A Multicentre, Randomised, Double-blind (Sponsor-unblinded), Placebo-controlled, Repeat Dose Study to Investigate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2982772 in Subjects With Active Plaque-type Psoriasis
Phase: PHASE2
Conditions: Psoriasis
Sponsor: GlaxoSmithKline

2015N251765_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
203167
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A multicentre, randomised, double-blind (sponsor-unblinded), 
placebo-controlled, repeat dose study to investigate the safety 
and tolerability, pharmacokinetics, pharmacodynamics, and 
efficacy of GSK2982772 in subjects with active plaque-type 
psoriasis
Compound Number:
GSK2982772
Development Phase:
IIA
Effective Date:
12-APR-2017
Protocol Amendment Number:  02
Author (s):
 
 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N251765_00
2016-MAR-22
Original
2015N251765_01
2016-MAY-25
Amendment No. 1
Regulatory feedback led to a requirement for additional concomitant medication 
restrictions. In addition, some administrative clarifications have been made.
2015N251765_02
2017-APR-12
Amendment No. 2
Addition of a second cohort of subjects in the study to evaluate a 60 mg three times daily 
(TID) dosing regimen.
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

PPD
PPD

2015N251765_02
CONFIDENTIAL
203167
3
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
Site Address
Primary 
Medical 
Monitor 
Tel      
Email:   
Mobile:  
Mobile:  
N/A
Stockley Park 
West, 1-3 
Ironbridge 
Road, Uxbridge, 
Middlesex, 
UB11 1BT, 
United Kingdom
Secondary 
Medical 
Monitor
Mobile
Email:  
Mobile
N/A
1250 S.
Collegeville Rd.
Collegeville PA 
19426, USA
SAE 
contact  
information 
Medical 
Monitor as 
above
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
PPD
PPD
PP
D
PPD
PPD
PPD
PPD
PPD
PPD
PPD

2015N251765_02
CONFIDENTIAL
203167
4
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 203167
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study.
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

2015N251765_02
CONFIDENTIAL
203167
5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 203167........................................................8
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................13
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................14
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................16
4.2.1.
Screening ....................................................................................17
4.2.2.
Treatment Period.........................................................................17
4.2.3.
Follow-up Period..........................................................................17
4.3.
Type and Number of Subjects.....................................................................17
4.4.
Design Justification.....................................................................................18
4.5.
Dose Justification........................................................................................18
4.6.
Benefit: Risk Assessment ...........................................................................20
4.6.1.
Risk Assessment .........................................................................21
4.6.2.
Benefit Assessment.....................................................................26
4.6.3.
Overall Benefit: Risk Conclusion..................................................26
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............26
5.1.
Inclusion Criteria.........................................................................................26
5.2.
Exclusion Criteria........................................................................................28
5.3.
Screening/Baseline/Run-in Failures............................................................31
5.4.
Withdrawal/Stopping Criteria.......................................................................31
5.4.1.
Individual Safety Stopping Rules .................................................32
5.4.2.
Group Safety Stopping Rules.......................................................33
5.4.3.
Liver Chemistry Stopping Criteria ................................................33
5.4.3.1.
Study Treatment Restart or Rechallenge....................34
5.4.4.
QTc Stopping Criteria ..................................................................34
5.4.5.
Haematologic Stopping Criteria ...................................................35
5.5.
Subject and Study Completion....................................................................35
6.
STUDY TREATMENT ............................................................................................35
6.1.
Investigational Product and Other Study Treatment....................................35
6.2.
Treatment Assignment................................................................................36
6.3.
Planned Dose Adjustments.........................................................................36
6.4.
Blinding.......................................................................................................37
6.5.
Packaging and Labeling..............................................................................37
6.6.
Preparation/Handling/Storage/Accountability..............................................38
6.7.
Compliance with Study Treatment Administration.......................................38
6.8.
Treatment of Study Treatment Overdose....................................................38
6.9.
Treatment after the End of the Study ..........................................................39
6.10.
Lifestyle and/or Dietary Restrictions............................................................39
6.10.1.
Sun Exposure and Activity...........................................................39
6.11.
Concomitant Medications and Non-Drug Therapies....................................39

2015N251765_02
CONFIDENTIAL
203167
6
6.11.1.
Permitted Medications and Non-Drug Therapies..........................39
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................40
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................41
7.1.
Time and Events Table...............................................................................43
7.2.
Screening and Critical Baseline Assessments ............................................45
7.3.
Safety .........................................................................................................45
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........45
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................45
7.3.1.2.
Method of Detecting AEs and SAEs ...........................46
7.3.1.3.
Follow-up of AEs and SAEs........................................46
7.3.1.4.
Cardiovascular and Death Events ..............................46
7.3.1.5.
Regulatory Reporting Requirements for SAEs............47
7.3.2.
Pregnancy ...................................................................................47
7.3.3.
Physical Exams ...........................................................................47
7.3.4.
Vital Signs....................................................................................48
7.3.5.
Electrocardiogram (ECG).............................................................48
7.3.6.
Clinical Safety Laboratory Assessments ......................................48
7.3.7.
Suicidal Risk Monitoring...............................................................50
7.4.
Efficacy.......................................................................................................50
7.4.1.
Patient Reported Outcomes.........................................................50
7.4.1.1.
Itch Visual Analogue Scale.........................................51
7.4.1.2.
Dermatology Life Quality Index...................................51
7.4.2.
Clinical Disease Assessments .....................................................51
7.4.2.1.
Body Surface Area (BSA)...........................................51
7.4.2.2.
Selection of Psoriasis Plaques and Plaque 
Lesion Severity Scoring (PLSS)..................................51
7.4.2.3.
Psoriasis Area Severity Index (PASI) .........................52
7.4.2.4.
Digital Photography ....................................................52
7.4.2.5.
Physician’s Global Assessment of Disease 
Activity........................................................................52
7.5.
Pharmacokinetics .......................................................................................53
7.5.1.
Blood Sample Collection..............................................................53
7.5.2.
Sample Analysis ..........................................................................53
7.5.3.
Punch Skin Biopsy for Pharmacokinetic Assay ............................53
7.5.4.
Sample Analysis ..........................................................................53
7.6.
Biomarker(s)/Pharmacodynamic Markers ...................................................53
7.6.1.
Skin Lesion Biopsy ......................................................................53
7.6.2.
Novel Pharmacodynamic Biomarkers ..........................................54
7.6.2.1.
RIP1 Target Engagement in Blood .............................54
7.6.2.2.
RIP1 Target Engagement in Tissue............................55
7.6.2.3.
RIP1 Pathway Markers in Tissue................................55
7.6.3.
Exploratory Novel Biomarkers......................................................55
7.7.
Genetics .....................................................................................................56
8.
DATA MANAGEMENT ...........................................................................................56
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................56
9.1.
Hypotheses.................................................................................................56
9.2.
Sample Size Considerations.......................................................................56
9.2.1.
Sample Size Assumptions ...........................................................56

2015N251765_02
CONFIDENTIAL
203167
7
9.2.2.
Sample Size Sensitivity................................................................58
9.2.3.
Sample Size Re-estimation or Adjustment...................................59
9.3.
Data Analysis Considerations .....................................................................59
9.3.1.
Analysis Populations....................................................................59
9.3.2.
Interim Analysis ...........................................................................60
9.3.3.
Primary Analyses.........................................................................60
9.3.4.
Secondary Analyses ....................................................................60
9.3.5.
Other Analyses ............................................................................61
9.3.5.1.
Exploratory Analyses..................................................61
10. STUDY GOVERNANCE CONSIDERATIONS........................................................61
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............61
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................61
10.3.
Quality Control (Study Monitoring) ..............................................................62
10.4.
Quality Assurance.......................................................................................62
10.5.
Study and Site Closure ...............................................................................63
10.6.
Records Retention......................................................................................63
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................64
11. REFERENCES.......................................................................................................65
12. APPENDICES........................................................................................................67
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................67
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................70
12.3.
Appendix 3 - Genetic Research ..................................................................72
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................75
12.4.1.
Definition of Adverse Events........................................................75
12.4.2.
Definition of Serious Adverse Events...........................................76
12.4.3.
Definition of Cardiovascular Events .............................................77
12.4.4.
Recording of AEs and SAEs ........................................................78
12.4.5.
Evaluating AEs and SAEs............................................................79
12.4.6.
Reporting of SAEs to GSK...........................................................80
12.5.
Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................81
12.5.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............81
12.5.2.
Collection of Pregnancy Information ............................................82
12.6.
Appendix 6: Protocol Changes....................................................................84
12.6.1.
Protocol Amendment 01 ..............................................................84
12.6.2.
Protocol Amendment 2 ................................................................89

2015N251765_02
CONFIDENTIAL
203167
8
1.
PROTOCOL SYNOPSIS FOR STUDY 203167
Rationale
This is the first study with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase 
inhibitor, in subjects with active, plaque-type psoriasis. 
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg twice daily and 60 mg three times daily for 84 days). In addition 
a number of experimental and clinical endpoints will be employed to obtain information 
on the pharmacokinetics, pharmacodynamics, and efficacy in subjects with active plaque-
type psoriasis (PsO).  Although no formal hypothesis will be tested, these endpoints will 
enable a fuller understanding of the mechanism of action and potential for clinical 
efficacy of GSK2982772 in PsO, by making full use of the information obtained from 
each subject enrolled.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 
60 mg twice daily doses and 60 mg three 
times daily doses of GSK2982772 in 
subjects with active plaque-type psoriasis.

