MR release duration and/or to evaluate the impact 
of food (high-fat meal) on the selected MR minitab formulation in a capsule.  There will 
also be the option to cancel Periods 5 and 6 if an optimal formulation is determined in 
Periods 1 or 2.
Part B of the study will be an open-label, repeat dose study in which the selected MR 
minitab formulation in a capsule will be evaluated following 3 days repeat dosing of 
GSK2982772 at target daily doses of 30, 60 and 240 mg.  In Part B, administration of the 
MR minitab formulation in a capsule will either be in the fasted state or with a standard 
meal (non-high fat), depending on the results of the food effect assessment in Part A.  
The frequency of dosing in Part B will either be QD or BID depending on the PK profile 
in Part A.  Whether dosing is QD or BID, the total daily doses will remain the same.
Number of Participants:
Sixteen participants will be enrolled into Part A of the study to allow for the completion 
of at least 12 evaluable participants. An evaluable participant will have completed the 
planned safety and PK assessments up to 32 hours after dosing (or 24 hours after dosing 
for Period 3; IR regimen).  An evaluable participant must also have received the relevant 
test and reference formulations for the comparisons of interest e.g. an MR formulation 
and the IR reference and/or the selected MR formulation in both the fed and fasted states.
Ten participants will be enrolled into Part B of the study to allow for the completion of at 
least 6 evaluable participants. An evaluable participant will have received all 3 doses and 
completed the planned safety and PK assessments up to 24 hours after the last dose.  
Treatment Groups and Duration:
In Part A, each participant will be enrolled in the study for approximately 8 to 13 weeks, 
dependent on screening and washout duration between periods.  Participation will include 
a screening evaluation within 28 days of study treatment administration and up to 
6 separate inpatient periods.  Subjects will be admitted to the clinic in the morning of the 
day before dosing (i.e. Day -1) of each inpatient period.  Each inpatient period will 
consist of 3 days and 2 nights followed by a minimum washout of 7 days between doses.  


2017N315344_00
CONFIDENTIAL
205017
9
A follow-up visit will occur at least 7 days after the last study treatment.  Participants will 
receive a single oral dose of study treatment during each inpatient period.
In Part B, each participant will be enrolled in the study for approximately 9 weeks.  
Participation will include a screening evaluation within 28 days of study treatment 
administration and 3 separate periods. Subjects will be admitted to the clinic in the 
morning of the day before dosing (i.e. Day -1) of each inpatient period.  Each inpatient 
period will consist of a 5 day, 4-night inpatient period with a minimum of 7 days washout 
between the last morning dose of one period and the first dose of the next period.  A 
follow-up visit will occur at least 7 days after the last study treatment. 


2017N315344_00
CONFIDENTIAL
205017
10
2.
SCHEDULE OF ACTIVITIES (SOA)
The schedules of activities for Part A and Part B are presented in Table 1 and Table 3, 
respectively.  The time points for the PK blood sample collection in Part A and Part B are 
presented in Table 2 and Table 4, respectively.
The timing and number of planned study assessments, including safety or 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. 
Any changes in the timing or addition of time points for any planned study assessments 
must be documented and approved by the relevant study team member and then archived 
in the sponsor and site study files, but will not constitute a protocol amendment. The 
ethics committee (EC) will be informed of any safety issues that constitute a substantial 
amendment and require alteration of the safety monitoring scheme or amendment of the 
informed consent form (ICF). The changes will be approved by the EC before 
implementation.
There are times where the protocol requires more than one procedure to be completed at 
the same time point. In these instances the following will apply to post-dose time points:
PK samples should take priority over other procedures scheduled at the same time point. 
As guidance, the preferred order of assessments is:
ECGs
Vital 
Signs
PK blood sampling
(nominal time)
Other assessments eg 
physical exams, 
Electrocardiograms (ECGs) should be taken prior to vital signs when both measurements 
are scheduled at the same time point. Other assessments, e.g. physical examinations etc, 
will be performed within the required time windows. All safety assessments will be 
timed and performed relative to the start of dosing.


2017N315344_00
CONFIDENTIAL
205017
11
Table 1
Schedule of Activities for Part A
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3, 4, 5, 6
Day
Follow-up/Study 
Discontinuation
(7 days post last dose)
Notes
–1
1
2
Informed consent
X
Inclusion and exclusion criteria1
X
1.
Recheck clinical status 
before 1st dose of study 
medication.
Demography
X
Demonstrate ability to swallow size 0-00 
capsules
X
Full physical examination including height 
and weight
X
Brief physical examination
X
X2
X
2.
Discharge
(32 h post-dose for 
Treatment Period 1, 2, 4, 
5 and 6
24 h post-dose for 
Treatment Period 3)
Medical history (includes substance 
usage)3
X
3.
Substances: Drugs, 
Alcohol, tobacco and 
caffeine
Past and current medical conditions  
X
FSH (as needed in women of non-
childbearing potential only)
X
Serum pregnancy test (WOCBP only)
X
X


2017N315344_00
CONFIDENTIAL
205017
12
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3, 4, 5, 6
Day
Follow-up/Study 
Discontinuation
(7 days post last dose)
Notes
–1
1
2
Urine pregnancy test (WOCBP only)
X
Human Immunodefeciency Virus (HIV),, 
Hepatitis B and C screening4
X
4.
If test otherwise 
performed within 3 
months prior to first dose 
of study treatment, testing 
at screening is not 
required
Tuberculosis (TB) Test
X
Urine drug screen
X
X
Alcohol breath test
X
X
Carbon monoxide breath test
X
X
Laboratory assessments (haematology, 
clinical chemistry and urinalysis)
X
X
X5
X5
X
5.
Pre-dose (Treatment 
Period 1 only) and 24 h 
post-dose
Allowable windows in 
Section 9.4.4
Glomerular filtration rate
X
C-reative protein (CRP)
X
12-lead ECG
X6
X
X7
X8
X
6.
In triplicate
7.
Pre-dose and 2 and 12 h 
post-dose
8.
24 h post-dose
Allowable windows in 
Section 9.4.3


2017N315344_00
CONFIDENTIAL
205017
13
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3, 4, 5, 6
Day
Follow-up/Study 
Discontinuation
(7 days post last dose)
Notes
–1
1
2
Vital signs
X
X
X9
X10
X
9.
Pre-dose and 2 and 12 h 
post-dose
10. 24 h post-dose
Allowable windows in 
Section 9.4.2
Study treatment
X
AE review
============================
X
Serious AE (SAE) review
X
============================
X
Concomitant medication review
============================
X
PK blood sample collection
X11
X11
11. Time points in Table 2


2017N315344_00
CONFIDENTIAL
205017
14
Table 2
Pharmacokinetic Blood Sample Collection Times – Part A
Treatment Periods 1, 2, 4, 5 and 6 (MR Formulations)
Time (h)
Pre-
dose
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
Dosing
X
PK sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Period 3 (IR Formulation)
Time (h)
Pre-
dose
0
0.33
0.66
1
1.5
2
3
4
6
8
10
12
24
Dosing
X
PK sampling
X
X
X
X
X
X
X
X
X
X
X
X
X


2017N315344_00
CONFIDENTIAL
205017
15
Table 3
Schedule of Activities for Part B
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
Informed consent
X
Inclusion and exclusion criteria1
X
1.
Recheck clinical status before 
1st dose of study medication.
Demography
X
Demonstrate ability to swallow size 
0-00 capsules
X
Full physical examination including 
height and weight
X
Brief physical examination
X
X2
X
2.
Discharge (24 h after the last 
dose)
Medical history (includes substance 
usage)3
X
3.
Substances: Drugs, Alcohol, 
tobacco and caffeine
Past and current medical conditions  
X
FSH (as needed in women of non-
childbearing potential only)
X
Serum pregnancy test (WOCBP only)
X
X
Urine pregnancy test (WOCBP only)
X


2017N315344_00
CONFIDENTIAL
205017
16
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
HIV, Hepatitis B and C screening4
X
4.
If test otherwise performed 
within 3 months prior to first 
dose of study treatment, 
testing at screening is not 
required
Tuberculosis Test
X
Urine drug screen
X
X
Alcohol breath test
X
X
Carbon monoxide breath test
X
X
Laboratory assessments 
(haematology, clinical chemistry and 
urinalysis)
X
X
X5
X6
X
5.
Pre-dose 
6.
24 h after the last dose
Allowable windows in Section 
9.4.4
Glomerular filtration rate
X
CRP 
X
ANA
X
X7
7.
24 h after the last dose


2017N315344_00
CONFIDENTIAL
205017
17
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
12-lead ECG 
X8
X
X9
X10
X9
X11
X
8.
In triplicate
9.
Pre-dose and 2 and 12 h 
post-dose
10. Pre-dose
11. 24 h after the last dose
Allowable windows in Section 
9.4.3
Time points may be subject to 
change depending on results 
from Part A
Vital signs 
X
X
X12
X13
X12
X14
X
12. Pre-dose and 2 and 12 h 
post-dose
13. Pre-dose 
14. 24 h after the last dose
Allowable windows in Section 
9.4.2
Time points may be subject to 
change depending on results 
from Part A
Columbia Suicide Risk questionnaire
X
X15
X16
15. Pre-dose
16. 24 h after last dose of each 
period
Study treatment
X
X
X
AE review
============================
X
SAE review
X
============================
X
Concomitant medication review
============================
X


2017N315344_00
CONFIDENTIAL
205017
18
Procedure
Screening 
(up to 28 days before Day 1)
Treatment Period 1, 2, 3
Day
Follow-up/Study 
Discontinuation
(7 days post last 
dose)
Notes
–1
1
2
3
4
PK blood sample collection
X17
X17
X17
X17
17. Time points in Table 4
Table 4
Pharmacokinetic Blood Sample Collection Times – Part B
Periods 1, 2 and 3
Days 1 and 3
Time (h)
Pre-
dose
0
2
4
6
8
10
12
14
16
18
20
22
24
Dosinga
X
PK samplingb
X
X
X
X
X
X
X
X
X
X
X
X
Xc
a Subjects will be dosed on Days 1, 2 and 3; however, no PK samples will be taken post-dose on Day 2
b PK sampling schedule may be amended based upon the PK data from Part A and/or if BID dosing is selected for Part B. If BID dosing is 
employed the number of PK samples may be reduced i.e. some of the samples between 14 and 24 h may not be required.  In addition, the 
12 h sample will be taken prior to administering the second daily dose. 
c Day 1 24 h post-dose sample should be taken prior to dosing on Day 2.


2017N315344_00
CONFIDENTIAL
205017
19
3.
INTRODUCTION
GSK2982772 is a first-in-class, highly selective, receptor-interacting protein-1 (RIP1)
kinase inhibitor being developed for the treatment of inflammatory bowel disease, plaque 
psoriasis (PsO), rheumatoid arthritis (RA) and other disease conditions.
3.1.
Study Rationale
Pharmacokinetic data from the first time in human (FTIH) study for GSK2982772 
(200975) [GlaxoSmithKline Document Number 2014N204126_02] showed that the
half-life of GSK2982772 was short (~2 to 3 hours).  As a result, BID and three times 
daily (TID) dosing regimens are being evaluated in three ongoing proof of mechanism 
studies.  A QD formulation would be more convenient from a patient perspective and 
could offer the advantage of providing a flatter GSK2982772 concentration time profile.  
This current study is being conducted to evaluate the feasibility of developing an MR 
formulation using a minitab approach filled into a capsule.  Each minitab will contain 
5 mg GSK2982772 and the amount of polymer can be adjusted to achieve the desired 
in-vitro release profile. In addition, the number of minitabs included in the capsule can be 
varied to adjust the dose.
The Clinical Trial Authorisation application for this study describes a flexible protocol 
design using the concept of formulation design space to allow decision-making in 
response to interim PK observations. The principles of a flexible protocol were discussed 
and agreed with the Medicines and Healthcare products Regulatory Agency (MHRA) at a 
Scientific Advice Meeting between the MHRA and Quotient Clinical (formerly 
Pharmaceutical Profiles).
Based upon the concept of formulation design space, specific Investigational Medicinal 
Products (IMPs) are not detailed within the Investigational Medicinal Product Dossier but 
rather a defined range of formulation inputs and corresponding performance outputs are 
described and justified based on in vitro studies.
There will be the option to test a range of formulations based on a 2-dimensional design 
space describing the dose level and release rate of the IMP (Figure 1).


2017N315344_00
CONFIDENTIAL
205017
20
Figure 1
Two-Dimensional Design Space for the Modified Release 
Formulation
3.2.
Background
RIP1 is a member of the receptor-interacting Serine/Threonine kinase family containing 
an amino-terminal kinase domain, an intermediate domain and a carboxy-terminal death 
domain. RIP1 is a key signalling node which plays an essential role in inflammation and 
cell death in response to signals including tumour necrosis factor (TNF) family cytokines, 
ligands for toll like receptor (TLR)3/TLR4, sensors of viral infection, and interferons 
[Ofengeim, 2013]. Through tight regulation by ubiquitylation, deubiquitylation and 
interaction with its receptors, RIP1 has dual roles as a kinase and a scaffolding protein, 
and serves as an upstream checkpoint for both cell death and survival [Ofengeim, 2013]. 
Detailed understanding of RIP1 kinase function has not been fully elucidated, but it is 
known that RIP1 exerts it signalling functions through both its catalytic kinase activity 
and by acting as a scaffolding protein for signalling complexes. Recent work has 
demonstrated that RIP1 catalytic kinase activity can regulate TNF-mediated necroptosis 
[Ofengeim, 2013] and noncanonical apoptosis [Wang, 2008, Dondelinger, 2013]. In 
addition, the production of certain inflammatory cytokines can be regulated by RIP1 
kinase activity. In contrast, RIP1’s scaffolding function acts to facilitate other immune 
processes including TNF mediated classical apoptosis and Nuclear factor-kappaB-
signalling [Ofengeim, 2013, Humphries, 2015]. With this, an inhibitor of RIP1 kinase 
activity with GSK2982772 may fill a unique niche in the treatment of inflammatory 
conditions, such as ulcerative colitis, chronic PsO and RA, through multiple mechanisms, 
including inhibition of inflammation-induced cell death (necroptosis and apoptosis) and 
inhibition of the production of certain pro-inflammatory cytokines.
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK2982772 is provided in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2014N204126_02].


2017N315344_00
CONFIDENTIAL
205017
21
3.3.
Benefit/Risk Assessment
To date, approximately 124 participants have been enrolled in 4 clinical studies with 
GSK2982772. In Study 200975, GSK2982772 was administered up to 120 mg BID for 
14 days.  A total of 67 participants received GSK2982772 and 26 participants received 
placebo (including crossover) in that study.  In the ongoing Phase 2a studies in PsO Study 
(203167), RA (Study 203168) and Ulcerative Colitis (Study 202152), a total of 
approximately 26 participants have been randomised to GSK2982772 60 mg BID.
Overall, GSK2982772 has been generally well tolerated and no drug-related SAEs have 
been reported.  In Study 203167, there was a death of a 19-year-old male participant due 
to an accidental overdose with 3,4-methylenedioxy-methamphetamine (MDMA) that was 
not considered drug related by the Principal Investigator (PI). 
There is currently limited information available about the relationship of adverse events 
(AEs) to administration of GSK2982772 in human subjects. Therefore, all SAEs are 
considered unexpected. Any SAE deemed related to the IMP will be reported as a 
Suspected Unexpected Serious Adverse Reaction (SUSAR), in compliance with local 
health authority safety reporting requirements (see Appendix 7).
Limited reproductive toxicity studies have been conducted with GSK2982772 to date.
The compound must not be administered to pregnant women or nursing mothers. 
Women of childbearing potential must use highly effective methods of contraception 
(<1% failure rate; Appendix 5) for 30 days prior to exposure to GSK2982772 until 
30 days after the last dose.
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of GSK2982772 may be found in the Investigator’s Brochure.


2017N315344_00
CONFIDENTIAL
205017
22
3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2982772
Central Nervous System (CNS) effects
Non-clinical data: 
In the 4-week Good Laboratory Practice (GLP) toxicology 
study, CNS findings were observed in 4/12 monkeys which 
were administered 100 or 300 mg/kg/day.  CNS findings 
included uncoordination, irregular gait, trembling, hunched 
appearance, and decreased activity. The clinical relevance 
of these findings in humans is not known.  The no 
observed adverse effect level (NOAEL) for this study was 
determined at 10 mg/kg/day.
In the 13-week GLP toxicology study, there were no CNS 
findings observed in monkeys administered 10, 30 or 100 
mg/kg/day.  The NOAEL for this study was determined at 
30 mg/kg/day.  
Clinical data:
A FTIH study with single ascending and multiple ascending 
dose study has been performed in 67 healthy male 
volunteers to date.  See Investigator’s Brochure (IB) 
[GlaxoSmithKline Document Number 2014N204126_02].  
No drug-associated CNS AEs were identified and no SAEs 
were reported.
Subject Selection:

Subjects with known history of significant neurologic 
disorders including but not limited to progressive 
multiple sclerosis (MS), Amyotrophic lateral sclerosis 
(ALS), Alzheimer’s and dementia will be excluded.

Individuals with potentially increased susceptibility for 
neurologic effects will be excluded based on medical 
history at screening.
Subject Monitoring:

Subjects will be monitored for standard CNS-related 
AEs.
Immunosuppression
The possibility of immunosuppression, including an 
increase in the frequency and/or severity of infection, may 
result from the intended pharmacologic effect of 
GSK2982772.  This may be enhanced in subjects taking 
other immunomodulating drugs or corticosteroids.
Subject Selection:

Subjects with recurrent, chronic or active infections 
will be excluded from the study.

Subjects will be screened for TB, HIV, Hepatitis B and 


2017N315344_00
CONFIDENTIAL
205017
23
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical data:
In the FTiH study, no SAEs were reported.  One subject 
experienced an Adverse Effect (AE) herpes zoster 
approximately 27 days after receiving his last dose with 
GSK2982772 or placebo.  The blinded Investigator 
determined this to be potentially drug-related.
C, and excluded from the study if positive.
Subject Monitoring:

Subjects will be monitored for signs of infection.

See Individual Stopping Criteria for atypical or 
opportunistic infections (Section 8.1.3).
Vaccinations
There is a theoretical risk that GSK2982772 could 
decrease an individual’s immune response to vaccines or 
allow symptoms to develop following vaccination with a live 
vaccine when administered while on therapy.
Subject Selection:

Attenuated or live vaccines should not be 
administered to subjects from 30 days prior to the first 
dose of GSK2982772, during the study and for 5 half-
lives plus 30 days (total 32 days) after GSK2982772 
is discontinued.

If indicated, non-live vaccines (eg, inactivated 
influenza vaccines) may be administered while 
receiving GSK2982772 based on a treating physician 
assessment of the benefit:risk (eg, risk of theoretical 
decreased responsiveness). 

Investigators will be expected to have followed local 
and/or national guidelines with respect to 
vaccinations, including against influenza and 
pneumococcus.
Respiratory
Non-clinical data:
In the single dose Safety Cardiovascular (CV) and 
Respiratory Study in monkeys, a decrease in minute 
volume and respiratory rate was observed at all doses (10, 
100, and 300 mg/kg).  These findings were noted to be 
reversible and mild in severity
In a 14-day repeat dose Safety Respiratory Study in 
monkeys, no respiratory effects on total pulmonary 
ventilation (minute volume) or respiratory rate were 
observed at doses of 1 or 10 mg/kg/day. See Investigtor’s 
Brochure for GSK2982772 [GlaxoSmithKline Document 
Number 2014N204126_02].
Subject Monitoring:

Subjects should be monitored for standard 
respiratory-related AEs.

Vital signs will be monitored during study visits.


2017N315344_00
CONFIDENTIAL
205017
24
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical data:
In the FTIH study, repeat doses of GSK2982772 were 
administered x 14 days in 36 healthy male volunteers. 
Extensive respiratory monitoring with end-tidal CO2, 
oxygen saturation and nocturnal respiratory rate monitoring 
was performed.  No SAEs occurred, and no drug-
associated respiratory-related AEs were identified.
Suicidality
GSK2982772 is considered to be a CNS-active drug based 
upon pre-clinical studies.
Clinical data:
In the FTIH study, there have been some reports of 
lethargy, abnormal dreams, and depressed mood.  No 
events of suicidal ideation or behaviour or changes in 
behaviour were reported. 
Subject Selection:

Subjects with a current history of suicidal ideation and 
behaviour (SIB) as measured using the Columbia 
Suicide Severity Rating Scale (C-SSRS)  or a history 
of attempted suicide will be excluded from the study.
Subject Monitoring:

Subjects receiving multiple doses should be 
monitored appropriately and observed closely for 
suicidal ideation and behaviour or any other unusual 
changes in behaviour.

