Clinical trial NCT03649412
Conditions: Autoimmune Diseases
Keywords: Tablet formulation Sequence Immediate release Pharmacokinetic
Sponsor: GlaxoSmithKline
Start date: 2018-09-26; Completion date: 2019-05-07
Enrollment: 33 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Previous clinical studies of immediate release (IR) formulations of GSK2982772 resulted in a high peak to trough ratio of GSK2982772. Additionally, the short half-life for GSK2982772 (approximately 2 to 3 hours) necessitates twice a daily (BID) or thrice daily (TID) dosing of an IR formulation. As a result, MR formulations using a polymer matrix approach with minitablets in capsule and MR tablet formulations were investigated. The emerging PK data of the MR formulations investigated to date have demonstrated that a once daily (QD) PK profile can be achieved in the fasted state but the polymer matrix formulation is susceptible to food effects when administered with a high fat breakfast. The purpose of this study is to evaluate MR prototype coated tablet formulations. This study will evaluate the PK of MR prototype coated tablet formulations of GSK2982772. The study is divided into two parts; Part A and Part B. The MR tablet coating used in Part A and the initial periods of Part B will have an aperture drilled into the enteric coating of either side of the tablet. This allows some drug release to commence in the stomach whilst providing controlled release throughout the gastrointestinal (GI) tract. In Part B only, a new investigational medicinal product (IMP) will be manufactured to allow comparison of the tablet coating either with apertures (i.e., drilled) or without apertures (i.e., full coat/non drilled). Part A will be a 6-period, 6-way fixed sequence design, up to 4 MR tablet prototype coated formulations will be evaluated in fasted state at 240 milligrams (mg). Periods 1, 2 and 3 will evaluate MR1, IR tablet and MR2 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 addition, the impact of food (high fat meal, standard breakfast or administration 30 or 60 minutes before a standard breakfast) on selected MR prototype coated tablet formulations may also be evaluated in Period 4, 5 or 6 of Part A. Each inpatient period for MR regimens (Periods 1, 3, 4 to 6) will consist of 4 days and 3 nights, and the inpatient period for the IR tablet (Period 2) will consist of 3 days and 2 nights. There will be a minimum washout of 7 days between doses, and a follow-up visit will occur at 7 to 9 days after the last study treatment. The Part B of the study will be a 7-period fixed sequence which will evaluate the selected MR prototype coated tablet formulation(s) at different tablet strengths or as multiple unit doses and with or without apertures in the tablet coatings. There will be an interim review after each period 1 to 5 of Part B to select the dose level, formulation and prandial status for each subsequent period. An interim data review after Part B Period 6 will determine if optional Period 7 is required and the dose level, dosing time (morning or evening), formulation and prandial status for that period. Each inpatient period will consist of a 4-day and 3-night with a minimum of 7 days washout between doses. A follow-up visit will occur at 7 to 9 days after the last study treatment. Approximately 33 subjects will be enrolled in the study. The total duration for Part A will be approximately 10-12 weeks and 10-14 weeks for Part B (including screening period of approximately 4 weeks).

Detailed description:

Arms: arm 1: Subjects in Part A will receive GSK2982772 MR (Period 1, 3, 4, 5 and 6) and GSK2982772 IR (Period 2). arm 2: Subjects in Part B will receive GSK2982772 MR.
Interventions: intervention 1: GSK2982772 Modified Release intervention 2: GSK2982772 Immediate Release
Intervention descriptions: intervention 1: GSK2982772 MR will be available as MR prototype coated tablet with unit dose strength of 240 mg in Part A. In Part B, GSK2982772 MR prototype coated tablet with unit dose strength of 120 mg (may be changed following interim review of Part B) will be administered by subjects. GSK2982772 MR will be administered orally with 240 milliliter (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 240 mg (8 tablets of dose strength 30 mg) orally with 240 mL of water

Protocol documents:
Prot_001.pdf: 
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TITLE PAGE
Protocol Title: A two part, non-randomised, open label study designed to assess the 
pharmacokinetic profile of modified release prototype coated tablet formulations of 
GSK2982772 relative to an immediate release reference tablet formulation at a fixed 
strength (Part A) and the pharmacokinetic profile of alternative tablet strengths of the 
selected modified release prototype coated tablet formulation (Part B, optional) in healthy
participants.
Protocol Number: 209261/Amendment 3
Quotient Reference Number: QSC201113
Short Title: A study to investigate the pharmacokinetics of modified release prototype 
coated tablet formulations of GSK2982772.
Compound Number:
Study Phase:
GSK2982772
Phase 1
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 2018-002370-48
Approval Date: 10-APR-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment 3
10-APR-2019
2018N367092_04
Amendment 2
26 FEB-2019
2018N367092_03
Amendment 1
28-AUG-2018
2018N367092_02
Original Protocol Republishing
08-AUG-2018
2018N367092_01
Original Protocol
23-JUL-2018
2018N367092_00
Amendment 3 10-APR-2019
Overall Rationale for the Amendment:
This amendment will incorporate an additional optional period (Period 7) to Part B of the 
study. This additional period will incorporate the additional options for a delayed high-fat 
or standard breakfast/evening meal given 30 min to 60 min post-dose and/or morning or 
evening dosing. 
 
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Section # and 
Name
Description of Change
Brief Rationale
Synopsis –
Objectives and 
Endpoints, Overall 
Study Design and 
Treatment Groups 
and Duration, 
Table 1 –
Schedule of
Activities for 
Parts A and B, 
Table 2 –
Pharmacokinetic 
Blood Sample 
Collection Times –
Part A and B, 
Section 3.3 –
Benefit/Risk 
Assessment, 
Section 4 -
Objectives and 
Endpoints, 
Section 5.1 –
Overall Design, 
Section 5.1.2 –
Part B, Figure 2 –
Part B Study 
Design – Tablet 
Strength, Section 
5.1.3 – Criteria for 
Interim Decisions, 
Section 5.4 –
Scientific 
Rationale for 
Study Design, 
Section 6.3.1 –
Meals and Dietary 
Restrictions, 
Section 7.1.2 –
Treatments 
Administered –
Part B, Section 9 
– Study 
Assessments and 
Procedures, 
Section 10.4.1 –
An additional optional Period 
(Period 7) has been added to 
Part B. The clinical protocol 
currently only allows for 
dosing in the morning of 
Day 1 in each period and 
administering a standard 
high-fat breakfast pre-dose. 
The protocol will be updated
to allow dosing in the evening 
and the potential for dosing a 
high-fat breakfast or evening 
meal 30 to 60 minutes 
post-dose (for Part B Period 7 
only).
Based on emerging data from Part B, the 
sponsor (GSK) would like the opportunity 
to investigate whether the 
between-subject variability in absorption 
time following administration of 480 mg 
tablet with a standard high-fat breakfast 
(administered in previous periods) can be 
reduced by changing feeding regimen or 
time of administration in an additional 
optional period (Period 7) to Part B of the 
study. This additional period will allow for 
the possibility of a delayed breakfast or 
evening meal at 30 or 60 minutes 
post-dose, morning or evening dosing 
and/or administration after a standard or 
high-fat breakfast or evening meal. 
 
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Section # and 
Name
Description of Change
Brief Rationale
Pharmacokinetic 
Analyses and 
Section 10.4.3 –
Interim Analyses
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................14
3.
INTRODUCTION....................................................................................................21
3.1.
Background ................................................................................................21
3.2.
Study Rationale ..........................................................................................21
3.3.
Benefit/Risk Assessment ............................................................................22
3.3.1.
Risk Assessment .........................................................................25
3.3.2.
Benefit Assessment.....................................................................31
3.3.3.
Overall Benefit:Risk Conclusion...................................................31
4.
OBJECTIVES AND ENDPOINTS...........................................................................31
5.
STUDY DESIGN ....................................................................................................34
5.1.
Overall Design ............................................................................................34
5.1.1.
Part A ..........................................................................................34
5.1.2.
Part B ..........................................................................................35
5.1.3.
Criteria for Interim Decisions........................................................38
5.2.
Number of Participants ...............................................................................42
5.3.
Participant and Study Completion...............................................................42
5.4.
Scientific Rationale for Study Design ..........................................................42
5.5.
Dose Justification........................................................................................44
6.
STUDY POPULATION...........................................................................................45
6.1.
Inclusion Criteria.........................................................................................45
6.2.
Exclusion Criteria........................................................................................47
6.3.
Lifestyle Considerations..............................................................................49
6.3.1.
Meals and Dietary Restrictions ....................................................49
6.3.2.
Activity .........................................................................................51
6.4.
Screen Failures...........................................................................................51
7.
TREATMENTS.......................................................................................................51
7.1.
Treatments Administered............................................................................52
7.1.1.
Treatments Administered - Part A................................................52
7.1.2.
Treatments Administered - Part B................................................53
7.2.
Dose Modification .......................................................................................55
7.3.
Method of Treatment Assignment ...............................................................55
7.4.
Blinding.......................................................................................................55
7.5.
Preparation/Handling/Storage/Accountability..............................................55
7.6.
Treatment Compliance................................................................................56
7.7.
Concomitant Therapy..................................................................................56
7.8.
Treatment after the End of the Study ..........................................................57
8.
DISCONTINUATION CRITERIA.............................................................................57
8.1.
Discontinuation of Study Treatment ............................................................57
8.1.1.
Liver Chemistry Stopping Criteria ................................................57
 
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8.1.1.1.
Study Intervention Restart or Rechallenge after 
liver stopping criteria met............................................58
8.1.2.
QTc Stopping Criteria ..................................................................58
8.1.3.
Individual Safety Stopping Criteria ...............................................58
8.1.4.
Temporary Discontinuation ..........................................................58
8.2.
Withdrawal from the Study..........................................................................59
8.3.
Lost to Follow Up........................................................................................59
8.4.
Study Stopping Criteria...............................................................................60
8.5.
Study Termination.......................................................................................60
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................61
9.1.
Efficacy Assessments.................................................................................62
9.2.
Adverse Events...........................................................................................62
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................62
9.2.2.
Method of Detecting AEs and SAEs.............................................62
9.2.3.
Follow-up of AEs and SAEs.........................................................62
9.2.4.
Regulatory Reporting Requirements for SAEs .............................63
9.2.5.
Pregnancy ...................................................................................63
9.3.
Treatment of Overdose...............................................................................63
9.4.
Safety Assessments ...................................................................................64
9.4.1.
Physical Examinations.................................................................64
9.4.2.
Vital Signs....................................................................................64
9.4.3.
Electrocardiograms......................................................................65
9.4.4.
Clinical Safety Laboratory Assessments ......................................65
9.4.5.
Suicidal Risk Monitoring...............................................................66
9.5.
Pharmacokinetics .......................................................................................66
9.6.
Pharmacodynamics ....................................................................................67
9.7.
Genetics .....................................................................................................67
9.8.
Biomarkers .................................................................................................67
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................67
10. STATISTICAL CONSIDERATIONS........................................................................68
10.1.
Hypotheses.................................................................................................68
10.2.
Sample Size Determination ........................................................................68
10.3.
Populations for Analyses ............................................................................69
10.4.
Statistical Analyses.....................................................................................69
10.4.1.
Pharmacokinetic Analyses...........................................................69
10.4.2.
Safety Analyses...........................................................................71
10.4.3.
Interim Analyses ..........................................................................72
10.4.4.
Stopping Criteria..........................................................................72
11. REFERENCES.......................................................................................................73
12. APPENDICES........................................................................................................74
12.1.
Appendix 1: Abbreviations and Trademarks................................................74
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................77
12.3.
Appendix 3: Study Oversight Considerations..............................................79
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting to GSK...........................84
 
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12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................90
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................94
12.7.
Appendix 7: Safety Reporting to Ethics Committee and Regulatory 
Authorities...................................................................................................96
12.8.
Appendix 8: Genetics..................................................................................98
12.9.
Appendix 9: Protocol Amendment History...................................................99
 
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1.
SYNOPSIS
Protocol Title: A two part, non-randomised, open label study designed to assess the 
pharmacokinetic profile of modified release prototype coated tablet formulations of 
GSK2982772 relative to an immediate release reference tablet formulation at a fixed 
strength (Part A) and the pharmacokinetic profile of alternative tablet strengths of the 
selected modified release prototype coated tablet formulations (Part B, optional) in 
healthy participants.
Short Title: A study to investigate the pharmacokinetics of modified release prototype 
formulations of GSK2982772.
Rationale: Previous clinical studies of immediate release (IR) formulations of 
GSK2982772 resulted in a high peak:trough ratio of GSK2982772. Additionally, the 
short half-life for GSK2982772 (~2 to 3 hours) necessitates twice daily (BID) or three 
times daily (TID) dosing of an IR formulation.  As a result, modified release (MR) 
formulations using a polymer matrix approach with minitablets in capsule and MR tablet 
formulations were investigated. The emerging pharmacokinetic (PK) data of the MR 
formulations investigated to date have demonstrated that a once daily (QD) PK profile 
can be achieved in the fasted state but the polymer matrix formulation is susceptible to 
food effects when administered with a high-fat breakfast. The purpose of this study is to 
evaluate MR prototype coated tablet formulations. The MR coated tablet formulation 
uses a combination of a controlled-release polymer matrix and controlled-release coating 
to achieve a modified-release of the drug. The MR tablet coating used in Part A and the 
initial periods of Part B will have an aperture drilled into the enteric coating of either side
of the tablet.  This allows some drug release to commence in the stomach whilst 
providing a controlled release throughout the GI tract.  This MR tablet coating has been 
used in other formulations (e.g. Lamictal XR) and in vivo has shown robustness against 
food effects. The hypromellose (HPMC) polymer has been shown to be effective in 
achieving a controlled delay to the drug release rate and thus lowering the maximum 
observed concentration (Cmax) and increasing the concentration at 24 hours post-dose
(C24h) of the product.  However, it is believed that the digestive mechanical action that 
the dosage form is exposed to in the fed stomach, and/or the longer stomach retention 
time when dosed in the fasted state, causes an increase in the rate of drug release.  
Application of an enteric coating with apertures will control the release rate when in the 
stomach.  In Part B only, a new IMP will be manufactured to allow comparison of the 
tablet coating either with apertures (i.e., drilled) or without apertures (i.e., full 
coat/non-drilled).  
Part A of the study is an adaptive crossover study that will optimise the MR prototype 
coated tablet formulation to provide a formulation suitable for QD dosing and has no 
clinically significant food effect.  The MR prototype coated tablet formulations have a 
matrix core containing hypromellose polymers.  The MR prototype coated tablet 
formulations will be optimised within a one-dimensional design space where release rate 
from the tablet will be adjusted by varying the polymer ratio in the tablet core.  The 
polymers will be hypromellose 2208 K3LV (polymer 1) and/or K100LV (polymer 2) 
and/or K4M (polymer 3).  The dose will be fixed at 240 mg, and the in vitro release rate 
will be targeted such that the tablet core of GSK2982772 MR prototype coated tablet
 
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formulation MR1 will have a dissolution profile that is similar to the release rate of the 
slowest release MR minitab formulation from Study 205017 (approximately 80% in vitro 
release at 12 hours).  GSK2982772 MR prototype coated tablet formulation MR2 will be 
designed such that the in vitro dissolution is slower than that of MR1, and will be the 
slowest available within the design space.  If neither MR1 nor MR2 provide an optimal 
profile, further MR prototype coated tablet formulations will be investigated.  The impact 
of food on the PK of GSK2982772 will also be evaluated for the selected formulation(s).  
After completion of Periods 3, 4 and 5, interim analyses will be conducted to determine 
the formulation and prandial status to be investigated in the next period.  After 
completion of Part A, an interim analysis will be conducted to identify the MR prototype 
coated tablet formulation(s) for progression into Part B.  If none of the MR prototype 
coated tablet formulations are suitable, then Part B of the study may not be conducted or 
Part B may be used to continue to optimise the formulation, which may include varying 
the tablet coating either with apertures (i.e., drilled) or without apertures (i.e., full 
coat/non-drilled) by the manufacture of a new IMP.
Optional Part B will assess the pharmacokinetics of alternative tablet strengths (120 mg 
and 480 mg, or alternative strengths) as allowed by the design space or tablets with 
apertures (i.e., drilled) or without apertures (i.e., full coat/non-drilled) or multiple dosing 
units of the optimum MR formulation selected from Part A.  If the in-vivo profile of 
either or both the 120 mg or 240 mg tablets (or alternative strengths) differs from the 
optimal profile with the 240 mg, the ratio of the polymers K3LV, K100LV and/or K4M 
may be adjusted within each of the alternative strengths. In order to assess the effect of 
the aperture on the in vivo performance of the formulation, a fully coated tablet (i.e.,
without apertures) may be assessed in Part B, Period 3 onwards. If fully coated tablet(s) 
are dosed, the core composition will match a previously dosed formulation to allow a 
valid comparison. Prior to initiation of Part B, a substantial amendment to the 
investigational medicinal product dossier (IMPD), will be submitted to the Medicines and 
Healthcare products Regulatory Agency (MHRA) for approval, to include updated 
information on the selected GSK2982772 MR prototype coated tablet formulations at 
alternative strengths.
Objectives and Endpoints:
Objective
Endpoint
Primary