Adverse events

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature)

12-Lead ECG monitoring
Secondary

To investigate the pharmacokinetics of 
GSK2982772 in blood following 60 mg 
twice daily doses and 60 mg three times 
daily doses of GSK2982772 in subjects 
with active plaque-type psoriasis.

Pre-dose plasma concentrations of 
GSK2982772 at Days 43 (Week 6) and 85 
(Week 12).

Post-dose plasma concentrations of 
GSK2982772 on Days 1 and 43 (Week 6) 
at 1, 2, 4 and 6 hours post dose.

To investigate the effect of 60 mg twice 
daily doses and 60 mg three times daily 
doses of GSK2982772 on inflammatory 
biomarkers in skin biopsies from psoriatic 
skin lesions in subjects with active plaque-
type psoriasis.

Change from baseline in histopathological 
scoring of psoriatic lesional biopsies which 
may include, but are not limited to the 
following as data permit:  K16, 
CD3/CD11c, CD161, elastase positive 
dermal cells and epidermal thickness.  

mRNA expression of inflammatory gene 
transcripts which may include, but are not 
limited to the following as data permit:  IL-
4, IL-10, IL-17, IL-21, IL-22, IL-23, TNF and 
IFNγ on Days 1 (Week 0) and 43 (Week 6).

2015N251765_02
CONFIDENTIAL
203167
9
Objectives
Endpoints

To investigate the effect of 60 mg twice 
daily doses and 60 mg three times daily 
doses of GSK2982772 on disease activity 
in subjects with active plaque-type 
psoriasis

Percentage change from baseline and 
actual Psoriatic Lesion Severity Sum 
(PLSS) scores in the index lesion.
Exploratory

To investigate the effect of 60 mg twice 
daily doses and 60 mg three times daily 
doses of GSK2982772 on disease activity 
in subjects with active plaque-type 
psoriasis

Change from baseline in Psoriasis Area 
Severity Index (PASI) scores.

The proportion of subjects who achieve 
PASI ≥ 50%, 75%, and 90% improvement 
from baseline score.

Change from baseline and actual
Physician Global Assessment (PGA).

The proportion of subjects who achieve 
“clear” (0) or “almost clear” (1) on (PGA).

Change from baseline in body surface area 
(BSA).

To investigate the effect of 60 mg twice 
daily doses and 60 mg three times daily 
doses of GSK2982772 on inflammatory 
biomarkers in the blood of subjects with 
active plaque-type psoriasis.

Change from baseline in blood 
inflammatory markers which may include, 
but are not limited to the following as data 
permit:  CRP, VEGF, S100A8, S100A9, IL-
17, IL-22, and TNF.

To investigate the effect of 60 mg twice 
daily doses and 60 mg three times daily 
doses of GSK2982772 on transcriptome 
profiling of both blood and skin of subjects 
with active plaque-type psoriasis.

Transcriptomic analysis of mRNA isolated 
from blood and skin at Day 1 (Week 0) and 
Day 43 (Week 6).

To investigate pathway and target 
engagement following 60 mg twice daily 
doses and 60 mg three times daily doses
of GSK2982772 in blood and skin biopsy 
tissue in subjects with active plaque-type 
psoriasis.

Pharmacology biomarker endpoints may 
include, but are not limited to the following 
Days 1 (Week 0), 43 (Week 6) and 85 
(Week 12),  as data permit:
o
Target Engagement Assay 
RiP1 (TEAR1) in blood and 
skin.
o
Total or phosphorylated RIP1, 
MLKL, and RIP3, cleaved and 
total caspase 3 and caspase 8
signatures in skin.

To investigate the concentration of 
GSK2982772 in the skin of subjects with 
active plaque-type psoriasis after 60 mg 

Pre-dose GSK2982772 concentrations in 
skin biopsies at Days 1 (Week 0) and 43 

2015N251765_02
CONFIDENTIAL
203167
10
Objectives
Endpoints
twice daily doses and 60 mg three times 
daily doses of GSK2982772.
(Week 6), as data permit.

To investigate the effect of 60 mg twice 
daily doses and 60 mg three times daily 
doses of GSK2982772 on the patient 
reported outcomes (PROs) of subjects with 
active plaque-type psoriasis.

Change from baseline in Dermatology Life 
Quality Index (DLQI) score.

Change from baseline and actual Visual 
Analogue Scale (VAS) itch score.
Overall Design
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled, 
repeat dose study to investigate the safety and tolerability, PK, PD, and preliminary 
efficacy of GSK2982772 in subjects with active plaque-type psoriasis.  The study design 
schematic is depicted in Figure 1 below.  There will be two cohorts of subjects.  Cohort 1 
will receive either GSK2982772 60 mg or placebo orally twice daily and Cohort 2 will 
receive either GSK2982772 60 mg or placebo orally three times daily.
Figure 1
Study Overview
Cohort 1
Cohort 2
Safety assessments, PK samples in skin and blood, PASI,
PLSS, DLQI, Itch VAS, PGA assessments, Target 
engagement, inflammatory biomarkers in skin and blood

2015N251765_02
CONFIDENTIAL
203167
11
Treatment Arms and Duration
Each subject will participate in the study for approximately 20 weeks.  This includes a 
screening period up to 30 days, an 84 day (12 week) treatment period, and a 28 day
follow-up visit after the last dose.
Subjects will attend the clinical site to be consented and if eligible for the study,
screening assessments will be completed.  Subjects will then enter the Treatment Period 
and be dosed (Day 1) within 30 days of the screening visit.
Punch skin biopsies will be performed on all subjects.  Two (2) target lesions will be 
identified (3cm x3 cm) on the trunk or extremities.  One target lesion will be used for 
lesion biopsy and the other for PLSS at baseline (pre-dose Day 1) and Day 43 (Week 6). 
A third biopsy will be performed at baseline only (pre-dose Day 1) from non-lesional 
skin.
The Post-Treatment Period is 28 days (4 weeks) long.
In Cohort 1 subjects who have completed screening assessments and are eligible will be 
randomised in a 2:1 ratio (active to placebo) to one of the following treatments:
60 mg GSK2982772 twice daily (BID) 
Placebo twice daily (BID) 
In Cohort 2 subjects who have completed screening assessments and are eligible will be 
randomised in a 3:1 ratio (active to placebo) to one of the following treatments:
60 mg GSK2982772 three times daily (TID) 
Placebo three times daily (TID) 
Type and Number of Subjects
In Cohort 1, a sufficient number of subjects will be screened so that approximately 30 
subjects with active PsO are randomised.  Additional or replacement subjects may be 
randomised (up to a maximum of 36) into the study at the discretion of the Sponsor, to 
ensure that approximately 24 evaluable subjects complete the study.
In Cohort 2, a sufficient number of subjects will be screened so that approximately 24 
subjects with active PsO are randomised.  Additional or replacement subjects may be 
randomised (up to a maximum of 32) into the study at the discretion of the Sponsor, to 
ensure that approximately 20 evaluable subjects complete the study. 
For both cohorts, a subject is considered evaluable if they have completed at least one 
post-treatment biopsy.

2015N251765_02
CONFIDENTIAL
203167
12
Analysis
The safety and tolerability of GSK2982772 following 12 weeks of treatment will be 
based on the review and displays of adverse events, clinical laboratory values, vital sign 
measurements and 12-lead ECG monitoring.
An ongoing review of available efficacy, pharmacodynamic and mechanistic endpoints 
will be conducted during the study by a Data Review Committee (DRC), consisting of a 
limited number of GSK individuals, some of whom are also members of the GSK study 
team who are not involved in the day-to-day running of the study.  The primary purpose 
of these reviews will be to monitor target engagement, inflammatory markers and the 
index lesion PLSS for internal decision making. A data review charter will outline in 
detail the activities of this review and how the integrity of the study will be maintained.  
An interim analysis will be conducted after the completion of Cohort 1.
Comparisons between treatment groups on any changes observed will be conducted for 
the secondary endpoints if deemed appropriate, e.g. changes in the mean target 
engagement, changes in inflammatory markers and percentage change in index lesion 
PLSS will be statistically analyzed using a repeated measures mixed effects model 
(MMRM) comparing each GSK2982772 arm with placebo at each time point.  
The relationship between each of the mechanistic endpoints and also with the clinical 
endpoints may also be graphically presented and analysed using an appropriate statistical 
model identifying any trends. The model will determine whether the mechanistic effect 
significantly explains or predicts the effect on the other mechanistic or clinical endpoints 
(e.g., index lesion PLSS score).  In addition, based on the data that we observe in the 
study, probabilities of success will be determined, where the definition of success will be 
dependent on the endpoint. For example, what is the probability that we would observe a 
certain percentage change in PLSS (i.e., comparatory rate), based on the data that we 
have observed in the study.  Further details regarding the statistical analysis will be 
outlined in the Reporting and Analysis Plan (RAP).
2.
INTRODUCTION
2.1.
Study Rationale
This is the first study with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase 
inhibitor, in subjects with active plaque-type psoriasis. 
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg twice daily and 60 mg three times daily for 84 days). In addition, 
a number of experimental and clinical endpoints will be employed to obtain information 
on the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy in 
subjects with active PsO.  Although no formal hypothesis will be tested, these endpoints 
will enable a fuller understanding of the mechanism of action and potential for clinical 
efficacy of GSK2982772 in PsO.