Baseline and treatment emergent assessment of 
suicidality will be conducted by trained site personnel 
using the C-SSRS in all subjects receiving multiple 
doses.  See Section 9.4.5.
Reproductive toxicity
Non-clinical data:
In an early rat embryofoetal development study, there was 
no maternal or developmental toxicity at doses 200 
mg/kg/day.
In a rabbit embryofoetal development study, GSK2982772 
was administered at doses of 0, 10, 100, 300 or 600 
mg/kg/day on gestation day 7 to 19.  No developmental 
toxicity was evident at doses up to 300 mg/kg/day.
Subject Selection:

Male and female subjects of childbearing potential will 
be included in this study only if they agree to use 
highly effective methods of contraception and avoid 
conception for 30 days before first administration of 
study drug until 30 days (females) and 90 days 
(males) after the last administration of study drug 
(Appendix 5). 

Females of childbearing potential will undergo serum 
pregnancy test at screening and follow-up and then 
urine pregnancy testing at regular intervals during the 
study. 


2017N315344_00
CONFIDENTIAL
205017
25
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Pregnant and lactating females are not eligible for 
inclusion in the study.
Withdrawal Criteria:

If a female subject should become pregnant during 
the study, study medication should be discontinued.  
The subject will be followed to determine the outcome 
of the pregnancy.  Any pregnancy complication or 
elective termination of a pregnancy will be reported as 
an AE or SAE.
Drug Interaction
Non-clinical data:
In vitro studies with GSK2982772 assessing potential drug-
drug interactions with Cytochrome P450 3A4 (CYP3A4) 
substrates, P-glycoprotein (Pgp) inhibitors and OAT3 
substrates were completed.  To date, formal drug 
interaction studies in humans have not been performed 
with GSK2982772. 
There is a low risk that GSK2982772 could be a 
perpetrator of OAT3 substrates.  
There is a low risk that GSK2982772 could be an inducer 
of CYP3A4 and therefore may lower circulating levels of 
concomitant medications that are metabolised by CYP3A4 
when co administered with GSK2982772.
GSK2982772 is a Pgp substrate and therefore co 
administration with concomitant medications that are Pgp 
inhibitors could increase circulating levels of GSK2982772.
See Section 4.3.6 of the GSK2982772 Investigators
Brochure [GlaxoSmithKline Document Number
2014N204126_02].
Subject Selection:

No concomitant medications will be permitted in this 
study 
with 
the 
exception 
of 
paracetamol/acetaminophen, hormonal contraception, 
hormone replacement therapy and other treatments 
required for AEs.
Subject Monitoring:

Caution is advised when dosing GSK292772 with 
CYP3A4 NTI substrates, OAT3 substrates or Pgp 
inhibitors.


2017N315344_00
CONFIDENTIAL
205017
26
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Cannulation 
During cannulation, more than one attempt may be needed 
to insert the cannula in a vein of a participant and it is 
possible that bruising and/or inflammation may be 
experienced at the site of cannulation.

A vein assessment will be conducted at screening to
ensure only volunteers with veins suitable for multiple 
venepuncture and cannulation are enrolled.  
Cannulation and venepuncture will only be performed 
by staff who are trained in these procedures.
Electrocardiograms
Electrocardiogram stickers on the participants' chests and 
limbs may cause some local irritation and may be 
uncomfortable to remove. 

Participants will be closely monitored to ensure any 
local irritation does not persist.


2017N315344_00
CONFIDENTIAL
205017
27
3.3.2.
Benefit Assessment
There is no intended direct health benefit to the participants in this study.  The benefit to 
participants include contributing to the process of developing new therapies in an area of 
unmet need and the medical evaluations/assessments associated with study procedures 
(eg, physical exam, ECG, Labs, etc).
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to healthy participants
participating in this study, the potential risks identified in association with GSK2982772
are justified by the anticipated benefits that may be afforded to patients with 
inflammatory conditions such as ulcerative colitis, PsO and RA.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the single dose PK profile of 
GSK2982772 from each test MR 
formulation in a capsule (120 mg) compared
to the IR formulation (120 mg)

GSK2982772 area under the curve from 
time zero to infinity (AUC(0-inf)), area under 
the curve from time zero to the last 
measurable concentration AUC(0-t), area 
under the curve from time zero to 24 hours 
AUC(0-24), area under the curve from time 
zero to 12 hours AUC(0-12), maximum 
observed concentration (Cmax), 
Concentration at 12 hours post-dose (C12h), 
Concentration at 24 hours post-dose (C24h) 
and ratio of Cmax : C1h2 and Cmax : C24h, 
relative bioavailability (Frelformulation) based 
on AUC and Cmax
Secondary

To assess the impact of high fat meal on 
the PK of GSK2982772 following single 
dose administration of the selected MR 
formulation in a capsule (120 mg)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax and 
time to Cmax (Tmax), FrelFE based on AUC 
and Cmax

To determine if there are any dose 
dependant changes in the absorption of 
GSK2982772 following repeat dose 
administration of the selected MR 
formulation in a capsule at target daily 
doses of 30, 60 and 240 mg

GSK2982772 AUC(0-24), Cmax and Tmax if 
once daily (QD) dosing, on Day 1 and Day 3

GSK2982772 AUC(0-12), AUC(12-24),, Cmax
and Tmax after morning dose, Cmax and Tmax
after evening dose if twice daily (BID) 
dosing, on Day 1 and Day 3

To assess the safety and tolerability of 

Adverse events (AEs)


2017N315344_00
CONFIDENTIAL
205017
28
Objectives
Endpoints
single doses of GSK2982772 IR formulation 
and single and repeat doses of the MR 
formulation in a capsule

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature)

12-Lead electrocardiogram (ECG) 
monitoring
5.
STUDY DESIGN
5.1.
Overall Design
This is an open label, single centre, two part, single and repeat dose study in healthy male 
and female participants to assess MR minitab formulations of GSK2982772 in a capsule.  
Assuming a suitable MR minitab formulation in a capsule is identified, the impact of 
food (high-fat meal) on the rate and extent of absorption will be evaluated as well as an 
assessment of the relationship between dose and systemic exposure to GSK2982772
following repeat dosing for 3 days. 
Part A of the study is a non-randomised 6 period, sequential, 6-way fixed sequence 
design in which up to 4 MR minitab formulations in a capsule may be evaluated 
following single dose administration in the fasted state (120 mg) (Figure 2).  Periods 1, 2 
and 3 will evaluate a slow MR release duration (nominally 24 hours), a fast MR release 
duration (nominally 10 hours), and IR tablet, respectively.  Periods 4, 5 and 6 will be 
flexible and the dosing regimen will be dependent on the outcome of Periods 1 to 3.  In 
Periods 4 to 6, there will be the option to optimise the MR release duration and/or to 
evaluate the impact of food (high-fat meal) on the selected MR minitab formulation in a 
capsule.  There will also be the option to cancel Periods 5 and 6 if an optimal formulation 
is determined in Periods 1 to 2.
Subjects will be admitted to the clinic in the morning of the day before dosing (i.e. 
Day -1) of each inpatient period.  Each inpatient period will consist of 3 days and 2 nights 
followed by a minimum washout of 7 days between doses.  A follow-up visit will occur 
at least 7 days after the last study treatment.  Participants will receive a single oral dose of 
study treatment during each inpatient period.


2017N315344_00
CONFIDENTIAL
205017
29
Figure 2
Part A Study Design – Formulation Optimisation and Food Effect
Part B of the study will be an open-label, repeat dose study in which the selected MR 
minitab formulation in a capsule will be evaluated following 3 days repeat dosing of 
GSK2982772 at target daily doses of 30, 60 and 240 mg (Figure 3).  The target dose may 
be subject to change based upon evaluation of the emerging data from Part A, e.g. if the 
bioavailability of 120 mg MR formulation in a capsule is less than the 120 mg IR tablet 
(reference) formulation.  In Part B, administration of the MR minitab formulation in a 
capsule will either be in the fasted state or with a standard meal (non-high fat), depending 
on the results of the food effect assessment in Part A.  The frequency of dosing in Part B
will either be QD or BID depending on the PK profile in Part A.  Whether dosing is QD 
or BID, the total daily doses will remain the same.  If BID dosing is selected the final 
dose will be the evening dose of Day 3. Subjects will be admitted to the clinic in the 
morning of the day before dosing (i.e. Day -1) of each inpatient period.  Each inpatient 
period will consist of 5 days and 4 nights.  There will be a minimum of 7 days washout 
between the last morning dose of one period and the first dose of the next period.  A 
follow-up visit will occur at least 7 days after the last study treatment.  
Figure 3
Part B Study Design – Dose Ranging
5.1.1.
Criteria for Interim Decisions
In Part A there will be an interim review following completion of Periods 1 to 3 to 
determine the formulation and the prandial state for Period 4. Similarly, there will be an 
interim review following Periods 4 and 5.  Following the final period of Part A, the 
formulation, doses, dosing frequency (QD or BID) and prandial state for Part B will be 
determined. However, the highest dosing regimen will be selected to ensure that the 
maximum daily dose will not exceed the equivalent of an IR dose of 240 mg, taking into 
account the bioavailability of MR relative to IR (i.e. if the bioavailability of MR is 50% 
that of IR, the maximum daily dose of MR to be administered would be 480 mg).  Interim 


2017N315344_00
CONFIDENTIAL
205017
30
decisions will only be made after a complete review of all relevant data collected from 
the previous dose group. Data must be available from a minimum of 12 participants who 
have completed the planned safety and PK assessments up to 32 hours after dosing (or 
24 hours after dosing for Period 3; IR regimen [Regimen C]). An evaluable participant 
must also have received the relevant test and reference formulations for the comparisons 
of interest e.g. an MR formulation and the IR reference and/or the selected MR 
formulation in both the fed and fasted states. If full data, as described below, are not 
available for 12 participants, the principal investigator (PI), scientific lead and sponsor 
will take a decision as to whether the data available are sufficient to support the 
formulation selection decision. If data in fewer than 16 participants are used in the 
decision process, additional participants will not be dosed to increase the number of 
participants in the completed regimen.
The following data will be provided to the sponsor by Quotient Clinical:

AEs, vital signs, ECGs, safety laboratory data and physical examinations.

Plasma concentrations of GSK2982772.

PK parameter estimates GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), AUC(0-12), Tmax,
Cmax, C12h, C24h and ratio of Cmax : C12h and Cmax : C24h, Frel based on AUC and Cmax
for test vs reference formulations and fed vs fasted, where relevant.  

Protocol deviations will be reviewed to ensure they have had no significant impact on 
the above data
The decision on formulation and prandial state selection or stopping the study will be 
made by the Quotient study team (i.e., PI, scientific lead and pharmacokineticist) and 
sponsor study team (as a minimum the sponsor’s medical monitor, Clinical 
Pharmacokinetics Modelling and Simulation [CPMS] and Global Clinical Safety and 
Pharmacovigilance [GCSP]). The decision will be documented and signed by the PI as 
per Quotient Clinical current standard operating procedure (SOP). Evidence of the 
decision will be retained in the Investigator Site File (ISF) and GSK Trial Master File.
5.2.
Number of Participants
In Part A, 16 healthy participants will be enrolled such that at least 12 evaluable 
participants complete the study.  An evaluable participant will have completed the 
planned safety and PK assessments up to 32 hours after dosing (or 24 hours after dosing 
for Period 3; IR regimen [Regimen C]).  An evaluable participant must also have 
received the relevant test and reference formulations for the comparisons of interest e.g. 
an MR formulation and the IR reference and/or the selected MR formulation in both the 
fed and fasted states. 
In Part B, 10 healthy participants will be enrolled such that at least 6 evaluable 
participants complete the study. An evaluable participant will have received all 3 days of 
dosing at 2 or more dose levels and completed the planned PK assessments up to 24 
hours after the first dose on day 3.


2017N315344_00
CONFIDENTIAL
205017
31
Participants withdrawn due to an IMP-related AE or termination of the study will not be 
replaced.  If participants prematurely discontinue the study for other reasons, additional
replacement participants may be recruited at the discretion of the Sponsor in consultation 
with the investigator.
Up to 8 replacement participants may be enrolled in Part A.  The maximum number of 
participants that may be dosed in Part A is 24. 
Up to 5 replacement participants may be enrolled in Part B.  The maximum number of 
participants that may be dosed in Part B is 15.
Replacement subjects enrolled will be dosed with the next planned treatment of the 
withdrawn subject, and they will not receive any treatment that the withdrawn subject has 
already received with the exception of the need to increase subject numbers to obtain the 
minimum number of evaluable subjects required for interim decisions, and to obtain data 
in any other treatment that is required for a valid comparison. Replacement subjects will 
receive the required treatments in the same order as planned for the original subject and 
the minimum washout period will be respected with regard to the timing of dosing of the 
IR formulation.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure shown in the SoA i.e. the 
follow-up visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
Pharmacokinetic data from the FTIH study for GSK2982772 [GlaxoSmithKline 
Document Number 2014N204126_02] showed that the half-life of GSK2982772 was 
shorter than predicted (~2 to 3 hours).  As a result, BID and TID dosing regimens are 
being evaluated in three ongoing Phase 2a studies in psoriasis, ulcerative colitis and RA.  
A QD formulation would be more convenient from a patient perspective and could offer 
the advantage of providing a flatter GSK2982772 concentration time profile.  Therefore,
switching to a QD formulation for the Phase 2b DR studies and subsequent Phase 3
studies would be advantageous.  
This current study is being conducted to evaluate the feasibility of developing an MR
formulation using a minitab approach filled into a capsule.  Each minitab will contain 
5 mg GSK2982772 and the amount of polymer can be adjusted to achieve the desired 
in-vitro release profile. The total weight of the minitab will be 20 mg and between 3 and
12 minitabs can be loaded into a capsule for oral administration.  Initially the PK profiles 
of slow (approximately 24 hours) and fast (approximately 10 hours) release rates of MR 
minitab will be compared to the PK profile of the IR tablet.  In subsequent arms of the 
study, the release rate may be adapted to achieve the target PK profile.  The effect of a 
high fat meal on the absorption of GSK2982772 when co-administered with the selected 


2017N315344_00
CONFIDENTIAL
205017
32
minitab MR formulation in a capsule will be evaluated to ensure that dose dumping does 
not occur.  In addition, a range of repeat doses will be evaluated to ensure that the MR 
formulation in a capsule can achieve a sufficient GSK2982772 systemic exposure range 
to support the Phase IIb DR studies.
As this is a Phase 1 study, the most relevant population is healthy participants which
allows characterisation of safety, tolerability and PK in a homogenous population without 
potential biases from a patient population. The European Medicines Agency (EMA)
recommends including participants aged 18 years and older with normal weight, who are 
non-smokers, without a history of alcohol or drug abuse. The latter criteria are proposed 
to avoid interaction on drug metabolism and to avoid non-compliance. Therefore, this 
study will enrol healthy male and female participants aged between 18 to 65 years of age.
5.5.
Dose Justification
In Part A, a single dose of 120 mg will be used for the MR minitab formulations in a 
capsule and for the IR tablet.  In Part B, it is planned to evaluate target daily doses of 30, 
60 and 240 mg for 3 days.  The selection of these dose levels are based on the doses 
being used in the ongoing Phase 2a studies (IR 60 mg BID) and the safety and PK data 
from the GSK2982772 FTIH study, where doses up to IR 120 mg BID for 14 days were 
administered.
In Part A, a single dose of 120 mg MR has been selected since this dose is anticipated to 
provide systemic exposure similar to the 60 mg BID regimen being used in the ongoing 
Phase 2a studies (assuming a relative bioavailability of 100%).  In the GSK2982772 
FTIH study, 120 mg of the IR formulation was well tolerated when administered as 
single and repeated doses (BID for 14 days).  A single 120 mg dose of the MR 
formulation in a capsule is expected to result in lower Cmax than for the 120 mg IR tablet, 
and overall systemic exposure (AUC) is expected to be similar or lower than a single 
120 mg IR tablet dose.
The administration of 120 mg MR with food is expected to maintain AUC and Cmax
values within the range of values observed following 120 mg dose in the FTIH study. In 
the worst case scenario of dose dumping with food, 120 mg MR would have a PK profile 
similar to a single dose of 120 mg IR.
In Part B, the target daily MR doses of 30, 60, 240 mg reflect the approximate dose range 
that is planned to be taken forward into the Phase 2b DR studies.  The actual dose level 
may be increased (by adding additional minitabs to the capsule or by giving multiple 
capsules) if the relative bioavailability of the selected MR at 120 mg is less than 100% 
compared to a 120 mg dose of the IR tablet.  Taking into account the bioavailability of 
MR relative to IR, it is planned that the highest dose of MR to be administered will be not
exceed a total daily dose equivalent to 240 mg IR (e.g. if the bioavailability of MR is 
50% that of IR, the maximum daily dose of MR to be administered would be 480 mg).


2017N315344_00
CONFIDENTIAL
205017
33
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Quotient Clinical must have a full medical history from each participant’s general 
practitioner within the last 12 months, prior to enrolment in the study. Participants will be 
recruited from the Quotient Clinical panel or by direct advertising to the public.
Before participants are admitted to the clinic, The Over Volunteering Prevention System 
will be checked to ensure that each participant has not participated in a study at another 
site within at least 3 months of the dosing date.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
Weight
3.
Body weight ≥50 kg and body mass index within the range 19.0 to 32.0 kg/m2
(inclusive).
Sex
4.
Male or female
a.
Male participants:
A male participant must agree to use a highly effective contraception as detailed in 
Appendix 5 of this protocol during the treatment period and for at least 90 days after 
the last dose of study treatment and refrain from donating sperm during this period.
b.
Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR


2017N315344_00
CONFIDENTIAL
205017
34
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 30 days before and 30 days after 
the last dose of study treatment.
Informed Consent
5.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal (GI), 
endocrine, haematological, or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs; constituting a risk when taking 
the study treatment; or interfering with the interpretation of data.
2.
Part A only: Any history of suicidal behaviour within the past 6 months or any 
history of attempted suicide in a participant’s lifetime. 
3.
Part B only: Participants with current history of Suicidal Ideation Behaviour as 
measured using the C-SSRS or a history of attempted suicide.
4.
History of clinically significant psychiatric disorders as judged by the investigator.  
Depression requiring treatment in the last 2 years.
5.
History of herpes zoster (shingles) reactivation.
6.
History or diagnosis of obstructive sleep apnoea.
7.
History of a significant respiratory disorder. Childhood asthma that has fully 
resolved is permitted.
8.
History or current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions.
9.
A positive diagnostic tuberculosis (TB) test at screening defined as a positive 
QuantiFERON-TB Gold test or T-spot test.  In cases where the QuantiFERON or 
T-spot test is indeterminate, the participant may have the test repeated once, but they 
will not be eligible for the study unless the second test is negative.
10. History of GI surgery (with exception of appendectomy).
11. History of cholecystectomy or gall stones.
12. Presence or history of clinically significant allergy requiring treatment, as judged by 
the investigator. Hayfever is allowed unless it is active.
13. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
14. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35% of total).


2017N315344_00
CONFIDENTIAL
205017
35
15. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome).
16. Corrected QT interval (QTc) >450 msec.
Notes: 
The QTc is the QT interval corrected for heart rate according to either Bazett’s 
formula (QTcB), QT interval corrected for heart rate according to Fridericia’s
formula (QTcF), or another method, machine or manual over read.
The specific formula that will be used to determine eligibility and discontinuation 
for an individual participant should be determined prior to initiation of the study.  
In other words, several different formulae cannot be used to calculate the QTc for 
an individual participant and the lowest QTc value used to include or discontinue 
the participant from the trial.
For purposes of data analysis, QTcB, QTcF, another QTc correction formula or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan.
Prior/Concomitant Therapy
17. Past or intended use of over-the-counter or prescription medication including herbal 
medications within 7 days prior to dosing (paracetamol/acetaminophen [up to 2 g per 
day], hormone replacement therapy and hormonal contraception are permitted).
18. Live or attenuated vaccine(s) within 30 days of enrolment, or plans to receive such 
vaccines during the study or plans to receive a vaccine within 30 days + 5 half-lives 
of the last dose of study medication.
Prior/Concurrent Clinical Study Experience
19. Participation in the study would result in loss of blood or blood products in excess of
500 mL within a 56 day period; therefore donation or loss of greater than 400 mL of 
blood within the previous 3 months.
20. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
21. Current enrolment or past participation within the last 3 months before signing of 
consent in this or any other clinical study involving an investigational study 
treatment or any other type of medical research.
22. Participants who have previously been enrolled in this study. Participants in Part A
of this study are not permitted to participate in Part B.
Diagnostic assessments
23. Current or history of renal disease or estimated glomerular filtration rate (GFR) by 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
calculation <60 mL/min/1.73m2 at screening.
24. Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C 
antibody test result at screening or within 3 months prior to first dose.  As potential 


2017N315344_00
CONFIDENTIAL
205017
36
for and magnitude of immunosuppression with this compound is unknown, 
participants with presence of hepatitis B core antibody (HBcAb) should be excluded.
Participants positive for HBsAg and/or positive for anti-HBc antibody (regardless of 
anti-HBs antibody status) are excluded.
25. An elevated C-reactive protein (CRP) outside the normal reference range.
26. Part B only: A positive anti-nuclear antibody (ANA) outside the normal reference 
range.
27. Confirmed positive pre-study drug/alcohol screen.
28. Positive human immunodeficiency virus (HIV) antibody test.
29. Regular use of known drugs of abuse, or history of drug or alcohol abuse in the past 
5 years.
Other Exclusions
30. Regular alcohol consumption within 6 months prior to the study 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.
31. Current use or history of regular use of tobacco- or nicotine-containing products 
within 6 months prior to screening.  A carbon monoxide breath test reading of 
greater than 10 parts per million (ppm)..
32. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study.
33. Unwilling or unable to swallow multiple size 0-00 capsules as part of study 
participation.
34. Participants who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator at screening.
35. Total cholesterol 300 mg/dL (7.77 millimole [mmol]/Liter [L]) or triglycerides 
250 mg/dL (2.82 mmol/L).
36. Participants who are study site employees, or immediate family members of a study 
site or sponsor employee.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from Seville 
oranges and grapefruit derivatives for 24 hours before admission to each study 
period until after collection of the final PK sample in that period.