To evaluate the single dose PK profile of 
GSK2982772 from each MR prototype coated 
tablet formulation (240 mg) compared to the 
IR formulation (240 mg) (Part A)

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)), maximum observed 
concentration (Cmax), concentration at 
24 hours post-dose (C24h), time to Cmax
(Tmax), terminal half-life (t1/2)
 
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Objective
Endpoint

To assess the impact of a high-fat breakfast 
on the PK of GSK2982772 following single 
dose administration of one or more selected 
MR prototype coated tablet formulations
(240 mg) (Part A or Optional Part B)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, 
Tmax, C24h,and t1/2, relative bioavailability 
(FrelFE), relative bioavailability 
(FrelFormulation), based on AUC and Cmax
Secondary

To assess the safety and tolerability of single 
doses of GSK2982772 (Part A)

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

To determine the bioavailability of 
GSK2982772 MR prototype coated tablet 
formulations relative to the IR reference, as 
appropriate (Part A)

Relative bioavailability (Frelformulation) 
based on AUC and Cmax
Exploratory

To assess the safety and tolerability of single 
doses of GSK2982772 (Optional Part B)

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

To evaluate the PK profile of alternative tablet 
strengths of selected GSK2982772 MR 
prototype coated tablet formulations (Optional 
Part B)

GSK2982772 AUC(0-inf), AUC(0-t), 
AUC(0-24), Cmax, C24h, t1/2, AUC/Dose and 
Cmax/Dose

To evaluate the impact of dosing 2 or more 
MR prototype coated tablets on the PK profile 
of GSK2982772 (Optional Part B)

GSK2982772 AUC(0-inf), AUC(0-t) or 
AUC(0-24), Cmax, Tmax and t1/2
 
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Objective
Endpoint

To determine if there are any dose dependent 
changes in the absorption of GSK2982772 
following single dose administration selected 
GSK2982772 MR prototype coated tablet 
formulations (Optional Part B)

GSK2982772 AUC(0-inf), AUC(0-t),
AUC(0-24), Cmax, C24h and Tmax

To assess the impact of a standard breakfast 
on the PK of GSK2982772 following single 
dose administration of one or more selected 
MR prototype coated tablet formulations
(240 mg) (Part A - optional)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, 
Tmax and t1/2, relative bioavailability 
(FrelFE), relative bioavailability 
(FrelFormulation), based on AUC and Cmax

To assess the impact of a delayed meal on 
the PK of GSK2982772 following single dose 
administration of one or more selected MR 
prototype coated tablet formulations (240 mg) 
(Part A - optional)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, 
Tmax and t1/2, relative bioavailability 
(FrelFE), relative bioavailability 
(FrelFormulation), based on AUC and Cmax

To assess the impact of evening dosing 
(Optional Part B, Period 7 only) on the PK of 
GSK2982772 following single dose 
administration selected GSK2982772 MR 
prototype coated tablet formulations.

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, 
Tmax and t1/2, relative bioavailability (Frel 
(time effect), based on AUC and Cmax
Overall Design:
This is an open label, non-randomised single centre, two part, single dose study in 
healthy male and female participants to assess MR prototype coated tablet formulations
of GSK2982772.  The impact of food (high-fat breakfast) on the rate and extent of 
absorption will be evaluated for suitable MR prototype coated tablet formulations, and an 
assessment of alternative tablet strengths, dosing of multiple dose units and 
presence/absence of apertures in the tablet may also be performed. An assessment of a 
standard or high-fat breakfast/evening meal or study drug administration 30 or 
60 minutes before a standard or high-fat (Part B, Period 7 only) breakfast or evening meal 
may also be included. The single dose may be given in the morning or evening (Part B,
Period 7 only).
Part A of the study is a non-randomised up to 6 period, 6-way fixed sequence design in 
which up to 4 MR prototype coated tablet formulations may be evaluated following 
single dose administration in the fasted state (240 mg).  Periods 1, 2 and 3 will evaluate
MR1 (similar in vitro dissolution to the slowest minitab MR formulation from study 
205017), IR tablet (240 mg) and MR2 (slower in vitro dissolution than MR1) 
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 evaluate the impact of a high-fat meal on one or more 
 
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already studied MR formulations. In addition, the impact of food (standard breakfast or 
administration 30 or 60 minutes before a standard breakfast) on selected MR prototype 
coated tablet formulations may also be evaluated in Period 5 or 6, as applicable.  There 
will also be the option to cancel Periods 5 and 6 if an optimal formulation is determined 
in Periods 1 or 3 which shows no clinically significant food effect with a high-fat meal in 
Period 4.  There will be interim decisions after Periods 3, 4 and 5, where appropriate, to 
determine the formulation and prandial status to be investigated in the next period.  
Following the final period of Part A, there will be an interim review to determine whether 
to proceed with optional Part B, and if so, the formulations and tablet strengths to be 
investigated in Part B.  
Optional Part B of the study is an open-label, non-randomised up to 7-period fixed 
sequence study design to evaluate the selected MR prototype coated formulation(s) at 
different tablet strengths or as multiple unit doses and with or without apertures in the
tablet coatings.  Up to 4 different MR prototype coated tablet formulations may be 
selected for investigation in Part B.  These will be selected from Part A and ongoing 
interim reviews in Part B; the selected formulations may be adjusted during interim 
reviews during Part B.  The tablet strengths and number of dosing units selected in Part B 
will be based on the exposure of GSK2982772 achieved in an ongoing high dose 
pharmacokinetic study in which doses of the IR tablet up to 240 mg TID are being 
administered, and the bioavailability of the selected MR prototype coated tablet 
formulations relative to the IR tablet (from Part A).  Up to 4 different dose levels (as 
different tablet strengths or multiple unit doses) may be administered in Part B.  The 
proposed dose levels are 120 mg, 480 mg, 960 mg and 1200 mg but these may be 
adjusted following review of the data from Part A or following the interim reviews during 
Part B, as appropriate.  In Part B, administration of the MR prototype coated tablet 
formulations will either be in the fed or fasted state, or administered 30 or 60 minutes
before a standard or high-fat (Period 7 only) breakfast/evening meal (Period 7 only), 
which will be based on emerging PK data.  There will be an interim review following 
each of Periods 1 to 5 of Part B to select the dose level, formulation and prandial status, 
as appropriate, for each subsequent period. An interim data review after Part B Period 6 
will determine if optional Period 7 is required and the dose level, dosing time (morning or 
evening), formulation and prandial status for that period.
 
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Number of Participants:
It is planned to enrol up to 16 participants into each part of the study to allow for 
sufficient data in at least 12 evaluable participants. For Part A, an evaluable participant
will have received the IR tablet formulation (reference) and at least one of the MR 
formulations and will have completed the planned safety and PK assessments up to 
24 hours after dosing.  For the food effect assessment, an evaluable subject will have 
received the chosen MR formulation in the fasted state and the relevant prandial state and 
will have completed the planned safety and PK assessments up to 48 hours after dosing.  
For Part B, an evaluable participant will have completed the planned safety and PK 
assessments up to 48 hours after dosing with at least one MR prototype coated tablet 
formulation.
Treatment Groups and Duration:
In Part A, each participant will be enrolled in the study for approximately 10 to 12 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 for the 
MR regimens (Periods 1 and 3 to 6) will consist of 4 days and 3 nights, and the inpatient 
period for the IR tablet (Period 2) will consist of 3 days and 2 nights.  There will be a 
minimum washout of 7 days between doses, and a follow-up visit will occur 7 to 9 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 10 to 14 weeks.  
Participation will include a screening evaluation within 28 days of study treatment 
administration and up to 7 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 4-day, 3-night inpatient period with a minimum of 
7 days washout between doses.  A follow-up visit will occur 7 to 9 days after the last 
study treatment. Participants will receive a single oral dose of study treatment during 
each inpatient period.
2.
SCHEDULE OF ACTIVITIES (SOA)
The schedules of activities for each part are presented in Table 1, and the time points for 
the pharmacokinetic (PK) blood sample collection in each part are presented in Table 2.
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 PK 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 
 
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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 e.g.
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.
 
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Table 1
Schedule of Activities for Parts A and B
Procedure
Screening 
(up to 28 days before Day 
1)
Treatment Period 1, 2, 3, 4, 5, 6 and in Part B 
only, 7
Day
Follow-up Visit
(7 to 9 days post last 
dose)
Notes
–1
1
2
3
Informed consent
X
Inclusion and exclusion criteria1
X
1.
Recheck clinical status 
before 1st dose of study 
medication.
Demography
X
Full physical examination including 
height and weight
X
Brief physical examination
X
X2
X2
X
2.
Discharge 
(48 h post-dose for
Part B, and Treatment 
Periods 1, 3, 4, 5 and 6
for Part A;
24 h post-dose for Part A 
Treatment Period 2 only)
Medical history (includes substance 
usage)3
X
3.
Substances: Drugs, 
Alcohol, tobacco and 
caffeine
Past and current medical conditions  
X
Follicle Stimulating Hormone (FSH) 
and estradiol (as needed in women 
of non-childbearing potential only)
X
Serum pregnancy test (WOCBP)
X
X
 
 
 
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Procedure
Screening 
(up to 28 days before Day 
1)
Treatment Period 1, 2, 3, 4, 5, 6 and in Part B 
only, 7
Day
Follow-up Visit
(7 to 9 days post last 
dose)
Notes
–1
1
2
3
Urine pregnancy test (WOCBP)
X
X4
X4
4.
Discharge 
(48 h post-dose for 
Part B, and Treatment 
Periods 1, 3, 4, 5 and 6 
for Part A;
24 h post-dose for Part A 
Treatment Period 2 only)
Human Immunodeficiency Virus 
(HIV), Hepatitis B and C screening5
X
5.
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
X6
X7
X
6.
Results must be available 
prior to dosing on Day 1
7.
24 h post-dose
Allowable windows in 
Section 9.4.4
Glomerular filtration rate
X
C-reactive protein (CRP)
X
 
 
 
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Procedure
Screening 
(up to 28 days before Day 
1)
Treatment Period 1, 2, 3, 4, 5, 6 and in Part B 
only, 7
Day
Follow-up Visit
(7 to 9 days post last 
dose)
Notes
–1
1
2
3
12-lead ECG
X8
X
X9
X10
X
8.
In triplicate
9.
Pre-dose and 2 and 12 h 
post-dose 
10. 24 h post-dose
Allowable windows in 
Section 9.4.3
Vital signs
X
X
X11
X12, 13
X13
X
11. Pre-dose and 2 and 12 h 
post-dose 
12. 24 h post-dose
Allowable windows in 
Section 9.4.2
13. Discharge 
(48 h post-dose for 
Part B, and Treatment 
Periods 1, 3, 4, 5 and 6 
for Part A;
24 h post-dose for Part A 
Treatment Period 2 only)
Genetics blood sample collection 
(optional)
X14
14. A blood sample is 
collected at the Day 1 
visit, after the participant 
has been randomised 
and provided informed 
consent for genetic 
research.  If the sample 
is not collected on Day 1, 
it can be collected at any 
time during the study 
after randomization.  
Subjects that decline to 
provide a sample will still 
be eligible for this study
 
 
 
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Procedure
Screening 
(up to 28 days before Day 
1)
Treatment Period 1, 2, 3, 4, 5, 6 and in Part B 
only, 7
Day
Follow-up Visit
(7 to 9 days post last 
dose)
Notes
–1
1
2
3
Study treatment
X15
15. Administration of IMP in 
Part B Period 7 may be in 
the morning or evening of 
Day 1. See Section 5.1.3
for more details.
AE review
===================================================
Serious AE (SAE) review
X
===================================================
Concomitant medication review
============================
PK blood sample collection
X16
X16
X16
16. Time points in Table 2
 
 
 
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Table 2
Pharmacokinetic Blood Sample Collection Times – Parts A and B
Treatment Periods 1, 3, 4, 5 and 6 (MR Formulations) for Part A and Part B (Treatment Periods 1 to 7a )
Time
Pre-
dose
0 h
2 
h
4 h
6 h
8 h
10 h
12 h
14 h
16 h
18 h
20 h
22 h
24 h
26 h
28 h
30 h
32 h
36 h
48 h
Dosing
X
PK sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Part A: Treatment Period 2 (IR Formulation)
Time
Pre-
dose
0 h
0.33 h
0.66 h
1 h
1.5 h
2 h
3 h
4 h
5 h
6 h
8 h
10 h
12 h
24 h
Dosing
X
PK sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a The time of dosing in Part B Period 7 (morning or evening) will be decided during the interim data review after Part B, Period 6.
 
 
 
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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.
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_03].
3.2.
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, twice daily (BID) and 
three times daily (TID) dosing regimens are being evaluated in three ongoing proof of 
mechanism studies.  A once daily (QD) formulation would be more convenient from a 
patient perspective and could offer the advantage of providing a flatter GSK2982772 
concentration time profile.  Pharmacokinetic data from a modified release (MR)
formulation study (205017) showed that a QD formulation was feasible; however, the 
MR formulation (minitabs in capsules) was susceptible to a food effect and a MR 
monolithic matrix tablet formulation may be mechanistically susceptible to a food effect 
as well.  This study will evaluate the feasibility of developing an MR prototype coated 
tablet formulation using a combination of a controlled release polymer matrix and 
 
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controlled-release coating.  The MR tablet coating used in Part A and the initial periods 
of Part B will have an aperture drilled into the enteric coating of either side of the tablet.  
This allows some drug release to commence in the stomach whilst providing controlled 
release throughout the GI tract.  This MR tablet coating has been used in other 
formulations (e.g. Lamictal XR) and in vivo has shown robustness against food effects. 
The hypromellose (HPMC) polymer has been shown to be effective in achieving a 
controlled delay to the drug release rate and thus lowering maximum observed 
concentration (Cmax) and increasing the concentration at 24 h post-dose (C24h) of the 
product.  However, it is believed that the digestive mechanical action that the dosage 
form is exposed to in the fed stomach, and/or the longer stomach retention time when 
dosed in the fasted state, causes an increase in the rate of drug release. Application of an 
enteric coating with apertures will control the release rate when in the stomach.  The MR 
prototype coated tablet formulations have a matrix core containing hypromellose
polymers.  The MR prototype coated tablet formulations will be optimised within a 
one-dimensional design space where release rate from the tablet will be adjusted by 
varying the polymer ratio in the tablet core. In Part B only, a new IMP will be 
manufactured to allow comparison of the tablet coating either with apertures (i.e., drilled) 
or without apertures (i.e., full coat/non-drilled).  
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.
3.3.
Benefit/Risk Assessment
As of 10 November 2018, approximately 296 participants have been enrolled in 8 clinical 
studies with GSK2982772. In completed Study 200975, GSK2982772 was administered 
up to 120 mg BID for 14 days (total daily dose 240 mg).  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.  No safety 
concerns were identified and no SAEs, including deaths, were reported in this study.
In ongoing Phase 1 studies (high dose PK Study [205184] and modified release 
formulation Study [205017]), a total of approximately 47 and 45 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 this ongoing Phase 1 study 209261, 
approximately 17 healthy subjects have been exposed to GSK2982772 as of 10 Nov 
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In the ongoing GSK2982772 study 205184 (A single-centre, randomized, double-blind 
(sponsor-unblinded), placebo-controlled study to evaluate the safety, tolerability and 
pharmacokinetics of GSK2982772 in repeat oral doses in healthy subjects), a subject 
experienced an asymptomatic non-serious adverse event of elevated ALT [7.5 × upper 
limit of normal (ULN)] and AST (4.5 × ULN) on study Day 15, one day after completing 
a 14 day treatment of GSK2982772 120 mg orally three times a day.  Due to the absence 
of another plausible explanation, the event was considered likely related to study drug 
and was severe in intensity. Bilirubin, prothrombin time, and work-up were all within 
normal limits and both ALT and AST returned to normal within 4 weeks.  Confounders 
included the following:
1. Subject received 1 g dose of paracetamol on study Day 13 for headache.
2. Subject had a history of mild aminotransferase elevation (1.7 and 1.3 × ULN for 
ALT and AST, respectively) in another healthy volunteer study while receiving an 
investigational monoclonal antibody.
3. Subject’s AST slightly increased (1.75 × ULN) during the follow-up period after 
initially declining to normal.  Creatine phosphokinase (CPK) was also elevated at 
that time and this elevation could be associated with physical activity.
The benefit/ risk profile is considered unchanged by this single, reversible and 
monitorable event.
In ongoing Study 205017 (A three-part, non-randomised, open label Phase 1 Study 
205017 assessing the PK of GSK2982772 modified release (MR) formulations relative to 
an immediate release (IR) reference formulation (Part A), the PK of escalating, repeat 
doses of a selected MR prototype (Part B), and the PK of GSK2982772 following 
administration of MR formulation in the fed and fasted state (Part C)), a completed 
suicide was reported 29 days after the subject received a single dose of GSK2982772. 
This subject had a prior undisclosed suicide attempt and the event was determined by the 
Investigator to be unlikely related to study drug. Given the short half-life of 
GSK2982772, there is no temporal relationship to support a causal association.
In the Phase 2a studies in PsO (Study 203167) and RA (Study 203168) and in the 
ongoing Ulcerative Colitis (Study 202152), approximately 107 participants (47 in the 
PsO study, 33 in the RA study) have been randomised/exposed to GSK2982772 60 mg 
BID or 60 mg TID. In Study 203167, there was a death of a 19-year-old male participant 
due to an accidental overdose with recreational drug 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 serious 
adverse events (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).
 