2015N251765_02
CONFIDENTIAL
203167
13
2.2.
Brief Background
GSK2982772 is a first-in-class, highly selective, receptor-interacting protein 1 kinase 
(RIP1) inhibitor being developed for the treatment of inflammatory disease conditions.
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 TNF family cytokines, ligands for 
TLR3/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 [GlaxoSmithKline 
Document Number 2014N204126_01].  In contrast, RIP1’s scaffolding function acts to 
facilitate other immune processes including TNF mediated classical apoptosis and NF-
kB-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 through multiple mechanisms, including inhibition of 
inflammation-induced cell death (necroptosis and apoptosis) and inhibition of the 
production of certain pro-inflammatory cytokines.
Plaque psoriasis (PsO) is a chronic relapsing inflammatory skin disease that is 
characterized by keratinocyte hyperproliferation and epidermal hyperplasia. In 
preclinical models, blockade of NFB or apoptosis pathways results in spontaneous TNF-
dependent dermal inflammation that resembles human PsO in murine models 
[Bonnet, 2011].  In contrast to UC, overt cellular necrosis is not a histologic feature of 
PsO; however, innate immune responses to DAMPs have been reported in preclinical 
PsO models [Chen, 2013].  Like Inflammatory Bowel Disease (IBD) and other chronic 
inflammatory diseases, its pathobiology is incompletely understood.  However, a number 
of inflammatory cytokines, including TNF, IL12/23, and IL17 family members, are 
thought to play a role in the pathogenesis of PsO, as evidenced by the clinical successes 
of several biologics targeting these signalling pathways.
Standard treatment generally requires long-term use of topical therapies, followed by 
systemic immunosuppressant therapies, Psoralen and ultraviolet A (PUVA), and 
Ultraviolet B (UVB) therapies to achieve and maintain adequate disease control. Novel 
oral therapies for PsO are becoming more widely used for moderate to severe disease, but 
may be limited by efficacy (apremilast) and safety/tolerability profiles (tofacitinib). 
Biologic therapies targeting TNF or Th17/IL22/IL23 pathways have demonstrated 
significant clinical efficacy for those patients who have had inadequate response to 
standard topical, UV, and/or oral therapy, but all biologics carry risks for loss of 
response, side effects, and anti-drug antibodies.  There remains a high unmet need for 

2015N251765_02
CONFIDENTIAL
203167
14
novel oral therapies which will achieve maximal sustained clearance of skin lesions and 
improvement in quality of life, balanced by favourable safety and tolerability profiles.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To investigate the safety and tolerability of
60 mg twice daily doses, and 60 mg three 
times daily doses, of GSK2982772 in 
subjects with active plaque-type psoriasis.

Adverse events

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature)

12-Lead ECG monitoring
Secondary

To investigate the pharmacokinetics of 
GSK2982772 in blood following 60 mg 
twice daily doses, and 60 mg three times 
daily doses, of GSK2982772 in subjects 
with active plaque-type psoriasis.

Pre-dose plasma concentrations of 
GSK2982772 at Days 43 (Week 6) and 85 
(Week 12).

Post-dose plasma concentrations of 
GSK2982772 on Days 1 and 43 (Week 6) 
at 1, 2, 4 and 6 hours post dose.

To investigate the effect of 60 mg twice 
daily doses, and 60 mg three times daily 
doses, of GSK2982772 on inflammatory 
biomarkers in skin biopsies from psoriatic 
skin lesions in subjects with active plaque-
type psoriasis.

Change from baseline in histopathological 
scoring of psoriatic lesional biopsies which 
may include, but are not limited to the 
following as data permit:  K16, 
CD3/CD11c, CD161, elastase positive 
dermal cells and epidermal thickness.  

mRNA expression of inflammatory gene 
transcripts which may include, but are not 
limited to the following as data permit:  IL-
4, IL-10, IL-17, IL-21, IL-22, IL-23, TNF and 
IFNγ on Days 1 (Week 0) and 43 (Week 6).

To investigate the effect of 60 mg twice 
daily doses, and 60 mg three times daily 
doses, of GSK2982772 on disease activity 
in subjects with active plaque-type 
psoriasis

Percentage change from baseline and 
actual Psoriatic Lesion Severity Sum 
(PLSS) scores in the index lesion.
Exploratory 

To investigate the effect of 60 mg twice 
daily doses, and 60 mg three times daily 
doses, of GSK2982772 on disease activity 
in subjects with active plaque-type 
psoriasis

Change from baseline in Psoriasis Area 
Severity Index (PASI) scores.

The proportion of subjects who achieve 
PASI ≥ 50%, 75%, and 90% improvement 
from baseline score.

2015N251765_02
CONFIDENTIAL
203167
15
Objectives
Endpoints

Change from baseline and actual
Physician Global Assessment (PGA).

The proportion of subjects who achieve 
“clear” (0) or “almost clear” (1) on PGA.

Change from baseline in body surface area 
(BSA).

To investigate the effect of 60 mg twice 
daily doses, and 60 mg three times daily 
doses, of GSK2982772 on inflammatory 
biomarkers in the blood of subjects with 
active plaque-type psoriasis.

Change from baseline in blood 
inflammatory markers which may include, 
but are not limited to the following as data 
permit:  CRP, VEGF, S100A8, S100A9, IL-
17, IL-22, and TNF.

To investigate the effect of 60 mg twice 
daily doses, and 60 mg three times daily 
doses, of GSK2982772 on transcriptome 
profiling of both blood and skin of subjects 
with active plaque-type psoriasis.

Transcriptomic analysis of mRNA isolated 
from blood and skin at Day 1 (Week 0) and 
Day 43 (Week 6).

To investigate pathway and target 
engagement following 60 mg twice daily 
doses, and 60 mg three times daily doses,
of GSK2982772 in blood and skin biopsy 
tissue in subjects with active plaque-type 
psoriasis.

Pharmacology biomarker endpoints may 
include, but are not limited to the following 
Days 1 (Week 0), 43 (Week 6) and 85 
(Week 12),  as data permit:
o
Target Engagement Assay 
RIP1 (TEAR1) in blood and 
skin.
o
Total or phosphorylated RIP1, 
MLKL, and RIP3, cleaved and 
total caspase 3 and caspase 8
signatures in skin.

To investigate the concentration of 
GSK2982772 in the skin of subjects with 
active plaque-type psoriasis after 60 mg 
twice daily doses, and 60 mg three times 
daily doses of GSK2982772.

Pre-dose GSK2982772 concentrations in 
skin biopsies at Days 1 (Week 0) and 43 
(Week 6), as data permit.

To investigate the effect of 60 mg twice 
daily doses, and 60 mg three times daily 
doses, of GSK2982772 on the patient 
reported outcomes (PROs) of subjects with 
active plaque-type psoriasis.

Change from baseline in Dermatology Life 
Quality Index (DLQI) score.

Change from baseline and actual Visual 
Analogue Scale (VAS) itch score.

2015N251765_02
CONFIDENTIAL
203167
16
4.
STUDY DESIGN
4.1.
Overall Design
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled, 
repeat dose study to investigate the safety and tolerability, PK, PD, and preliminary 
efficacy of GSK2982772 in subjects with active plaque-type psoriasis.  The study design 
schematic is depicted in Figure 2 below.  There will be two cohorts of subjects.  Cohort 1 
will receive either GSK2982772 60 mg or placebo orally twice daily and Cohort 2 will 
receive either GSK2982772 60 mg or placebo orally three times daily.
Figure 2
Study Overview
Cohort 1
Cohort 2
Safety assessments, PK samples in skin and blood, PASI,
PLSS, DLQI, Itch VAS, PGA assessments, Target 
engagement, inflammatory biomarkers in skin and blood
4.2.
Treatment Arms and Duration
It is anticipated that the total duration of participation in the study will be approximately 
20 weeks from screening to the last study visit.