Refrain from consumption of poppy seeds for 48 hours before screening, and from 
48 hours before admission to each study period until after collection of the final PK
sample in that period.


2017N315344_00
CONFIDENTIAL
205017
37

For fasted dosing, no water is allowed from 1 hour before dosing until 1 hour after 
dosing with the exception of the 240 mL water provided with each dose. Water is 
allowed ad libitum at all other times.

For fasted dosing, participants will be provided with a light snack on the evening 
before dosing and will be required to fast from all food and drink (except water) for a 
minimum of 10 hours before dosing until approximately 4 hours after dosing. Lunch 
will be provided approximately 4 hours after dosing, an evening meal will be 
provided approximately 10 hours after dosing and an evening snack will be provided 
approximately 14 hours after dosing.
If BID dosing in the fasted state is selected for Part B, participants will be dosed in 
the evening approximately 12 hours after the morning dose. Meals will be provide as 
described above (i.e., no food will be permitted 2 hours before and 2 hours after 
dosing).

For dosing after a high fat breakfast (Part A) or a standard breakfast (Part B), 
participants will be provided with a light snack and will fast from all food and drink 
(except water) until the following morning, when they will be provided with the 
appropriate breakfast. The breakfast should be consumed over a maximum period of 
25 min, with dosing occurring 30 min after the start of breakfast. Participants should 
be encouraged to eat their meal evenly over the 25 min period. It is acknowledged 
that some participants will take less time to eat, but dosing should still occur 30 min 
after the start of breakfast.  Lunch will be provided approximately 4 hours after 
dosing, an evening meal will be provided approximately 10 hours after dosing and an 
evening snack will be provided approximately 14 hours after dosing.
If BID dosing administered with food is selected for Part B, participants will be 
dosed in the evening following a standard evening meal. Meals will be provided as 
described above (with evening dosing approximately 30 minutes after the start of the 
evening meal).

If drug administration in Part B is in the fasted stated, then on Day 2 when PK 
samples are not being collected, meals will be provided at appropriate times, i.e., a 
standard breakfast at approximately 2 hours post-morning dose, lunch at 
approximately 4 hours post-morning dose, dinner at approximately 10 hours 
post-morning dose and an evening snack at approximately 14 hours post-morning 
dose.

If drug administration in Part B is in the fed state, then on Day 2 when PK samples 
are not being collected, meals will be provided at appropriate times, i.e., a standard 
breakfast 30 mins prior to the morning dose, lunch at approximately 4 hours
post-morning dose, dinner at approximately 10 hours post-morning dose and an 
evening snack at approximately 14 hours post-morning dose.

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for
24 hours before admission until after collection of the final PK sample in that period.

Participants will abstain from alcohol for 24 hours before screening. During each 
dosing session, participants will abstain from alcohol from 24 hours before 
admission until after collection of the final PK sample in that period.


2017N315344_00
CONFIDENTIAL
205017
38

Current smokers or users of other tobacco products will not be enrolled in this study.
6.3.2.
Activity

Participants will abstain from strenuous exercise for 72 hours before screening and 
then from 72 hours before admission until discharge from the study. Participants 
may participate in light recreational activities during studies (eg, watching television, 
reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened at the discretion of the investigator if the reasons for the screening 
failure are expected to be temporary. Rescreened participants will be assigned a new 
screening number and will be re-consented.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


2017N315344_00
CONFIDENTIAL
205017
39
7.1.
Treatments Administered
7.1.1.
Treatments Administered - Part A
Regimen
A
B
C
D
E (Optional)
F (Optional)
Study Treatment 
Name:
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
Dosage formulation:
Prototype MR 
Minitablet in 
Capsule
Formulation A
Prototype MR
Minitablet in 
Capsule
Formulation B
IR Tablet
Reference
Prototype MR
Minitablet in Capsule
Formulation A, B or C
Prototype MR
Minitablet in Capsule
Formulation A, B, C or 
D
Prototype MR
Minitablet in 
Capsule
Formulation A, 
B, C or D
Unit dose strength(s)/
Dosage level(s):
60 mg / 
120 mg
60 mg / 
120 mg
30 mg /
120 mg
60 mg / 
120 mg
60 mg / 
120 mg
60 mg / 
120 mg
Route of 
Administration 
Oral with 240 mL water
Dosing instructions:
2 capsules, on 
the morning of 
Day 1 following 
an overnight 
fast
2 capsules, on 
the morning of 
Day 1 following 
an overnight fast
4 tablets in the 
morning of 
Day 1 
following an 
overnight fast
2 capsules, on the 
morning of Day 1 
following an overnight 
fast (if Formulation C) 
or following a high fat 
breakfast (if 
Formulation A or B)
2 capsules, on the 
morning of Day 1 
following an overnight 
fast (if Formulation D) 
or following a high fat
breakfast (if 
Formulation A, B or C)
2 capsules, on 
the morning of 
Day 1 following 
a high fat 
breakfast


2017N315344_00
CONFIDENTIAL
205017
40
Regimen
A
B
C
D
E (Optional)
F (Optional)
Packaging and 
Labelling
Study Treatment will be provided in 60 mL Duma bottle. Each Duma bottle will be labelled as required per country 
requirement. 
Manufacturer
Quotient
Quotient
Quotient
Quotient
Quotient
Quotient


2017N315344_00
CONFIDENTIAL
205017
41
7.1.2.
Treatments Administered - Part B
Regimen
G
H
I
Study Treatment 
Name:
GSK2982772
GSK2982772
GSK2982772
Dosage formulation:
Prototype MR Minitablet in Capsule
Formulation X
Prototype MR Minitablet in Capsule
Formulation X
Prototype MR Minitablet in Capsule
Formulation X
Unit dose strength(s)/
Daily Dosage level(s)a:
15 or 30 mg / 
30 mg
30 or 60 mg / 
60 mg
60 mg / 
240 mg
Route of 
Administration 
Oral with 240 mL water
Dosing instructions:
1 x 30 mg capsule in the morning of 
Days 1 to 3
or
1 x 15 mg capsule in the morning and 
evening of Days 1 to 3; dosing will be 
12 hours apart
Fasted or Fed (non-high fat meal)
1 x 60 mg capsule in the morning of 
Days 1 to 3
or
1 x 30 mg capsule in the morning and 
evening of Days 1 to 3; dosing will be 
12 hours apart
Fasted or Fed (non-high fat meal)
4 x 60 mg capsule in the morning of Days 
1 to 3
or
2 x 60 mg capsule in the morning and 
evening of Days 1 to 3; dosing will be 12 
hours apart
Fasted or Fed (non-high fat meal)
Packaging and 
Labelling
Study Treatment will be provided in 60 mL Duma bottle. Each Duma bottle will be labelled as required per country 
requirement. 
Manufacturer
Quotient
Formulation X is the formulation selected from Part A
a Daily dosage levels are the anticipated dose levels for Part B; but may be subject to change depending on the results from Part A.


2017N315344_00
CONFIDENTIAL
205017
42
7.2.
Dose Modification
This protocol allows some alteration from the currently outlined dosing schedule (see 
Section 5.1 and Section 5.5). The dosing regimens in Part B will be selected based on PK 
and safety data from a minimum of 12 participants in Part A, and the maximum daily 
dose will not exceed a total daily dose equivalent to 240 mg IR taking into account the 
bioavailability of MR relative to IR (i.e. if the bioavailability of MR is 50% that of IR, 
the maximum daily dose of MR to be administered would be 480 mg).
The decision to proceed to the next dose level of GSK2982772 (either an increase or a 
decrease) will be made by the sponsor and investigator based on safety, tolerability, and 
PK data obtained in at least 12 participants at the prior dose level, as described in 
Section 5.1.1.
7.3.
Method of Treatment Assignment
This is an open-label, non-randomised study. A treatment allocation list will take the 
place of the randomisation schedule, which will be developed by the sponsor.
At screening, a unique Subject Number will be assigned to any subject who has at least 
one screening procedure performed, other than informed consent. The unique Subject 
Number will be used to identify individual subjects during the course of the study, and 
will start with 
A treatment allocation list will be produced by GSK Clinical Statistics prior to the start of 
the study, using the validated internal software, which will dictate the treatments that 
should be administered to each participant in each period. The master treatment 
allocation list will be sent to the site and retained in the ISF.
Participant numbers will be allocated on the morning of dosing of Period 1 according to 
the code 
to 
for Part A and 
to 
for Part B, using the lowest number 
available. Replacement subjects will be assigned Subject Numbers 
 to 
 for Part A 
and 
 to 
 for Part B.
7.4.
Blinding
This is an open-label study.
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants 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 labeled storage conditions with access 
limited to the investigator and authorized site staff.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2017N315344_00
CONFIDENTIAL
205017
43
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the technical agreement. 

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.
7.6.
Treatment Compliance

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment and study 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.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded in the source workbook and 
electronic Case Report Form (eCRF) along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or nonprescription 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) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. 
Paracetamol/Acetaminophen, at doses of 2 grams/day, is permitted for use any time 
during the study. Use of hormonal contraception and hormone replacement therapy is 
permitted provided use is stable during the study.  Other concomitant medication may be 
considered on a case-by-case basis by the investigator in consultation with the Medical 
Monitor if required to treat AEs.


2017N315344_00
CONFIDENTIAL
205017
44
7.8.
Treatment after the End of the Study
There is no treatment after the end of the study. 
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
See the SoA for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. Discontinuation of study 
treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm below or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes that study treatment discontinuation is in the 
best interest of the participant.
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
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*


2017N315344_00
CONFIDENTIAL
205017
45
8.1.2.
QTc Stopping Criteria
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the participant has been enrolled.
For example, if a participant is eligible for the protocol based on QTcB, then QTcB must 
be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception. 

The QTc should be based on averaged QTc values of triplicate ECGs obtained 
over a brief (e.g., 5-10 minute) recording period.  
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  

QTc >500 msec

Change from baseline (pre-dose Day 1) of QTc >60 msec
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.3.
Individual Safety Stopping Criteria

If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The participant becomes pregnant.

The participant initiates treatment with any prohibited medications.

The participant develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria or QTc stopping criteria are met.

The participant experiences any signs of suicidal ideation or behaviour.
8.1.4.
Temporary Discontinuation
If a participant is not dosed when planned in a particular period (eg in case of unexpected 
personal circumstances or AEs that occur between treatment periods), they may be dosed 
at a later date (if a subject cannot re-attend within 28 days, they should be considered 
withdrawn), provided the following criteria are met: 

The AE has resolved or stabilised.

The AE preventing dosing was not considered related to the IMP.

The participant has not met any individual stopping criteria.

It is considered safe to continue to dose in the opinion of the investigator.


2017N315344_00
CONFIDENTIAL
205017
46
8.1.5.
Rechallenge
8.1.5.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons.  If a participant withdraws 
from the study, he/she may request destruction of any samples taken, and the 
Investigator must document this in the site study records.  The reason for 
withdrawal should be documented in the Case Report Form (CRF).

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

The Sponsor’s request, for reasons such as significant protocol deviations or 
participant safety concern (and after discussion with the Investigator).

If a participant is withdrawn from study treatment, this participant is also 
considered to be withdrawn from the study following completion of follow-up 
assessments.

Study is terminated by the Sponsor.

Refer to the SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s source workbook.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 


2017N315344_00
CONFIDENTIAL
205017
47
8.4.
Study Stopping Criteria
The study will be halted, and the risk to other participants evaluated, prior to a decision as 
to whether to terminate the study if any of the following criteria are met: 

The occurrence of an SAE, considered at least possibly related to the IMP 
administration in one participant. 

The occurrence of severe non-serious AEs considered as, at least, possibly 
related to the IMP administration in 2 participants at the same dose level
Relatedness will be determined by the investigator. If the study is halted, a temporary halt 
will be submitted to the MHRA and EC in the form of a substantial amendment. The 
study will not be resumed until a further substantial amendment to resume the study is 
submitted and approved by MHRA and EC.
8.5.
Study Termination
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the sponsor and investigator without consultation with the MHRA 
and EC. The end of the trial must be notified to the MHRA and EC immediately and at 
the latest within 15 days after the study is halted, clearly explaining the reasons. A 
description of follow up measures taken for safety reasons if applicable, should also be 
provided.
If the study is abandoned prior to commencement of any protocol activities, the PI or 
sponsor must notify the EC and MHRA by letter outlining the reasons for abandonment 
of the trial.
Once exposure to GSK2982772 has begun, the study will be completed as planned unless 
the following criteria are satisfied that require temporary suspension or early termination 
of the study.

The occurrence of serious or severe AE(s), as defined in Appendix 4, if 
considered to be related to the IMP.

New information regarding the safety of the IMP that indicates a change in the 
risk/benefit profile for the compound, such that the risk/benefit is no longer 
acceptable for participants in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the 
ability to achieve the primary study objectives or compromises participant
safety.
If any of the above occurs, the study may be terminated if careful review of the overall 
risk/benefit analysis described in Section 3.3 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable. In these circumstances 
termination can only take place with the agreement of the investigator and sponsor. The 
MHRA and EC will be informed of study termination.


2017N315344_00
CONFIDENTIAL
205017
48
If it becomes necessary to consider termination of the study after dosing has begun, 
dosing may be suspended pending discussion between the investigator and sponsor. 
Dosing will be stopped immediately on safety grounds.
The study may be terminated or suspended at the request of the MHRA or EC.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management or by 
generic screening (e.g., blood count) and obtained before signing of ICF may be 
utilized for screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
550 mL in a 56-day period.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

A participant will be allowed to leave the premises following completion of 
study-specific procedures at 32 hours post-dose (Part A, Treatment Periods 1, 2, 4, 5, 
6) or 24 hours post-dose (Part A, Treatment Period 3) or 24 hours after the last dose 
(Part B Treatment Periods 1, 2 and 3; if BID dosing selected this will be after the last 
evening dose) providing that:
−
No AEs have been reported during the study visit
−
The participant responds positively when asked “How are you feeling?”
If any of these conditions are not met, then the participant may only be allowed to 
leave the clinical unit with the authorisation of the investigator or appropriately 
qualified delegate.
9.1.
Efficacy Assessments
Not applicable.


2017N315344_00
CONFIDENTIAL
205017
49
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit
at the time points specified in the SoA (Section 2).

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 
24 hours, as indicated in Appendix 4. 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 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.


2017N315344_00
CONFIDENTIAL
205017
50
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and sponsor policy and forwarded to investigators as 
necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.

Further details can be found in Appendix 7.
9.2.5.
Pregnancy

Details of all pregnancies in female participants and, female partners of male 
participants will be collected after the start of study treatment and until 30 days after 
the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of GSK2982772 greater than that intended in this study will be 
considered an overdose.
There is no specific antidote for overdose with GSK2982772.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 48 hours following the last 
dose of GSK2982772).
3.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).


2017N315344_00
CONFIDENTIAL
205017
51
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, GI and neurological systems. Height and 
weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, heart rate and 
respiratory rate.

The acceptable deviations from the nominal vital signs measurement time points 
are:
−
The pre-dose vital signs measurements will be taken ≤2 hours before 
dosing.
−
Post-dose vital signs measurements will be taken ± 15 minutes from the 
nominal post-dose time points.
−
Discharge vital signs measurements will be taken ± 1 hour from the 
nominal time point.

If a participant shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution if 
required. Additional measurements may be taken as deemed necessary by the 
investigator.

Any clinically significant abnormality, including changes from baseline
(pre-dose Day 1), must be reported as an AE.
9.4.3.
Electrocardiograms

Triplicate 12-lead ECGs will be obtained at screening and single 12-lead ECGs 
will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc
intervals. If a single ECG shows a QTc increase of ≥ 60 msec from baseline


2017N315344_00
CONFIDENTIAL
205017
52
(pre-dose Day 1), two further ECGs should be performed over a brief period 
(e.g. 5 to 10 minutes) and the assessment made on the mean QTc of the triplicate 
ECGs.  Refer to Section 8.1.2 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.

The QTc should be based on averaged QTc values of triplicate ECGs obtained 
over a brief (e.g. 5 to 10 minutes) recording period.

The acceptable deviations from the nominal ECG measurement time points are:
−
The pre-dose ECG measurements will be taken ≤2 hours before dosing
−
Post-dose ECG measurements will be taken ± 15 minutes from the 
nominal post-dose time point.
−
Discharge ECG measurements will be taken ± 1 hour from the nominal 
time point.

ECGs are to be measured after participant has been in a semi-supine or supine 
position after approximately 5 minutes rest.

If a participant shows an abnormal assessment at any stage, repeat 
measurements may be made and the abnormality followed to resolution if 
required. Additional measurements may be taken as deemed necessary by the 
investigator.

Any clinically significant abnormality, including changes from baseline
(pre-dose Day 1), will be reported as an AE.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

Blood samples for scheduled laboratory assessments will be taken following an 
overnight fast.

The acceptable deviations from the nominal blood sampling time points for 
laboratory assessments are:
−
The pre-dose blood sample will be taken ≤2 hours before dosing
−
Post-dose blood samples will be taken ± 1 hour from the nominal blood 
sampling time except when the time point coincides with the PK blood 
sampling time. In this situation, the time window for the PK sample applies.

The acceptable deviations from the nominal urine sampling time points for 
urinalysis are:
−
The pre-dose urine sample will be taken ≤3 hours before dosing or the first 
void of the day
−
Post-dose urine samples will be taken ± 2 hour from the nominal urine 
sampling time.

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 


2017N315344_00
CONFIDENTIAL
205017
53
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

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 (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.4.5.
Suicidal Risk Monitoring
GSK2982772 is considered to be a CNS-active drug.  There has been some concern that 
some CNS-active drugs may be associated with an increased risk of suicidal thinking or 
behaviour when given to some patients with disease.  Although this drug has not been 
shown to be associated with an increased risk of suicidal thinking or behaviour when 
given to healthy volunteers, GSK considers it important to monitor for such events before 
or during clinical studies with compounds such as this.   
Participants being treated with GSK2982772 should be monitored appropriately for 
suicidal ideation and behaviour or any other unusual changes in behaviour. Study 
medication must be immediately discontinued in all participants who experience signs of 
suicidal ideation or behaviour.
Families and caregivers of patients being treated with GSK2982772 should be alerted 
about the need to monitor participants for the emergence of unusual changes in 
behaviour, as well as the emergence of suicidal ideation and behaviour and to report such 
symptoms immediately to the study Investigator.
At Screening and baseline (pre-dose Day 1), the ‘Baseline/Screening C-SSRS’ will be 
completed in Part B only.  Assessments done at Day 4, the ‘Since Last Visit C-SSRS’ 
will be completed in Part B only.  GSK Version 4.1 of both rating scales will be used.
Participant s who answer ‘yes’ to any suicidal behaviour or ‘yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their General Practitioner or appropriate psychiatric 
care and be discontinued from study medication.  The Medical Monitor will be notified.  
If appropriate, an AE or SAE should be reported (see Section 9.2).  In addition, the 
Investigator should complete a Possible Suicidality Related Adverse Event (PSRAE) 
form to collect detailed information on the circumstances of the reported AEs which, in 


2017N315344_00
CONFIDENTIAL
205017
54
the Investigator’s opinion, are possibly suicidality-related.  These may include, but are 
not limited to, an event involving suicidal ideation, a preparatory act toward imminent 
suicidal behaviour, a suicide attempt, or a completed suicide.
9.5.
Pharmacokinetics

Blood samples of approximately 2 mL will be collected for measurement of 
plasma concentrations of GSK2982772 as specified in the SoA (see Section 2).
Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded.