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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 (area under 
concentration vs time curve [AUC] of 1270 µg.h/mL and Cmax of 153 µg/mL).  Non-
clinical studies show no evidence of genotoxicity or teratogenicity.
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 the 
follow-up visit for the final dosing period (7-9 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.
 
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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 
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.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
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.
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.
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 
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
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 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 (e.g., inactivated 
influenza vaccines) may be administered while 
receiving GSK2982772 based on a treating physician 
assessment of the benefit:risk (e.g., risk of theoretical 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 Investigator’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 carbon 
dioxide (CO2), oxygen saturation and nocturnal respiratory 
rate monitoring was performed.  No SAEs were reported, 
and no drug-associated respiratory-related AEs were 
identified.
Subject Monitoring:

Subjects 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. 
Subject Selection:

Subjects with a current history of suicidal ideation and 
behaviour (SIB) or a history of attempted suicide will 
be excluded from the study.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
In the open-label modified release formulation study 
(205017), a completed suicide was reported 29 days after 
the subject received a single dose of GSK2982772. This 
subject had a prior undisclosed suicide attempt and the 
event was determined by the Investigator to be unlikely 
related to study drug. Given the short half-life of 
GSK2982772, there is no temporal relationship to support 
a causal association.
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.
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).
When GSK2982772 was given to F0 female rats from 
gestation day (GD) 6 through lactation day (LD) 21, there 
was no maternal toxicity observed up to a dose of 
300 mg/kg/day, the highest dose tested.  There were no 
effects on F1 viability up to 300 mg/kg/day, or F1 growth 
and development up to 100 mg/kg/day.  At 300 mg/kg/day, 
mean pup weight was lower than the control from 
post-natal day (PND) 1 through PND 21.
In female rats, GSK2982772 was given for 15 days prior to 
cohabitation, through cohabitation and on GD 0 to 6.  
There was decreased body weight gain and food 
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 study completion (Appendix 5). 

Females of childbearing potential will undergo serum 
pregnancy test at screening 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 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
consumption prior to mating at 400 mg/kg/day and during 
gestation at >200 mg/kg/day.  At the dose level of 
400 mg/kg/day, there were effects on reproductive 
performance (decreased mean numbers of corpora lutea, 
implantations and mean live litter size and increased 
post-implantation loss).  The NOAEL for female fertility and 
early embryonic development in rats was considered to be 
200 mg/kg/day.
In male rats, there were no effects on mating, fertility and 
organ weights, and no male-mediated foetal 
developmental toxicity following administration of 10, 60 or 
200 mg/kg/day for 44-45 days.  Therefore, the NOAEL for 
reproductive performance and for male-mediated 
developmental toxicity is 200 mg/kg/day. 
The mutagenic and clastogenic potential of GSK2982772 
has been assessed using in vitro tests in bacteria and 
cultured mammalian cells and also in an in vivo rodent 
bone marrow micronucleus assessment to test for 
induction of structural chromosomal damage and/or 
aneuploidy. Appropriate vehicle and positive controls were 
included in each test. In addition, an assessment of the 
route of synthesis for GSK2982772 has been conducted to 
determine if there are any impurities which are known or 
suspected deoxyribonucleic acid (DNA)-reactive mutagens 
are likely to be present in the final drug substance.
Non-clinical studies show no evidence of genotoxicity or 
teratogenicity.
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 
Subject Selection:

No concomitant medications will be permitted in this 
study with the exception of 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 a drug interaction with 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_03 ].
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.
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.
 
 
 
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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.
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise 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
Objective
Endpoint
Primary

To evaluate the single dose PK profile of 
GSK2982772 from each MR prototype
coated tablet formulation (240 mg) 
compared to the IR formulation (240 mg) 
(Part A)

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)), maximum observed 
concentration (Cmax), concentration at 
24 hours post-dose (C24h), time to Cmax
(Tmax), terminal half-life (t1/2)

To assess the impact of a high-fat breakfast
on the PK of GSK2982772 following single 
dose administration of one or more selected 
MR prototype coated tablet formulations
(240 mg) (Part A or Optional Part B)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, Tmax,
C24h, and t1/2, relative bioavailability (FrelFE),
relative bioavailability (FrelFormulation), based 
on AUC and Cmax
Secondary

To assess the safety and tolerability of 
single doses of GSK2982772 (Part A)

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
 
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Objective
Endpoint

To determine the bioavailability of 
GSK2982772 MR prototype coated tablet 
formulations relative to the IR reference, as 
appropriate (Part A)

Relative bioavailability (Frelformulation) based 
on AUC and Cmax
Exploratory

To assess the safety and tolerability of 
single doses of GSK2982772 (Optional 
Part B)

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
 
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Objective
Endpoint

To evaluate the PK profile of alternative 
tablet strengths of selected GSK2982772 
MR prototype coated tablet formulations 
(Optional Part B)

GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), 
Cmax, C24h, t1/2, AUC/Dose and Cmax/Dose

To evaluate the impact of dosing 2 or more 
MR prototype coated tablets on the PK 
profile of GSK2982772 (Optional Part B)

GSK2982772 AUC(0-inf), AUC(0-t) or AUC(0-24), 
Cmax, Tmax and t1/2

To determine if there are any dose 
dependent changes in the absorption of 
GSK2982772 following single dose 
administration selected GSK2982772 MR 
prototype coated tablet formulations 
(Optional Part B)

GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), 
Cmax, C24h and Tmax

To assess the impact of a standard 
breakfast on the PK of GSK2982772 
following single dose administration of one 
or more selected MR prototype coated 
tablet formulations (240 mg) (Part A -
optional)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, Tmax 
and t1/2, relative bioavailability (FrelFE), 
relative bioavailability (FrelFormulation), based 
on AUC and Cmax

To assess the impact of a delayed meal on 
the PK of GSK2982772 following single 
dose administration of one or more selected 
MR prototype coated tablet formulations
(240 mg) (Part A - optional)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, Tmax 
and t1/2, relative bioavailability (FrelFE), 
relative bioavailability (FrelFormulation), based 
on AUC and Cmax

To assess the impact of evening dosing 
(Optional Part B, Period 7 only) on the PK 
of GSK2982772 following single dose 
administration selected GSK2982772 MR 
prototype coated tablet formulations.

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, Tmax 
and t1/2, relative bioavailability (Frel (time 
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5.
STUDY DESIGN
5.1.
Overall Design
This is an open label, non-randomised single centre, two part, single dose study in 
healthy male and female participants to assess MR prototype coated tablet formulations 
of GSK2982772.  The impact of food (high-fat breakfast) on the rate and extent of 
absorption will be evaluated for suitable MR prototype coated tablet formulations, and an 
assessment of alternative tablet strengths, dosing of multiple dose units and 
presence/absence of apertures in the tablet may also be performed. An assessment of a 
standard or high-fat breakfast/evening meal or study drug administration 30 or 
60 minutes before a standard or high-fat breakfast or evening meal (Part B, Period 7 only) 
may also be included. The single dose may be given in the morning or evening (Part B, 
Period 7 only).
5.1.1.
Part A
Part A of the study is a non-randomised up to 6 period, 6-way fixed sequence design in 
which up to 4 MR tablet prototype coated formulations may be evaluated following 
single dose administration in the fasted state (240 mg) (Figure 1).  Periods 1, 2 and 3 will 
evaluate MR1 (similar in vitro dissolution to the slowest minitab MR formulation from 
study 205017), IR Tablet (240 mg) and MR2 (slower in vitro dissolution than MR1) 
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 evaluate the impact of a high-fat meal of one or more
already studied MR formulations.  In addition, the impact of food (standard breakfast or 
administration 30 or 60 minutes before a standard breakfast) on selected MR prototype 
coated tablet formulations may also be evaluated in Period 5 or 6, as applicable.  There 
will also be the option to cancel Periods 5 and 6 if an optimal formulation is determined 
in Periods 1 or 3 which shows no clinically significant food effect with a high-fat meal in 
Period 4.  There will be interim decisions after Periods 3, 4 and 5, where appropriate, to 
determine the formulations and prandial status to be investigated in the next period.  
Following the final period of Part A, there will be an interim review to determine whether 
to proceed with optional Part B, and if so, the formulations and tablet strengths to be 
investigated in Part B.  
Each inpatient period for the MR regimens (Periods 1, 3, 4 to 6) will consist of 4 days 
and 3 nights, and the inpatient period for the IR tablet (Period 2) will consist of 3 days 
and 2 nights.  There will be a minimum washout of 7 days between doses, and a 
follow-up visit will occur at 7 to 9 days after the last study treatment.  Participants will 
receive a single oral dose of study treatment during each inpatient period.
 
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Figure 1
Part A Study Design – Formulation Optimisation and Food Effect
Period 1:
240 mg MR 
prototype
coated 
tablet  MR1
Fasted
Period 2:
8 x 30 mg 
IR tablet    
Fasted
Period 3:
240 mg 
MR 
prototype 
coated 
tablet
MR2
Fasted
Period 4:
240 mg MR3 
prototype
coated tablet
Fasted 
(alternative 
formulation) 
or Fed 
(previously 
dosed 
formulation)
Period 5:
240 mg MR4 
prototype
coated tablet
Fasted 
(alternative 
formulation) 
or Fed –
alternative 
meal or meal 
timing 
(previously 
dosed 
formulation)
Period 6:
240 mg MR 
prototype
coated tablet
Fasted 
(alternative 
formulation) 
or Fed –
alternative 
meal or meal 
timing 
(previously 
dosed 
formulation)
Min 7 day 
washout
Min 7 day 
washout
Min 7 day 
washout
Min 7 day 
washout
Min 7 day 
washout
5.1.2.
Part B
Optional Part B of the study is an open-label, non-randomised up to 7-period fixed 
sequence study design to evaluate the selected MR prototype coated tablet formulation(s)
at different tablet strengths or as multiple unit doses and with or without apertures in the 
tablet coatings (Figure 2).  Up to 4 different MR prototype coated tablet formulations 
may be selected for investigation in Part B.  These will be selected from Part A and 
ongoing interim reviews in Part B; the selected formulations may be adjusted during 
interim reviews in Part B.  The tablet strengths and the number of dosing units selected in 
Part B will be based on the exposure of GSK2982772 achieved in an ongoing high dose 
PK study in which doses of the IR tablet up to 240 mg TID are being administered, and 
the bioavailability of the selected MR prototype coated tablet formulations relative to the 
IR tablet (from Part A).  Up to 4 different dose levels (as different tablet strengths or 
multiple unit doses) may be administered in Part B.  The proposed dose levels are 
120 mg, 480 mg, 960 mg and 1200 mg but these may be adjusted following review of the 
data from Part A or following the interim reviews during Part B, as appropriate.  In 
Part B, administration of the MR prototype coated tablet formulations will either be in the 
fed or fasted state, or administered 30 or 60 minutes before a standard or high-fat 
(Period 7 only) breakfast/evening meal (Period 7 only), which will be based on emerging 
PK data.  There will be an interim review following each of Periods 1 to 5 of Part B to 
select the dose level, formulation and prandial status, as appropriate, for each subsequent 
period. An interim data review after Part B Period 6 will determine if optional Period 7 is 
required and the dose level, dosing time (morning or evening), formulation and prandial 
status for that period.
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 4-day, 3-night 
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. One of the regimens investigated in Periods 4, 5 or 6 will include 
fed dosing
 
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inpatient period with a minimum of 7 days washout between doses.  A follow-up visit 
will occur at 7 to 9 days after the last study treatment.
 
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Figure 2
Part B Study Design – Tablet Strength
Period 1:
120 mg1    
MRX 
prototype 
coated tablet    
Fed status:  
tbc2
Period 2:
yy ×
xxx mg3
MRX 
prototype
coated tablet
Fed status: 
tbc2
Optional 
Period 3:
yy × xxx mg3
MRX4 or 
MRX14
prototype 
coated tablet    
Fed status: 
tbc2
Optional 
Period 4:
yy × xxx mg3
MRX4 or 
MRX1 
prototype 
coated tablet 
Fed status: 
tbc2
Optional 
Period 5:
yy × xxx mg3
MRX4, 
MRX1 or 
MRX2 
prototype 
coated tablet    
Fed status: 
tbc2
Optional 
Period 6:
yy × xxx mg3
MRX? 4
prototype 
coated tablet     
Fed status: 
tbc2
Optional 
Period 75:
yy × xxx mg3
MRX? 4
prototype 
coated tablet    
Fed status: 
tbc2
Min 7 day 
washout
Min 7 day 
washout
Min 7 day 
washout
Min 7 day 
washout
Min 7 day 
washout
Min 7 day 
washout
Interim decisions based on PK and safety data. Periods 2 to 7 are 
flexible and the dosing regimen will be dependent on the outcome 
of the preceding periods. 
1 Proposed dose levels that may be adjusted following review of 
the data from Part A
2 Administration of the MR prototype coated tablet formulations 
will either be in the fed or fasted state or administered 30 or 60 
minutes before a standard or high-fat (Period 7 only)
breakfast/evening meal (Period 7 only). 
3 Different tablet unit strengths may be used to achieve the 
required dose level
4 Tablet may be manufactured with or without apertures (i.e., 
drilled or non-drilled). Tablets without apertures will be 
manufactured based on a formulation which has already been 
dosed.
5 Dosing will either be in the morning or evening of Day 1.
 
 
 
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5.1.3.
Criteria for Interim Decisions
In Part A there will be an interim review following completion of Period 3, Period 4 and 
Period 5, where appropriate, to decide whether to dose a different MR prototype coated 
tablet formulation (created by adjusting the percentage polymer content in the core or the 
polymer ratios) or whether to dose one of the previously dosed formulation in the fed 
state (high-fat breakfast). Once the impact of a high-fat meal on a selected MR has been 
studied, the subsequent periods may be dosed in the fasted or fed state (a high-fat 
breakfast or standard breakfast) or dosing 30 or 60 minutes before a standard breakfast.  
There will also be the option to cancel Periods 5 and 6 if an optimal formulation is 
determined in Periods 1 or 3 which shows no clinically significant food effect with a 
high-fat meal in Period 4.  Following the final period of Part A, there will be an interim
review to determine whether to proceed with optional Part B, and if so, the formulations 
and tablet strengths to be investigated in Part B.  The decision to progress to Part B will 
be based upon identifying a formulation from Part A that has an appropriate exposure 
profile and does not show a clinically significant food effect with 1 or more of the food 
states described above. There will be an interim review following each of Periods 1 to 5 
of Part B to select the dose level, formulation and prandial status, as appropriate, for each 
subsequent period. An interim data review after Part B Period 6 will determine if optional 
Period 7 is required and the dose level, dosing time (morning or evening), formulation 
and prandial status for that period.
The highest dose level may be adjusted based on observed relative bioavailability of the 
MR tablet but will be planned that the mean AUC(0-24) and mean Cmax will not exceed the 
GSK2982772 systemic exposure associated with the single day administration of 240 mg 
IR TID (i.e., mean AUC(0-24) of 45.0 µg.h/mL and mean Cmax of 4.3 µg/mL).  These 
exposures are below those achieved at the monkey and rat no observed adverse effect 
levels in the 13-week toxicology studies.
Interim decisions will only be made after a complete review of all relevant data collected 
from the previous dose group. Data should be available from a minimum of 
12 participants who have completed the planned safety and PK assessments up to 
24 hours after dosing, or 48 hours after dosing for the food effect assessment and for 
Part B; if full data, as described below, are not available for 12 participants, the PI, 
scientific lead and sponsor will take a decision as to whether the data available are 
sufficient to support the formulation selection decision. 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 data in fewer than 12 participants are used in the 
decision process, replacement participants will not be dosed with previous regimens 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.
 
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
PK parameter estimates GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), Tlag ,Tmax, Cmax, 
C24h, (C12h for IR only) t1/2, Frel based on AUC and Cmax for test vs reference 
formulations and fed vs fasted, where relevant (Part A).

PK parameter estimates GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), Tmax, Cmax, C24h, 
t1/2 (Part B).  