2015N251765_02
CONFIDENTIAL
203167
17
4.2.1.
Screening
Subjects will attend the clinical unit for a screening visit and if eligible and consenting 
may enter the Treatment Period of the study.
4.2.2.
Treatment Period
In Cohort 1, subjects will be randomly assigned to either GSK2982772 60mg or placebo 
orally twice daily (approximately 12 hours apart) for 84 days.  In Cohort 2 subjects will 
be randomly assigned to either GSK2982772 60 mg or placebo orally three times daily 
(approximately 8 hours apart) for 84 days.  Further guidance and information for study 
treatment and dosing are provided in the Study Reference Manual (SRM).  
Punch skin biopsies will be performed on all subjects.  Two (2) target lesions will be 
identified (3 cm by 3 cm) on the trunk or extremities.  One target lesion will be used for 
lesion biopsy and the other for PLSS at baseline (pre-dose Day 1) and Day 43 (Week 6). 
A third biopsy will be performed at baseline only (pre-dose Day 1) from non-lesional 
skin. Photographs will be taken by the investigator or designee to illustrate any visible 
changes in psoriasis target lesions during the course of the study.
During the 12 week treatment period, subjects will return to the clinical site for visits on 
Days 8, 15, 29 and 43, and then every 2 weeks thereafter until Day 85.  At specific visits, 
subjects must not take study treatment prior to their scheduled visit (see Section 7.1).  On 
Days 22, 36, 50, 64 and 78 each subject will be contacted by telephone and asked about 
their general health. Subjects will be given a diary card at each visit, in which will they 
will be instructed to record their daily study medication and concomitant medication 
administration and any adverse events while away from the clinical site.
4.2.3.
Follow-up Period
After the Treatment Period, the subject enters the Follow-up Period for 28 days, to 
complete follow-up assessments per the Time and Events table (Section 7.1).
4.3.
Type and Number of Subjects
In Cohort 1, a sufficient number of subjects will be screened so that approximately 30 
subjects with active PsO are randomised.  Additional or replacement subjects may be 
randomised (up to a maximum of 36) into the study at the discretion of the Sponsor, to 
ensure that approximately 24 evaluable subjects complete the study.
In Cohort 2, a sufficient number of subjects will be screened so that approximately 24 
subjects with active PsO are randomised.  Additional or replacement subjects may be 
randomised (up to a maximum of 32) into the study at the discretion of the Sponsor, to 
ensure that approximately 20 evaluable subjects complete the study.
For both cohorts, a subject is considered evaluable if they have completed at least one 
post-treatment biopsy.

2015N251765_02
CONFIDENTIAL
203167
18
4.4.
Design Justification
As this is the first trial of GSK2982772 in subjects with PsO, the primary endpoint is the 
safety and tolerability of GSK2982772.  In addition, this study will include assessments 
of target engagement and downstream pathway PD effects of GSK2982772, to 
understand whether GSK2982772 is inhibiting the pathway of interest in this disease.
Skin biopsies are being taken at pre-dose on Days 1 (Week 0) and 43 (Week 6) to 
measure PK, target and pathway engagement and effects on inflammatory markers in the 
skin.  It is felt that six weeks of treatment allows adequate time to assess histological 
improvement in the skin.
The 12 week duration of treatment is based on review of previous proof of mechanism 
and proof of concept studies in PsO and is limited by the supporting 13 week toxicology 
studies. It is expected that an effective therapy should cause group level changes in the 
mechanistic parameters by the 12 week time point.  
In Cohort 1 the subjects will be randomised in a 2:1 ratio to GSK2982772 60 mg BID 
and placebo respectively.  In Cohort 2 the subjects will be randomised in a 3:1 ratio to 
GSK2982772 60 mg TID and placebo respectively. The primary objective of this study is 
safety and tolerability and assessment of this is most valuable in a placebo controlled, 
blinded study. The placebo group was deemed necessary as autoimmune diseases 
naturally fluctuate in severity.  However, the size of the placebo group has been kept to a 
minimum.  Subjects will not be allowed to continue standard of care therapy including 
topical (not permitted on biopsy areas), oral and biologic therapy.  A washout period of 
specific therapies can be found in Section 6.11.
4.5.
Dose Justification
The initial selection of the 60 mg BID dose being tested in this study is based on the 
safety, PK, and PD data from the GSK2982772 First Time in Human (FTiH) study, 
200975.  GSK2982772 administered at 60 mg BID for 14 days was well tolerated and no 
safety concerns were identified. A BID dosing regimen was initially selected over a QD 
dosing regimen due to the short half-life of GSK2982772 in humans (~2 hours).  Based 
on preliminary PK/PD modelling of ex-vivo RIP1 target engagement and GSK2982772 
concentrations from the multiple dose ascending part of Study 200975, a 60 mg BID dose 
was predicted to have on average 95% RIP1 target engagement in blood and 
approximately 90% of subjects are predicted to have >90% RIP1 target engagement in 
blood at Cmin using a novel in-house ex-vivo PD/target engagement assay based solely on 
the TNF pathway which is believed to be a key component of the RIP1 pathway.  
Assuming a skin: blood ratio of 0.4 (as observed in the rat), the average RIP1 target 
engagement in skin is predicted to be 92%.  At Cmin, 44% of subjects are predicted to 
have >90% RIP1 target engagement in the skin and 90% of subjects are predicted to have 
>80% RIP1 target engagement in the skin.
However, based on final PK/PD modelling from the full repeat dose part of the Study 
200975 (up to 120 mg BID), a 60 mg BID dose is now predicted to have on average 99% 
RIP1 target engagement in blood and approximately 90% of subjects will have >85% 
target engagement at Cmin.  In skin, assuming the same skin: blood ratio of 0.4 as noted 

2015N251765_02
CONFIDENTIAL
203167
19
above, the average RIP target engagement at 60 mg BID in skin is predicted to be 96%.  
At Cmin, 43% of subjects are predicted to have >90% RIP1 target engagement in the skin 
and 90% of subjects are predicted to have >70% RIP1 target engagement in the skin. 
In review of this final FTiH data, it is believed that the Cmin target exposure may not be 
achieved with a 60mg BID dosing regimen.  The Cmin values at 60 mg TID are predicted 
to be approximately 3.5 fold higher than for 60 mg BID.  Therefore, a 60 mg TID cohort 
is now being proposed.
Using the final PK/PD, a 60 mg TID dose is predicted to have on average 99% RIP1 
target engagement in blood and approximately 90% of subjects will have  > 96% target 
engagement at Cmin.  In skin, the average RIP target engagement at 60 mg TID is 
predicted to be 98%.  At Cmin, 91% of subjects are predicted to have >90% RIP1 target 
engagement in the skin and 90% of subjects are predicted to have >91% RIP1 target 
engagement in the skin.
In addition, because of the short half-life, a modified release formulation is now being 
developed with the aim to provide a once daily dosing regimen.  By increasing the 
frequency of dosing to three times daily (TID) with the current immediate release 
formulation, this will more closely match the PK, safety and efficacy profile of a 
preferred once daily modified release formulation.
The safety of increasing the dose frequency to 60 mg TID is justified based on 
nonclinical safety findings to date with GSK2982772. It is anticipated that a human dose 
of 60 mg TID (180 mg/day) will produce AUC(0-24) and Cmax values of approximately 9.9 
ug.h/mL and 0.8 ug/mL, respectively, which are approximately 1/5th and 1/15th of the 
gender-averaged AUC (48.4 ug.h/mL) and Cmax (12.3 ug/mL) achieved in the 13 week 
monkey study at the no adverse effect level (NOAEL) dose of 30 mg/kg/day. Please see 
GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_01].
Up to 03 Apr 2017, a total of approximately 93 subjects across 4 clinical studies have 
been randomised to receive GSK2982772. In Study 200975, GSK2982772 administered 
up to 120 mg BID for 14 days and was well tolerated and no safety concerns were 
identified. A total of 9 subjects had received 120 mg BID in that study.  Please see 
GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_01]. In this 
current study, 203167, approximately 22 of 33 subjects have been randomised to 
GSK2982772 60 mg BID. In other Phase 2a studies in Rheumatoid Arthritis [(RA); Study 
203168] and Ulcerative Colitis [(UC); Study 202152], a total of 4 subjects have been 
randomised to GSK2982772 60 mg BID. GSK2982772 was well tolerated and no drug-
related SAEs have been reported.  There was a death of a 19 year old male subject in this 
current study due to an accidental overdose with 3,4-methylenedioxy-methamphetamine 
(MDMA) that was not considered drug related by the Principal Investigator (PI).  
The proposed 60 mg TID dose regimen is predicted to have mean Cmax (0.80 µg/mL) and 
AUC(0-24) (9.9 µg.hr/mL ) that are approximately 10% and 50% higher, respectively than 
for 60 mg BID (0.70 µg/mL and 6.6 µg.hr/mL).  This exposure is well within the 
observed Cmax and AUC(0-24) values at 120 mg BID in Study 200975.