Processing, storage and shipping procedures are provided in the Study Reference 
Manual (SRM) or equivalent.

The acceptable deviations from the nominal post-dose blood sampling times are 
as follows:
−
The pre-dose blood sample will be taken ≤1 hour before dosing. 
−
Post-dose samples will be taken within ± 10 minutes of the nominal post-
dose sampling time 

Samples will be used to evaluate the PK of GSK2982772. Samples collected for 
analyses of GSK2982772 plasma concentration may also be used to evaluate 
safety aspects related to concerns arising during or after the study.

Genetic analyses will not be performed on these plasma samples. Participant 
confidentiality will be maintained. 
Plasma analysis will be performed under the control of Platform Technology & Science 
(PTS), In Vitro/In Vivo Translation (IVIVT) and Third Party Resourcing (TPR), GSK.  
Concentrations of GSK2982772 will be determined in plasma using the current approved 
bioanalytical methodology.  Raw data will be archived at the Bioanalytical site as 
detailed in the SRM or equivalent.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.


2017N315344_00
CONFIDENTIAL
205017
55
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
No formal hypothesis will be tested. However, point estimates and corresponding 90% 
confidence intervals will be derived for Cmax, AUC(0- inf), C12 and C24 and peak to trough 
concentration ratio for each test minitab MR formulation in a capsule (120 mg) relative to 
the IR formulation (120 mg).
10.2.
Sample Size Determination
10.2.1.
Sample Size Determination - Part A
To date, there are no MR formulation variability data available. The maximum between-
subject coefficient of variation (CVb) for the PK parameters observed in Study 200975 
following GSK2982772 capsule formulation were used for precision estimates; CVb (%) 
for AUC(0-inf) and Cmax for 120 mg GSK2982772 IR capsule formulation were 29.0 and 
31.5 respectively.  Therefore, the estimates of within subject coefficient of variation 
(CVw [%]) are 20.3% and 18.8% for AUC(0-inf) and Cmax, respectively. Based on these 
estimates of variability and a sample size of 12 completers, it is estimated that the lower 
and upper bounds of the 90% confidence interval (CI) for the geometric mean ratio 
(MR/IR) of AUC and Cmax will be within approximately 15.3% and 14.2% of the point 
estimate respectively. 
Since it is expected that the MR formulation is to reduce the Cmax by 50% whilst 
maintaining the AUC, a sample size of 12 ensures that the 90% CI is within the region 
0.8-1.25 for AUC and 0.4-0.625 for Cmax, if the observed geometric ratio is 0.93-1.08 for
AUC and 0.47-0.54 for Cmax. 
Sample Size Sensitivity – Part A
Using estimates of parameter (this can be any PK parameter AUC, Cmax) variability
observed in Study 200975, the precision of these estimates calculated as half width of a 
90% confidence interval for the mean ratio (MR/IR) and expressed as distance from 
mean to limits for 10, 12, 14 and 16 participants has been calculated (Table 5).


2017N315344_00
CONFIDENTIAL
205017
56
Table 5
Precision Estimate of Mean – Part A
CVw (%)
Precision of Mean (%)
N=10
N=12
N=14
N=16
15
12.70
11.30
10.30
9.50
18.8
16.00
14.20
12.90
11.90
20
17.30
15.30
13.90
12.90
For example, based upon the estimate of variability (CVw%) of 20 and a sample size of 
14, it is estimated that the lower and upper bounds of the 90% confidence interval for the 
means of the PK parameter (eg, AUC, Cmax) will be within approximately 13.9% of the 
point estimate.
10.2.2.
Sample Size Determination - Part B
No repeat dose MR formulation variability data are currently available. Therefore, the 
maximum CVb for the PK parameters were observed in the study 200972 following 
repeat dose of GSK2982772 capsule formulation; CVb (%) for AUC(0-τ) and Cmax for 
20mg QD GSK2982772 IR capsule formulation on Day 1 is 36.1 and 27.1 respectively. 
Therefore, the estimates of equivalent CVw (%) are 23.2 and 17.6 for Cmax and AUC(0-τ)
respectively. Based on these estimates of variability and a sample size of 8 completers, it 
is estimated that the lower and upper bounds of the 90% confidence interval for the 
means of AUC(0-τ) and Cmax will be within approximately 12.1% and 16.7% of the point 
estimate respectively.
Sample Size Sensitivity – Part B
Using estimates of parameter (this can be any PK parameter AUC, Cmax) variability, the 
precision of these estimates calculated as half width of a 90% confidence interval for the 
mean and expressed as distance from mean to limits for  4, 6, 8 and 10 participants has 
been calculated (Table 6).


2017N315344_00
CONFIDENTIAL
205017
57
Table 6
Precision Estimate of Mean – Part B
CVb (%)
Precision of Mean (%)
N=4
N=6
N=8
N=10
18.4%
23.6
16.0
12.8
11.0
19.3%
25.1
16.9
13.6
11.6
24.4%
32.6
21.8
17.4
14.9
25.5%
34.2
22.8
18.2
15.6
For example, based upon the estimate of variability (CVb%) of 19.3 and a sample size of 
4, it is estimated that the lower and upper bounds of the 90% confidence interval for the 
means of the PK parameter (eg, AUC, Cmax) will be within approximately 25.1% of the 
point estimate.
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Subjects
All participants who receive at least 1 dose of study treatment and 
will be the population for reporting of safety and study population 
data. Participants will be analyzed according to the treatment they 
actually received.
PK
Participants in the ‘All Subjects Population’ for whom a PK sample 
was obtained and analysed and will be the population for reporting 
of PK data.
10.4.
Statistical Analyses
10.4.1.
Pharmacokinetic Analyses
All PK analyses will be performed on the PK Population. 
For both parts of the study, plasma GSK2982772 concentration-time data will be 
analysed by non-compartmental methods.  
In Part A, from the plasma concentration-time data for each of the regimens, the 
following PK parameters will be determined, as data permit: 

maximum observed plasma concentration (Cmax).


2017N315344_00
CONFIDENTIAL
205017
58

time to Cmax (Tmax).

the elapsed time from dosing at which GSK2982772 was first quantifiable in a 
concentration vs time profile (Tlag).

observed concentration at 12 hours and 24 hours post-dose (C12h and C24h).

area under the plasma concentration vs time curve (AUC(0-t), AUC(0-24), AUC(0-
12) and AUC(0-inf)).  

the percentage of AUC extrapolated beyond the last measured time point
(AUC%extrap).

terminal half-life (t1/2).

Cmax to C12h and Cmax to C24h ratios.

relative bioavailability (Frelformulation) of test formulations vs reference formulation 
based on AUC(0-24) and AUC(0-inf) (or AUC(0-t) if AUC(0-inf) can’t be derived) and 
Cmax.

relative bioavailability (FrelFE) of fed vs fasted based on AUC and Cmax.
In Part B, from the plasma concentration-time data for each of the regimens, the 
following PK parameters will be determined, for Day 1 and Day 3, as data permit: 

maximum observed plasma concentration (Cmax) for QD dosing.  If BID dosing, Cmax
after morning dose and evening dose.

time to Cmax (Tmax) for QD dosing.  If BID dosing, Tmax after morning dose and 
evening dose.

observed concentration at 12 hours and 24 hours post-dose (C12h and C24h).

area under the plasma concentration-time curve (AUC(0-24)) for QD dosing.  If BID 
dosing, AUC(0-12) and AUC(12-24).

Cmax to C12 and Cmax to C24 ratios.

Dose normalised Cmax, C12h, C24h, AUC(0-tau) (for BID dosing), AUC(0-24) and 
AUC(0-inf).
Descriptive statistics (n, arithmetic mean, standard deviation [SD], 95% CI, minimum, 
median and maximum,) will be calculated by treatment for all PK concentrations over 
time and for the derived PK parameters. In addition, for loge-transformed PK parameter 
variables geometric mean, 95% CI and %CVb (100 * √ (exp(SD2) -1)) will be provided, 
where the SD is the standard deviation of log-transformed data.


2017N315344_00
CONFIDENTIAL
205017
59
Endpoint
Statistical Analysis Methods
Primary
The primary PK endpoints to compare MR formulations with IR formulations will 
be summarised descriptively. Ratio of AUC(0-inf) , AUC(0-24), (AUC(0-t), if AUC(0-inf)
cannot be derived), Cmax, C12 and C24 for MR formulation to IR formulation will be 
computed with 90% CI. Cmax to C12h and Cmax to C24h ratio for each minitab MR 
formulation (120 mg) and the IR formulation (120 mg) will be computed with 90% 
CI.  
Secondary
The secondary endpoints for food effect will be summarised descriptively. In 
addition, log-transformed AUC(0-inf)(AUC(0-t), if AUC(0-inf) cannot be derived), C12h, 
C24h, and Cmax will be analysed using a mixed effects model with regimen as a 
fixed effect and subject within sequence as a random effect.  Point estimates and
corresponding 90% CI will be computed for the differences in GSK2982772 MR 
formulation (120 mg) taken in the fed state (test) vs in the fasted state (reference) 
using the residual error from the model (MSE). The point and interval estimates 
on the log-scale will then be exponentially back transformed to give estimates of 
the ratios of geometric means and 90% CI.
Within-subject coefficients of variation for AUC(0-inf)and Cmax will be calculated 
based on the loge-Normal distribution: CVw (%) = sqrt[exp(mse) - 1] x 100, where 
MSE is the residual error from the model.
Statistical analysis of the PK endpoint Tmax of GSK2982772 of GSK2982772 
(120 mg) administered under both fed and fasted conditions will be separately 
analysed non-parametrically [Hauschke, 1990]. The point estimates for the 
medians for each treatment, the median difference and 90% CI for the median 
difference will be calculated for the contrast (test-reference).
Secondary
The secondary PK endpoints for the selected MR formulation at target daily 
doses of 30, 60 and 240 mg will be summarised descriptively. 
Plots of dose vs dose normalised AUC(0-24), AUC(0-12) (AUC(12-24) BID dosing), C12h, 
C24h and Cmax (after morning and evening doses if BID dosing) will be generated 
to determine if there are any dose dependent changes in the absorption of 
GSK2982772 following repeat dose administration of the selected minitab MR 
formulation.
The Reporting and Analysis Plan will describe the planned PK analyses in greater detail.
10.4.2.
Safety Analyses
All safety analyses will be performed on the All Subjects Population. 
Endpoint
Statistical Analysis Methods
Secondary
The safety endpoints will be summarised descriptively. 


2017N315344_00
CONFIDENTIAL
205017
60
The Reporting and Analysis Plan will describe the planned safety analyses in greater 
detail.
10.4.3.
Interim Analyses
No formal statistical analyses are planned. However, after Periods 1 to 3 are complete, 
the PK data will be analysed which will guide Periods 4, 5 and 6. Periods 4, 5 and 6 will 
be flexible and the dosing regimen will be dependent on the outcome of preceding 
periods.  There will be the option to either optimise the MR release duration and/or to 
evaluate the impact of food on the selected MR minitab formulation in a capsule.  There 
will also be the option to cancel Periods 5 and 6 if an optimal formulation is determined 
in Periods 1 or 2.
There will be an interim review following final period of Part A to determine the 
formulation, doses, dosing frequency (QD or BID) and prandial state for Part B.  The data 
will be sent to the sponsor by Quotient, from which the decision on formulation and 
prandial state selection or stopping the study will be made by the Quotient study team 
(i.e., PI, scientific lead and pharmacokineticist) and sponsor study team (as a minimum 
the sponsor’s medical monitor, CPMS and GCSP).  The decision will be documented and 
signed by the PI as per Quotient Clinical current SOP.  Evidence of the decision will be 
retained in the ISF and GSK Trial Master File.
There will be no interim analysis during Part B of the study. 
See Section 5.1.1 for full details on the criteria for interim decisions.
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
10.4.4.
Stopping Criteria
After data is available and analysed for Period 1, 2 and 3, a decision to stop the study 
could be triggered if:

The PK profile of IR and MR are similar , based on visual judgement of 
concentration-time curves or if the PK profiles indicate that a QD or BID dosing 
regimen isn’t feasible.  Consideration of PK parameters, AUC(0-inf) and Cmax will 
assist with this judgement but no formal quantitative no-go will be defined due to 
the exploratory and flexible nature of the study.

Administration of MR with a high-fat meal shows dose dumping 


2017N315344_00
CONFIDENTIAL
205017
61
11.
REFERENCES
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E et al. 
RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions 
of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death & Differ, 2013;20:1381-92.
GlaxoSmithKline Document Number 2014N204126_02.  GSK2982772 Investigator 
Brochure.  Effective Date 27-JAN-2017 
Hauschke D1, Steinijans VW, Diletti E. A distribution-free procedure for the statistical 
analysis of bioequivalence studies. Int J Clin Pharmacol Ther Toxicol, 1990;28(2):72-8.
Humphries F, Yang S, Wang B, Moynagh P N. RIP kinases: key decision makers in cell 
death and innate immunity. Cell Death & Differ, 2015;22:225-236.
Ofengeim D and Yuan J. Regulation of RIP1 kinase signaling at the crossroads of 
inflammation and cell death. Nature Reviews Molecular Cell Biology, 2013;14:727-36.
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. 
Cell, 2008; 133(4):693-703.


2017N315344_00
CONFIDENTIAL
205017
62
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
List of Abbreviations
Abbreviation
Definition
AE
Adverse event
ALT
Alanine transaminase
ANA
Anti-nuclear antibody
AUC
Area under the concentration vs time curve
AUC(0-12),
Area under the curve from time zero to 12 hours
AUC(0-24)
Area under the curve from time zero to 24 hours
AUC(0-t)
Area under the curve from time zero to the last measurable concentration
BID
Twice daily
BUN
Blood Urea Nitrogen
C12
Concentration at 12 h post-dose
C24
Concentration at 24 h post-dose
CI 
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacokinetics Modelling and Simulation
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
CRP
C-reactive protein
C-SSRS
Columbia Suicide Severity Rating Scale
CV
Cardiovascular
CVb
Between subject coefficient of variation
CVw
Within subject coefficient of variation
DR
Dose ranging
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
FTIH
First time in human
Frel
Relative bioavailability
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GFR
Glomerular filtration rate
GI
Gastrointestinal
GLP
Good Laboratory Practice
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen


2017N315344_00
CONFIDENTIAL
205017
63
hCG
Human Chorioninc Gonadotropin
HIV
Human immunodeficiency virus
HIPPA
Health Insurance Portability and Accountability Act
HRT
Hormonal Replacement Therapy
ICF
Informed consent form
IEC
Independent Ethics Committees
IMP
Investigational medicinal product
INR
International normalized ratio
IR
Immediate release
IRB
Institutional Review Board
ISF
Investigator site file
IVIVT
In Vitro/In Vivo Translation
L
Litre
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
mg
milligrams
MHRA
Medicines and Healthcare products Regulatory Agency
mins
Minutes
mL
Millilitres
mmol
Millimole
MR
Modified release
MSDS
Material Safety Data Sheet
msec
Milliseconds
NOAEL
No observed adverse effect level
Pgp
P-glycoprotein
PI
Principal investigator
PIS
Participant Information Sheet
PK
Pharmacokinetic(s)
ppm
Parts per million
PsO
Plaque psoriasis
PSRAE
Possible Suicidality Related Adverse Event
PTS
Platform Technology & Science
QD
Once daily
QTc
Corrected QT interval
QTcB
QT interval corrected for heart rate according to Bazett’s formula
QTcF
QT interval corrected for heart rate according to Fridericia’s formula
RA
Rheumatoid arthritis
RBC
Red blood cells
RIP1
Receptor-interacting protein-1
SAE
Serious adverse event
SD
Standard deviation
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SoA
Schedule of activities
SRM
Study Reference Manual
SOP
Standard operating procedure


2017N315344_00
CONFIDENTIAL
205017
64
SUSAR
Suspected unexpected serious adverse reaction
TB
Tuberculosis
TID
Three times daily
TLR
Toll like receptor
Tmax
Time to Cmax
TNF
Tumour necrosis factor
TPR
Third Party Resourcing
ULN
Upper limit of normal
WBC
White blood cells
WOCBP
Woman of childbearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Chiron RIBA
SAS
WinNonlin


2017N315344_00
CONFIDENTIAL
205017
65
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 7 will be performed by The Doctors Laboratory, with 
the exception of routine urinalysis, urine pregnancy test, urine drug screen, 
alcohol and carbon monoxide breath tests. These tests will be performed on-site. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

All laboratory tests with values that are considered clinically significantly 
abnormal during participation in the study should be repeated until the values 
return to normal or baseline.  If such values do not return to normal within a 
period judged reasonable by the Investigator, the etiology should be identified 
and the sponsor notified.
Table 7
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
MCV
MCH
MCHC
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Haemoglobin
Haematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin (direct 
only if total is 
elevated)
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Albumin
Chloride
Cholesterol 
(Total)
Triglycerides
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 


2017N315344_00
CONFIDENTIAL
205017
66
Laboratory 
Assessments
Parameters
leukocytes by dipstick

Microscopic examination (if blood, protein or leukocytes are abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) at screening only

urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)

alcohol breath test

carbon monoxide breath test

Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)

Serum hCG pregnancy test (as needed for women of childbearing potential)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis
C virus antibody) at screening only

Tuberculosis test (QuantiFERON) at screening only

C-reactive protein (CRP) at screening only

Anti-nuclear antibody (ANA) in Part B only
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 6 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE.


2017N315344_00
CONFIDENTIAL
205017
67
12.3.
Appendix 3: Study Governance Considerations
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 GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Prior to the initiation of the study, the Clinical Trial Authorisation application 
must be approved by the MHRA. A copy of this approval and any 
correspondence with the MHRA will be available at the clinical and sponsor 
sites. A copy of the MHRA approval will be provided to the EC.

Any substantial amendments to the protocol will require MHRA and IEC/IRB 
approval before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study participants
(urgent safety measure). 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Protocol Amendments and Deviations
Amendments
After the protocol has been submitted to the MHRA and/or EC, any amendment must be 
agreed by the investigator after discussion with the sponsor and will be formally 
documented.
All substantial amendments will be submitted to the MHRA and/or EC for an opinion as 
required by current regulations. 


2017N315344_00
CONFIDENTIAL
205017
68
If the participant information sheet (PIS) and ICF are updated as a result of an 
amendment, the new versions will be used to re-consent currently enrolled participants
and must be provided to additional participants prior to their entry into the study.
Protocol Deviations
The study must be conducted in accordance with the Clinical Protocol. Should a protocol 
deviation occur, it must be promptly assessed in order to decide whether any of these 
non-compliances should be reported to the MHRA as a serious breach of GCP and the 
Clinical Protocol.
Protocol waivers are not acceptable.
Deviations from the protocol will be recorded in the source workbook as noted by the 
clinical staff. If necessary, the sponsor will be informed of the deviation.
Any protocol deviations assessed as major will be discussed with the sponsor in order to 
determine if the withdrawal criteria stated in Section 8 have been met.
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.
Informed Consent Process

Participants will be provided with a written explanation of the study at least one 
day before the screening visit.

The investigator or his/her representative will explain the nature of the study, its 
purpose, expected duration and the benefits and risks involved in study 
participation to the participant and answer all questions regarding the study. 
Participants will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that 
carry out clinical studies in the local area.

Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study centre. 

The source workbook 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.


2017N315344_00
CONFIDENTIAL
205017
69

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. 

Participants who are rescreened are required to sign a new ICF.
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 IRB/IEC members, and by inspectors from 
regulatory authorities.
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 multicentre studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

Following completion of the study, a clinical study report will be prepared. 

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
policy and will be made available to the EC/MHRA within 1 year of the 
declaration of the end of trial.
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 (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 


2017N315344_00
CONFIDENTIAL
205017
70

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/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 from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
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. 
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

A study-specific source documentation list will be finalised by the sponsor 
before the start of the clinical phase of the study. The document will identify 
what data should be considered source data for this study.