Protocol deviations will be reviewed to ensure they have had no significant impact on 
the above data
The decision on formulation, tablet strength, dose level, dosing time (Part B Period 7 
only) 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 GlaxoSmithKline (GSK) Trial Master File.
The following decision criteria will be used as a guide to MR formulation selection 
during the study.
Since the aim of the MR development programme in to provide a QD formulation with as 
high as possible Cmin, the decision criteria will be based on this PK parameter.  To avoid 
issues with potential outliers at a single nominal time point (e.g. defining C24h as 
minimum observed concentration [Cmin]), the decision criteria will be based on the 
nominal PK sampling times between 18 and 24 hours.  Other PK parameters may also be 
taken into consideration in the MR formulation selection including, but not limited, to 
bioavailability relative to IR, ratios of Cmax:C18h, Cmax:C20h, Cmax:C22h and Cmax:C24h and 
between subject coefficient of variation (CVb) of C18h, C20h, C22h and C24h.  The duration 
of drug release may also be taken into consideration since shorter drug release durations 
using weaker polymers may be more susceptible to food effect whereas longer release 
duration will be more susceptible to PK variability due to inter- and intra-subject 
differences in gastrointestinal transit time.
Food effect arm/s may be conducted with one or more MR formulations and/or one or 
more fed states.
N.B. The release rate of MR1 is planned to be similar to the slowest release minitab in 
study 205017 (~12h for 80% release) and the release rate of MR2 will be the slowest 
available within the design space.
 
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Decision Criteria for Part 1:  Period 4 
Criteria/ Action
Illustration 
Rationale
If in the majority of 
nominal PK sampling 
time points between 
18 and 24 hours, the 
ratio of the geometric 
mean GSK2982772 
concentrations for 
MR2:MR1 is between 
0.9 and 1.1, 
then evaluate a 
release duration faster 
than MR1
0
50
100
150
200
250
300
350
0
2
4
6
8
10
12
14
16
18
20
22
24
GSK29827772 Conc (ng/mL)
Time after dosing (hours)
MR1
MR2
No benefit of 
extending drug 
release beyond 
12 hours
If in the majority of 
nominal PK sampling 
time points between 
18 and 24 hours, the 
ratio of the geometric 
mean GSK2982772 
concentrations for 
MR2:MR1 >1.1, then 
evaluate an 
intermediate release 
duration between 
MR1 and MR2
0
50
100
150
200
250
300
350
0
2
4
6
8
10
12
14
16
18
20
22
24
GSK29827772 Conc (ng/mL)
Time after dosing (hours)
MR1
MR2
If MR2 >MR1, 
the MR2 (with a 
longer duration of 
drug release) will 
be more 
susceptible to 
variability in 
gastrointestinal 
(GI) transit time 
therefore want to 
see if shorter 
duration of 
release than MR2 
will still provide 
higher
concentrations 
between 18 and 
24 hours than 
MR1
 
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If in the majority of 
nominal PK sampling 
time points between 
18 and 24 hours, the 
ratio of the geometric 
mean GSK2982772 
concentrations for 
MR2:MR1 <0.9 
then evaluate a 
release duration faster 
than MR1
0
50
100
150
200
250
300
350
400
0
2
4
6
8
10
12
14
16
18
20
22
24
GSK29827772 Conc (ng/mL)
Time after dosing (hours)
MR1
MR2
Want to see if 
shorter duration 
of release than 
MR1 will provide 
even higher Cmin
than MR1
Decision Criteria for Part 1:  Period 5
If an intermediate release rate (MR3) is evaluated in Period 4, then a 2nd intermediate 
release rate (MR4) between MR3 and either MR1 or MR2 may be evaluated using the 
same criteria as in Period 4.  If the criteria for evaluating an intermediate release rate in 
Period 5 are not met, then either MR1, MR2 or MR3 will be administered with a high-fat 
meal in Period 5.
If a faster release rate than MR1 is evaluated in Period 4, then an even faster release rate 
or an interim release rate between MR3 and MR1 or MR2 may be evaluated based on the 
same criteria as Period 4.  If the criteria for evaluating an even faster release rate on an 
intermediate release rate in Period 5 are not met, then either MR1 or MR3 will be 
administered with a high-fat meal in Period 5.
Decision on which MR Formulation to be used for assessment of High-Fat Meal:  
Periods 4, 5 and/or 6
The MR formulation to be selected for the food effect arm will ideally have the highest 
GSK2982772 concentrations in the majority of timepoints between C18h and C24h along 
with the lowest CVb.
Decision on which MR Formulation to be taken to Part 2
The duration of release for the 120 mg and 480 mg MRX formulations in Periods 1 and 2 
will have a similar release rate duration as the optimal MRX formulation from Part A, 
where optimal is defined in the same way as for the food effect arm (e.g. the highest 
GSK2982772 concentrations in the majority of timepoints between C18h and C24h along 
with the lowest CVb).
Decision of whether to evaluate 480 mg or 120 mg MRYh in Part B
If dose normalised Cmin is 10% different compared to the 240 mg dose normalised Cmin, 
 
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then the MR release duration may be adjusted in Period 3 and/or Period 4.
5.2.
Number of Participants
It is planned to enrol up to 16 participants into each part of the study to allow for 
sufficient data in at least 12 evaluable participants.  For Part A, an evaluable participant 
will have received the IR tablet formulation (reference) and at least one of the MR 
formulations and will have completed the planned safety and PK assessments up to 
24 hours after dosing.  For the food effect assessment, an evaluable subject will have
received the chosen MR formulation in the fasted state and the relevant prandial state and 
will have completed the planned safety and PK assessments up to 48 hours after dosing.  
For Part B, an evaluable participant will have completed the planned safety and PK 
assessments up to 48 hours after dosing with at least one MR prototype coated tablet 
formulation.
Participants withdrawn due to an IMP-related AE that is at least moderate in severity 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 4 replacement participants may be enrolled in each part of the study. The 
maximum number of participants that may be dosed in each part of the study is 20. 
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 unless required 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 participants and the 
minimum washout period will be respected with regard to the timing of dosing.
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 definition of the end of the study is defined as the point at which the sponsor 
determines that any remaining optional groups are not required to meet the objectives of 
the trial i.e., signed dose decision document. If all optional groups are used, completion 
of the last follow-up visit will be considered the end of the study.
5.4.
Scientific Rationale for Study Design
Previous clinical studies of IR formulations of GSK2982772 resulted in a high 
peak:trough ratio of GSK2982772.  Additionally, the short half-life for GSK2982772 
(~2 to 3 hours) necessitates BID or TID dosing of an IR formulation.  As a result, MR 
formulations using a polymer matrix approach with minitablets in capsule and MR tablet 
 
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formulations were investigated.  The emerging PK data of the MR formulations 
investigated to date have demonstrated that a QD PK profile can be achieved in the fasted 
state but the polymer matrix formulation is susceptible to food effects when administered 
with a high-fat breakfast. The purpose of this study is to evaluate MR prototype coated 
tablet formulations.  The MR prototype coated tablet formulation uses a combination of a 
controlled-release polymer matrix and controlled-release coating to achieve a 
modified-release of the drug.  The MR tablet coating used in Part A and the initial 
periods of Part B will have an aperture drilled into the enteric coating of either side of the 
tablet.  This allows some drug release to commence in the stomach whilst providing
controlled release throughout the GI tract.  This MR tablet coating has been used in other 
formulations (e.g. Lamictal XR) and in vivo has shown robustness against food effects.  
The HPMC polymer has been shown to be effective in achieving a controlled delay to the 
drug release rate and thus lowering Cmax and increasing the C24h of the product.  
However, it is believed that the digestive mechanical action that the dosage form is 
exposed to in the fed stomach, and/or the longer stomach retention time when dosed in 
the fasted state, causes an increase in the rate of drug release.  Application of an enteric 
coating with apertures will control the release rate when in the stomach.  In Part B only, a 
new IMP will be manufactured to allow comparison of the tablet coating either with 
apertures (i.e., drilled) or without apertures (i.e., full coat/non-drilled).  
Part A of the study is an adaptive crossover study that will optimise the MR prototype 
coated tablet formulation to provide a formulation suitable for QD dosing and has no 
clinically significant food effect.  The MR prototype coated tablet formulations have a 
matrix core containing hypromellose polymers.  The MR prototype coated tablet 
formulations will be optimised within a one-dimensional design space where release rate 
from the tablet will be adjusted by varying the polymer ratio in the tablet core.  The 
polymers will be hypromellose 2208 K3LV (polymer 1) and/or K100LV (polymer 2) 
and/or K4M (polymer 3).  The dose will be fixed at 240 mg, and the in vitro release rate 
will be targeted such that the tablet core of GSK2982772 MR prototype coated tablet 
formulation MR1 will have a dissolution profile that is similar to the release rate of the 
slowest release MR minitab formulation from Study 205017 (approximately 80% in vitro 
release at 12 hours).  GSK2982772 MR prototype coated tablet formulation MR2 will be 
designed such that the in vitro dissolution is slower than that of MR1, and will be the 
slowest available within the design space.  If neither MR1 nor MR2 provide an optimal 
profile, further MR prototype coated tablet formulations will be investigated.  The impact 
of food on the pharmacokinetics of GSK2982772 will also be evaluated for the selected 
formulation(s).  After completion of Periods 3, 4 and 5, interim analyses will be 
conducted to determine the formulation and prandial status to be investigated in the next 
period.  After completion of Part A, an interim analysis will be conducted to identify MR 
prototype coated tablet formulations for progression into Part B.  If none of the MR 
prototype coated tablet formulations are suitable, then Part B of the study may not be 
conducted or Part B may be used to continue to optimise the MR prototype coated tablet 
formulations, which may include varying the tablet coating either with apertures (i.e. 
drilled) or without apertures (i.e., full coat/non-drilled) by the manufacture of a new IMP. 
Optional Part B will assess the pharmacokinetics of alternative tablet strengths (120 mg 
and 480 mg, or alternative strengths) as allowed by the design space or tablets with 
apertures (i.e., drilled) or without apertures (i.e., full coat/non-drilled) or multiple dosing 
 
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units of the optimum MR formulation selected from Part A.  If the in-vivo profile of 
either or both the 120 mg or 240 mg tablets (or alternative strengths) differs from the 
optimal profile with the 240 mg, the ratio of the polymers K3LV, K100LV and/or K4M 
may be adjusted within each of the alternative strengths.  In order to assess the effect of 
the aperture on the in vivo performance of the formulation, a fully coated tablet (i.e.,
without apertures) may be assessed in Part B, Period 3 onwards. If fully coated tablet(s) 
are dosed, the core composition will match a previously dosed formulation to allow a 
valid comparison.  To investigate whether the between-subject variability in absorption 
time observed following administration of 480 mg tablet with a high-fat breakfast 
(administered in previous periods) can be reduced; a change to the food regimen or time 
of administration may be explored in Part B, Period 7.  Subjects may be dosed in the 
fasted state or fed state (standard or high-fat breakfast/evening meal) or in the fasted state 
followed by a delayed standard or high-fat breakfast/evening meal, on the morning or 
evening of Day 1.  Prior to initiation of Part B, a substantial amendment to the 
investigational medicinal product dossier (IMPD), will be submitted to the MHRA for 
approval, to include updated information on the selected GSK2982772 MR prototype 
coated tablet formulations at alternative strengths.
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 the blinded high dose PK study (205184) in healthy participants, single doses up to 
720 mg/day appear to be well-tolerated with no safety concerns identified. No SAEs or 
deaths have been reported. Repeat dosing with up to 720 mg/day x 14 days is ongoing.
Single doses are to be used in this study since single doses are generally more sensitive 
than steady-state dosing in assessing rate and extent of release of the drug substance from 
the drug product into the systemic circulation. In addition, GSK 2982772 has time in-
dependent pharmacokinetics as demonstrated with similar single and repeat dose PK 
profiles following 14 days dosing with GSK2992772 Immediate Release (Study 200975) 
and following 3 days dose with minitab MR (Study 205017).  Single doses are also 
required for development of in-vitro / in-vivo correlation which may be developed for the 
DiffCore formulation at a later date”.
In Part A, a dose of 240 mg has been selected as this is expected to be safe and well 
tolerated, and is within the expected dose range that is planned to be taken forward into 
the Phase 2b dose ranging studies.
In Part B, the selection of the doses will be based on the results from Part A.  The highest 
dose will not be predicted to exceed the GSK2982772 systemic exposure associated with 
the single day administration of 240 mg TID (i.e., mean AUC(0-24) of 45.0 µg.h/mL and 
 
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mean Cmax of 4.3 µg/mL).  These exposures are below those achieved at the monkey and 
rat no observed adverse effect levels in the 13-week toxicology studies.
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:
Male participants are eligible to participate if they agree to the following during the 
intervention period until completion of the final follow up visit after the last dose of study 
treatment:

Refrain from donating sperm
Plus either:
 
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
Be abstinent from heterosexual or homosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 
OR

Must agree to use contraception/barrier as detailed below
o
Agree to use a male condom and should also be advised of the benefit 
for a female partner to use a highly effective method of contraception 
as a condom may break or leak when having sexual intercourse with a 
woman of childbearing potential who is not currently pregnant
o
Agree to use male condom when engaging in any activity that allows 
for passage of ejaculate to another person.
b. Female Participants: 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
o
Is not a woman of childbearing potential (WOCBP) 
OR
o
Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as 
described in Appendix 5 for at least 30 days before first dose until completion 
of the final follow up visit after the last dose of study treatment and agrees not 
to donate eggs (ova, oocytes) for the purpose of reproduction from Day 1 until 
3 months after the last dose. The investigator should evaluate the effectiveness 
of the contraceptive method in relationship to the first dose of study 
intervention.

A WOCBP must have a negative highly sensitive serum pregnancy test within 24 
hours before the first dose of study intervention. 

Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 5.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy
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.
 
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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.
Any history of suicidal behaviour within the past 6 months or any history of 
attempted suicide in a participant’s lifetime. 
3.
History of clinically significant psychiatric disorders as judged by the investigator.  
Depression requiring treatment in the last 2 years.
4.
History of herpes zoster (shingles) reactivation.
5.
History or diagnosis of obstructive sleep apnoea.
6.
History of a significant respiratory disorder. Childhood asthma that has fully 
resolved is permitted.
7.
History or current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions.
8.
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.
9.
History of GI surgery (with exception of appendectomy).
10. History of cholecystectomy or gall stones.
11. Presence or history of clinically significant allergy requiring treatment, as judged by 
the investigator. Hayfever is allowed unless it is active.
12. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
13. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35% of total).
14. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome).
15. Corrected QT interval (QTcF) >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 
 
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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
16. 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).
17. 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
18. 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.
19. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
20. 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.
21. 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
22. Current or history of renal disease or estimated glomerular filtration rate by Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation calculation
<60 mL/min/1.73m2 at screening.
23. 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 
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.
24. An elevated C-reactive protein (CRP) outside the normal reference range.
25. Confirmed positive pre-study drug/alcohol screen.
26. Positive human immunodeficiency virus (HIV) antibody test.
27. Regular use of known drugs of abuse, or history of drug or alcohol abuse in the past 
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Other Exclusions
28. 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 or 1 (25 mL) measure of 
spirits, 1.5 to 2 units is 1 glass (125 mL) of wine, depending on type.
29. 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).
30. 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.
31. Participants who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator at screening.
32. Total cholesterol 300 mg/dL (7.77 millimole [mmol]/Litre [L]) or triglycerides 
250 mg/dL (2.82 mmol/L).
33. Participants who are study site or sponsor employees, or immediate family members 
of a study site or sponsor employee.
6.3.
Lifestyle Considerations
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.

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.

For dosing after a high-fat breakfast or a standard breakfast, participants will be 
provided with a light snack on the evening of Day -1 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 minutes, with dosing occurring 30 minutes (5 minutes, Part B Period 7 
 
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only) after the start of breakfast. Participants should be encouraged to eat their meal
evenly over the 25 minutes period. It is acknowledged that some participants will 
take less time to eat, but dosing should still occur 30 minutes after the start of 
breakfast.  Subjects must complete 90% of the meal to be dosed.  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.

For dosing before a standard meal, 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 1 hour 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.

For evening dosing (Part B Period 7 only):
o
For fasted dosing, participants will be provided with a light snack on the day 
of dosing (Day 1) and will be required to fast from all food and drink (except 
water) for a minimum of 4 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 
1 hour after dosing.  De-caffeinated fluids will be allowed ad-libitum from 
4 hours post-dose.  Participants will be provided with a snack at 4 hours 
post-dose.
o
For dosing before a standard or high-fat meal (delayed meal), participants will 
be provided with a light snack on the day of dosing (Day 1) and will be 
required to fast from all food and drink (except water) for a minimum of 4
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 1 hour after dosing or after 
administration of the standard or high-fat evening meal (which will contain 
the same content as the breakfast), whichever is sooner.  A standard or 
high-fat evening meal will be provided either 30 or 60 minutes after dosing.
De-caffeinated fluids will be allowed ad-libitum from 4 hours post-dose. 
Participants will be provided with a snack at 4 hours post-dose.
o
For dosing after a high-fat or a standard evening meal (which will contain the 
same content as the breakfast), participants will be provided with a light snack 
on the day of dosing (Day 1) and will fast from all food and drink (except 
water), until the appropriate time when they will be provided with the 
appropriate meal.  The meal should be consumed over a maximum period of 
25 minutes, with dosing occurring 30 minutes (5 minutes) after the start of 
the meal.  Participants should be encouraged to eat their meal evenly over the 
25 minutes period.  It is acknowledged that some participants will take less 
 
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time to eat, but dosing should still occur 30 minutes after the start of the meal.  
Subjects must complete 90% of the meal to be dosed.  De-caffeinated fluids 
will be allowed ad-libitum from 4 hours post-dose.  Participants will be 
provided with a snack at 4 hours post-dose.