2015N251765_02
CONFIDENTIAL
203167
20
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2982772 can be found in the Investigator’s Brochure.  The following section 
outlines the risk assessment and mitigation strategy for this protocol:  

2015N251765_02
CONFIDENTIAL
203167
21
4.6.1.
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 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 NOAEL for this study was determined at 10 mg/kg/day.
In the 13-week GLP toxicology study, there were no CNS findings observed 
in monkeys administered 10, 30 or 100 mg/kg/day.  The NOAEL for this 
study was determined at 30 mg/kg/day.
Clinical data:
A First Time in Human (FTiH) study with single ascending and multiple 
ascending dose study has been performed in 67 healthy male volunteers to 
date (see Investigators Brochure (IB) [GlaxoSmithKline Document Number 
2014N204126_01].  No drug-associated CNS adverse events were identified 
and no Serious Adverse Effects (SAEs) were reported.
Subject Selection:

Subjects with known history of significant neurologic disorders
including but not limited to progressive multiple sclerosis (MS), 
Amyotrophic lateral sclerosis (ALS), Alzheimer’s and dementia will 
be excluded.

Individuals with potentially increased susceptibility for neurologic 
effects will be excluded based on medical history at screening.
Subject Monitoring:

Subjects will be monitored for standard CNS-related adverse 
events.
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 experienced an 
Adverse Effect (AE) herpes zoster approximately 27 days after receiving his 
last dose with GSK2982772 or placebo.  The blinded investigator determined 
this to be potentially drug-related.
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.

Investigators are expected to follow local and/or national guidelines 
with respect to vaccinations, including against influenza and 
pneumococcus, in subjects with PsO.

2015N251765_02
CONFIDENTIAL
203167
22
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Subject Monitoring:

Subjects will be monitored for signs of infection.

See Individual Stopping Criteria for atypical or opportunistic 
infections (Section 5.4.1).
Vaccinations
There is a theoretical risk that GSK2982772 could decrease an individual’s 
immune response to vaccines or allow symptoms to develop following 
vaccination with a live vaccine when administered while on therapy.
Subject Selection:

Attenuated or live vaccines should not be administered to subjects 
from 30 days prior to the first dose of GSK2982772, during the 
study and for 5 half-lives plus 30 days (total 32 days) after
GSK2982772 is discontinued.

If indicated, non-live vaccines (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 decreased responsiveness). 

Investigators will be expected to have followed local and/or national 
guidelines with respect to vaccinations, including against influenza 
and pneumococcus, in subjects with PsO.
Respiratory
Non-clinical data:
In the single dose Safety Cardiovascular and Respiratory Study in monkeys, 
a decrease in minute volume (MV) 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 oral dose respiratory function study, no respiratory effects 
on respiratory function (e.g., tidal volume, 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_01].
Clinical data:
In the FTiH study, repeat doses of GSK2982772 were administered x 14 
days in 36 healthy male volunteers. Extensive respiratory monitoring with 
end-tidal CO2 (ETCO2), oxygen saturation (SpO2) and nocturnal respiratory 
Subject Monitoring:

Subjects should be monitored for standard respiratory-related 
adverse events.

Vital signs will be monitored during study visits.

2015N251765_02
CONFIDENTIAL
203167
23
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
rate monitoring was performed.   No SAEs occurred, and no drug-associated 
respiratory-related adverse events were identified.
CNS/Suicidality
GSK2982772 is considered to be a CNS-active drug based on pre-clinical 
studies.
Clinical data:
In the FTiH study, there have been some reports of lethargy, abnormal 
dreams, and depressed mood.  No events of suicidal ideation or behaviour 
or changes in behaviour were reported.    
Subject selection:

Subjects with a current history of Suicidal Ideation Behaviour (SIB) 
as measured using the Columbia Suicide Severity Rating Scale (C-
SSRS) or a history of attempted suicide will be excluded from the 
study.
Subject Monitoring:

Subjects should be monitored appropriately and observed closely 
for suicidal ideation and behaviour or any other unusual changes in 
behaviour.

Baseline and treatment emergent assessment of suicidality will be 
conducted by trained site personnel using the Columbia Suicide 
Severity Rating Scale (C-SSRS) in all subjects.  See Section 7.3.7.
Reproductive 
toxicity
Non-clinical data:
In the rat embryofetal development study, was no maternal or developmental 
toxicity at doses 200 mg/kg/day.
In the rabbit embryofetal development study, GSK2982772 was administered 
at doses of 0, 10, 100, 300 or 600 mg/kg/day on gestation day 7 to 19.  No 
developmental toxicity was evident at doses up to 300 mg/kg/day.
Subject selection:

Male and female subjects of childbearing potential will be included 
in this study only if they agree to use highly effective methods of 
contraception and avoid conception for defined periods of time 
before first administration of study drug until 30 days (females) and 
90 days (males) after the last administration of study drug 
(Appendix 5).

Females of childbearing potential will undergo serum pregnancy 
test at screening and then urine pregnancy testing at regular 
intervals during the study. 

Pregnant and lactating females are not eligible for inclusion in the 
study.

2015N251765_02
CONFIDENTIAL
203167
24
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Withdrawal criteria:

If a female subject should become pregnant during the study, study 
medication should be discontinued.  The subject will be followed to 
determine the outcome of the pregnancy.  Any pregnancy 
complication or elective termination of a pregnancy will be reported 
as an AE or SAE.
Drug Interaction
Non-clinical data:
In vitro studies with GSK2982772 assessing potential drug-drug interactions 
with Cytochrome P450 3A4 (CYP3A4) substrates and P-glycoprotein (Pgp) 
inhibitors 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 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 GSK2982772 IB [GlaxoSmithKline Document Number 
2014N204126_01].
Subject Selections:

Subjects who are taking concomitant medications known to inhibit 
Pgp or are CYP3A4 narrow therapeutic index (NTI) substrates will 
be excluded from the study.  See Section 6.11.2 for a 
comprehensive list of medications.
Subject Monitoring:

Subjects’ concomitant medication usage will be reviewed prior to 
inclusion and monitored throughout the study.
Subjects should be monitored throughout the study for potential effects 
of interaction between GSK2982772 and other concomitant medications.
Study Procedures
Punch skin lesion
biopsies
Potential risks of the procedure include discomfort, infection or bleeding.
Subject selection:

Subjects with history of hypertrophic scarring or keloid, or known 
allergy to lidocaine or other local anaesthetics will not be included 
in the study.

Subjects with a platelet count <100x 109/L will be excluded from 
participation.

2015N251765_02
CONFIDENTIAL
203167
25
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Subject management:

A local anaesthetic will be administered before each skin biopsy is 
taken (as per local practice) to reduce the risk of pain.  The biopsy 
procedure will be done only by experienced personnel to reduce 
the risk of bleeding and scarring.  Aseptic technique will be utilized 
to reduce the risk of infection.

The risk of infection, although low given the low invasiveness of the 
procedure, will be reduced by dressing the site after biopsy.  
Subjects will be advised to keep the site covered and dry for 24-48 
hours before leaving open to the air.  Subjects will be instructed as 
to the signs and symptoms of infection, and to contact site 
personnel should they develop.  This information will also be 
contained in the patient information leaflet.

Biopsy site healing will be monitored during the study as part of AE 
review.

2015N251765_02
CONFIDENTIAL
203167
26
4.6.2.
Benefit Assessment
There are additional treatment options available for subjects who have an inadequate 
response to current therapies for PsO.  It is possible that treatment with GSK2982772 
may be effective in the treatment of PsO, as the FTiH study demonstrated that the drug 
engaged with the target and produced ex vivo PD effects in RIP1-dependent cytokines 
MIP1and MIP1[GlaxoSmithKline Document Number 2014N204126_01].  There will 
be limited direct benefit to the subject for participating in this trial.  However, subjects 
will indirectly benefit through their contribution to the process of developing new 
therapies in an area of unmet need.  
4.6.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with GSK2982772 are justified by the 
anticipated benefits that may be afforded to subjects with PsO by contributing to the 
understanding of the disease and the development of new therapies for patients with these 
conditions in the future.  
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number 2014N204126_01].
In addition, investigators are expected to follow local and/or national guidelines with 
respect to vaccinations, including against influenza and pneumococcus, in subjects with 
PsO.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
For both cohorts, a subject will be eligible for inclusion in this study only if all of the 
following criteria apply:
AGE
1. Between 18 and 75 years of age inclusive, at the time of signing the informed 
consent.