2017N315344_00
CONFIDENTIAL
205017
71
Declaration of the End of the Study
The definition of the end of the study is defined as the last visit of the last participant
(eg follow-up assessment). Any changes to this definition will be notified as a substantial 
amendment.
The EC and MHRA should be notified in writing of the conclusion of the study within 
90 days of the end of the study, or within 15 days if the study is terminated early, clearly 
explaining the reasons for the termination.
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 
IRB/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


2017N315344_00
CONFIDENTIAL
205017
72
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting to GSK
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 (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, 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 (eg, 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 


2017N315344_00
CONFIDENTIAL
205017
73
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 (eg, 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 fulfils 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, diarrhoea, influenza, 
and accidental trauma (eg, 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 


2017N315344_00
CONFIDENTIAL
205017
74
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.
Definition of an Adverse Drug Reaction (ADR)
An ADR is defined as any untoward medical occurrence that, at any dose:

where a causal relationship with the IMP is at least a reasonable possibility (possibly 
related or related)
Definition of SUSAR
A SUSAR is defined as any untoward medical occurrence that, at any dose:

Is believed to be related to an IMP and is both unexpected (ie the nature or severity is 
not expected from the information provided in the Investigator’s Brochure) and 
serious. SUSARs are subject to expedited reporting to the MHRA, European 
Medicines Agency (EMA), EC (see Appendix 7)
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF (ie the 
date and time of onset, a description of the AE, severity, duration, actions taken, 
outcome and an investigator’s current opinion on the relationship between the study 
treatment and the event).

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.


2017N315344_00
CONFIDENTIAL
205017
75
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; intervention may be needed.

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 
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.


2017N315344_00
CONFIDENTIAL
205017
76
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 via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (eg, check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the Communication Plan.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 


2017N315344_00
CONFIDENTIAL
205017
77
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 in the Communication Plan.


2017N315344_00
CONFIDENTIAL
205017
78
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
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 WOCBP
1.
Premenarchal
2.
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.
3.
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 (ie 
≥40 IU/L) 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 enrolment.
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 during the protocol-defined 
time frame in Section 6.1: 

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 Table 8 when having 
penile-vaginal intercourse with a woman of childbearing potential 


2017N315344_00
CONFIDENTIAL
205017
79

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 3 months after study 
completion or from last dose.

As there is a significant risk of drug exposure through the ejaculate (which also 
applies to vasectomised males) that might be harmful to the sexual partners 
(both male and female), including pregnant partners of male participants, a 
condom should be used by all male participants during the protocol-defined time 
frame in Section 6.1.
Female participants
Female participants who are not of childbearing potential do not need to use any methods 
of contraception.
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 8. 
Table 8
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 
ovulationb

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 WOCBP and the absence of sperm has been confirmed. If 


2017N315344_00
CONFIDENTIAL
205017
80
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

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test 

Additional pregnancy testing will be performed at admission to each study period
and at the follow-up visit

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Urine pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using 
the SureScreen Diagnostics test in accordance with instructions provided in its 
package insert at each admission. Serum pregnancy testing, with a sensitivity of
5.8 mIU/mL will be performed and assayed in the certified local laboratory (The 
Doctors Laboratory)  
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 foetal
status (presence or absence of anomalies) or indication for procedure. 


2017N315344_00
CONFIDENTIAL
205017
81
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of foetal status (presence 
or absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will be withdrawn 
from the study 


2017N315344_00
CONFIDENTIAL
205017
82
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
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 subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
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 2 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 paracetamol/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:


2017N315344_00
CONFIDENTIAL
205017
83
Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. NOTE: not required in 
China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants
3.
Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM
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.


2017N315344_00
CONFIDENTIAL
205017
84
12.7.
Appendix 7: Safety Reporting to Ethics Committee and 
Regulatory Authorities
Events Requiring Expedited Reporting
SUSARs are subject to expedited reporting to the MHRA, EMA and EC.
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of an IMP or that would be 
sufficient to consider changes in the IMPs administration or in the overall conduct of the 
study, for instance:

an increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important

SAEs that occur after the participant has completed the clinical study where the 
sponsor considers them to be a SUSAR

new events related to the conduct of the study or the development of the IMPs and 
likely to affect the safety of the participants, such as:
−
an SAE which could be associated with the study procedures and which could 
modify the conduct of the study
−
a major safety finding from a newly completed animal study (such as 
carcinogenicity)
−
any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same IMPs in another country by the same sponsor
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible.
Expedited Reporting of Events
It is the responsibility of the sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible.
Where expedited reporting is required, the following procedures should be followed.
Fatal or life-threatening SUSARs
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA and EMA as soon as possible, but no later than 7 calendar days after they first 
became aware of the reaction. This responsibility may be delegated to the 
pharmacovigilance provider.
The investigator is required to notify the EC of any SUSAR as soon as possible, but no 
later than 7 calendar days after they first became aware of the reaction.
Any additional relevant information should be sent within 8 days of the report.


2017N315344_00
CONFIDENTIAL
205017
85
Other SUSARs
It is the responsibility of the sponsor to report other SUSARs to the MHRA and EMA as 
soon as possible, but no later than 15 calendar days after they first became aware of the 
reaction. This responsibility may be delegated to the pharmacovigilance provider.
The investigator is required to notify the EC of other SUSARs as soon as possible, but no 
later than 15 calendar days after they first became aware of the reaction.
Any additional relevant information should be sent within 8 days of the report.
Urgent Safety Measures
If Quotient Clinical or any of its staff or contractors becomes aware of an actual or 
potential urgent safety issue, then the sponsor must be immediately contacted so that 
appropriate urgent safety measures can be agreed. An urgent safety issue is defined as: 

An immediate hazard to the health or safety of participants enrolled in a clinical study

A serious risk to human health or potentially a serious risk to human health
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe conduct 
of the study or that pose a risk to study participants.
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, Quotient Clinical may take urgent safety measures before informing 
the sponsor, but the sponsor must be informed immediately after the hazard has resolved. 
Quotient Clinical will take responsibility for informing appropriate competent authorities, 
and the EC.
Reporting of Urgent Safety Issues
Quotient Clinical is required to inform the appropriate competent authorities and the EC
within 3 calendar days of the urgent safety issue.
Serious Breaches
It is the responsibility of the sponsor to notify the licensing authority of any serious 
breach, which is likely to affect, to a significant degree, the safety or mental integrity of 
the participants of the study or the scientific value of the study. 
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach.

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205017
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A three part, non-
randomised, open label study designed to assess the 
pharmacokinetics of GSK2982772 following administration 
of minitab modified release formulations in capsule relative 
to an immediate release reference tablet formulation (Part A), 
the pharmacokinetics of escalating, repeat doses of a selected 
minitab modified release prototype (Part B) in healthy 
subjects, and the pharmacokinetics of GSK2982772 
following administration of modified release tablet 
formulations in the fed and fasted state (Part C) in healthy 
participants.
Compound Number 
:
GSK2982772
Effective Date 
:
24-JAN-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205017.

This RAP is intended to describe the PK, safety and tolerability analyses required 
for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
24-JAN-2019
Email
Principal Statistician (II Clinical Statistics)
Principal Statistician (II Clinical Statistics)
23-JAN-2019
Email
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205017
2
RAP Team Approvals:
Approver
Date
Approval Method
23-JAN-2019
Email
Clinical Development Manager (GCSD)
23-JAN-2019
Email
Clinical Development Director, Discovery 
Medicine
 
23-JAN-2019
Email
Director (CPMS)
Project Physician Lead, iiTA
23-JAN-2019
Email
Senior Medical Director, GCSP SERM
23-JAN-2019
Email
23-JAN-2019
Email
Principal Data Manager (GCDO)
23-JAN-2019
Email
Principal Programmer (iiTA R&D PCPS)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
24-JAN-2019
e-Signature
Senior Statistics Director (II Clinical Statistics)
24-JAN-2019
e-Signature
Programming Manager (II Clinical Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
205017
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
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)...............................................................6
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses .................................................9
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 DATA HANDLING 
CONVENTIONS.....................................................................................................12
5.1.
Study Treatment & Sub-group Display Descriptors.....................................12
5.2.
Baseline Definitions ....................................................................................13
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Study Population Analyses........................................14
7.
SAFETY ANALYSES .............................................................................................15
7.1.
Adverse Events Analyses ...........................................................................15
7.2.
Clinical Laboratory Analyses.......................................................................15
8.
PHARMACOKINETIC ANALYSES.........................................................................16
8.1.
Primary Pharmacokinetic Analyses – Part A (Periods 1 – 3) and 
Part C (Periods 1 & 2).................................................................................16
8.1.1.
Endpoint / Variables.....................................................................16
8.1.1.1.
Drug Concentration Measures....................................16
8.1.1.2.
Derived Pharmacokinetic Parameters.........................16
8.1.2.
Summary Measure ......................................................................16
8.1.3.
Population of Interest...................................................................17
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................17
8.1.5.
Statistical Analyses / Methods .....................................................17
8.1.5.1.
Statistical Methodology Specification..........................17
8.2.
Secondary Pharmacokinetic Analyses  - Part A (Periods 4-6), Part 
B, and Part C (Periods 3-6).........................................................................18
8.2.1.
Endpoint / Variables.....................................................................18
8.2.1.1.
Drug Concentration Measures....................................18
8.2.1.2.
Derived Pharmacokinetic Parameters.........................19
8.2.2.
Summary Measure ......................................................................20
8.2.3.
Population of Interest...................................................................20
8.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................20


CONFIDENTIAL
205017
4
8.2.5.
Statistical Analyses / Methods .....................................................20
8.2.5.1.
Statistical Methodology Specification (Part A).............21
8.2.5.2.
Statistical Methodology Specification (Part B).............21
8.2.5.3.
Statistical Methodology Specification (Part C) ............22
9.
REFERENCES.......................................................................................................25
10. APPENDICES........................................................................................................26
10.1.
Appendix 1: Protocol Deviation Management .............................................26
10.2.
Appendix 2: Schedule of Activities ..............................................................27
10.2.1.
Protocol Defined Schedule of Events...........................................27
10.3.
Appendix 3: Assessment Windows .............................................................32
10.3.1.
Definitions of Assessment Windows for Analyses........................32
10.4.
Appendix 4: Study/Treatment Phases and Adverse Events ........................33
10.4.1.
Treatment Phases .......................................................................33
10.4.2.
Treatment States .........................................................................33
10.4.3.
Treatment States for AE Data......................................................33
10.4.4.
Treatment Phases for Concomitant Medication............................33
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................34
10.5.1.
Reporting Process .......................................................................34
10.5.2.
Reporting Standards....................................................................34
10.6.
Appendix 6: Derived and Transformed Data ...............................................36
10.6.1.
General........................................................................................36
10.6.2.
Study Population..........................................................................36
10.6.3.
Safety ..........................................................................................37
10.6.4.
Pharmacokinetic ..........................................................................37
10.6.4.1.
Non-Compartmental Analysis .....................................37
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................39
10.7.1.
Premature Withdrawals................................................................39
10.7.2.
Handling of Missing Data.............................................................39
10.7.2.1.
Handling of Missing and Partial Dates ........................39
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................40
10.8.1.
Laboratory Values........................................................................40
10.8.2.
ECG.............................................................................................41
10.8.3.
Vital Signs....................................................................................41
10.9.
Appendix 9: Pharmacokinetic Analyses ......................................................42
10.9.1.
Systems.......................................................................................42
10.10. Appendix 10: Abbreviations & Trade Marks ................................................43
10.10.1. Abbreviations...............................................................................43
10.10.2. Trademarks .................................................................................44
10.11. Appendix 11: List of Data Displays..............................................................45
10.11.1. Data Display Numbering..............................................................45
10.11.2. Mock Example Shell Referencing ................................................45
10.11.3. Deliverables.................................................................................45
10.11.4. Study Population Tables..............................................................46
10.11.4.1. Study Population Tables Part A..................................46
10.11.4.2. Study Population Tables Part B..................................48
10.11.4.3. Study Population Tables Part C..................................50
10.11.5. Safety Tables...............................................................................51
10.11.5.1. Safety Tables Part A...................................................51
10.11.5.2. Safety Tables Part B...................................................54
10.11.5.3. Safety Tables Part C ..................................................57


CONFIDENTIAL
205017
5
10.11.6. Safety Figures .............................................................................59
10.11.6.1. Safety Figures Part A .................................................59
10.11.6.2. Safety Figures Part B .................................................60
10.11.6.3. Safety Figures Part C .................................................60
10.11.7. Pharmacokinetic Tables...............................................................61
10.11.7.1. Pharmacokinetic Tables Part A ..................................61
10.11.7.2. Pharmacokinetic Tables Part B ..................................63
10.11.7.3. Pharmacokinetic Tables Part C ..................................64
10.11.8. Pharmacokinetic Figures .............................................................66
10.11.8.1. Pharmacokinetic Figures Part A .................................66
10.11.8.2. Pharmacokinetic Figures Part B .................................68
10.11.8.3. Pharmacokinetic Figures Part C .................................69
10.11.9. ICH Listings .................................................................................71
10.11.9.1. ICH Listing Part A.......................................................71
10.11.9.2. ICH Listings Part B .....................................................76
10.11.9.3. ICH Listing Part C.......................................................82
10.11.10.Non-ICH Listings..........................................................................87
10.11.10.1.
Non-ICH Listings Part A..........................87
10.11.10.2.
Non-ICH Listings Part B..........................88
10.11.10.3.
Non-ICH Listings Part C .........................88


CONFIDENTIAL
205017
6
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
2017N315344_00
07-Jul-2017
Original
2017N315344_01
18-Sep-2017
Amendment 01
2017N315344_02
14-Jun-2018
Amendment 02
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol (Dated: 07-Jul-2017).
Protocol amendment 1: There were no changes or deviations to the originally planned 
statistical analysis specified in the protocol (Dated: 18-Sep-2017).
Protocol amendment 2: Additional analyses were added for the inclusion of Part C that 
mirror what was specified for Part A (14-Jun-2018).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the single dose PK 
profile of GSK2982772 from each 
test minitab Modified Release (MR)
formulation in a capsule (120 mg) 
compared to the IR formulation 
(120 mg)

GSK2982772 area under the curve from time zero to 
infinity (AUC(0-inf)), area under the curve from time 
zero to the last measurable concentration AUC(0-t), 
area under the curve from time zero to 24 hours 
AUC(0-24), area under the curve from time zero to 
12 hours AUC(0-12), maximum observed 
concentration (Cmax), Concentration at 12 hours 
post-dose (C12h), Concentration at 24 hours post-
dose (C24h) and ratio of Cmax : C12h and Cmax : 
C24h, relative bioavailability (Frelformulation) based 
on AUC and Cmax

To evaluate the single dose PK 
profile of GSK2982772 from a 
(matrix monolithic) MR tablet 
(240mg) compared to the IR 
formulation (240mg). 

GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), 
AUC(0-12), Cmax, C12h, C24h, Cmax:C12h and 
Cmax:C24h, Frelformulation based on AUC and Cmax.
Secondary Objectives
Secondary Endpoints

To assess the impact of high fat 
meal on the PK of GSK2982772 
following single dose 

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, time to 
Cmax (Tmax), FrelFE based on AUC and Cmax, 


CONFIDENTIAL
205017
7
Objectives
Endpoints
administration of the selected 
minitab MR formulation in a 
capsule (120 mg)

To determine if there are any dose 
dependant changes in the 
absorption of GSK2982772 
following repeat dose 
administration of the selected 
minitab MR formulation in a 
capsule at target daily doses of 30, 
60 and 240 mg

GSK2982772 AUC(0-24), Cmax, and Tmax if once 
daily (QD) dosing, on Day 1 and Day 3

GSK2982772 AUC(0-12), AUC(12-24), Cmax, and 
Tmax after morning dose, Cmax and Tmax after 
evening dose if twice daily (BID) dosing, on Day 1 
and Day 3

To assess the impact of food on 
the PK of GSK2982772 following 
single dose administration of the 
(matrix monolithic) MR tablet (dose 
corrected, as appropriate).

GSK2982772 AUC(0-inf), AUC(0-t) or AUC(0-24), 
Cmax, and time to Cmax (Tmax), FrelFE based on 
AUC and Cmax (dose corrected as appropriate).

To determine if there are any dose 
dependent changes in the 
absorption of GSK2982772 
following single dose 
administration or BID dose 
administration of the (matrix 
monolithic) MR tablet. 

GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), 
Cmax, C24, Cmax:C24, and Tmax

GSK2982772 AUC(0-12), C12, and Cmax:C12 if BID 
dosing

To assess the safety and 
tolerability of single doses of 
GSK2982772 IR formulation and 
single and repeat doses of the 
(matrix monolithic) MR and minitab 
MR formulations in a capsule

Adverse events (AEs)

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, heart rate, 
respiratory rate and body temperature)

12-Lead electrocardiogram (ECG) monitoring
Exploratory

To assess the impact of a standard 
meal on the PK of GSK2982772 
following administration of the 
selected minitab MR formulation in 
a capsule.

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, Tmax, 
and FrelFE based on AUC and Cmax (dose corrected 
as appropriate).


CONFIDENTIAL
205017
8
2.3.
Study Design
Overview of Study Design and Key Features
Part A:
Part B:
Part C:
Design
Features

An open label, single centre, three part, single and repeat dose study in 
healthy male and female participants to assess (matrix monolithic) MR and 
minitab MR formulations of GSK2982772 in a capsule and impact of food on 
absorption.

Part A – 6 period, sequential, 6-way fixed sequence design, with up to 4 MR 
minitab formulations evaluated after single dose of GSK2982772 120mg in the 
fasted state. 

Part B – open-label, repeat dose to evaluate selected minitab MR formulation 


CONFIDENTIAL
205017
9
Overview of Study Design and Key Features
(from Part A) following a 3 day repeat dosing of GSK2982772 at target daily 
doses of 30, 60 and 240mg (120mg, 240mg, 300mg actual daily doses). 

Part C – 6 period, sequential, 6-way fixed sequence design, with MR (matrix 
monolithic) formulations evaluated after single dose of GSK2982772 240mg in 
the fasted state.
Dosing
Part A:

Single dose of GSK2982772 120mg will be evaluated. Periods 1, 2 and 3 
will evaluate a slow minitab MR release duration, a fast minitab MR 
release formulation and IR tablet respectively. Periods 4, 5 and 6 will be 
flexible and depend on outcomes from Periods 1 to 3 and may be used to 
optimise the MR release durations and/or to evaluate the food effect.
Part B:

Target total daily doses of GSK2982772 30, 60 and 120mg QD or BID 
(depending on Part A findings) will be evaluated for 3 days.  This 
corresponds to actual daily doses of 120, 240, and 300mg, respectively.
Administration of the minitab MR formulation will either be in fasted state or 
with a standard meal (depending on Part A findings)
Part C:

Single dose of GSK2982772 240mg will be evaluated.  Periods 1 and 2 will
evaluate a (matrix monolithic) MR formulation and an IR tablet, respectively.  
Periods 3 through 6 will be flexible and the dosing regimen will be dependent on 
the outcome of Periods 1 and 2, and may evaluate higher doses, the impact of a 
high-fat meal, and/or standard meal after dosing or BID dosing.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

This is an open-label, non-randomised study. A treatment allocation list will 
take the place of the randomisation schedule, which will be developed by the 
sponsor using RandAll NG.
Interim 
Analysis

No formal interim analysis is planned for the study.

Analysed PK data will be reviewed after completion of Periods 1 to 3 of part A which 
will guide Periods 4, 5 and 6.

In Part C, there will be an interim review following completion of Periods 1 and 
2 to determine the dose for Periods 3 and 4 (360 mg or 480 mg). Similarly, 
there will be an interim review following Periods 4 and 5 to determine dose, 
prandial state and and dosing regimen (QD or BID).

Data will be reviewed following completion of Part A to determine the formulation, 
doses, dosing frequency (QD or BID) and prandial state for Part B.
2.4.
Statistical Hypotheses / Statistical Analyses
No formal hypothesis will be tested.  However, point estimates and corresponding 90% 
confidence intervals will be derived for the ratio between each minitab MR formulation 
relative to the IR formulation for the geometric mean of Cmax, Cmin, C12, C24, peak-to-
trough ratio, AUC(0-inf), AUC(0-12), and AUC(0-24).  PK parameters at the 12 hour 
time point will only be included if BID dosing is used.


CONFIDENTIAL
205017
10
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal statistical analyses are planned.
Part A
After Periods 1 to 3 are complete, the PK and safety data will be analysed which will 
guide Periods 4, 5 and 6. Periods 4, 5 and 6 will be flexible and the dosing regimen will 
be dependent on the outcome of preceding periods.  There will be the option to either 
optimise the MR release duration and/or to evaluate the impact of food on the selected 
MR minitab formulation in a capsule.  There will also be the option to cancel Periods 5 
and 6 if an optimal formulation is determined in Periods 1 or 2.
There will be an interim data review following final period of Part A to determine the 
formulation, doses, dosing frequency (QD or BID) and prandial state for Part B.  The 
data, consisting of summary report of PK and safety endpoints will be sent to the sponsor 
by Quotient, from which the decision on formulation and prandial state selection or 
stopping the study will be made by the Quotient study team (i.e., PI, scientific lead and 
pharmacokineticist) and sponsor study team (as a minimum the sponsor’s medical 
monitor, CPMS and GCSP).  The decision will be documented and signed by the PI as 
per Quotient Clinical current SOP.  Evidence of the decision will be retained in the ISF 
and GSK Trial Master File.
Part B
There will be no interim analysis during Part B of the study. 
Part C
In Part C, there will be an interim review following completion of Periods 1 and 2 to 
determine the dose for Periods 3 and 4 (360 mg or 480 mg). Similarly, there will be an 
interim review following Periods 4 and 5 to determine dose, prandial state and dosing 
regimen (QD or BID).  The data, consisting of summary report of PK and safety 
endpoints will be sent to the sponsor by Quotient, from which the decision on 
formulation and prandial state selection or stopping the study will be made by the 
Quotient study team (i.e., PI, scientific lead and pharmacokineticist) and sponsor study 
team (as a minimum the sponsor’s medical monitor, CPMS and GCSP).  The decision 
will be documented and signed by the PI as per Quotient Clinical current SOP.  Evidence 
of the decision will be retained in the ISF and GSK Trial Master File.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:


CONFIDENTIAL
205017
11
1.
All participants have completed the study as defined in the protocol. 
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects

All participants who were screened for eligibility
and allocated a subject number.