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., 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 (e.g., 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 
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7.1.
Treatments Administered
7.1.1.
Treatments Administered - Part A
Regimen
A
B
C
D
E
F
Study Treatment 
Name:
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
Dosage formulation:
MR prototype
Coated 
Tablet
MR1
IR Tablet 
Reference
MR prototype 
Coated 
Tablet 
MR2
MR prototype Coated 
Tablet
MR1, MR2 or MR3
MR prototype Coated 
Tablet
MR1, MR2, MR3 or M4
MR prototype Coated 
Tablet
MR1, MR2, MR3, or M4
Unit dose strength(s)/
Dosage level(s):
240 mg / 
240 mg
30 mg / 
240 mg 
240 mg / 
240 mg 
240 mg / 
240 mg
240 mg / 
240 mg
240 mg / 
240 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 an 
overnight fast (if 
alternative formulation) 
or following a high-fat 
breakfast (if previous 
formulation)
1 tablet, on the morning 
of Day 1 following an 
overnight fast (if
alternative formulation) 
or following a high-fat 
breakfast, standard 
breakfast or delayed 
meal (if previous 
formulation)
1 tablet, on the morning 
of Day 1 following an 
overnight fast (if 
alternative formulation) 
or following a high-fat 
breakfast, standard
breakfast or delayed 
meal (if previous 
formulation)
Packaging and 
Labelling
100 cc HDPE 
white bottle
45 cc HDPE 
white bottle
100 cc HDPE 
white bottle 
100 cc HDPE white 
bottle
100 cc HDPE white 
bottle
100 cc HDPE white 
bottle
Each HDPE bottle will be labelled as required per country requirement. 
Manufacturer
GSK
GSK
GSK
GSK
GSK
GSK
 
 
 
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7.1.2.
Treatments Administered - Part B
Regimen
G
H
I (Optional)
J (Optional)
K (Optional) 
L 
M (Optional)
Study Treatment 
Name:
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
GSK2982772
Dosage formulation:
MR prototype
Coated Tablet
MRX
MR prototype
Coated 
Tablet
MRX
MR prototype
Coated Tablet
MRX or MRX1
MR prototype
Coated 
Tablet
MRX or 
MRX1
MR prototype
Coated Tablet
MRX, MRX1 or 
MRX2
MR prototype
Coated Tablet
MRX, MRX1 or 
MRX2
MR prototype
Coated Tablet
MRX, MRX1 or 
MRX2
Unit dose strength(s)/
Dosage level(s):
120 mg / 
120 mg
(may be 
changed 
following 
review of Part 
A data)
tbc / 
tbc
tbc / 
tbc
tbc / 
tbc
tbc / 
tbc
tbc / 
tbc
tbc / 
tbc
Route of 
Administration 
Oral with 240 mL water
Dosing instructions:
1 tablet, on the 
morning of 
Day 1
Food status: 
tbc
xx tablets, on 
the morning 
of Day 1
Food status: 
tbc
xx tablets, on 
the morning of 
Day 1
Food status: 
tbc
xx tablets, on 
the morning 
of Day 1 
Food status: 
tbc
xx tablets, on 
the morning of 
Day 1 
Food status: 
tbc
xx tablets, on 
the morning of 
Day 1
Food status: 
tbc
xx tablets, on 
the morning 
OR evening of 
Day 1
Food status: 
tbc
 
 
 
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Regimen
G
H
I (Optional)
J (Optional)
K (Optional) 
L 
M (Optional)
Packaging and 
Labelling
100 cc HDPE white bottle labelled as required per country requirement.
Manufacturer
Quotient
Quotient
Quotient
Quotient
Quotient
Quotient
Quotient
MRX is the formulation selected from Part A. MRX1 and MRX2 are alternative MR formulations that may be investigated from Part A.
Tablets in Periods 1 and 2 will be manufactured with apertures. Tablets may be manufactured with or without apertures (i.e., drilled or 
non-drilled) from Period 3 onwards.  Tablets without apertures will be manufactured based on a formulation which has already been 
dosed.
 
 
 
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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 participants in Part A, and the mean AUC(0-24) and Cmax will not 
exceed a total daily dose equivalent to the systemic exposure for IR 240 mg TID (i.e.,
mean AUC(0-24) 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 on the dose of GSK2982772 to be administered in Part B 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 5.1.3.
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 Participant 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 
authorised 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 authorised site staff.
 
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3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
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 data 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.
 
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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
In rare instances, it may be necessary for a participant to permanently discontinue study 
treatment. See the SoA (Section 2) 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 7.
 
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8.1.1.1.
Study Intervention Restart or Rechallenge after liver stopping criteria 
met
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
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 (eg, 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 (Section 2) 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 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: 
 
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
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.
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 source data.

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 (Section 2) 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 data.
 
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
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: 

A serious adverse reaction (i.e., a serious adverse event considered at least 
possibly related to the IMP administration) in one subject.

Severe non-serious adverse reactions (i.e., severe non-serious adverse events 
considered as, at least possibly related to the IMP administration) in two subjects, 
independent of within or not within the same system organ class.
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 may be resumed or terminated; however, it 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 terminated, clearly explaining the reasons. A 
description of follow up measures taken for safety reasons, if applicable, will 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 a temporary halt 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 will 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,
 
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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 summarised in the SoA (Section 2). 

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
(Section 2), 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 (eg, blood count) and obtained before signing of ICF may be 
utilised for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time frame defined in the 
SoA (Section 2).

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 70-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 48 hours post-dose (Part A, Treatment Periods 1, 3, 4, 5, 
6 and Part B, all periods) or 24 hours post-dose (Part A, Treatment Period 2)
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.
 
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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 source data 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, stabilised, otherwise explained, or the participant is lost to follow-up (as 
 
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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 e.g., 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 the follow-up 
visit at the time points specified in the SoA (Section 2).

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 (e.g., spontaneous abortion, foetal 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.
 
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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 source.
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 (Section 2).
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.
 
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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 (Section 2) 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 (eg, 
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 (eg, 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 (Section 2) 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:
−
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:
−
Post-dose urine samples will be taken ± 2 hour from the nominal urine 
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
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 study database. The laboratory reports must be filed with the 
source documents. Clinically significant abnormal laboratory findings are those 
that 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 (Section 2).

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 source.
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.
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 
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
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

A 6 mL blood sample for DNA isolation will be collected from participants who 
have consented to participate in the genetics analysis component of the study, as 
specified in the SoA (see Section 2). Participation is optional. Participants who do 
not wish to participate in the genetic research may still participate in the study.

In the event of DNA extraction failure, a replacement genetic blood sample may 
be requested from the participant. Signed informed consent will be required to 
obtain a replacement sample unless it was included in the original consent.

See Appendix 8 for information regarding genetic research. Details on processes 
for collection and shipment and destruction of these samples can be found in the 
SRM or equivalent.
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.
 
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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(0-24), AUC(0-inf) and C24h.
10.2.
Sample Size Determination
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), Cmax, C18h, C20h, C22h, and C24h were 48.7%, 58.5%, 68.5%, 68.7%, 65.1%, and 
73.2%, respectively. Therefore, the respective estimates of within subject coefficient of 
variation (CVw [%]) are 30.9%, 36.7%, 42.3%, 42.5%, 40.4%, and 44.9%. 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 24.3% and 29.2% of the point 
estimate, respectively.  Similarly, it is estimated that the lower and upper bounds of the 
90% confidence interval for the geometric mean ratio (MR2/MR1) of C18h, C20h, C22h, and 
C24h will be within approximately 32.3%, 33.9%, 34.1%, and 36.2% of the point estimate, 
respectively. 
Since it is expected that the MR1 tablet formulation vs IR is to reduce Cmax by 80% and 
AUC by 40%, a sample size of 12 ensures that the 90% CI is within the region 
0.459-0.796 for AUC and 0.132-0.310 for Cmax if the observed geometric ratio is 
0.57-0.64 for AUC and 0.17-0.24 for Cmax.  Since it is expected that the MR2 tablet 
formulation will increase C18h, C20h, C22h, and C24h by 28%, 43%, 44%, and 27%, 
respectively vs MR1, a sample size of 12 ensures that the 90% CI is within the region 
0.945-1.746 for C18h, 1.046-1.968 for C20h, 1.051-1.985 for C22h, and 0.910-1.784 for C24h
if the observed geometric mean ratio is 1.25-1.32 for C18h, 1.40-1.47 for C20h, 1.41-1.48
for C22h, and 1.24-1.31 for C24h.
Sample Size Sensitivity
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% confidence interval for the mean ratio (MR/IR or MR2/MR1) and 
expressed as distance from mean to limits for 10, 12, 14 and 16 participants has been 
calculated (Table 3).
 
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Table 3
Precision Estimate of Mean Ratio
Parameter
CVw (%)
Precision of Mean Ratio (%)
N=10
N=12
N=14
N=16
AUC
30.9
27.5
24.3
22.0
20.3
Cmax
36.7
33.1
29.2
26.4
24.3
C18h
42.3
36.7
32.3
29.2
26.8
C20h
42.5
38.6
33.9
30.6
28.1
C22h
40.4
38.8
34.1
30.8
28.3
C24h
44.9
41.1
36.2
32.6
29.9
For example, based upon the estimate of variability (CVw%) of 30.9 and a sample size of 
16, it is estimated that the lower and upper bounds of the 90% confidence interval for the 
geometric mean ratio of the PK parameter (eg, AUC, Cmax) will be within approximately 
20.3% 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.  
 
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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 24 hours post-dose (C24h).

observed concentration at 8 and 12 hours post-dose (C8h and C12h) for IR only.

area under the plasma concentration vs time curve (AUC(0-t), AUC(0-24) and 
AUC(0-inf)).  

the percentage of AUC extrapolated beyond the last measured time point 
(AUC%extrap).

terminal half-life (t1/2).

relative bioavailability (Frelformulation) of test formulations (under fed or fasted 
conditions) 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 (high-fat breakfast or high-fat evening meal, 
standard breakfast or standard evening meal or delayed meal (30 or 60 minutes) vs
fasted based on AUC and Cmax.

relative bioavailability (Frel(time effect) of evening dosing vs morning dosing based 
on AUC and Cmax)

relative bioavailability (FrelMRFormulation) of MR prototype coated tablet formulations 
relative to each other, as appropriate, based on AUC and Cmax (optional Part B only) 

Cmax/Dose and AUC/Dose (optional Part B only) 
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.
Endpoint
Statistical Analysis Methods
Primary
The primary PK endpoints to compare MR formulations with IR formulations will be 
summarised descriptively. Ratios of AUC(0-inf), AUC(0-24), (AUC(0-t), if AUC(0-inf) cannot 
be derived), Cmax, C24h for MR formulation to IR formulation will be computed with 
90% CI.
Primary
The primary 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), 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
 
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Endpoint
Statistical Analysis Methods
be computed for the differences in GSK2982772 MR formulation 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 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
The secondary PK endpoints for the selected MR formulations at different tablet 
strengths and multiple dose units will be summarised descriptively. 
For Part B, plots of dose vs dose normalised AUC(0-24), C24h and Cmax will be 
generated to determine if there are any dose dependent changes in the absorption of 
GSK2982772 following administration of different tablet strengths and multiple dose 
units of the selected MR formulation(s).
For Part B, dose proportionality will be assessed by visual inspection of dose 
normalised AUC(0-24), AUC(0-inf) [or if not available AUC(0-t)] and Cmax values versus 
dose. Analysis of these loge-transformed parameters may be carried out, using the 
power model.
For Part B Period 7, the relative bioavailability of time effect (Frel(time effect)) will be 
assessed by comparing AUC(0-inf), AUC(0-t), Cmax, Tmax, between evening dosing (test) 
versus morning dosing in the same prandial state (reference).
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. 
The Reporting and Analysis Plan will describe the planned safety analyses in greater 
detail.
 
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10.4.3.
Interim Analyses
No formal statistical analyses are planned. However, after Periods 1 to 3, 4 and 5 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 (safety and PK) of preceding periods.  There will be the option to optimise the 
MR release duration and/or to evaluate the impact of a high-fat meal on the selected MR 
formulation(s). If an optimal formulation is identified in Part A, Part B will proceed.  If 
none of the MR prototype coated tablet formulations are suitable, then Part B of the study 
may not be conducted or Part B may be used to continue to optimise the MR prototype 
coated tablet formulations. This will be based upon identifying a formulation that has an 
appropriate exposure profile that does not show a significant food effect. 
In Part B, there will be an interim review following completion of each of Periods 1 to 5
to determine the dose level, formulation and prandial status, as appropriate, to be used in 
subsequent periods. There will also be an interim review following completion of 
Period 6 to determine if optional Period 7 is required and the dose level, dosing time 
(morning or evening), formulation and prandial status for that period.
See Section 5.1.3 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:

The PK profile of IR and MR are similar, based on visual judgement of 
concentration-time curves.  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.
 
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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.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
List of Abbreviations
Abbreviation
Definition
AE
Adverse event
ALT
Alanine transaminase
ALS
Amyotrophic lateral sclerosis
AST
Aspartate Aminotransferase
AUC
Area under the concentration vs time curve
AUC(0-inf)
Area under the curve from time zero to infinity
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
C24h
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
Cmin
Minimum observed concentration 
CPMS
Clinical Pharmacokinetics Modelling and Simulation
CPK
Creatine phosphokinase
CNS
Central nervous system
CO2
Carbon dioxide
CONSORT
Consolidated Standards of Reporting Trials
CRP
C-reactive protein
CSR
Clinical Study Report
CV
Cardiovascular
CVb
Between subject coefficient of variation
CVw
Within subject coefficient of variation
EC
Ethics Committee
ECG
Electrocardiogram
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
GD
Gestation day
GI
Gastrointestinal
GLP
Good Laboratory Practice
GNA
Grounds for Non-Acceptance
 
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GSK
Glaxosmithkline 
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
hCG
Human Chorioninc Gonadotropin
HIV
Human immunodeficiency virus
HIPAA
Health Insurance Portability and Accountability Act
HPMC
Hypromellose
HRT
Hormonal Replacement Therapy
IB
Investigator’s Brochure
ICF
Informed consent form
IEC
Independent Ethics Committees
IMP
Investigational medicinal product
IMPD
Investigational medicinal product dossier 
INR
International normalized ratio
IR
Immediate release
IRB
Institutional Review Board
ISF
Investigator site file
IUD
Intrauterine device 
IUS
Intrauterine hormone-releasing system 
IVIVT
In Vitro/In Vivo Translation
L
Litre
Kg
Kilograms 
LD
lactation day
LDH
Lactate dehydrogenase 
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
MDMA
3,4-methylenedioxy-methamphetamine 
Mg
Milligrams
MHRA
Medicines and Healthcare products Regulatory Agency
Min
Minute
mL
Millilitres
Mmol
Millimole
MR
Modified release
MSDS
Material Safety Data Sheet
MS
Multiple sclerosis 
Msec
Milliseconds
NOAEL
No observed adverse effect level
NSA
Non-substantial amendments
Pgp
P-glycoprotein
PGx
Pharmacogenomics 
PI
Principal investigator
PIS
Participant Information Sheet
PK
Pharmacokinetic(s)
PND
Post-natal day
Ppm
Parts per million
PsO
Plaque psoriasis
 
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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
SIB
Suicidal ideation and behaviour 
SGPT
Serum Glutamic-Pyruvic Transaminase
SoA
Schedule of activities
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
T1/2
Terminal half-life 
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
LAMICTAL XR
None
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 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 4
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
Routine 
Urinalysis

Specific gravity
 
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Laboratory 
Assessments
Parameters

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], hepatitis B 
core antibody [HBcAb] and hepatitis C virus antibody) at screening only

Tuberculosis test (QuantiFERON) at screening only

C-reactive protein (CRP) at screening only
The results of each test must be entered into the source.
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 7. 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.
 
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12.3.
Appendix 3: Study Oversight 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. 
 
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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 data 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 data 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 authorised person obtaining the informed consent 
must also sign the ICF.
 
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
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 authorised 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 
source 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 source. 
 
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
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the study database. 

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 data verification to confirm that data 
entered into the study database by authorised 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 captured into the study database 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.
Declaration of the End of the Study
The definition of the end of the study is defined as the point at which the sponsor 
determines that any remaining optional groups are not required to meet the objectives of 
the trial ie signed dose decision document. If all optional groups are used, completion of 
the last follow-up visit will be considered the end of the study. Any changes to this 
definition will be notified as a substantial amendment.
 