2015N251765_02
CONFIDENTIAL
203167
27
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Subjects that do not have any medical conditions, other than active plaque-type 
psoriasis, that in the opinion of the Investigator put the subject at unacceptable risk or 
interfere with study assessments or integrity of the data. All medical conditions must 
be stable for the duration of the study.
3. Presence of active chronic plaque-type psoriasis as determined by the Investigator for 
at least 6 months (confirmed by the subject or medical record) before first dose of 
study treatment (Day 1).  
4. Subject has psoriasis plaques involving Body Surface Area (BSA) ≥ 3% assessed at 
Screening and before dosing on Day 1.
5. Physician Global Assessment (PGA) ≥3.
6. Subject must agree to avoid prolonged exposure to natural sunlight, tanning beds or 
phototherapy devices for the duration of the study. See Section 6.11.2.
7. Subject has at least two stable plaques assessed at Screening and before dosing on
Day 1.  

Both must be of a suitable size (3 cm by 3 cm) and one in a site suitable for 
repeat biopsy, and one in a site suitable for index lesion Psoriatic Lesion 
Severity Sum (PLSS) scoring.

Both plaques must have a PLSS lesional score 2 for the induration 
component (moderate or above), ≥1 for erythema and scaling with a total 
score of 5.

The biopsy lesion must not be on the face, groin, scalp, knees, elbows, or on 
the palmar/plantar surfaces of the hands/feet, and must be shielded from 
natural light with clothing.
8. Subject is naive to any biologic therapies for PsO, OR has had previous exposure to a 
single anti-TNF biologic agent in the context of a previous clinical trial.  The anti-
TNF biologic agent must have been discontinued more than 8 weeks prior to 
screening visit (12 weeks or 5 half lives whichever is longer from first dose).
WEIGHT
9. A body mass index BMI within the range of 18.5 – 35 kg/m2 (inclusive).
SEX
10. Male and Female subjects
Males:
Male subjects with female partners of child bearing potential must comply with the 
contraception requirements in Appendix 5. 
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin (hCG) test), not lactating, and at least 
one of the following conditions applies:

2015N251765_02
CONFIDENTIAL
203167
28
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish 
to continue their HRT during the study.  Otherwise, they must discontinue 
HRT to allow confirmation of post-menopausal status prior to study 
enrolment.
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 5) from 30 days prior to the first dose of 
study medication and until 30 days after the last dose of study medication and 
completion of the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
11. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
For both cohorts, a subject will not be eligible for inclusion in this study if any of the 
following criteria apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL)
1. Subjects with clinically overt concurrent psoriatic arthritis who are receiving chronic 
DMARD therapy (other than NSAIDs), as judged by the Investigator.
2. Has nonplaque forms of psoriasis (e.g. erythrodermic, guttate, or pustular), as judged 
by the Investigator.
3. Has current drug-induced psoriasis (e.g., a new onset of psoriasis or an exacerbation 

2015N251765_02
CONFIDENTIAL
203167
29
from beta blockers, calcium channel blockers, or lithium).
4. Subject with current history of Suicidal Ideation Behaviour (SIB) as measured using 
the Columbia Suicide Severity Rating Scale (C-SSRS) or a history of attempted 
suicide.
5. An active infection, or a history of infections as follows:

Hospitalisation for treatment of infection within 60 days before first dose 
(Day 1).

Currently on any suppressive therapy for a chronic infection (such as 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and 
atypical mycobacteria).

Use of parenteral (IV or intramuscular) antibiotics (antibacterials, antivirals, 
antifungals, or antiparasitic agents) within 60 days before first dose.

A history of opportunistic infections within 1 year of screening (e.g. 
pneumocystis jirovecii, CMV pneumonitis, aspergillosis).  This does not 
include infections that may occur in immunocompetent individuals, such as 
fungal nail infections or vaginal candidiasis, unless it is of an unusual severity 
or recurrent nature.

Recurrent or chronic infection or other active infection that, in the opinion of 
the investigator might cause this study to be detrimental to the patient.

History of TB, irrespective of treatment status.

A positive diagnostic TB test at screening defined as a positive 
QuantiFERON-TB Gold test or T-spot test.
o
In cases where the QuantiFERON or T-spot test is indeterminate, the 
subject may have the test repeated once, but they will not be eligible 
for the study unless the second test is negative.
o
In cases where the QuantiFERON or T-spot test is positive, but a 
locally-read follow up chest X-ray, shows no evidence of current or 
previous pulmonary tuberculosis, the subject may be eligible for the 
study at the discretion of the Investigator and medical monitor.
6. QTc >450msec or QTc >480msec in subjects with bundle branch block.

The QTc is the QT interval corrected for heart rate according to either 
Bazett’s formula (QTcB), 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 subject should be determined prior to 
initiation of the study. In other words, several different formulae cannot be 
used to calculate the QTc for an individual subject and then the lowest QTc 
value used to include or discontinue the subject from the trial. For purposes of 
data analysis, QTcB, QTcF, another QT correction formula, or a composite of 
available values of QTc will be used as specified in the Reporting and 
Analysis Plan (RAP). 
7. ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%) at screening.
8. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).

2015N251765_02
CONFIDENTIAL
203167
30
9. Current or history of renal disease or estimated glomerular filtrate rate (GFR) by 
Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) <60 
mL/min/1.73 m2.
10. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency.
11. A major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem 
cell/marrow transplant.
12. A planned surgical procedure that, in the opinion of the investigator, makes the 
subject unsuitable for the study.
13. A history of malignant neoplasm within the last 5 years, except for adequately treated 
cancers of the skin (basal or squamous cell carcinoma) or carcinoma in situ of the 
uterine cervix that has been fully treated and shows no evidence of recurrence.
14. A history of hypertrophic scarring or keloid formation, or known allergy to lidocaine 
or other local anaesthetics.
CONCOMITANT MEDICATIONS
15. The subject has received treatment with the therapies listed in Section 6.11, or 
changes to those treatments, within the specified timeframe.  If in doubt, or the 
therapy is not listed please consult with the medical monitor.

Other medications (including vitamins, herbal and dietary supplements) will 
be considered on a case-by-case basis, and will be allowed if in the opinion of 
the investigator the medication will not interfere with the study procedures or 
compromise subject safety.
RELEVANT HABITS
16. History of alcohol or drug abuse that would interfere with the ability to comply with 
the study.
17. Subject intends to sunbathe or use a tanning device (sun bed or solarium) within 14 
days prior to Day 1 and until completion of the follow up visit (Day 112).
CONTRAINDICATIONS 
18. History of sensitivity to any of the study treatments, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
19. Received a live or attenuated vaccine within 30 days of randomization OR plan to 
receive a vaccination during the study until completion of the follow-up visit.
20. The subject has participated in a clinical trial and has received an investigational 
product within 30 days or 5 half-lives, whichever is longer before the first dose of 
study medication, or plans to take part in another clinical trial at the same time as 
participating in this clinical trial. Subjects who were randomized into Cohort 1 are not 
eligible to be re-randomized into Cohort 2.

2015N251765_02
CONFIDENTIAL
203167
31
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
21. Haemoglobin <11 g/dL; haematocrit <30%, white blood cell count ≤3000/mm3 (≤3.0 
x 109/L); platelet count ≤ 100,000/µL (≤100 x 109/L); absolute neutrophil count ≤1.5
x 109/L at the screening visit.
22. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.  As 
potential for and magnitude of immunosuppression with this compound is unknown, 
subjects with presence of hepatitis B core antibody (HBcAb) should be excluded.
Subjects positive for HBsAg and/or positive for anti-HBc antibody (regardless of 
anti-HBs antibody status) are excluded.
23. A positive serology for human immunodeficiency virus (HIV) 1 or 2 at screening.
24. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months.
25. Exposure to more than 4 investigational medicinal products within 12 months prior to 
the first dosing day.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.5).
Subjects who do not qualify to participate in the study due to a screening laboratory value 
or ECG abnormality can repeat the test once within the original screening time window, 
if the Investigator believes there is a reasonable possibility that the subject would be 
eligible if re-tested. 
Subjects can be re-screened only on approval of the GSK Medical Monitor and only 
once. Re-screening is allowed when a subject failed inclusion/exclusion criteria or some 
other screening condition initially, but the Investigator believes there is a reasonable 
probability that the subject would be eligible if re-screened.
5.4.
Withdrawal/Stopping Criteria
Subjects may be withdrawn from the study for any of the following reasons:

A subject may withdraw from study treatment at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural or administrative reasons.  If a subject withdraws from the study, 
he/she may request destruction of any samples taken, and the investigator must 
document this in the site study records.  The reason for withdrawal should be 
documented in the Case Report Form (CRF).

2015N251765_02
CONFIDENTIAL
203167
32

The Sponsor may request a subject withdraw for reasons such as significant 
protocol deviations (after discussion with the investigator).

If a subject is withdrawn from study treatment, this subject is also considered to 
be withdrawn from the study.