Selected Study 
Population
Safety

All participants who receive at least 1 dose of study 
treatment and will be the population for reporting of 
safety and study population data. Participants will 
be analyzed according to the treatment they 
actually received.

Safety and Study 
Population
PK

Participants in the ‘Safety Population’ for whom a 
PK sample was obtained and analysed will be the 
population for reporting of PK data.

PK
Refer to Appendix 11: List of Data Displays which details the population used for each display.
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 (PDMP) 25-Sep-2018 
Version 001. See Section 10.1 for further details.
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.


CONFIDENTIAL
205017
12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
Part A
A
GSK2982772 120mg minitab MR 
RR1 oral single dose
MT-12h 120mg Fasted
2
B
GSK2982772 120mg minitab MR 
RR2 oral single dose
MT-8h 120mg Fasted
3
C
GSK2982772 120mg IR oral single 
dose
IR 120mg Fasted
1
D
GSK2982772 120mg minitab MR 
RR3 oral single dose
MT-12h 120mg Fed (Standard)
4
E
GSK2982772 120mg minitab MR 
RR4 oral single dose
n/a
5
F
GSK2982772 120mg minitab MR 
fed state 
n/a
6
Part B
G
GSK2982772 minitab MR Repeat 
Dose 1
MT-12h 120mg Fasted
1
H
GSK2982772 minitab MR Repeat 
Dose 2
MT-12h 240mg Fasted
2
J
GSK2982772 minitab MR Repeat 
Dose 3
MT-12h 300mg Fed 
(Standard) 
3
Part C
K
GSK2982772 240mg (matrix 
monolithic) MR oral single dose
MM-12h 240mg Fasted
2
L
GSK2982772 240mg IR oral single 
dose
IR 240mg Fasted
1
M
GSK2982772 360mg or 480mg 
(matrix monolithic) MR oral single 
dose
MM-12h 480mg Fasted
3
N*
GSK2982772 240mg (matrix 
monolithic) MR fed state
MM-12h 480mg Fed
(Standard)
4
P
GSK2982772 360mg or 480mg 
(matrix monolithic) MR delayed fed 
(standard meal) or fed (high-fat 
meal)
MM-12h 480mg Delayed 
Fed (Standard)
5
Q
GSK2982772 dose tbd (matrix 
monolithic) MR QD or BID prandial 
state tbd.
MM-12h 240 mg Delayed 
Fed (High-Fat)
6


CONFIDENTIAL
205017
13
* The randomization description for Period 4 of Part C (code N) indicates 240 mg, but 
the label has been updated to 480 mg to reflect the actual treatment administered.
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline.
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
Vital signs
X
X
X
Day 1 (Pre-Dose)
12-lead ECG
X
X
X
Day 1 (Pre-Dose)
Laboratory 
(Haematology, 
clinical chemistry 
and urinalysis)
X
X
X
Day 1 (Pre-Dose)
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Reporting Standards for Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance


CONFIDENTIAL
205017
14
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Safety population, unless otherwise 
specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 11: List of Data Displays.


CONFIDENTIAL
205017
15
7.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 11: List of Data Displays.
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 11: List of Data Displays.
In additional to GSK Core Data Standards, Lipids (Total Cholesterol and Triglycerides) 
outside the normal range will be summarised. Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. Suicide risk monitoring 
including analyses of Colombia Suicide Severity Rating Scale (C-SSRS) and Possible 
Suicidality Related Adverse Event (PSRAE) will be based on GSK Core Data Standards, 
unless otherwise specified. The details of the planned displays are presented in Appendix 
11: List of Data Displays.


CONFIDENTIAL
205017
16
8.
PHARMACOKINETIC ANALYSES
8.1.
Primary Pharmacokinetic Analyses – Part A (Periods 1 – 3)
and Part C (Periods 1 & 2)
8.1.1.
Endpoint / Variables
8.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.2
Reporting Standards for Pharmacokinetic)
8.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin . All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the plasma
concentration-time data, as data permits.
Parameter
Parameter Description
Parts A and C Relative Bioavailability of MR vs IR
AUC(0-inf)
Area under the curve from time zero to infinity
AUC(0-t)1
Area under the curve from time zero to the last quantifiable concentration
AUC(0-24)
Area under the curve from time zero to 24 hours
AUC(0-12)[2]
Area under the curve from time zero to 12 hours, 
AUC%extrap
Percentage of AUC extrapolated beyond the last measured time point.
t1/2
Terminal half-life
Tlag
Time from dosing to first quantifiable concentration.
Tmax
Time of maximum observed concentration
Cmax
Maximum observed concentration
C24h
Concentration at 24 hours post-dose
C12h2
Concentration at 12 hours post-dose
Cmax:C12h2
Ratio of maximum and 12 hour concentrations
Cmax:C24h
Ratio of maximum and 24 hour concentrations
NOTES:

Additional parameters may be included as required.

No log transformation for Tmax nor any ratio (relative) endpoint.

[1]: AUC(0-t) if AUC(0-inf) cannot be derived 

[2]: If BID
8.1.2.
Summary Measure
For each release rate in Periods 1 through 3 of Part A, and Periods 1 and 2 of Part C, 
descriptive statistics (n, arithmetic mean, standard deviation [SD], 95% CI, minimum, 
median and maximum,) will be calculated by treatment for all PK concentrations over 


CONFIDENTIAL
205017
17
time and for the derived PK parameters. In addition, for loge-transformed PK parameter 
variables geometric mean, 95% CI, and %CVb will be provided, where %CVb =(100 * √ 
(exp(SD2) -1)) and SD is the standard deviation of log-transformed data.
8.1.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events

Participant study completion (i.e. as specified in the protocol) was defined as 
completing all phases of the study including the follow-up visit.

Withdrawn participants may be replaced in the study. Replacement participants
enrolled will be dosed with the next planned treatment of the withdrawn participant, 
and they will not receive any treatment that the withdrawn participant has already 
received with the exception of the need to increase participant numbers to obtain the 
minimum number of evaluable participants required for interim decisions, and to 
obtain data in any other treatment that is required for a valid comparison. 
Replacement participants will receive the required treatments in the same order as 
planned for the original participant and the minimum washout period will be 
respected with regard to the timing of dosing of the IR formulation.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified. 
8.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.1.5.1.
Statistical Methodology Specification
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles).
Endpoint (log scale)

AUC(0-inf) 

AUC(0-t) if AUC(0-inf) cannot be derived 

AUC(0-12) if BID

AUC(0-24h)


CONFIDENTIAL
205017
18

Cmax

C12h if BID

C24h
Model Specification

For each endpoint a mixed model will be fit with 3 observations per participant expected in Part 
A, and 2 observations per participant in Part C.  The model will contain formulation as a fixed, 
categorical effect, and a random intercept for 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.
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments may be made based on the 
data.

In the event the model fails to converge, the RANDOM statement will be removed and 
alternative covariance structures such as CS, CSH, or UN for the R matrix will be used by 
specifying ‘type=’ on the REPEATED line.  Akaike's Information Criteria (AIC) will be used to 
assist with the selection of covariance structure.

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 models will be 
explored using appropriate transformed data.

If outliers are detected, an additional table will be produced with outlying observations omitted.
Model Results Presentation

Point estimates and corresponding 90% CI will be computed for the differences in the endpoint 
for each GSK2982772 MR formulation vs GSK2982772 IR formulation.

The relative bioavailability ratio, Frelformulation ,and 90% CI will be calculated by back-
transforming the difference between the least square means for each of the two formulation 
comparisons. See Section 10.6.4
8.2.
Secondary Pharmacokinetic Analyses - Part A (Periods 4-6),
Part B, and Part C (Periods 3-6)
8.2.1.
Endpoint / Variables
8.2.1.1.
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.2
Reporting Standards for Pharmacokinetic)


CONFIDENTIAL
205017
19
8.2.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the plasma
concentration-time data, as data permits.
Parameter
Parameter Description
Part A - Food Effect
AUC(0-inf)
Area under the curve from time zero to infinity
AUC(0-t)1
Area under the curve from time zero to last quantifiable concentration
AUC(0-12)2
Area under the curve from time zero to 12 hours
AUC(0-24)3
Area under the curve from time zero to 24 hours
Cmax
Maximum observed concentration 
C12h2
Concentration at 12 hours post-dose
C24h
Concentration at 24 hours post-dose
Cmax:C12h2
Ratio of maximum and 12 hour concentrations
Cmax:C24h
Ratio of maximum and 24 hour concentrations
Tmax
Time of maximum observed concentration
Part B – Repeat Dose
AUC(0-12)2
Area under the curve from time zero to 12 hours
AUC(12-24)2
Area under the curve from time 12hours to 24 hours
AUC(0-24)3
Area under the curve from time zero to 24 hours
Cmax
Maximum observed concentration 
C12h2
Concentration at 12 hours post-dose
C24h
Concentration at 24 hours post-dose
Cmax:C12h2
Ratio of maximum and 12 hour concentrations
Cmax:C24h
Ratio of maximum and 24 hour concentrations
Tmax
Time of maximum observed concentration
Part C – High Dose Food Effect
AUC(0-inf)
Area under the curve from time zero to infinity
AUC(0-t)1
Area under the curve from time zero to the last quantifiable concentration
AUC(0-24)3
Area under the curve from time zero to 24 hours
AUC(0-12)1
Area under the curve from time zero to 12 hours
Tmax
Time of maximum observed concentration
Cmax
Maximum observed concentration 
Cmin
Minimum observed concentration
C24h
Concentration at 24 hours post-dose
C12h2
Concentration at 12 hours post-dose


CONFIDENTIAL
205017
20
Parameter
Parameter Description
Cmax:C12h2
Ratio of maximum and 12 hour concentrations
Cmax:C24h
Ratio of maximum and 24 hour concentrations
NOTES:

Additional parameters may be included as required.

No log transformation for Tmax nor any ratio (relative) endpoint.

[1]: AUC(0-t) if AUC(0-inf) cannot be derived

[2]: If BID formulation.

[3]: QD formulation only.
8.2.2.
Summary Measure
For each fed/fasted state in Parts A and C, and for day 1 and day 3 of every dose (period) 
in Part B, descriptive statistics (n, arithmetic mean, standard deviation [SD], 95% CI, 
minimum, median and maximum,) will be calculated by treatment for all PK 
concentrations over time and for the derived PK parameters. In addition, for loge-
transformed PK parameter variables geometric mean, 95% CI and %CVb will be 
provided, where %CVb =(100 * √ (exp(SD2) -1)) and SD is the standard deviation of log-
transformed data.
For Part B, log-scale dose normalized Cmax, C12h (for BID), C24h, AUC(0-12) (for BID 
dosing) AUC(12-24) (for BID dosing), and AUC(0-24) will also be summarized.  Plots of 
dose vs log-scale dose normalised AUC(0-24), (AUC(0-12) and AUC(12-24) for BID dosing), 
C12h (for BID), C24h, and Cmax (after morning and evening doses if BID dosing) will be 
generated to determine if there are any dose dependent changes in the absorption of 
GSK2982772 following repeat dose administration of the selected minitab MR 
formulation.
8.2.3.
Population of Interest 
The secondary pharmacokinetic analyses will be based on the Pharmacokinetic
population, unless otherwise specified.
8.2.4.
Strategy for Intercurrent (Post-Randomization) Events

See Section 8.1.4.
8.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.


CONFIDENTIAL
205017
21
8.2.5.1.
Statistical Methodology Specification (Part A)
Endpoint (log scale)

AUC(0-inf) 

AUC(0-t) if AUC(0-inf) cannot be derived 

Cmax
Model Specification

For each endpoint a mixed model will be fit with 2 observations per subject expected.  The 
model will contain state [[fed/fasted] as a fixed, categorical effect and a random intercept for 
subject.

The Kenward & Roger (KR) degreed of freedom approach will be used.
Model Checking & Diagnostics

See Section 8.1.5.1
Model Results Presentation

Point estimates and corresponding 90% CI will be computed for the differences in the endpoint 
for GSK2982772 MR formulation (120 mg) taken in the fed state (test) vs in the fasted state 
(reference) using the residual error from the model (MSE). 

The point and interval estimates on the log-scale will then be exponentially back transformed to 
give estimates of the ratios of geometric means, FrelFE ,and 90% CI.  See Section 10.6.4
Endpoint 

Tmax
Model Specification

Exact non-parametric Hodges-Lehmann estimation of location shift will be fitted.  

Only the dose of GSK2982772 administered under both fed and fasted conditions will be used.
Model Results Presentation

GSK2982772 MR formulation in fed (test) will be compared to fasted (reference) state. 

Median difference and 90% CI for median difference will be presented.
8.2.5.2.
Statistical Methodology Specification (Part B)
Endpoint (log scale)

AUC(0-24h) (QD)

AUC(0-12h)(if BID)

AUC(12-24h)(if BID)

Cmax (morning) (QD or BID)

Cmax (evening) (if BID)


CONFIDENTIAL
205017
22
Model Specification

For each endpoint a mixed model will be fit with 6 observations per subject expected.  The 
model will contain dose (120, 240, 300) and day (1,3) as fixed, categorical effects, and their 
interaction.  

A direct product (UN@CS) covariance pattern will be fit using period and day (in that order) as 
the effects in the REPEATED statement.

The Kenward & Roger (KR) degrees of freedom approach will be used.
Model Checking & Diagnostics

See Section 8.1.5.1.  Additionally, in the event the model fails to converge a compound 
symmetric covariance pattern will be fit using day*dose as the effect on the REPEATED 
statement, with type=CS, group=period, and subject id specified in the subject= option to 
account for the correlation between days within period.  A random intercept effect will also be 
included to account for the correlation between days across period.

In the event the above model fails to converge, a compound symmetric covariance pattern will 
be fit using day*dose as the effect on the REPEATED statement, with type=CS and subject id 
specified in the subject= option.  A random period effect will also be included.

In the event the above model fails to converge, a compound symmetric covariance pattern will 
be fit using day*dose as the effect on the REPEATED statement, with type=CS and subject id 
specified in the subject= option.

In the event the above model fails to converge, all other covariance patterns will be explored, 
including unstructured.

If outliers are detected, an additional table will be produced with outlying observations omitted.
Model Results Presentation

Point estimates and corresponding 90% CI will be computed for the differences in the endpoint 
between Day 1 and Day 3 for Period 1 (120mg daily), Period 2 (240mg daily), and Period 3 
(300mg daily) for GSK2982772 minitab MR dose. 

The point and interval estimates on the log-scale will then be exponentially back transformed to 
give estimates of the ratios of geometric means, FrelDay , and 90% CI.  See Section 10.6.4
8.2.5.3.
Statistical Methodology Specification (Part C)
Bioavailability of Food Effect
Endpoint (log scale)

AUC(0-inf)

AUC(0-t) if AUC(0-inf) not available

Cmax

Model Specification

For each endpoint a mixed model will be fit with 5 observations per subject expected.  The 
model will contain dose (240mg, 480mg) and prandial state [fed (standard)/delayed fed 


CONFIDENTIAL
205017
23
(standard)/delayed fed (high-fat)/fasted] as a fixed, categorical effect and a random intercept 
for subject.

A direct product (UN@CS) covariance pattern will be fit using dose and state (in that order) as 
the effects in the REPEATED statement.

The Kenward & Roger (KR) degrees of freedom approach will be used.
Model Checking & Diagnostics

See Section 8.1.5.1.  
Model Results Presentation

Point estimates and corresponding 90% CI will be computed for the differences in the endpoint 
for GSK2982772 MR formulation (240 mg or 480 mg) taken in the fed state (test) vs in the 
fasted state (reference) using the residual error from the model (MSE). 

The point and interval estimates on the log-scale will then be exponentially back transformed to 
give estimates of the ratios of geometric means, FrelFE ,and 90% CI.  See Section 10.6.4
Endpoint 

Tmax
Model Specification

Exact non-parametric Hodges-Lehmann estimation of location shift will be fitted.

Only the dose of GSK2982772 administered under both fed and fasted conditions will be used.
Model Results Presentation

GSK2982772 MR formulation in fed (test) state will be compared to fasted (reference) state. 

Median difference and 90% CI for median difference will be presented.
Bioavailability of Dose
Endpoint (log scale)

AUC(0-inf)

AUC(0-t) if AUC(0-inf) not available

AUC(0-24)

Cmax

C24
Model Specification

For each endpoint a mixed model will be fit with 2 observations per subject expected.  The 
model will contain dose (480 mg and 240 mg in the fasted state) as a fixed, categorical effect, 
and a random intercept for 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.


CONFIDENTIAL
205017
24
Model Checking & Diagnostics

See Section 8.1.5.1.  
Model Results Presentation

Point estimates and corresponding 90% CI will be computed for the differences in the endpoint 
for GSK2982772 MR dose (480 mg vs 240 mg) using the residual error from the model (MSE). 

The point and interval estimates on the log-scale will then be exponentially back transformed to 
give estimates of the ratios of geometric means, FrelDOSE ,and 90% CI.  See Section 10.6.4
Endpoint 

Tmax
Model Specification

Exact non-parametric Hodges-Lehmann estimation of location shift will be fitted.

Only GSK2982772 administered at 240 mg and 480 mg.
Model Results Presentation

GSK2982772 MR formulation at 480 mg (test) state will be compared to 240 mg (reference). 

Median difference and 90% CI for median difference will be presented.


CONFIDENTIAL
205017
25
9.
REFERENCES
GlaxoSmithKline Document Number 2017N315344_02. A three part, non-randomised, 
open label study designed to assess the pharmacokinetics of GSK2982772 following 
administration of minitab modified release formulations in a capsule relative to an 
immediate release reference tablet formulation (Part A), the pharmacokinetics of 
escalating, repeat doses of a selected minitab modified release prototype (Part B), and the 
pharmacokinetics of GSK2982772 following administration of modified release tablet 
formulations in the fed and fasted state (Part C) in healthy participants. Effective Date: 
14-JUN-2018
Hauschke D1, Steinijans VW, Diletti E. A distribution-free procedure for the statistical 
analysis of bioequivalence studies. Int J Clin Pharmacol Ther Toxicol, 1990;28(2):72-8.


CONFIDENTIAL
205017
26
10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management 

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.


CONFIDENTIAL
205017
27
10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
Schedule of Activities for Parts A and C


CONFIDENTIAL
205017
28


CONFIDENTIAL
205017
29
Pharmacokinetic Blood Sample Collection Times for Parts A and C
Schedule of Activities for Part B


CONFIDENTIAL
205017
30


CONFIDENTIAL
205017
31
Pharmacokinetic Blood Sample Collection Times for Part B
PK samples should take priority over other procedures scheduled at the same time point.  
As guidance, the preferred order of assessments is:
Electrocardiograms (ECGs) should be taken prior to vital signs when both measurements 
are scheduled at the same time point.  Other assessments, e.g. physical examinations etc, 
will be performed within the required time windows.  All safety assessments will be 
timed and performed relative to the start of dosing.


CONFIDENTIAL
205017
32
10.3.
Appendix 3: Assessment Windows
10.3.1.
Definitions of Assessment Windows for Analyses
No Assessment Windows will be defined for Analysis, and summaries and analyses will 
be based on nominal visits.


CONFIDENTIAL
205017
33
10.4.
Appendix 4: Study/Treatment Phases and Adverse Events
10.4.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to
dosing.
Treatment Phase
Definition
Pre-Treatment 
Date[1] ≤ Study Treatment Start Date[1]
On-Treatment
Study Treatment Start Date[1]  < Date[1]  ≤ Study Treatment Stop Date[1]
Post-Treatment
Date[1]  > Study Treatment Stop Date[1]  
[1] Datetime if Time is present for assessments or events
10.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment.
10.4.3.
Treatment States for AE Data
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop date.
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date
Post-Treatment
If AE onset date is after the treatment stop date.
AE Start Date > Study Treatment Stop Date 
Onset Time  
Since 1st Dose 
(Days)
If Treatment Start Date ˃  AE Onset Date = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on [Inform/CRF OR value is missing].
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.
10.4.4.
Treatment Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.