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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
 
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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.
 
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
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
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 
 
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not be immediately life-threatening or result in death or hospitalization but may 
jeopardise the participant or may require medical or surgical intervention to prevent 
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 source (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 source.

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 
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
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities; 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 utilised 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 
 
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reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognised 
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 source data.

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 study database (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 study database.

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.
 
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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.
 
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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)
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
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
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
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-estrogen 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.
 
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Table 5
Highly Effective Contraceptive Methods

CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner

Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of
contraception should be used. Spermatogenesis cycle is approximately 90 days.

Highly Effective Methodsb That Are User Dependent 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
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
Oral
Injectable

Sexual abstinence

Note: 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 intervention. 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
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly.
c.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction)
 
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Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test 

Additional pregnancy testing will be performed at admission to each study period 
and discharge from each study period

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. 

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. 
 
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
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons 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 
 
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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 source, 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:
 
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liver event follow up assessments within 24-
72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilise 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 source 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 source. 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, et.al.. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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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.
 
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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.
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.
 
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12.8.
Appendix 8: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis.

DNA samples will be used for research related to GSK2982772 or 
immuno-inflammatory and related diseases. They may also be used to develop 
tests/assays including diagnostic tests) related to GSK2982772 (or study treatments 
of this drug class) and immuno-inflammatory diseases. Genetic research may consist 
of the analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome [or analysis of the entire genome] (as appropriate)

DNA samples will be analyzed for UDP-glucuronosyltransferase 1-9 family, 
polypeptide A cluster enzyme that is encoded by the UGT1A9 gene complex.  
Additonal analyses may be conducted if it is hypothesised that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK2982772 or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK2982772 (or study treatments of 
this class) continues but no longer than 15 years after the last subject last visit or 
other period as per local requirements.
 
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12.9.
Appendix 9: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 1 28-AUG-2018
Overall Rationale for the Amendment:
This amendment addresses the Grounds for Non-Acceptance (GNA) received by MHRA 
noting that an Investigator should only have the responsibility of determining causality of 
a SAE or severe clinically significant AE without sponsor consultation.
Section # 
and Name
Description of Change
Brief Rationale
Section 8.1.3
Removal of GSK MM consultation 
for determining causality of a SAE 
or severe clinically significant AE.
The determination of causality for individual 
subject withdrawal should be at the 
responsibility of an Investigator only.
Amendment 2 26 FEB 2019
Overall Rationale for the Amendment
This amendment includes a new investigational medicinal product (IMP), requested by 
the sponsor, in order to compare the type of coating for GSK2982772 Modified Release 
(MR) prototype coated tablets. This substantial amendment will also incorporate protocol 
non-substantial amendments (NSA) 03 to 06, which were implemented after 
Amendment 1 approval date 28 AUG 2018. 
 
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Section # and 
Name
Description of Change
Brief Rationale
Synopsis –
Rationale and 
Overall Study 
Design, Section 
3.2 – Study 
Rationale, Section 
5.1 – Overall 
Study Design, 
Section 5.1.2 –
Part B, Figure 2 –
Part B Study 
Design – Tablet 
Strength, Section 
5.4 – Scientific 
Rationale for 
Study Design, 
Section 7.1.2 –
Treatments 
Administered –
Part B
The clinical protocol currently 
only allows variance of the 
polymer content of the tablets 
core. Tablets are currently 
manufactured with an 
aperture on either side of the 
tablet (i.e., drilled). A new IMP 
will be manufactured without 
apertures (i.e., full coat/non-
drilled).
The sponsor would like to compare the 
current modified release tablet, which has 
an aperture drilled into the coating on 
each side of the tablet, with a fully coated 
tablet. The composition of the coat will not 
change between formulations. An 
additional IMP will be manufactured to 
allow comparison of the tablet coating -
without apertures (i.e., full coat/non-
drilled) or with apertures (i.e., drilled). 
Section 7.1 –
Treatments 
Administered
Updates made based on 
protocol Non-Substantial 
Amendment 03. The MR 
prototype tablets will be 
provided in a 100 cc HPDE 
white bottle (corrected from 
85 cc)
The packaging details for the MR 
prototype coated tablets are incorrect. The 
MR prototype coated tablets will be 
supplied in 100 cc HDPE bottles instead 
of 85 cc HDPE bottles. 
Synopsis – Overall 
Design, Treatment 
Groups and 
Duration, Table 1-
Schedule of 
Activities for Parts A 
and B, Table 2 –
Pharmacokinetic 
Blood Sample 
Collection Times –
Parts A and B, 
Section 5.1.1 –
Part A, 
Section 5.1.3 –
Criteria for Interim 
Decisions, Section 
7.1.1 – Treatments 
Administered –
Updates made based on 
protocol Non-Substantial 
Amendment 04. Update to the 
period in which the immediate 
release (IR) tablet is dosed. 
The IR tablet will be dosed in 
Period 2 (Regimen B) and the 
MR prototype coated tablet 
MR2 will be dosed in Period 3 
(Regimen C). 
The Sponsor requested that the 
immediate release reference tablet is to 
be dosed in Period 2 instead of Period 3. 
There have been some issues with some 
of the supplied modified release tablet 
batches and the Sponsor required time to 
investigate the quality of the product and 
assess if a re-manufacture was required 
before dosing in the clinic.
 
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Section # and 
Name
Description of Change
Brief Rationale
Part A and 
Section 9 – Study 
Assessments and 
Procedures
Synopsis –Overall 
Rationale and 
Study Design, 
Section 5.1.2 –
Part B, Figure 2 –
Part B Study 
Design – Tablet 
Strength, 
Section 5.4 –
Scientific 
Rationale for 
Study Design and 
Section 7.1.2 –
Treatments 
Administered –
Part B
Updates made based on 
protocol Non-Substantial 
Amendment 05. Updated to 
allow multiple dosing units to 
be administered in Part B, 
Periods 2 to 6. 
Following review of clinical data from 
Part A of this study and data generated as 
part of other studies used for dose 
prediction, the highest dose in Part B 
would require dosing multiple units rather 
than only one tablet of high strength. The 
sponsor would like to have the option to 
dose at a higher strength based on 
emerging data.
Section 3.3 –
Benefit/Risk 
Assessment
Updates made based on 
emerging safety results from 
two ongoing GSK2982772 
studies, Study 205184 and 
Study 205017.
The protocol has been updated to
incorporate available data describing 
number of subjects dosed and safety from 
two ongoing GSK2982772 studies.
Figure 2 – Part B 
Study Design –
Tablet Strength 
and Section 7.1.2 
– Treatments 
Administered –
Part B
Updates made based on 
protocol Non-Substantial 
Amendment 06. Updates to 
allow an alternative 
formulation which has already 
been dosed previously to be 
dosed in 
Part B Periods 3 to 5. 
The protocol currently only allows for an 
alternative composition of tablet to be 
dosed in Part B Periods 3 to 5. Following 
review of clinical data from Part B 
Periods 1 and 2, the sponsor would like to 
have the option to dose a formulation 
which has already been dosed previously 
at an alternative dose level in Part B 
Periods 3 to 5.  
Minor formatting corrections made throughout.
 
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SAP_000.pdf: 
CONFIDENTIAL
GlaxoSmithKline group of companies
209261
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a two part, non-randomised, 
open label study designed to assess the pharmacokinetic 
profile of modified release prototype coated tablet 
formulations of GSK2982772 relative to an immediate 
release reference tablet formulation at a fixed strength (Part 
A) and the pharmacokinetic profile of alternative tablet 
strengths of the selected modified release prototype coated 
tablet formulation (Part B, optional) in healthy participants.
Compound Number 
:
GSK2982772
Effective Date 
:
18-JUN-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 209261.

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
18-JUN-2019
Email
Principal Statistician (II Clinical Statistics)
18-JUN-2019
Email
Principal Statistician (II Clinical Statistics) 
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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RAP Team Approvals:
Approver
Date
Approval Method
17-JUN-2019
Email
Clinical Development Manager (GCSD)
17-JUN-2019
Email
Clinical Development Director, Discovery 
Medicine
17-JUN-2019
Email
Director (CPMS)
17-JUN-2019
Email
Project Physician Lead, iiTA
18-JUN-2019
Email
Senior Medical Director, GCSP, SERM
17-JUN-2019
Email
Principal Data Manager, (GCDO)
18-JUN-2019
Email
Principal Programmer, (iiTA R&D PCPS)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
17-JUN-2019
e-Signature
Senior Statistics Director (II Clinical Statistics)
17-JUN-2019
e-Signature
Programming Manager (II Clinical Programming)
 
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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 .................................................8
3.
PLANNED ANALYSES ............................................................................................8
3.1.
Interim Analyses ...........................................................................................8
3.2.
Final Analyses ..............................................................................................8
4.
ANALYSIS POPULATIONS .....................................................................................8
4.1.
Protocol Deviations.......................................................................................9
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................10
5.1.
Study Treatment & Sub-group Display Descriptors.....................................10
5.2.
Baseline Definitions ....................................................................................11
5.3.
Multicentre Studies .....................................................................................11
5.4.
Examination of Covariates, Other Strata and Subgroups............................11
5.5.
Multiple Comparisons and Multiplicity .........................................................11
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................11
6.
STUDY POPULATION ANALYSES .......................................................................12
6.1.
Overview of Planned Study Population Analyses........................................12
7.
SAFETY ANALYSES .............................................................................................12
7.1.
Adverse Events Analyses ...........................................................................12
7.2.
Clinical Laboratory Analyses.......................................................................12
7.3.
Other Safety Analyses ................................................................................12
8.
PHARMACOKINETIC ANALYSES.........................................................................13
8.1.
Primary, Secondary, and Exploratory Pharmacokinetic Analyses –
Part A and Part B........................................................................................13
8.1.1.
Endpoint / Variables.....................................................................13
8.1.1.1.
Drug Concentration Measures....................................13
8.1.1.2.
Derived Pharmacokinetic Parameters.........................13
8.1.2.
Summary Measure ......................................................................13
8.1.3.
Population of Interest...................................................................14
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................14
8.1.5.
Statistical Analyses / Methods .....................................................14
8.1.5.1.
Statistical Methodology Specification..........................14
9.
REFERENCES.......................................................................................................18
10. APPENDICES........................................................................................................19
 
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10.1.
Appendix 1: Protocol Deviation Management .............................................19
10.2.
Appendix 2: Schedule of Activities ..............................................................20
10.2.1.
Protocol Defined Schedule of Events...........................................20
10.3.
Appendix 3: Assessment Windows .............................................................23
10.3.1.
Definitions of Assessment Windows for Analyses........................23
10.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................24
10.4.1.
Study Phases ..............................................................................24
10.4.1.1.
Study Phases for Concomitant Medication .................24
10.4.2.
Treatment Emergent Flag for Adverse Events .............................24
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................25
10.5.1.
Reporting Process .......................................................................25
10.5.2.
Reporting Standards....................................................................25
10.6.
Appendix 6: Derived and Transformed Data ...............................................27
10.6.1.
General........................................................................................27
10.6.2.
Study Population..........................................................................27
10.6.3.
Efficacy........................................................................................28
10.6.4.
Safety ..........................................................................................28
10.6.5.
Pharmacokinetic ..........................................................................29
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................31
10.7.1.
Premature Withdrawals................................................................31
10.7.2.
Handling of Missing Data.............................................................31
10.7.2.1.
Handling of Missing and Partial Dates ........................31
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................33
10.8.1.
Laboratory Values........................................................................33
10.8.2.
ECG.............................................................................................34
10.8.3.
Vital Signs....................................................................................34
10.9.
Appendix 9: Abbreviations & Trade Marks ..................................................35
10.9.1.
Abbreviations...............................................................................35
10.9.2.
Trademarks .................................................................................36
10.10. Appendix 10: List of Data Displays..............................................................37
10.10.1. Data Display Numbering..............................................................37
10.10.2. Mock Example Shell Referencing ................................................37
10.10.3. Deliverables.................................................................................37
10.10.4. Study Population Tables..............................................................38
10.10.4.1. Study Population Tables Part A..................................38
10.10.4.2. Study Population Tables Part B..................................40
10.10.5. Safety Tables...............................................................................41
10.10.5.1. Safety Tables Part A...................................................41
10.10.5.2. Safety Tables Part B...................................................44
10.10.6. Safety Figures .............................................................................47
10.10.6.1. Safety Figures Part A .................................................47
10.10.6.2. Safety Figures Part B .................................................48
10.10.7. Pharmacokinetic Tables...............................................................49
10.10.7.1. Pharmacokinetic Tables Part A ..................................49
10.10.7.2. Pharmacokinetic Tables Part B ..................................50
10.10.8. Pharmacokinetic Figures .............................................................52
10.10.8.1. Pharmacokinetic Figures Part A .................................52
10.10.8.2. Pharmacokinetic Figures Part B .................................55
10.10.9. ICH Listings .................................................................................57
10.10.9.1. ICH Listings Part A .....................................................57
10.10.9.2. ICH Listing Part B.......................................................60
 
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10.10.10.Non-ICH Listings..........................................................................63
10.10.10.1.
Non-ICH Listings Part A..........................63
10.10.10.2.
Non-ICH Listings Part B..........................64
10.11. Appendix 11: Example Mock Shells for Data Displays ................................65
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
2018N367092_00
23-JUL-2018
Original
2018N367092-01
08-Aug-2018
Follow up call changed to follow up visit
2018N367092-02
28-Aug-2018
Grounds for Non-Acceptance regarding SAEs
2018N367092-03
26-Feb-2019
New investigational medicinal product to compare type of 
coating of GSK2982772.
2018N367092-04
10-Apr-2019
Additional optional Period 7in Part B to explore prandial 
states.
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: 23/JUL/2018).
C8h has been collected as a PK endpoint since dosing in the PoC studies (203167 
(psoriasis), 203168 (rheumatoid arthritis) and 202152 (ulcerative colitis)) was changed 
from BID to TID dosing with the immediate release (IR) formulation of GSK2982772.   
On further reflection, comparisons of C8h and C12h following single dose are not relevant 
comparisons and will not be included in the analyses.
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 
MR prototype coated tablet 
formulation (240 mg) compared to 
the IR formulation (240 mg) (Part A)

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)), maximum observed 
concentration (Cmax), concentration at 24 hours 
post-dose (C24h), time to Cmax (Tmax), terminal 
half-life (t1/2).  

To assess the impact of a high-fat 
breakfast on the PK of GSK2982772 
following single dose administration 
of one or more selected MR 
prototype coated tablet formulations 
(240 mg) (Part A or Optional Part B)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, Tmax, 
C24h, and t1/2, relative bioavailability (FrelFE), 
relative bioavailability (FrelFormulation) to IR 
based on AUC and Cmax
Secondary Objectives
Secondary Endpoints

To assess the safety and tolerability 

Adverse events (AEs)
 
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Objectives
Endpoints
of single doses of GSK2982772 
(Part A)

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

To determine the bioavailability of 
GSK2982772 MR prototype coated 
tablet formulations relative to the IR 
reference, as appropriate (Part A) [1]

Relative bioavailability (Frelformulation) based on 
AUC and Cmax
Exploratory Objectives
Exploratory Endpoints

To assess the safety and tolerability 
of single doses of GSK2982772 
(Optional Part B)

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

To evaluate the PK profile of 
alternative tablet strengths of 
selected GSK2982772 MR prototype 
coated tablet formulations (Optional 
Part B)

GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), 
Cmax, C24h, t1/2, AUC/Dose and Cmax/Dose

To evaluate the impact of dosing 2 or 
more MR prototype coated tablets on 
the PK profile of GSK2982772 
(Optional Part B)

GSK2982772 AUC(0-inf), AUC(0-t) or AUC(0-24), 
Cmax, Tmax and t1/2

To determine if there are any dose 
dependent changes in the absorption 
of GSK2982772 following single 
dose administration selected 
GSK2982772 MR prototype coated 
tablet formulations (Optional Part B)

GSK2982772 AUC(0-inf), AUC(0-t), AUC(0-24), 
Cmax, C24h and Tmax

To assess the impact of a standard 
breakfast on the PK of GSK2982772 
following single dose administration 
of one or more selected MR 
prototype coated tablet formulations 
(240 mg) (Part A - optional)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, Tmax 
and t1/2, relative bioavailability (FrelFE), relative 
bioavailability (FrelFormulation), based on AUC 
and Cmax

To assess the impact of a delayed 
meal on the PK of GSK2982772 
following single dose administration 
of one or more selected MR 
prototype coated tablet formulations 
(240 mg) (Part A - optional)

GSK2982772 AUC(0-inf), AUC(0-t), Cmax, Tmax 
and t1/2, relative bioavailability (FrelFE), relative 
bioavailability (FrelFormulation), based on AUC 
and Cmax
 
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2.3.
Study Design
See Section 5 of the protocol for the study design.
2.4.
Statistical Hypotheses / Statistical Analyses
No formal hypothesis will be tested. However, point estimates and corresponding 90% 
confidence intervals will be derived for Cmax, AUC(0-t), AUC(0-inf) and C24h.
3.
PLANNED ANALYSES 
3.1.
Interim Analyses
No formal statistical analyses are planned. However, after Period 3 of Part A is 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 (safety and PK) of 
preceding periods. There will be the option to optimise the MR release duration and/or to 
evaluate the impact of a high-fat, standard, or delayed meal on the selected MR 
formulation(s). If an optimal formulation is identified in Part A, Part B will proceed. If 
none of the MR prototype coated tablet formulations are suitable, then Part B of the study 
may not be conducted or Part B may be used to continue to optimise the MR prototype 
coated tablet formulations. This will be based upon identifying a formulation that has an 
appropriate exposure profile that does not show a significant food effect.
In Part B, there will be an interim review following completion of each of Periods 1 to 5 
to determine the dose level, formulation and prandial status, as appropriate, to be used in 
subsequent periods.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
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 

Safety and Study 
 
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Population
Definition / Criteria
Analyses Evaluated
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.
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 10: 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) [26-APR-2019 
version 1.01]. 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.
 