Study is terminated by the Sponsor.
If a subject is withdrawn, the Sponsor may decide to replace that subject and this will be 
done through the Interactive Response Technology System (IRTS).
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
If a subject chooses to withdraw from the study after dosing, the investigator must make 
every effort to complete the follow up assessments detailed in the Time and Events Table 
(Section 7.1).
5.4.1.
Individual Safety Stopping Rules
Study medication will be discontinued in the event of any of the following:

If a subject experiences a serious or severe clinically significant AE that in the 
clinical judgement of the investigator, after consultation with the medical monitor, 
there is a reasonable possibility that the AE is related to investigational product.

The subject becomes pregnant.

The subject initiates treatment with any prohibited medication for the treatment of 
PsO as listed in Section 6.11.2.

The subject develops a serious opportunistic or atypical infection.

If the liver chemistry stopping criteria (Section 5.4.3), QTc stopping criteria 
(Section 5.4.4), or haematologic stopping criteria (Section 5.4.5) are met.

2015N251765_02
CONFIDENTIAL
203167
33

The subject experiences any signs of suicidal ideation or behaviour (Section 
7.3.7).
5.4.2.
Group Safety Stopping Rules
In addition to the criteria specified above, AEs, SAEs, laboratory abnormalities, ECG 
abnormalities and changes in vital signs occurring across all randomised subject will be 
regularly reviewed by the Sponsor Safety Review Team (SRT) in order to ensure 
appropriate subject safety.  Any changes to the study due to safety reasons will be 
promptly communicated to the appropriate Regulatory Authorities.
5.4.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf

2015N251765_02
CONFIDENTIAL
203167
34
Figure 3
Phase II Liver Chemistry Stopping and Increased Monitoring 
Algorithm
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
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 2.
5.4.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.4.
QTc Stopping Criteria
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTc >500 msec or Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:

2015N251765_02
CONFIDENTIAL
203167
35
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
<450 msec
>500 msec
450–480 msec
530 msec

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB must 
be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the same 
formula must continue to be used for that subject for all QTc data being collected for 
data analysis.  Safety ECGs and other non-protocol specified ECGs are an 
exception.  

The decision to withdraw a subject will be based on an average QTc value of 
triplicate ECGs.  If an ECG demonstrates a prolonged QTc, obtain 2 more ECGs 
over a brief period (5-10 minutes), and then use the averaged QTc values of the 3 
ECGs to determine whether the subject should be discontinued from the study.
5.4.5.
Haematologic Stopping Criteria
Study treatment will be stopped for a subject if any of the following haematological 
stopping criteria is met:

Haemoglobin <9 g/dL or an absolute decrease of ≥3 g/dL from baseline (pre-
dose Day 1)

Platelets <50 × 109/L
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.

2015N251765_02
CONFIDENTIAL
203167
36
Study Treatment
Product name:
GSK2982772
Placebo
Dosage form:
Tablet
Tablet
Unit dose strength(s)/Dosage 
level(s):
30 mg
NA
Route of Administration
For oral use only
For oral use only
Dosing instructions for Cohort 
1:
Take TWO tablets in the 
MORNING and TWO tablets in the 
EVENING as directed
Take TWO tablets in the 
MORNING and TWO tablets in the 
EVENING as directed
Dosing instructions for Cohort 
2:
Take TWO tablets THREE times 
daily as directed by your physician
Take TWO tablets THREE times 
daily as directed by your physician
Physical description
White to almost white, round, film 
coated tablet
White to almost white, round film 
coated tablet
Source of procurement
Study medication is supplied by 
GlaxoSmithKline
Placebo is supplied by 
GlaxoSmithKline
6.2.
Treatment Assignment
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. 
Subjects who meet screening eligibility criteria will be randomised to a treatment group 
through Interactive Response Technology System (IRTS).  The IRTS will confirm the 
subject’s CRF number (Subject Number) and provide the randomisation number, where:

A randomisation number will be assigned from a randomisation schedule generated 
by Clinical Statistics, prior to the start of the study, using validated internal software.  
Once assigned, this number must not be reassigned to any other subject in the study.
The randomisation is centrally controlled by the IRTS.
In Cohort 1, subjects will take study medication every day, twice a day, approximately 12 
hours apart.   Subjects will be randomised to receive either GSK2982772 or placebo in a 
2:1 ratio. In Cohort 2, subjects will take study medication every day, three times a day, 
with approximately 8 hours between each dose.  Subjects will be randomised to receive 
either GSK2982772 or placebo in a 3:1 ratio.
Subjects will be administered the first daily dose of study medication by site staff during 
the site visit for Day 1 (week 0) and Day 43 (week 6). Subjects will self-administer all 
other doses of study medication and will record the date and time in the diary cards 
provided to them.
6.3.
Planned Dose Adjustments
No dose adjustments are allowed.

2015N251765_02
CONFIDENTIAL
203167
37
6.4.
Blinding
This will be a double blind (sponsor unblind) study and the following will apply. 

Sponsor unblinded refers only to the Data Review Committee (DRC) consisting 
of the GSK Project Physician Lead (PPL), the study statistician, the study 
pharmacokineticist, Pattern Recognition Receptor (PRR) Discovery Performance 
Unit (DPU) Head, the Early Development Leader (EDL), the Safety Review Team 
(SRT) leader, or their designees on an ongoing basis. A physician external to the 
GSK2982772 project team may also be involved in the data review.  A data 
review charter will identify the specific GSK individuals involved; outline in 
detail the activities of this review, and how the integrity of the study will be 
maintained. The rest of the core GSK study team will remain blinded.

The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator. Investigators have direct access to the subject’s individual study 
treatment.

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the CRF.

A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the 
event or condition which led to the unblinding) will be recorded in the CRF. 

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject with an SAE. If the SAE requires that an
expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.

2015N251765_02
CONFIDENTIAL
203167
38
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.7.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment. 
When subjects self-administer study treatment(s) at home, compliance with GSK2982772 
will be assessed through querying the subject during the site visits and documented in the 
source documents (diary cards) and CRF.  A record of the number of GSK2982772 or 
placebo tablets dispensed to and taken by each subject must be maintained and reconciled 
with study treatment and compliance records.  Treatment start and stop dates, including 
dates for treatment delays and/or dose reductions will also be recorded in the CRF.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2982772 >120 mg daily will be considered an overdose
in Cohort 1 and any dose of GSK2982772 >180 mg daily will be considered an overdose 
in Cohort 2.  GSK does not recommend specific treatment for an overdose.  The 
investigator will use clinical judgement to treat any overdose as and when they are made 
aware of this.
In the event of an overdose the investigator or treating physician should:
1. Contact the Medical Monitor immediately.

2015N251765_02
CONFIDENTIAL
203167
39
2. Closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until GSK2982772 can no longer be detected 
systemically (at least 2 days for GSK2982772).
3. Obtain a plasma sample for pharmacokinetic (PK) analysis if requested by the 
Medical Monitor (determined on a case-by-case basis)
4. Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.10.
Lifestyle and/or Dietary Restrictions

Subjects must adhere to the contraceptive requirements listed in Appendix 5.

Subjects must abstain from alcohol for 24 hours before all clinic visits.
6.10.1.
Sun Exposure and Activity
Subjects must not sunbathe or use a tanning device (sun bed or solarium) for 14 days 
prior to Day 1 until the follow up visit (Day 112).  Subjects will be advised that when 
they are outdoors they should wear protective clothing (e.g. sun hat, long sleeves) 
covering the selected target lesions for biopsy and PLSS scoring as well as use a broad 
spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) on exposed areas when outdoors.
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.  
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Selected medications for the treatment of PsO may be taken, with specific requirements 
listed in Table 1, and as long as they are not prohibited (Section 6.11.2).  All concomitant 
medications taken during the study will be recorded in the CRF.  The minimum 
requirement is that drug name and dates of administration are recorded.