CONFIDENTIAL
205017
34
10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software

The currently supported versions of SAS software and WIN-NonLin will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Area
Final
: \arprod\gsk2982772\ mid205017\final_01
QC Spreadsheet
: \arwork\gsk2982772\mid205017\documents
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards.
Generation of RTF Files

RTF files will be generated for SAC tables.
10.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings

All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects CDISC and GSK 
Data Display Standards terminology.
Formats

All data will be reported according to the actual treatment the subject receives unless otherwise states.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.

PK Summary Statistics:  3 significant figures for the lowest value of each PK parameter.  The 
summary statistics for higher values will be reported to the same number of decimal places as 
the lowest value
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.


CONFIDENTIAL
205017
35

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or 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 Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


CONFIDENTIAL
205017
36
10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Analysis Time Point

If there are two values within a time window (as per Section 10.3.1) 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.

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
10.6.2.
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

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.


CONFIDENTIAL
205017
37
10.6.3.
Safety
ECG Parameter
RR Interval 

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fridericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as            
                 
Laboratory Parameters 

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of 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. 
o
Example 1: 2 Decimal Places=  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Decimal Places   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Decimal Places = ‘< x’ becomes x – 1    
10.6.4.
Pharmacokinetic
10.6.4.1.
Non-Compartmental Analysis 
The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices using WinNonlin Version 6.3 or higher.
Pharmacokinetic Endpoints
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.


CONFIDENTIAL
205017
38
Pharmacokinetic Endpoints
AUC(0-∞) (Day 1) 

Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC = AUC(0-t) + C(t) / lambda_z
where lambda_z is the terminal phase rate constant.
AUC(0-24) for QD dosing 
Area under the concentration-time curve from time zero to 24 h post dose will be calculated using the linear 
trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(0-12) for BID dosing 
Area under the concentration-time curve from time zero to 12 h post dose will be calculated using the linear 
trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(12-24) for BID dosing
Area under the concentration-time curve from time 12 h to 24 h post dose will be calculated using the 
linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid.
AUC%extrap
Percentage of AUC extrapolated beyond the last measured time point
Cmax
Maximum observed concentration, determined directly from the concentration-time data
C12hfor BID dosing
Observed concentration at 12 hours, determined directly from the concentration-time data
C24h
Observed concentration at 24 hours, determined directly from the concentration-time data
Tmax
Time to reach Cmax, determined directly from the concentration-time data.
Tlag
Time from dosing at which GSK2982772 was first quantifiable in a concentration vs time profile
t1/2
Terminal half-life
Notes

Additional parameters may be included as required 
Relative Bioavailability (Frel)

Frel will be calculated as follows:
Frel will be calculated using AUC(0-inf) and Cmax. If for any reason the AUC(0-inf) is not calculable then an 
alternative AUC such as AUC(0-last), AUC(0- ) or AUC over a partial area may be used. The following 
comparisons will be made:
o
MR Formulation (test) vs IR Formulation (reference)
o
Fed (test) vs Fasted (reference)                
o
Day 3 vs Day 1 (reference)


CONFIDENTIAL
205017
39
10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as one who 
completes all phases of the study including the last scheduled procedure shown in the 
SoA i.e. the follow-up visit.

Withdrawn subjects may be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will 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.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


CONFIDENTIAL
205017
40
10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
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
White Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
G/L
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
1.3 X ULN
Creatinine
umol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
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
1.5x ULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


CONFIDENTIAL
205017
41
10.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
≤ 450 
> 450 
<480
≥ 480 
<500
≥ 500 
Absolute PR Interval
msec
< 110 
> 220 
Absolute QRS Interval
msec
< 75 
> 110 
Change from Baseline
Increase from Baseline QTc
msec
≤  30
msec
> 30  
<60f
msec
≥ 60  
10.8.3.
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
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 20
≥ 40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥ 10
≥ 20
≥ 10
≥ 20
Heart Rate
bpm
≥ 15
≥ 30
≥ 15
≥ 30


CONFIDENTIAL
205017
42
10.9.
Appendix 9: Pharmacokinetic Analyses
10.9.1.
Systems
N/A


CONFIDENTIAL
205017
43
10.10.
Appendix 10: Abbreviations & Trade Marks
10.10.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Friderica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 


CONFIDENTIAL
205017
44
10.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
SAS
WinNonlin


CONFIDENTIAL
205017
45
10.11.
Appendix 11: List of Data Displays
10.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Safety
2.1 to 2.n
2.1 to 2.n
Pharmacokinetic
3.1 to 3.n
3.1 to 3.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
10.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.11.3.
Deliverables
Delivery [Priority] [1]
Description
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


CONFIDENTIAL
205017
46
10.11.4.
Study Population Tables
10.11.4.1. Study Population Tables Part A
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition 
1.1.
Safety
ES1A
Summary of Subject Disposition: Part A
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.2.
All Subjects
ES6
Summary of Reasons for Screen Failure: Part A
Journal Requirements
SAC
Protocol Deviation 
1.3.
Safety
DV1
Summary of Important Protocol Deviations: Part A
ICH E3
SAC
1.4.
All Subjects
IE2
Summary of Inclusion/Exclusion Criteria Deviations: Part A
IDSL
SAC
Population Analysed
1.5.
All Subjects
SP1
Summary of Study Populations and Exclusions: Part A
IDSL
SAC
Demographic and Baseline Characteristics 
1.34.
All Subjects
DM11
Summary of Age Ranges: Part A 
ICH E3, GSK CTR, FDAAA, EudraCT
Only include age ranges applicable to 
the study (‘Adult (18-64 years)’ and 
‘>=65-84 years’).
SAC
1.6.
Safety
DM1
Summary of Demographic Characteristics: Part A
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.7.
Safety
DM5
Summary of Race and Racial Combinations: Part A
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
SAC
1.8.
Safety
DM6
Summary of Race and Racial Combination Details: Part A
ICH E3, FDA
SAC


CONFIDENTIAL
205017
47
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
1.9.
Safety
MH4
Summary of Current/Past Medical Conditions: Part A
ICH E3 
Separate summaries for Current & Past 
conditions, if collected.
SAC
1.10.
Safety
CM1
Summary of Concomitant Medications: Part A
ICH E3
SAC
Exposure and Treatment Compliance 
1.11.
Safety
EX1
Summary of Exposure to Study Treatment: Part A
ICH E3
Dose and/or time on treatment, as 
applicable. 
SAC


CONFIDENTIAL
205017
48
10.11.4.2. Study Population Tables Part B
Study Population Tables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition 
1.12.
Safety
ES1A
Summary of Subject Disposition: Part B 
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.13.
All Subjects
ES6
Summary of Reasons for Screen Failure: Part B 
Journal Requirements
SAC
Protocol Deviation 
1.14.
Safety
DV1
Summary of Important Protocol Deviations: Part B 
ICH E3
SAC
1.15.
All Subjects
IE2
Summary of Inclusion/Exclusion Criteria Deviations: Part B
IDSL
SAC
Population Analysed
1.16.
All Subjects
SP1
Summary of Study Populations and Exclusions: Part B
IDSL
SAC
Demographic and Baseline Characteristics 
1.35.
All Subjects
DM11
Summary of Age Ranges: Part B 
ICH E3, GSK CTR, FDAAA, EudraCT
Only include age ranges applicable to 
the study (‘Adult (18-64 years)’ and 
‘>=65-84 years’).
SAC
1.17.
Safety
DM1
Summary of Demographic Characteristics: Part B 
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.18.
Safety
DM5
Summary of Race and Racial Combinations: Part B 
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
SAC
1.19.
Safety
DM6
Summary of Race and Racial Combination Details: Part B 
ICH E3, FDA
SAC


CONFIDENTIAL
205017
49
Study Population Tables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
1.20.
Safety
MH4
Summary of Current/Past Medical Conditions: Part B
ICH E3 
Separate summaries for Current & Past 
conditions, if collected.
SAC
1.21.
Safety
CM1
Summary of Concomitant Medications: Part B 
ICH E3
SAC
Exposure and Treatment Compliance 
1.22.
Safety
EX1
Summary of Exposure to Study Treatment: Part B
ICH E3
Dose and/or time on treatment, as 
applicable. 
SAC


CONFIDENTIAL
205017
50
10.11.4.3. Study Population Tables Part C
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition 
1.23.
Safety
ES1A
Summary of Subject Disposition: Part C 
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.24.
All Subjects
ES6
Summary of Reasons for Screen Failure: Part C 
Journal Requirements
SAC
Protocol Deviation 
1.25.
Safety
DV1
Summary of Important Protocol Deviations: Part C 
ICH E3
SAC
1.26.
All Subjects
IE2
Summary of Inclusion/Exclusion Criteria Deviations: Part C
IDSL
SAC
Population Analysed
1.27.
All Subjects
SP1
Summary of Study Populations and Exclusions: Part C
IDSL
SAC
Demographic and Baseline Characteristics 
1.36.
All Subjects
DM11
Summary of Age Ranges: Part C 
ICH E3, GSK CTR, FDAAA, EudraCT
Only include age ranges applicable to 
the study (‘Adult (18-64 years)’ and 
‘>=65-84 years’).
SAC
1.28.
Safety
DM1
Summary of Demographic Characteristics: Part C 
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.29.
Safety
DM5
Summary of Race and Racial Combinations: Part C 
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
SAC
1.30.
Safety
DM6
Summary of Race and Racial Combination Details: Part C 
ICH E3, FDA
SAC


CONFIDENTIAL
205017
51
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
1.31.
Safety
MH4
Summary of Current/Past Medical Conditions: Part C
ICH E3 
Separate summaries for Current & Past 
conditions, if collected.
SAC
1.32.
Safety
CM1
Summary of Concomitant Medications: Part C 
ICH E3
SAC
Exposure and Treatment Compliance 
1.33.
Safety
EX1
Summary of Exposure to Study Treatment: Part C
ICH E3
Dose and/or time on treatment, as 
applicable. 
SAC
10.11.5.
Safety Tables
10.11.5.1. Safety Tables Part A
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.1.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term: Part A
See Table 2.02 from 200975
SAC
2.2.
Safety
AE5a
Summary of All Adverse Events by System Organ Class and 
Maximum Intensity: Part A
ICH E3
SAC


CONFIDENTIAL
205017
52
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.3.
Safety
AE3
Summary of Common (>10%) Adverse Events by Overall 
Frequency: Part A
GSK CTR
SAC
2.4.
Safety
AE5a
Summary of All Drug-Related Adverse Events by System Organ 
Class and Maximum Intensity: Part A
GSK CTR
SAC
Serious and Other Significant Adverse Events
2.5.
Safety
AE1 
Summary of Serious Adverse Events by System Organ Class: 
Part A
IDSL / GSK CTR
SAC
2.6.
Safety
AE3
Summary of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment by Overall 
Frequency: Part A
IDSL
SAC
2.7.
Safety
AE16
Summary of Subjects and Number of Occurrences of Serious, 
Drug-Related Serious, Fatal Serious, and Drug-Related Fatal 
Serious Adverse Events: Part A
FDAAA, EudraCT
SAC
Laboratory: Chemistry 
2.8.
Safety
LB1
Summary of Clinical Chemistry Changes from Baseline: Part A
ICH E3
Includes Baseline values.
Includes pre-specified parameters 
repeated in conventional units.
SAC
2.9.
Safety
LB1
Summary of Clinical Chemistry Values: Part A
SAC
2.10.
Safety
LB3
Summary of Emergent Clinical Chemistry Results by Potential 
Clinical Importance Criteria: Part A  
SAC
2.66.
Safety
LB17
Summary of Worst Case Lipids Outside Laboratory Normal 
Range Post-Baseline Relative to Baseline: Part A
SAC


CONFIDENTIAL
205017
53
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hematology
2.11.
Safety
LB1
Summary of Hematology Changes From Baseline: Part A
ICH E3
Includes baseline values.
SAC
2.12.
Safety
LB1
Summary of Hematology Values: Part A
ICH E3
Includes baseline values.
SAC
2.13.
Safety
LB3
Summary of Emergent Hematology Results by Potential Clinical 
Importance Criteria: Part A  
SAC
Laboratory: Urinalysis
2.14.
Safety
UR3
Summary of Microscopy Results for Subjects with Abnormal 
Urinalysis Dipstick Results: Part A
ICH E3
Includes Baseline values.
SAC
Laboratory: Hepatobiliary (Liver)
2.15.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting: Part A
IDSL
SAC
2.16.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities: Part A
SAC
ECG
2.17.
Safety
EG1
Summary of ECG Findings: Part A
IDSL
SAC
2.18.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit: Part 
A
IDSL
SAC
2.19.
Safety
CP_EG12
Summary of Maximum Change from Baseline in QTc Values by 
Category: Part A
IDSL
SAC


CONFIDENTIAL
205017
54
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
2.20.
Safety
VS1
Summary of Change From Baseline in Vital Signs by Visit: Part 
A
ICH E3
Includes Baseline values.
SAC
2.21.
Safety
VS1
Summary of Vital Signs by Visit: Part A
SAC
10.11.5.2. Safety Tables Part B
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.22.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term: Part B
See Table 2.02 from 200975
SAC
2.23.
Safety
AE5a
Summary of All Adverse Events by System Organ Class and 
Maximum Intensity: Part B
ICH E3
SAC
2.24.
Safety
AE3
Summary of Common (>10%) Adverse Events by Overall 
Frequency: Part B
GSK CTR
SAC
2.25.
Safety
AE5a
Summary of All Drug-Related Adverse Events by System Organ 
Class and Maximum Intensity: Part B
GSK CTR
SAC
Serious and Other Significant Adverse Events
2.26.
Safety
AE1 
Summary of Serious Adverse Events by System Organ Class: 
Part B
IDSL / GSK CTR
SAC


CONFIDENTIAL
205017
55
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.27.
Safety
AE3
Summary of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment by Overall 
Frequency: Part B
IDSL
SAC
2.28.
Safety
AE16
Summary of Subjects and Number of Occurrences of Serious, 
Drug-Related Serious, Fatal Serious, and Drug-Related Fatal 
Serious Adverse Events: Part B
FDAAA, EudraCT
SAC
Laboratory: Chemistry 
2.29.
Safety
LB1
Summary of Clinical Chemistry Changes from Baseline: Part B
ICH E3
Includes Baseline values.
Includes pre-specified parameters 
repeated in conventional units.
SAC
2.30.
Safety
LB1
Summary of Clinical Chemistry Values: Part B
SAC
2.31.
Safety
LB3
Summary of Emergent Clinical Chemistry Results by Potential 
Clinical Importance Criteria: Part B  
SAC
2.67.
Safety
LB17
Summary of Worst Case Lipids Outside Laboratory Normal 
Range Post-Baseline Relative to Baseline: Part B
SAC
Laboratory: Hematology
2.32.
Safety
LB1
Summary of Hematology Changes From Baseline: Part B
ICH E3
Includes baseline values.
SAC
2.33.
Safety
LB1
Summary of Hematology Values: Part B
ICH E3
Includes baseline values.
SAC
2.34.
Safety
LB3
Summary of Emergent Hematology Results by Potential Clinical 
Importance Criteria: Part B  
SAC


CONFIDENTIAL
205017
56
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Urinalysis
2.35.
Safety
UR3
Summary of Microscopy Results for Subjects with Abnormal 
Urinalysis Dipstick Results: Part B
ICH E3
Includes Baseline values.
SAC
Laboratory: Hepatobiliary (Liver)
2.36.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting: Part B
IDSL
SAC
2.37.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities: Part B
SAC
ECG
2.38.
Safety
EG1
Summary of ECG Findings: Part B
IDSL
SAC
2.39.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit: Part 
B
IDSL
SAC
2.40.
Safety
CP_EG12
Summary of Maximum Change from Baseline in QTc Values by 
Category: Part B
IDSL
SAC
Vital Signs
2.41.
Safety
VS1
Summary of Change From Baseline in Vital Signs by Visit: Part 
B
ICH E3
Includes Baseline values.
SAC
2.42.
Safety
VS1
Summary of Vital Signs by Visit: Part B
SAC
CSSRS
2.43.
Safety
CSSRS1
Summary of Subjects with C-SSRS Suicidal Ideation or 
Behaviour during Treatment: Part B
SAC


CONFIDENTIAL
205017
57
10.11.5.3. Safety Tables Part C
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.44.
Safety
AE1
Summary of All Adverse Events by System Organ Class and
Preferred Term: Part C
See Table 2.02 from 200975
SAC
2.45.
Safety
AE5a
Summary of All Adverse Events by System Organ Class and 
Maximum Intensity: Part C
ICH E3
SAC
2.46.
Safety
AE3
Summary of Common (>10%) Adverse Events by Overall 
Frequency: Part C
GSK CTR
SAC
2.47.
Safety
AE5a
Summary of All Drug-Related Adverse Events by System Organ 
Class and Maximum Intensity: Part C
GSK CTR
SAC
Serious and Other Significant Adverse Events
2.48.
Safety
AE1 
Summary of Serious Adverse Events by System Organ Class: 
Part C
IDSL / GSK CTR
SAC
2.49.
Safety
AE3
Summary of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment by Overall 
Frequency: Part C
IDSL
SAC
2.50.
Safety
AE16
Summary of Subjects and Number of Occurrences of Serious, 
Drug-Related Serious, Fatal Serious, and Drug-Related Fatal 
Serious Adverse Events: Part C
FDAAA, EudraCT
SAC
Laboratory: Chemistry 
2.51.
Safety
LB1
Summary of Clinical Chemistry Changes from Baseline: Part C 
ICH E3
Includes Baseline values.
Includes pre-specified parameters 
repeated in conventional units.
SAC
2.52.
Safety
LB1
Summary of Clinical Chemistry Values: Part C
SAC


CONFIDENTIAL
205017
58
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.53.
Safety
LB3
Summary of Emergent Clinical Chemistry Results by Potential 
Clinical Importance Criteria: Part C  
SAC
2.68.
Safety
LB17
Summary of Worst Case Lipids Outside Laboratory Normal 
Range Post-Baseline Relative to Baseline: Part C
SAC
Laboratory: Hematology
2.54.
Safety
LB1
Summary of Hematology Changes From Baseline: Part C
ICH E3
Includes baseline values.
SAC
2.55.
Safety
LB1
Summary of Hematology Values: Part C
ICH E3
Includes baseline values.
SAC
2.56.
Safety
LB3
Summary of Emergent Hematology Results by Potential Clinical 
Importance Criteria: Part C  
SAC
Laboratory: Urinalysis
2.57.
Safety
UR3
Summary of Microscopy Results for Subjects with Abnormal 
Urinalysis Dipstick Results: Part C
ICH E3
Includes Baseline values.
SAC
Laboratory: Hepatobiliary (Liver)
2.58.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting: Part C
IDSL
SAC
2.59.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities: Part C
SAC
ECG
2.60.
Safety
EG1
Summary of ECG Findings: Part C 
IDSL
SAC
2.61.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit: Part 
C
IDSL
SAC


CONFIDENTIAL
205017
59
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.62.
Safety
CP_EG12
Summary of Maximum Change from Baseline in QTc Values by 
Category: Part C
IDSL
SAC
Vital Signs
2.63.
Safety
VS1
Summary of Change From Baseline in Vital Signs by Visit: Part 
C
ICH E3
Includes Baseline values.
SAC
2.64.
Safety
VS1
Summary of Vital Signs by Visit: Part C
SAC
10.11.6.
Safety Figures
10.11.6.1. Safety Figures Part A
Safety : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events 
2.1.
Safety
AE10
Plot of Common Adverse Events and Relative Risk: Part A
IDSL
SAC
Hepatobilary (Liver)
2.2.
Safety
LIVER14
Scatter Plot of Maximum vs Baseline for ALT: Part A
SAC
2.3.
Safety
LIVER9
Scatter Plot for Maximum ALT va Maximum Total Bilirubin: Part 
A
SAC


CONFIDENTIAL
205017
60
10.11.6.2. Safety Figures Part B
Safety : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events 
2.4.
Safety
AE10
Plot of Common Adverse Events and Relative Risk: Part B
IDSL
SAC
Hepatobilary (Liver)
2.5.
Safety
LIVER14
Scatter Plot of Maximum vs Baseline for ALT: Part B
SAC
2.6.
Safety
LIVER9
Scatter Plot for Maximum ALT va Maximum Total Bilirubin: Part 
C
SAC
10.11.6.3. Safety Figures Part C
Safety : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events 
2.7.
Safety
AE10
Plot of Common Adverse Events and Relative Risk: Part C
IDSL
SAC
Hepatobilary (Liver)
2.8.
Safety
LIVER14
Scatter Plot of Maximum vs Baseline for ALT: Part C
SAC
2.9.
Safety
LIVER9
Scatter Plot for Maximum ALT va Maximum Total Bilirubin: Part 
C
SAC