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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 240mg MR RR1 
oral single dose
MR-12h 240mg Fasted
2
B*
GSK2982772 240mg MR RR2 
oral single dose
IR 240mg Fasted
1
C*
GSK2982772 240mg IR oral 
single dose
MR-18h 240mg Fasted
3
D
GSK2982772 240mg MR RR3 
oral single dose
MR-18h 240mg Fed (High-Fat)
5
E
GSK2982772 240mg MR RR4 
oral single dose
MR-12h 240mg Fed (High-Fat)
4
F
GSK2982772 240mg MR fed 
state
MR-16h 240mg Fasted
6
Part B
G
GSK2982772 120mg MR oral 
single dose
MR-16h 480mg Fasted
1
H
GSK2982772 480mg MR oral 
single dose
MR-16h 960mg Fasted
5
J
GSK2982772 MR oral single 
dose 1
MR-16h 480mg Fed (High-Fat) 
3
K
GSK2982772 MR oral single 
dose 2
MR-16h 120mg Fasted
6
L
GSK2982772 MR oral single 
dose 3
MR-16h 480mg Fed (High-Fat) 
(Enteric Coated)
4
M
GSK2982772 MR oral single 
dose 4
MR-16h 480mg Fed 
(Standard)
2
* In Part A, the treatments for Period 2 and 3 were reversed in order due to availability of 
the drug at site.  For Period 2 participants received “GSK2982772 240mg IR oral single 
dose” and Period 3 participants received “GSK2982772 240mg MR RR2 oral single 
dose”.
Safety listings may be presented chronologically instead of in the order suggested above.
 
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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.  Unless otherwise stated, the mean of replicate assessments at 
any given time point will be used as the value for that time point.
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.
Multicentre Studies
This is a single centre study. 
5.4.
Examination of Covariates, Other Strata and Subgroups
There are no covariates, strata or subgroups to be investigated in this study. 
5.5.
Multiple Comparisons and Multiplicity
No adjustments for multiplicity will be required. 
5.6.
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
 
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Section
Component
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
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 will be based on GSK Core Data Standards.  Details of the planned displays 
are presented in Appendix 10: List of Data Displays.
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 Adverse 
Events (SAEs) and other significant AEs will be based on GSK Core Data Standards. The 
details of the planned displays are provided in Appendix 10: 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 provided in Appendix 10: List of Data
Displays.
In additional to GSK Core Data Standards, Lipids (Total Cholesterol and Triglycerides) 
outside the normal range will be summarised.
7.3.
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. The details of the 
planned displays are provided in Appendix 10: List of Data Displays.
 
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8.
PHARMACOKINETIC ANALYSES
8.1.
Primary, Secondary, and Exploratory Pharmacokinetic 
Analyses – Part A and Part B
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)
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
AUC(0-inf)
Area under the curve from time zero to infinity
AUC(0-t)
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%extrap
Percentage of AUC extrapolated beyond the last measured time point.
t1/2
Terminal half-life
Tlag
Time from dosing to first quantifiable concentration.
Tlast
Time of last measurable concentration
Tmax
Time of maximum observed concentration
Cmax
Maximum observed concentration 
C24h
Concentration at 24 hours post-dose
NOTES:

Additional parameters may be included as required.

No log transformation for Tmax nor any ratio (relative) endpoint.
8.1.2.
Summary Measure
For each period in Part A and Part B period,  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.
 
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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

Subject study completion (i.e. as specified in the protocol) was defined as completing 
all phases of the study including the follow-up visit.

Withdrawn subjects may be replaced in the study. 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.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified. 
8.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 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).
Parts A and B 
Model Specification: AUC, Cmax, C24h in log scale

Include covariates and handling of multicentre studies (if appropriate), additional information 
can be included in other relevant sections of the RAP and cross reference provided.

For each study part and each endpoint a mixed model will be fit with up to 6 observations per 
participant expected in Part A, corresponding to periods 1 through 6.  Similarly for Part B.  The 
model will contain formulation (PATRTGRP) 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.
 
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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.
Model Results Presentation

Point estimates and corresponding 90% CI will be computed for the differences in the endpoint 
for each treatment period.

The relative bioavailability ratio, Frel, 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
Model Specification: Tmax

Include covariates and handling of multicentre studies (if appropriate), additional information 
can be included in other relevant sections of the RAP and cross reference provided.

Exact non-parametric Hodges-Lehmann estimation of location shift will be fitted.
Model Results Presentation

For each relative bioavailability, the median difference and 90% CI for median difference will 
be presented.
Part A - Formulation
Endpoint (AUC, Cmax, C24h in log scale) 

AUC(0-inf) 

AUC(0-t) 

AUC(0-24h)

Cmax 

C24h

Tmax
Relative Bioavailability 

MR-12h 240mg Fasted vs IR 240mg Fasted

MR-18h 240mg Fasted vs IR 240mg Fasted
 
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
MR-16h 240mg Fasted vs IR 240mg Fasted

MR-18h 240mg Fed (High-Fat) vs MR-12h 240mg Fed (High-Fat)
Part A – Food Effect
Endpoint (AUC, Cmax in log scale)

AUC(0-inf) 

AUC(0-t) 

Cmax

Tmax
Relative Bioavailability

MR-18h 240mg Fed (High-Fat) vs MR-18h 240mg Fasted

MR-12h 240mg Fed (High-Fat) vs MR-12h 240mg Fasted
Part B – Dose Effect
Endpoint (AUC, Cmax, C24h in log scale)

AUC(0-inf) 

AUC(0-t) 

AUC(0-24h)

Cmax 

C24h

Tmax
Relative Bioavailability

MR-16h 960mg Fasted vs MR-16h 120mg Fasted

MR-16h 480mg Fasted vs MR-16h 120mg Fasted

MR-16h 960mg Fasted vs MR-16h 480mg Fasted
 
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Part B – Food Effect
Endpoint (AUC, Cmax in log scale)

AUC(0-inf) 

AUC(0-t) 

Cmax

Tmax
Relative Bioavailability

MR-16h 480mg Fed (High-Fat) vs MR-16h 480mg Fasted
Part B – Enteric Coating Effect
Endpoint (AUC, Cmax, C24h in log scale)

AUC(0-inf) 

AUC(0-t)  

Cmax

C24h 

Tmax
Relative Bioavailability

MR-16h 480mg Fed (High-Fat) (Enteric Coating) vs MR-16h 480mg Fed (High-Fat)
 
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9.
REFERENCES
GlaxoSmithKline Document Number 2018N367092_02. A two part, non-randomised, 
open label study designed to assess the pharmacokinetic profile of modified release 
prototype coated tablet formulations of GSK2982772 relative to an immediate release 
reference tablet formulation at a fixed strength (Part A) and the pharmacokinetic profile 
of alternative tablet strengths of the selected modified release prototype coated tablet 
formulation (Part B, optional) in healthy participants. Effective Date: 28-AUG-2018.
SAS Institute Inc. 2017. SAS/STAT® 14.3 User’s Guide. Cary, NC: SAS Institute Inc.
 
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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.
 
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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
 
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Table 2 from Protocol
 
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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.
 
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10.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
10.4.1.
Study 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
10.4.1.1.
Study 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.
10.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date. (plus washout or protocol-specified time limit (e.g. half-life of drug, certain 
number of days, etc.).

Study Treatment Start Date ≤ AE Start Date ≤Study Treatment Stop Date.

For studies with greater than one treatment period (e.g., crossover study), if AE 
onset is during one period and worsens during a later period it would be counted 
in both periods. For the initial period the logic would be as above. For the later 
period the logic would use the treatment dates associated with the later period:

Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop Date.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
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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\ mid209261\final_01
QC Spreadsheet
: \arwork\gsk2982772\mid209261\final_01\documents
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK Integrated Data Standards Library (IDSL) 
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
Formats

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.

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).
 
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
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, except where appropriate.

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, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
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)
 
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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window (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.

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
Date of Birth

Only the year of birth will be captured, and therefore the date of birth is then derived as follows:
Year of birth = YYYY → Date of birth = 30th June YYYY
Age

Calculated as the integer part of (date of screening – date of birth) 
Age = integer part (date of screening – 30th June YYYY)/365.25.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
Treatment Compliance

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * 
Frequency)

Frequency is 2 for BID and 1 for QD. Treatment compliance could be greater than 100% if there are 
events of overdose. Cumulative compliance (since Day 1) at each visit will be calculated.
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
 
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Treatment Compliance
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.
10.6.3.
Efficacy
N/A
10.6.4.
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            
                 
ECG Parameter
Units
QTc Categories
Lower
Upper
Absolute
Absolute QTc Interval
msec
≤  450
> 450 
≤480 
> 480 
≤500 
> 500 
Change from Baseline
 
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ECG Parameter
Units
QTc Categories
Lower
Upper
Increase from Baseline QTc
msec
≤  30 
> 30
≤ 60 
> 60  
See Section 8.1.2 of the protocol for QTc stopping criteria.  In addition to the two 
stopping criteria outlined in the protocol, 

QTc >500 msec

Change from baseline (pre-dose Day 1) of QTc >60 msec
a third criteria will be flagged for summary purposes:

Change from triplicate screening of QTc >60 msec
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    
10.6.5.
Pharmacokinetic
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.
AUC(0-∞) 

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.
 
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Pharmacokinetic Endpoints
AUC(0-24)
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%extrap
Percentage of AUC extrapolated beyond the last measured time point
Cmax
Maximum observed concentration, 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.
Tlast
Time of last measurable concentration
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) , AUC(0-last), C24h, and Cmax. 
o
MR Formulation (test) vs IR Formulation (reference)
o
MR Fed (test) vs MR Fasted (reference)  
o
Enteric Coated (test) vs MR (reference)              
MR refers to DiffCORE
 
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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. 
See study protocol for liver chemistry, QTc, and nervous system early 
stopping criteria.
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 
 
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Element
Reporting Detail
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
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10.8.
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
µmol/L
1.3 X ULN
Creatinine
µmol/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
 
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10.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 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
≤ 60
msec
> 60
E.g. H1=”>450 - <=480”   H2=”>480 - <=500”   H3=”>500” to be used as the flagging 
for Absolute QTc Interval in the corresponding displays.
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
 
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10.9.
Appendix 9: Abbreviations & Trade Marks
10.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
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
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
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
 
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Abbreviation
Description
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
10.9.2.
Trademarks
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
[SAS]
[WinNonlin]
 
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10.10.
Appendix 10: List of Data Displays
10.10.1.
Data Display Numbering
The following numbering will be 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
10.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays.
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.’
10.10.3.
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
 
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10.10.4.
Study Population Tables
10.10.4.1. 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.
Safety
SP1
Summary of Study Populations and Exclusions: Part A
IDSL
SAC
Demographic and Baseline Characteristics 
1.6.
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’). Additional ranges of 
<18 and >=85 are also included, though 
these should have zero counts.
SAC
1.7.
Safety
DM3
Summary of Demographic Characteristics: Part A 
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.8.
Safety
DM5
Summary of Race and Racial Combinations: Part A 
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
SAC
1.9.
Safety
DM6
Summary of Race and Racial Combination Details: Part A 
ICH E3, FDA
SAC
Prior and Concomitant Medications
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.10.
Safety
MH4
Summary of Current/Past Medical Conditions: Part A
ICH E3 
Separate summaries for Current & Past 
conditions, if collected.
SAC
1.11.
Safety
CM1
Summary of Concomitant Medications: Part A 
ICH E3
SAC
Exposure and Treatment Compliance 
1.12.
Safety
EX1
Summary of Exposure to Study Treatment: Part A
ICH E3
Dose and/or time on treatment, as 
applicable. 
SAC
 
 
 
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10.10.4.2. Study Population Tables Part B
Study Population Tables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable
[Priority]
Subject Disposition 
1.13.
Safety
ES1A
Summary of Subject Disposition: Part B 
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.14.
All Subjects 
ES6
Summary of Reasons for Screen Failure: Part B 
Journal Requirements
SAC
Protocol Deviation 
1.15.
Safety
DV1
Summary of Important Protocol Deviations: Part B 
ICH E3
SAC
1.16.
All Subjects
IE2
Summary of Inclusion/Exclusion Criteria Deviations: Part B
IDSL
SAC
Population Analysed
1.17.
Safety
SP1
Summary of Study Populations and Exclusions: Part B
IDSL
SAC
Demographic and Baseline Characteristics 
1.18.
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
1.19.
Safety
DM3
Summary of Demographic Characteristics: Part B 
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.20.
Safety
DM5
Summary of Race and Racial Combinations: Part B 
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
SAC
1.21.
Safety
DM6
Summary of Race and Racial Combination Details: Part B 
ICH E3, FDA
SAC
Prior and Concomitant Medications
 
 
 
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Study Population Tables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable
[Priority]
1.22.
Safety
MH4
Summary of Current/Past Medical Conditions: Part B
ICH E3 
Separate summaries for Current & Past 
conditions, if collected.
SAC
1.23.
Safety
CM1
Summary of Concomitant Medications: Part B 
ICH E3
SAC
Exposure and Treatment Compliance
1.24.
Safety
EX1
Summary of Exposure to Study Treatment: Part B
ICH E3
Dose and/or time on treatment, as 
applicable. 
SAC
10.10.5.
Safety Tables
10.10.5.1. 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 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
 
 
 
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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
2.11.
Safety
LB17
Summary of Worst Case Lipids Outside Laboratory Normal 
Range Post-Baseline Relative to Baseline: Part A
SAC
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hematology
2.12.
Safety
LB1
Summary of Hematology Changes From Baseline: Part A
ICH E3
Includes baseline values.
SAC
2.13.
Safety
LB1
Summary of Hematology Values: Part A
ICH E3
Includes baseline values.
SAC
2.14.
Safety
LB3
Summary of Emergent Hematology Results by Potential Clinical 
Importance Criteria: Part A  
SAC
Laboratory: Urinalysis
2.15.
Safety
UR3
Summary of Urinalysis Dipstick Results: Part A
ICH E3
Includes Baseline values.
SAC
Laboratory: Hepatobiliary (Liver)
2.16.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting: Part A
IDSL
SAC
2.17.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities: Part A
SAC
ECG
2.18.
Safety
EG1
Summary of ECG Findings: Part A 
IDSL
As above for Chemistry, using ECG 
findings categories (and change from 
baseline categories, if applicable). No 
need to present Heart Rate (not 
collected with ECG data).
SAC
2.19.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit: Part 
A
IDSL. No need to display Heart Rate.
SAC
2.20.
Safety
EG2
Summary of Change from Triplicate Screening in ECG Values 
by Visit: Part A
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.21.
Safety
CP_EG12
Summary of Maximum Change from Baseline in QTc Values by 
Category: Part A
IDSL.
Footnote: "Increase of <=30 msec" 
category also includes No Change or 
Decreases in Change from Baseline
SAC
2.22.
Safety
CP_EG12
Summary of Maximum Change from Triplicate Screening in QTc 
Values by Category: Part A
IDSL.
Footnote: "Increase of <=30 msec" 
category also includes No Change or 
Decreases in Change from Baseline
SAC
Vital Signs
2.23.
Safety
VS1
Summary of Change From Baseline in Vital Signs by Visit: Part 
A
ICH E3
Includes Baseline values.
SAC
2.24.
Safety
VS1
Summary of Vital Signs by Visit: Part A
SAC
10.10.5.2. Safety Tables Part B
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.25.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term: Part B
See 2.02 from 200975
SAC
2.26.
Safety
AE5a
Summary of All Adverse Events by System Organ Class and 
Maximum Intensity: Part B
ICHE3
SAC
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.27.
Safety
AE3
Summary of Common (>10%) Adverse Events by Overall 
Frequency: Part B
GSK CTR
SAC
2.28.
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
2.29.
Safety
AE1 
Summary of Serious Adverse Events by System Organ Class: 
Part B
IDSL / GSK CTR
SAC
2.30.
Safety
AE3
Summary of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment by Overall 
Frequency: Part B
IDSL
SAC
2.31.
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 
2.32.
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
2.33.
Safety
LB1
Summary of Clinical Chemistry Values: Part B
SAC
2.34.
Safety
LB3
Summary of Emergent Clinical Chemistry Results by Potential 
Clinical Importance Criteria: Part B  
SAC
2.35.
Safety
LB17
Summary of Worst Case Lipids Outside Laboratory Normal 
Range Post-Baseline Relative to Baseline: Part B
SAC
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hematology
2.36.
Safety
LB1
Summary of Hematology Changes From Baseline: Part B
ICH E3
Includes baseline values.
SAC
2.37.
Safety
LB1
Summary of Hematology Values: Part B
ICH E3
Includes baseline values.
SAC
2.38.
Safety
LB3
Summary of Emergent Hematology Results by Potential Clinical 
Importance Criteria: Part B  
SAC
Laboratory: Urinalysis
2.39.
Safety
UR3
Summary of Urinalysis Dipstick Results: Part B
ICH E3
Includes Baseline values.
SAC
Laboratory: Hepatobiliary (Liver)
2.40.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting: Part B
IDSL
SAC
2.41.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities: Part B
SAC
ECG
2.42.
Safety
EG1
Summary of ECG Findings: Part B 
IDSL
As above for Chemistry, using ECG 
findings categories (and change from 
baseline categories, if applicable). No 
need to present Heart Rate (not 
collected with ECG data).
SAC
2.43.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit: Part 
B
IDSL.  No need to display Heart Rate.
SAC
2.44.
Safety
EG2
Summary of Change from Triplicate Screening in ECG Values 
by Visit: Part B
IDSL.  No need to display Heart Rate.
SAC
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.45.
Safety
CP_EG12
Summary of Maximum Change from Baseline in QTc Values by 
Category: Part B
IDSL
SAC
2.46.
Safety
CP_EG12
Summary of Maximum Change from Triplicate Screening in QTc 
Values by Category: Part B
IDSL
SAC
Vital Signs
2.47.
Safety
VS1
Summary of Change From Baseline in Vital Signs by Visit: Part 
B
ICH E3
Includes Baseline values.
SAC
2.48.
Safety
VS1
Summary of Vital Signs by Visit: Part B
SAC
10.10.6.
Safety Figures
10.10.6.1. 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
Common defined as >10%
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 vs Maximum Total Bilirubin: Part 
A
SAC
 
 
 
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10.10.6.2. 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
Common defined as >10%
SAC
Hepatobilary (Liver)
2.5.
Safety
LIVER14
Scatter Plot of Maximum vs Baseline for ALT: Part B
SAC
2.6.
Safety
LIVER9
Scatter Ploy for Maximum ALT vs Maximum Total Bilirubin: Part 
B
SAC
 
 
 
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10.10.7.
Pharmacokinetic Tables
10.10.7.1. 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 Concentration-Time (ug/mL) 
Data by Formulation and Prandial State: Part A
SAC
PK Derived Parameters
3.2.
PK
PKPT1
Summary Statistics of Derived Plasma GSK2982772
Pharmacokinetic Parameters by Formulation and Prandial State: 
Part A
Parameters with units.  
SAC
3.3.
PK
PKPT3
Summary Statistics of Log-Transformed Derived Plasma 
GSK2982772 Pharmacokinetic Parameters by Formulation and 
Prandial State: Part A
Parameters with units.  
SAC
PK Analyses
3.4.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (AUC & Cmax) Assessing Formulation Effect 
Relative Bioavailability: Part A
Include AUC(0-t) and AUC(0-inf)
SAC
3.5.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (Tmax) Assessing Formulation Effect Relative 
Bioavailability: Part A
Tmax
SAC
3.6.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (AUC & Cmax) Assessing Food Effect Relative 
Bioavailability: Part A
Include AUC(0-t) and AUC(0-inf)
SAC
 
 
 
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Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.7.
PK
PK_T1
Summary of Statistical Analysis of Plasma GSK2982772 
Parameters (Tmax) Assessing Food Effect Relative
Bioavailability: Part A
Tmax
SAC
10.10.7.2. 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 Concentration-Time (ug/mL) 
Data by Dose and Prandial State: Part B
SAC
PK Derived Parameters
3.9.
PK
PKPT1
Summary Statistics of Derived Plasma GSK2982772 
Pharmacokinetic Parameters by Dose and Prandial State: Part B
Parameters with units 
SAC
3.10.
PK
PKPT3
Summary Statistics of Log-Transformed Derived Plasma 
GSK2982772 Pharmacokinetic Parameters by Dose and 
Prandial State: 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 Prandial State : Part B
Parameters with units 
SAC
 
 
 
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Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Analyses
3.12.
PK
PK_T2
Summary of Statistical Analysis of Plasma GSK2982772 PK 
Parameters (AUC & Cmax) Assessing Dose Relative 
Bioavailability: Part B
960 mg MR fasted vs 480 mg MR 
fasted
960 mg MR fasted vs 120 mg MR 
fasted
480 mg MR fasted vs 120 mg MR 
fasted
SAC
3.13.
PK
PK_T2
Summary of Statistical Analysis of Plasma GSK2982772 PK 
Parameters (Tmax) Assessing Dose Relative Bioavailability: 
Part B
960 mg MR fasted vs 480 mg MR 
fasted
960 mg MR fasted vs 120 mg MR 
fasted
480 mg MR fasted vs 120 mg MR 
fasted
SAC
3.14.
PK
PK_T2
Summary of Statistical Analysis of Plasma GSK2982772 PK 
Parameters (AUC & Cmax) Assessing Food Effect Relative 
Bioavailability: Part B
SAC
3.15.
PK
PK_T2
Summary of Statistical Analysis of Plasma GSK2982772 PK 
Parameters (Tmax) Assessing Food Effect Relative 
Bioavailability: Part B
SAC
3.16.
PK
PK_T2
Summary of Statistical Analysis of Plasma GSK2982772 PK 
Parameters (AUC & Cmax) Assessing Aperture Relative 
Bioavailability: Part B
SAC
3.17.
PK
PK_T2
Summary of Statistical Analysis of Plasma GSK2982772 PK 
Parameters (Tmax) Assessing Aperture Relative Bioavailability: 
Part B
SAC
 
 
 
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10.10.8.
Pharmacokinetic Figures
10.10.8.1. 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 (ug/mL) 
Plot by Subject: Part A
Paginate by Subject.  Semi-log not 
required.
SAC
3.2.
PK
PKCF1P
Individual GSK2982772 Plasma Concentration-Time (ug/mL) 
Plot by Formulation and Prandial State: Part A
Paginate by Formulation.  This 
includes the fed state.  Semi-log not 
required.
SAC
Mean / Median Concentration Plots
3.3.
PK
PKCF2
Mean Plasma GSK2982772 Concentration-Time (ug/mL) Plots 
by Formulation and Prandial State: Part A
Paginate by Formulation.  This 
includes the fed state.  Semi-log not 
required.
Page 1:240 mg IR and MR-12h, 
MR-16h and MR-18h
Page 2: MR-12h Fasted and Fed 
High Fat
MR-18h Fasted and Fed High Fat
SAC
 
 
 
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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.4.
PK
PKCF3
Median Plasma GSK2982772 Concentration-Time (ug/mL) 
Plots by Formulation and Prandial State: Part A
Paginate by Formulation.  This 
includes the fed state. Semi-log not 
required.
Page 1: 240 mg IR and MR-12h, 
MR-16h and MR-18h
Page 2: MR-12h Fasted and Fed 
High Fat
MR-18h Fasted and Fed High Fat
SAC
3.5.
PK
PK_F1
Plot of Individual Subject (+Geometric Mean and 95% CI) 
Plasma GSK2982772 PK Parameters vs Formulation and 
Prandial State: Part A
Page 1: 240 mg IR and MR-12h, 
MR-16h and MR-18h
Page 2: MR-12h Fasted and Fed 
High Fat
MR-18h Fasted and Fed High Fat
SAC
3.6.
PK
PK_F2
Plot of Geometric Mean Ratio and 90% CI of Plasma 
GSK2982772 PK Parameters Assessing Formulation Relative 
Bioavailability: Part A
Page 1: MR-12h 240mg vs IR 
fasted
MR-16h 240mg vs IR fasted
MR-18h 240mg vs IR fasted
Page 2: MR-18h 240mg Fed (High-
Fat) vs MR-12h 240mg Fed (High-
Fat)
SAC
 
 
 
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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 Food Effect Relative 
Bioavailability: Part A
SAC
 
 
 
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10.10.8.2. 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 (ug/mL) 
Plot by Subject: Part B
Paginate by Subject.  Semi-log not 
required.
SAC
3.9.
PK
PKCF1P
Individual GSK2982772 Plasma Concentration-Time (ug/mL) 
Plot by Dose and Prandial State: Part B
Paginate by Dose.  Semi-log not 
required.
SAC
Mean / Median Concentration Plots
3.10.
PK
PKCF2
Mean Plasma GSK2982772 Concentration-Time (ug/mL) Plots 
by Dose, Prandial State, and Aperture: Part B
Page 1: MR-16h 120 mg fasted
MR-16h 480 mg fasted
MR-16h 960 mg fasted
Page 2: MR-16h 480 mg Fasted
MR-16h 480 mg Fed (High Fat)
Page 3: MR-16h 480 Fed (High Fat)
MR-16h 480 Fed (High Fat) (Enteric 
Coated)
SAC
 
 
 
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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.11.
PK
PKCF3
Median Plasma GSK2982772 Concentration-Time (ug/mL) 
Plots by Dose, Prandial State, and Aperture: Part B
Page 1: MR-16h 120 mg fasted
MR-16h 480 mg fasted
MR-16h 960 mg fasted
Page 2: MR-16h 480 mg Fasted
MR-16h 480 mg Fed (High Fat)
Page 3: MR-16h 480 Fed (High Fat)
MR-16h 480 Fed (High Fat) (Enteric 
Coated)
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
MR-16h 120 mg fasted
MR-16h 480 mg fasted
MR-16h 960 mg fasted
SAC
3.13.
PK
PK_F2
Plot of Geometric Mean Ratio and 90% CI of Plasma 
GSK2982772 PK Parameters Assessing Dose Relative 
Bioavailability: Part B
960 mg MR fasted vs 480 mg MR 
fasted
960 mg MR fasted vs 120 mg MR 
fasted
480 mg MR fasted vs 120 mg MR 
fasted
SAC
3.14.
PK
PK_F2
Plot of Geometric Mean Ratio and 90% CI of Plasma 
GSK2982772 PK Parameters Assessing Food Effect Relative 
Bioavailability : Part B
MR-16h 480 mg Fed (High Fat) vs 
MR-16h 480 mg Fasted
SAC
 
 
 
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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.15.
PK
PK_F2
Plot of Geometric Mean Ratio and 90% CI of Plasma 
GSK2982772 PK Parameters Assessing Aperture Relative 
Bioavailability: Part B
MR-16h 480 Fed (High Fat) (Enteric 
Coated) vs MR-16h 480 Fed (High 
Fat)
SAC
3.16.
PK
PKCF2
Mean Plasma GSK2982772 Concentration-Time (ug/mL) Plots 
by Dose in Fasted State (Semi-log): Part B
Page 1: MR-16h 120 mg fasted
MR-16h 480 mg fasted
MR-16h 960 mg fasted
SAC
3.17.
PK
PKCF3
Median Plasma GSK2982772 Concentration-Time (ug/mL) 
Plots by Dose in Fasted State (Semi-log): Part B
Page 1: MR-16h 120 mg fasted
MR-16h 480 mg fasted
MR-16h 960 mg fasted
SAC
10.10.9.
ICH Listings
10.10.9.1. ICH Listings 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
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Protocol Deviations
4.
Safety
DV2A
Listing of Important Protocol Deviations: Part A 
ICH E3
SAC
5.
All Subjects
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations: 
Part A
ICH E3
SAC
Populations Analysed
6.
Safety
SP3
Listing of Subjects Excluded 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
 
 
 
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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 Subjects with Liver Stopping 
Events: Part A
IDSL
SAC
18.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events: Part A
IDSL
SAC
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
21.
Safety
LB6
Listing of all Lipid Data for Subjects with Any Value Outside of 
Laboratory Normal Range: Part A
SAC
22.
Safety
LB14
Listing of Microscopy Results for Subjects with Abnormal 
Urinalysis Dipstick Results: Part A
SAC
ECG
23.
Safety
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance: Part A
IDSL. No need to display Heart Rate.
SAC
24.
Safety
EG4
Listing of ECG Values of Potential Clinical Importance: Part A
IDSL. No need to display Heart Rate.
SAC
25.
Safety
EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding: Part A
IDSL. No need to display Heart Rate.
SAC
26.
Safety
EG6
Listing of Abnormal ECG Findings: Part A
IDSL. No need to display Heart Rate.
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
27.
Safety
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance: Part A
IDSL
SAC
28.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance: Part A
IDSL
SAC
10.10.9.2. ICH Listing Part B
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
29.
All Subjects
ES7
Listing of Reasons for Screen Failure: Part B
Journal Guidelines
SAC
30.
Safety
ES3
Listing of Reasons for Study Withdrawal: Part B
ICH E3
SAC
31.
Safety
TA2
Listing of Planned and Actual Treatments: Part B
IDSL
SAC
Protocol Deviations
32.
Safety
DV2A
Listing of Important Protocol Deviations: Part B 
ICH E3
SAC
33.
All Subjects
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations: 
Part B
ICH E3
SAC
Populations Analysed
34.
Safety
SP3
Listing of Subjects Excluded from Any Population: Part B
ICH E3
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
35.
Safety
DM4
Listing of Demographic Characteristics: Part B
ICH E3
SAC
36.
Safety
DM10
Listing of Race: Part B
ICH E3
SAC
Prior and Concomitant Medications
37.
Safety
CP_CM3
Listing of Concomitant Medications: Part B
IDSL
SAC
Exposure and Treatment Compliance
38.
Safety
EX4
Listing of Exposure Data: Part B
ICH E3
SAC
Adverse Events
39.
Safety
AE9CP
Listing of All Adverse Events: Part B
ICH E3
SAC
40.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events: Part B
ICH E3
SAC
41.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text: Part B
IDSL
SAC
Serious and Other Significant Adverse Events
42.
Safety
AE9CP 
Listing of Serious Adverse Events: Part B
ICH E3
SAC
43.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event: 
Part B
ICH E3
SAC
44.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment: Part B
ICH E3
SAC
Hepatobiliary (Liver)
45.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events: Part B
IDSL
SAC
46.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events: Part B
IDSL
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
All Laboratory
47.
Safety
LB6
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance/Outside Normal Range: Part B
ICH E3
SAC
48.
Safety
LB6
Listing of Laboratory Values of Potential Clinical Importance: 
Part B
SAC
49.
Safety
LB6
Listing of All Lipid Data for Subjects with Any Value Outside of 
Laboratory Normal Range: Part B
SAC
50.
Safety
LB14
Listing of Microscopy Results for Subjects with Abnormal 
Urinalysis Dipstick Results: Part B
ICH E3
SAC
ECG
51.
Safety
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance: Part B
IDSL
SAC
52.
Safety
EG4
Listing of ECG Values of Potential Clinical Importance: Part B
IDSL
SAC
53.
Safety
EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding: Part B
IDSL
SAC
54.
Safety
EG6
Listing of Abnormal ECG Findings: Part B
IDSL
SAC
Vital Signs
55.
Safety
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance: Part B
IDSL
SAC
56.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance: Part B
IDSL
SAC
 
 
 
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10.10.10. Non-ICH Listings
10.10.10.1. Non-ICH Listings Part A
Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
57.
PK
PKCL1X
Listing of Plasma GSK2982772 Pharmacokinetic Concentration-
Time (ug/mL) Data: Part A
SAC
58.
PK
PKPL1X
Listing of Derived Plasma GSK2982772 Pharmacokinetic 
Parameters: Part A
SAC
Meal Times
59.
Safety
CP_ML1x
Listing of Dosing Times, Meal Start and End Times on Fed 
Treatment Days: Part A
SAC
 
 
 
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10.10.10.2. Non-ICH Listings Part B
Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
60.
PK
PKCL1X
Listing of Plasma GSK2982772 Pharmacokinetic Concentration-
Time (ug/mL) Data: Part B
SAC
61.
PK
PKPL1X
Listing of Derived Plasma GSK2982772 Pharmacokinetic 
Parameters: Part B
SAC
Meal Times
62.
Safety
CP_ML1x
Listing of Dosing Times, Meal Start and End Times on Fed 
Treatment Days: Part B
SAC
 
 
 
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10.11.
Appendix 11: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request.
 
 
 
2019N407804_00