CONFIDENTIAL
205017
61
10.11.7.
Pharmacokinetic Tables
10.11.7.1. Pharmacokinetic Tables Part A
Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration
3.1.
PK
PK01
Summary of Plasma GSK2982772 Pharmacokinetic 
Concentration-Time Data by Formulation: Part A
Includes fed state.
SAC
PK Derived Parameters
3.2.
PK
PKPT1
Summary Statistics of Derived Plasma GSK2982772
Pharmacokinetic Parameters by Formulation: Part A
Parameters with units.  Includes fed 
state.
SAC
3.3.
PK
PKPT3
Summary Statistics of Log-Transformed Derived Plasma 
GSK2982772 Pharmacokinetic Parameters by Formulation: 
Part A
Parameters with units.  Includes fed 
state.
SAC
PK Analyses
3.4.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (AUC & C) Assessing Relative Bioavailability of 
Formulation: Part A
SAC
3.5.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (Tmax) Assessing Relative Bioavailability of 
Formulation: Part A
Tmax
SAC


CONFIDENTIAL
205017
62
Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.6.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (AUC & C) Assessing Relative Bioavailability of 
Food Effect: Part A
SAC
3.7.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (Tmax) Assessing Relative Bioavailability of Food 
Effect: Part A
Tmax
SAC
3.23.
PK
PK_T1
Sensitivity: Summary of Statistical Analysis of Plasma 
GSK2982772 Parameters (AUC & C) Assessing Relative 
Bioavailability of Formulation: Part A Excluding Subject 
SAC
3.24.
PK
PK_T1
Sensitivity: Summary of Statistical Analysis of Plasma 
GSK2982772 Parameters (Tmax) Assessing Relative 
Bioavailability of Formulation: Part A Excluding Subject 
Tmax
SAC
3.25.
PK
PK_T1
Sensitivity: Summary of Statistical Analysis of Plasma 
GSK2982772 Parameters (AUC & C) Assessing Relative 
Bioavailability of Food Effect: Part A Excluding Subject 
SAC
3.26.
PK
PK_T1
Sensitivity: Summary of Statistical Analysis of Plasma 
GSK2982772 Parameters (Tmax) Assessing Relative 
Bioavailability of Food Effect: Part A Excluding Subject 
Tmax
SAC
PPD
PPD
PPD
PPD


CONFIDENTIAL
205017
63
10.11.7.2. Pharmacokinetic Tables Part B
Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration
3.8.
PK
PK01
Summary of Plasma GSK2982772 Pharmacokinetic 
Concentration-Time Data by Dose and Day: Part B
SAC
PK Derived Parameters
3.9.
PK
PKPT1
Summary Statistics of Derived Plasma GSK2982772
Pharmacokinetic Parameters by Dose and Day: Part B
Parameters with units 
SAC
3.10.
PK
PKPT3
Summary Statistics of Log-Transformed Derived Plasma 
GSK2982772 Pharmacokinetic Parameters by Dose and Day: 
Part B
Parameters with units 
SAC
3.11.
PK
PKPT3
Summary Statistics of Log-Transformed Derived Plasma 
GSK2982772 Dose-Normalized Pharmacokinetic Parameters 
by Dose and Day: Part B
Parameters with units 
SAC
PK Analyses
3.12.
PK
PK_T2
Summary of Statistical Analysis of Plasma GSK2982772 PK 
Parameters (AUC & C) Assessing Relative Bioavailability of 
Repeat Dose: Part B
SAC


CONFIDENTIAL
205017
64
10.11.7.3. Pharmacokinetic Tables Part C
Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration
3.13.
PK
PK01
Summary of Plasma GSK2982772 Pharmacokinetic 
Concentration-Time Data by Formulation/Prandial State: Part C
Includes fed state.
SAC
PK Derived Parameters
3.14.
PK
PKPT1
Summary Statistics of Derived Plasma GSK2982772
Pharmacokinetic Parameters by Formulation/Prandial State: 
Part C
Parameters with units.  Includes fed 
state.
SAC
3.15.
PK
PKPT3
Summary Statistics of Log-Transformed Derived Plasma 
GSK2982772 Pharmacokinetic Parameters by Formulation/
Prandial State: Part C
Parameters with units.  Includes fed 
state.
SAC
3.16.
PK
Summary Statistics of Log-Transformed Derived Plasma 
GSK2982772 Dose-Normalized Pharmacokinetic Parameters by 
Formulation/Prandial State: Part C 
PK Analyses
3.17.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (AUC & C) Assessing Relative Bioavailability of 
Formulation: Part C
SAC
3.18.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (Tmax) Assessing Relative Bioavailability of 
Formulation: Part C
Tmax
SAC


CONFIDENTIAL
205017
65
Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.19.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (AUC & C) Assessing Relative Bioavailability of 
Food Effect: Part C
SAC
3.20.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (Tmax) Assessing Relative Bioavailability of Food 
Effect: Part C
Tmax
SAC
3.21.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (AUC & C) Assessing Relative Bioavailability of 
Dose: Part C
SAC
3.22.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (Tmax) Assessing Relative Bioavailability of Dose: 
Part C
SAC


CONFIDENTIAL
205017
66
10.11.8.
Pharmacokinetic Figures
10.11.8.1. Pharmacokinetic Figures Part A
Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Concentration Plots
3.1.
PK
PKCF1P
Individual GSK2982772 Plasma Concentration-Time Plot by 
Subject (Linear and Semi-Log): Part A
Paginate by Subject
SAC
3.2.
PK
PKCF1P
Individual GSK2982772 Plasma Concentration-Time Plot by 
Formulation (Linear and Semi-Log): Part A
Paginate by Formulation.  This 
includes the fed state.
SAC
Mean / Median Concentration Plots
3.3.
PK
PKCF2
Mean Plasma GSK2982772 Concentration-Time Plots by 
Formulation (Linear and Semi-log): Part A
Paginate by Formulation.  This 
includes the fed state.
SAC
3.4.
PK
PKCF3
Median Plasma GSK2982772 Concentration-Time Plots by 
Formulation (Linear and Semi-log): Part A
Paginate by Formulation.  This 
includes the fed state.
SAC
3.5.
PK
PK_F1
Plot of Individual Subject (+Geometric Mean and 95% CI) 
Plasma GSK2982772 PK Parameters vs Formulation: Part A
SAC
3.6.
PK
PK_F2
Plot of Geometric Mean Ratio and 90% CI of Plasma 
GSK2982772 PK Parameters Assessing Relative Bioavailability 
of Formulation: Part A
SAC


CONFIDENTIAL
205017
67
Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.7.
PK
PK_F2
Plot of Geometric Mean Ratio and 90% CI of Plasma 
GSK2982772 PK Parameters Assessing Relative Bioavailability 
of Food Effect: Part A
SAC


CONFIDENTIAL
205017
68
10.11.8.2. Pharmacokinetic Figures Part B
Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Concentration Plots
3.8.
PK
PKCF1P
Individual GSK2982772 Plasma Concentration-Time Plot by 
Subject (Linear and Semi-Log): Part B
Paginate by Subject
SAC
3.9.
PK
PKCF1P
Individual GSK2982772 Plasma Concentration-Time Plot by 
Dose (Linear and Semi-Log): Part B
Paginate by Dose
SAC
Mean / Median Concentration Plots
3.10.
PK
PKCF2
Mean Plasma GSK2982772 Concentration-Time Plots by Dose
(Linear and Semi-log): Part B
Paginate by Dose
SAC
3.11.
PK
PKCF3
Median Plasma GSK2982772 Concentration-Time Plots by 
Dose (Linear and Semi-log): Part B
Paginate by Dose
SAC
3.12.
PK
PK_F1
Plot of Individual Subject (+Geometric Mean and 95% CI) 
Plasma GSK2982772 Dose-Normalized PK Parameters vs 
Dose: Part B
SAC
3.13.
PK
PK_F2
Plot of Geometric Mean Ratio and 90% CI of Plasma 
GSK2982772 PK Parameters Assessing Relative Bioavailability 
of Repeat Dose: Part B
SAC


CONFIDENTIAL
205017
69
10.11.8.3. Pharmacokinetic Figures Part C
Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Concentration Plots
3.14.
PK
PKCF1P
Individual GSK2982772 Plasma Concentration-Time Plot by 
Subject (Linear and Semi-Log): Part C
Paginate by Subject
SAC
3.15.
PK
PKCF1P
Individual GSK2982772 Plasma Concentration-Time Plot by 
Formulation (Linear and Semi-Log): Part C
Paginate by Formulation.  This 
includes the fed state.
SAC
Mean / Median Concentration Plots
3.16.
PK
PKCF2
Mean Plasma GSK2982772 Concentration-Time Plots by 
Formulation (Linear and Semi-log): Part C
Paginate by Formulation.  This 
includes the fed state.
SAC
3.17.
PK
PKCF3
Median Plasma GSK2982772 Concentration-Time Plots by 
Formulation (Linear and Semi-log): Part C
Paginate by Formulation.  This 
includes the fed state.
SAC
3.18.
PK
PK_F1
Plot of Individual Subject (+Geometric Mean and 95% CI) 
Plasma GSK2982772 PK Parameters vs Formulation: Part C
SAC
3.19.
PK
PK_F2
Plot of Geometric Mean Ratio and 90% CI of Plasma 
GSK2982772 PK Parameters Assessing Relative Bioavailability 
of Formulation: Part C
SAC
3.20.
PK
PK_F2
Plot of Geometric Mean Ratio and 90% CI of Plasma 
GSK2982772 PK Parameters Assessing Relative Bioavailability 
of Food Effect: Part C
SAC


CONFIDENTIAL
205017
70
Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.21.
PK
PK_F2
Plot of Geometric Mean Ratio and 90% CI of Plasma 
GSK2982772 PK Parameters Assessing Relative Bioavailability 
of Dose: Part C
SAC


CONFIDENTIAL
205017
71
10.11.9.
ICH Listings
10.11.9.1. ICH Listing Part A
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
All Subjects
ES7
Listing of Reasons for Screen Failure: Part A
Journal Guidelines
SAC
2.
Safety
ES3
Listing of Reasons for Study Withdrawal: Part A
ICH E3
SAC
3.
Safety
TA2 
Listing of Planned and Actual Treatments: Part A
IDSL
SAC
Protocol Deviations
4.
Safety
DV2
Listing of Important Protocol Deviations: Part A
ICH E3
SAC
5.
All Subjects
IE4
Listing of Subjectswith Inclusion/Exclusion Criteria Deviations: 
Part A
ICH E3
SAC


CONFIDENTIAL
205017
72
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Populations Analysed
6.
Safety
SP3
Listing of SubjectsExcluded from Any Population: Part A
ICH E3
SAC
Demographic and Baseline Characteristics
7.
Safety
DM4
Listing of Demographic Characteristics: Part A
ICH E3
SAC
8.
Safety
DM10
Listing of Race: Part A
ICH E3
SAC
Prior and Concomitant Medications
9.
Safety
CP_CM3
Listing of Concomitant Medications: Part A
IDSL
SAC
Exposure and Treatment Compliance
10.
Safety
EX4
Listing of Exposure Data: Part A
ICH E3
SAC
Adverse Events
11.
Safety
AE9CP
Listing of All Adverse Events: Part A
ICH E3
SAC
12.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events: Part A
ICH E3
SAC
13.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text: Part A
IDSL
SAC
Serious and Other Significant Adverse Events
14.
Safety
AE9CP
Listing of Serious Adverse Events: Part A
ICH E3
SAC
15.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event: 
Part A
ICH E3
SAC


CONFIDENTIAL
205017
73
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
16.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment: Part A
ICH E3
SAC
Hepatobiliary (Liver)
17.
Safety
MH2
Listing of Medical Conditions for Subjectswith Liver Stopping 
Events: Part A
IDSL
SAC
18.
Safety
SU2
Listing of Substance Use for Subjectswith Liver Stopping 
Events: Part A
IDSL
SAC


CONFIDENTIAL
205017
74
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
All Laboratory
19.
Safety
LB6
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance/Outside Normal Range: Part A
ICH E3
SAC
20.
Safety
LB6
Listing of Laboratory Values of Potential Clinical Importance: 
Part A
SAC
93.
Safety
LB6
Listing of All Lipid Data for Subjects with Any Value Outside of 
Laboratory Normal Range: Part A
SAC
21.
Safety
LB14
Listing of Microscopy Results for Subjects with Abnormal 
Urinalysis Dipstick Results: Part A
ICH E3
SAC


CONFIDENTIAL
205017
75
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
22.
Safety
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance: Part A
IDSL
SAC
23.
Safety
EG4
Listing of ECG Values of Potential Clinical Importance: Part A
IDSL
SAC
24.
Safety
EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding: Part A
IDSL
SAC
25.
Safety
EG6
Listing of Abnormal ECG Findings: Part A
IDSL
.
SAC


CONFIDENTIAL
205017
76
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
26.
Safety
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance: Part A
IDSL
SAC
27.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance: Part A
IDSL
SAC
10.11.9.2. ICH Listings Part B
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
28.
All Subjects
ES7
Listing of Reasons for Screen Failure: Part B
Journal Guidelines
SAC
29.
Safety
ES3
Listing of Reasons for Study Withdrawal: Part B
ICH E3
SAC
30.
Safety
TA2 
Listing of Planned and Actual Treatments: Part B
IDSL
SAC
Protocol Deviations
31.
Safety
DV2
Listing of Important Protocol Deviations: Part B 
ICH E3
SAC


CONFIDENTIAL
205017
77
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
32.
All Subjects
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations: 
Part B
ICH E3
SAC
Populations Analysed
33.
Safety
SP3
Listing of Subjects Excluded from Any Population: Part B
ICH E3
SAC
Demographic and Baseline Characteristics
34.
Safety
DM4
Listing of Demographic Characteristics: Part B
ICH E3
SAC
35.
Safety
DM10
Listing of Race: Part B
ICH E3
SAC
Prior and Concomitant Medications
36.
Safety
CP_CM3
Listing of Concomitant Medications: Part B
IDSL
SAC
Exposure and Treatment Compliance
37.
Safety
EX4
Listing of Exposure Data: Part B
ICH E3
SAC
Adverse Events
38.
Safety
AE9CP
Listing of All Adverse Events: Part B
ICH E3
SAC
39.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events: Part 
B
ICH E3
SAC
40.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text: Part B
IDSL
SAC


CONFIDENTIAL
205017
78
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
41.
Safety
AE9CP
Listing of Serious Adverse Events: Part B
ICH E3
SAC
42.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse 
Event: Part B
ICH E3
SAC
43.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment: Part B
ICH E3
SAC
Hepatobiliary (Liver)
44.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events: Part B
IDSL
SAC
45.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events: Part B
IDSL
SAC


CONFIDENTIAL
205017
79
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
All Laboratory
46.
Safety
LB6
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance/Outside Normal Range: Part B
ICH E3
SAC
47.
Safety
LB6
Listing of Laboratory Values of Potential Clinical Importance: 
Part B
SAC
94.
Safety
LB6
Listing of All Lipid Data for Subjects with Any Value Outside of 
Laboratory Normal Range: Part B
SAC
48.
Safety
LB14
Listing of Microscopy Results for Subjects with Abnormal 
Urinalysis Dipstick Results: Part B
ICH E3
SAC


CONFIDENTIAL
205017
80
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
49.
Safety
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance: Part B
IDSL
SAC
50.
Safety
EG4
Listing of ECG Values of Potential Clinical Importance: Part B
IDSL
SAC
51.
Safety
EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding: Part B
IDSL
SAC
52.
Safety
EG6
Listing of Abnormal ECG Findings: Part B
IDSL
SAC


CONFIDENTIAL
205017
81
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
53.
Safety
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance: Part B
IDSL
SAC
54.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance: Part B
IDSL
SAC
C-SSRS
55.
Safety
CSSRS4  
Listing of C-SSRS Suicidal Ideation and Behavior Data: Part B
IDSL 
SAC
56.
Safety
CSSRS5  
Listing of C-SSRS Suicidal Behavior Details: Part B
IDSL 
SAC
PSRAE
57.
Safety
PSRAE1  
Listing of Possible Suicidality-Related Adverse Event Data:
Event and Description (Section 1 - Section 2): Part B
IDSL
SAC


CONFIDENTIAL
205017
82
10.11.9.3. ICH Listing Part C
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
58.
All Subjects
ES7
Listing of Reasons for Screen Failure: Part C
Journal Guidelines
SAC
59.
Safety
ES3
Listing of Reasons for Study Withdrawal: Part C
ICH E3
SAC
60.
Safety
TA2 
Listing of Planned and Actual Treatments: Part C
IDSL
SAC
Protocol Deviations
61.
Safety
DV2
Listing of Important Protocol Deviations: Part C 
ICH E3
SAC
62.
All Subjects
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations: 
Part C
ICH E3
SAC


CONFIDENTIAL
205017
83
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Populations Analysed
63.
Safety
SP3
Listing of Subjects Excluded from Any Population: Part C
ICH E3
SAC
Demographic and Baseline Characteristics
64.
Safety
DM4
Listing of Demographic Characteristics: Part C
ICH E3
SAC
65.
Safety
DM10
Listing of Race: Part C
ICH E3
SAC
Prior and Concomitant Medications
66.
Safety
CP_CM3
Listing of Concomitant Medications: Part C
IDSL
SAC
Exposure and Treatment Compliance
67.
Safety
EX4
Listing of Exposure Data: Part C
ICH E3
SAC
Adverse Events
68.
Safety
AE9CP
Listing of All Adverse Events: Part C
ICH E3
SAC
69.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events: Part 
C
ICH E3
SAC
70.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text: Part C
IDSL
SAC
Serious and Other Significant Adverse Events
71.
Safety
AE9CP
Listing of Serious Adverse Events: Part C
ICH E3
SAC


CONFIDENTIAL
205017
84
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
72.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse 
Event: Part C
ICH E3
SAC
73.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment: Part C
ICH E3
SAC
Hepatobiliary (Liver)
74.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events: Part C
IDSL
SAC
75.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events: Part C
IDSL
SAC


CONFIDENTIAL
205017
85
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
All Laboratory
76.
Safety
LB6
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance/Outside Normal Range: Part C
ICH E3
SAC
77.
Safety
LB6
Listing of Laboratory Values of Potential Clinical Importance: 
Part C
SAC
95.
Safety
LB6
Listing of All Lipid Data for Subjects with Any Value Outside of 
Laboratory Normal Range: Part C
SAC
78.
Safety
LB14
Listing of Microscopy Results for Subjects with Abnormal 
Urinalysis Dipstick Results: Part C
ICH E3
SAC


CONFIDENTIAL
205017
86
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
79.
Safety
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance: Part C
IDSL
SAC
80.
Safety
EG4
Listing of ECG Values of Potential Clinical Importance: Part C
IDSL
SAC
81.
Safety
EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding: Part C
IDSL
SAC
82.
Safety
EG6
Listing of Abnormal ECG Findings: Part C
IDSL
SAC


CONFIDENTIAL
205017
87
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
83.
Safety
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance: Part C
IDSL
SAC
84.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance: Part C
IDSL
SAC
10.11.10. Non-ICH Listings
10.11.10.1. Non-ICH Listings Part A
Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
85.
PK
PKCL1X
Listing of Plasma GSK2982772 Pharmacokinetic Concentration-
Time (ng/mL) Data: Part A
IA
SAC
86.
PK
PKPL1X
Listing of Derived Plasma GSK2982772 Pharmacokinetic 
Parameters: Part A
IA
SAC
Meal Times
87.
Safety
CP_ML1x
Listing of Dosing Times, Meal Start and End Times on Fed 
Treatment Days: Part A
IA
SAC


CONFIDENTIAL
205017
88
10.11.10.2. Non-ICH Listings Part B
Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
88.
PK
PKCL1
Listing of Plasma GSK2982772 Pharmacokinetic Concentration-
Time (ng/mL) Data: Part B
IA
SAC
89.
PK
PKPL1
Listing of Derived Plasma GSK2982772 Pharmacokinetic 
Parameters: Part B
IA
SAC
10.11.10.3. Non-ICH Listings Part C
Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
90.
PK
PKCL1X
Listing of Plasma GSK2982772 Pharmacokinetic Concentration-
Time (ng/mL) Data: Part C
IA
SAC
91.
PK
PKPL1X
Listing of Derived Plasma GSK2982772 Pharmacokinetic 
Parameters: Part C
IA
SAC
Meal Times
92.
Safety
CP_ML1x
Listing of Dosing Times, Meal Start and End Times on Fed 
Treatment Days: Part C
IA
SAC