2015N251765_02
CONFIDENTIAL
203167
40
Table 1
Specific Requirements for Permitted Medications During the Study
Therapy
Requirement
Emollients (excluding those containing salicylic 
acid)
Omit on day of study visits until after all skin 
assessments have been performed.  May be 
used at other times.
Medicinal shampoos that contain tar and/or 
salicylic acid (but not corticosteroids)
Permitted at any time on scalp area.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Table 2 lists prohibited medications for defined periods of time before and during the 
study until after the follow up visit (Day 112). 
Subjects who start prohibited medications or therapies as a treatment for PsO or other 
reasons during the study may be withdrawn from study treatment for safety reasons.  If in 
any doubt, investigators are advised to discuss medications with the medical monitor.
Table 2
Prohibited Medications
Therapy
Time period 
Biologic therapies for the treatment of chronic 
plaque-type psoriasis

Exception:  Can have only been 
exposed to one anti-TNF biologic 
previously administered in a clinical 
study setting. 
12 weeks or 5 half-lives (whichever is longer) 
prior to first dose.  Otherwise, cannot have 
been on an anti-TNF biologic treatment at any 
time during the study.
Photochemotherapy with psoralens and 
ultraviolet A (PUVA) therapy
4 weeks prior to first dose until after the follow 
up visit (Day 112).
Phototherapy (e.g., UVB or self treatment with 
tanning beds)
14 days
Topical therapies (e.g., corticosteroids, 
cyclosporine, calcineurin inhibitors, coal tar, 
vitamin A or D analog preparations, anthralin, 
calcipotrienen, retinoids, tazarotene, 
methoxsalen, trimethy psoralens).
2 weeks prior to first dose until after the follow 
up visit (Day 112).
Systemic immunomodulating medications for 
other medical conditions that are known to affect 
psoriasis, including but not limited to oral 
corticosteroids cyclosporine, methotrexate, 
cyclophosphamide, and beta-adrenergic 
blockers.
Intravenous or oral calcineurin inhibitors (e.g., 
tacrolimus).
4 weeks prior to first dose until after the follow 
up visit (Day 112).
P-glycoprotein (Pgp) inhibitors including but not 
limited to amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, 
cyclosporine, diltiazem, dronedarone, 
4 weeks prior to first dose until after the follow 
up visit (Day 112).

2015N251765_02
CONFIDENTIAL
203167
41
Therapy
Time period 
erythromycin, felodipine, itraconazole, 
ketoconazole, lopinavir, ritonavir, quercetin, 
quinidine, ranolazine, ticagrelor, verapamil [FDA,
2012].
Narrow therapeutic index (NTI) CYP3A4 
substrates including but not limited to alfentanil, 
astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, 
terfenadine [FDA, 2012].
4 weeks prior to the first dose until after the 
follow up visit (Day 112).
Live vaccination
Vaccinations (either live, attenuated) are not 
permitted within 30 days of randomization or 
plan to receive a vaccination during the study 
until follow-up visit.  If indicated, non-live 
vaccines (e.g. inactivated influenza vaccines) 
may be administered whilst receiving 
GSK2982772 based on an assessment of the 
benefit: risk (e.g. risk of decreased 
responsiveness).  Investigators are expected to 
follow local and/or national guidelines with 
respect to vaccinations, including against 
pneumococcus and influenza, in subjects with 
PsO.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 7.1), are essential and required for study 
conduct.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the SRM.  The SRM will provide the site personnel with administrative and 
detailed technical information that does not impact subject safety.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1.
The following points must be noted:

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
a.
Patient Reported Outcomes (PROs)
b.
12-lead ECG
c.
vital signs

2015N251765_02
CONFIDENTIAL
203167
42
d.
blood draws  
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker or other assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

The Institutional Review Board/ Independent Ethics Committee (IRB/IEC) will 
be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form. 
A table defining the allowed variance in timings of assessments without being considered 
a protocol deviation will be included in the Study Reference Manual (SRM).

2015N251765_02
CONFIDENTIAL
203167
43
7.1.
Time and Events Table
Procedures
Screening
Treatment Period
Early Withdrawal 14
Follow Up
Notes
Day 1 
Day 8 
Day 15
Day 22
Day 29
Day 36
Day 43
(week 6)
Day 50
Day 57
Day 64
Day 71
Day 78
Day 85
(week 12)
Visit windows
Screening: up to 30d before Day 1.
Treatment Period (except Day 1 & 
85): 3d. Day 1 NA; Day 85 2d.
Early Withdrawal: NA
Follow Up: 28d after last dose 3d
Screening Procedures
Screening procedures in addition to those listed below are (outpatient visit): informed consent; inclusion/ exclusion criteria; demography; medical history (includes past and 
current conditions, medication history, and family history of premature CV disease); HIV, Hep B and Hep C screen; serum pregnancy test (WCBP only).
Site Visit
X
X
X
X
X
X
X
X
X
X
X
1. Full physical exam: height/weight at 
Screening, height not required at later 
timepoints.
2. Vitals: BP, HR, RR, temperature. 
ECG triplicate at Screening only.
3. Urinalysis not required on Days 29, 
57 and 71. 
4. If urine test is positive, confirmatory 
serum test must be performed.
5. Pre-dose
6. In Cohort 1, subjects must take study 
medication twice a day approx. 12h
apart. In Cohort 2, subjects must take 
study medication three times a day 
approx. 8h apart. Exact time of dosing 
to be recorded in diary cards. On Days 
43 and 85, subjects must not take 
medication at home in the morning. 
Subjects will complete pre-dose 
assessments and then will be 
administered their morning dose of 
medication at site on Day 43 only. On 
Day 85, subjects no longer dosed.
7. Diary card checked by site staff and 
new diary card dispensed at every 
study visit.
8.  Blood samples for inflammatory 
Phone call
X
X
X
X
X
Safety Assessments
Full physical exam1
X
X
X
X
Brief physical exam
X5
X
X
X5
X
X
12-lead ECG, vital signs2
X
X5
X
X
X
X5
X
X
X
X
X
Columbia Suicide Severity 
Rating Scale (C-SSRS)
X
X5
X5
X
X
Hematology, chemistry,
urinalysis 
X
X5
X
X
X3
X5
X3
X3
X
X
X
FSH & estradiol  (if 
applicable)
X
Serum pregnancy (WCBP)
X
Urine pregnancy test 
(WCBP only)4
X5
X
X
X
X5
X
X
X
X
X
Study Treatment
Randomisation
X
Study medication6
X
X-------------------------------------------------------------------------------------------------X
Dispensing of study 
medication
X
X
X
Dispensing of diary cards7
X
X
X
X
X
X
X
PROs/ Disease Assessments

2015N251765_02
CONFIDENTIAL
203167
44
Procedures
Screening
Treatment Period
Early Withdrawal 14
Follow Up
Notes
Day 1 
Day 8 
Day 15
Day 22
Day 29
Day 36
Day 43
(week 6)
Day 50
Day 57
Day 64
Day 71
Day 78
Day 85
(week 12)
Visit windows
Screening: up to 30d before Day 1.
Treatment Period (except Day 1 & 
85): 3d. Day 1 NA; Day 85 2d.
Early Withdrawal: NA
Follow Up: 28d after last dose 3d
Psoriatic Body Surface 
Area
X
X5
X
X
biomarkers and mRNA taken pre-dose 
on Day 1, Day 43 and Day 85. 
9. PK blood samples taken pre-dose on 
Day 43. Post-dose serial PK samples 
taken on Day 1 and Day 43 at 1, 2, 4, 
and 6 hours post-dose.
10. Pre-dose Day 1 one biopsy taken 
from non-lesional skin and two biopsies 
taken from biopsy target lesion.
11. On Day 43, two biopsies taken from 
the same target lesion that was 
selected at Day 1. Punch biopsies on 
Day 43 are to be taken pre-dose.
12. Biopsy only required at Early 
Withdrawal visit if completed at least 14 
days of treatment and prior to Day 43.
13. PGx sample collected at Day 1, 
after randomization and separate 
informed consent. If sample not 
collected at Day 1, can be collected at 
any time post-randomization. 
14. If subject withdraws early, every 
effort will be made for the subject to 
complete an Early Withdrawal visit prior 
to Follow Up. 
PASI, PGA, PLSS, Itch
X
X5
X
X
X5
X
X
X
X
DLQI
X
X5
X5
X
X
Photograph of lesions
X5
X5
X
X
Other Assessments and Procedures
Blood sample for 
inflammatory biomarkers8
X5
X5
X
X
Blood sample for mRNA 
analysis8
X5
X5
X
X
Blood sample for Target 
Engagement
X5
X5
X
X
PK blood samples9
X
X5
X
X
Skin punch biopsies for 
PK, inflammatory 
biomarkers, mRNA, target 
engagement & pathway 
engagement
X5,10
X11
X12
Pharmacogenetic sample 
(PGx)
X13
Con med review & AE/SAE 
reporting
X-------------------------------------------------------------------------------------------------------------------------X

2015N251765_02
CONFIDENTIAL
203167
45
7.2.
Screening and Critical Baseline Assessments
After written informed consent, screening assessments will be performed as outlined in 
the Time and Events Table (Section 7.1).
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5. 
Cardiovascular medical history/risk factors and smoking history (as detailed in the CRF) 
will be assessed at screening. 
Procedures conducted as part of the subject’s routine clinical management (e.g. blood
count) and obtained prior to signing of informed consent may be utilized for Screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed in the timeframe of the study.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests such as vital signs, physical exams 
and laboratory safety tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
The investigator will be responsible for determining the clinical significance of any 
results the fall outside of the laboratory normal ranges.
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT), 
which will include 203167 study team members, will review blinded safety data, 
including clinical laboratory parameters and adverse events, at appropriate intervals 
during the period of study conduct.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

2015N251765_02
CONFIDENTIAL
203167
46

AEs will be collected from the start of study treatment on Day 1 until the follow-
up contact (see Section 7.3.1.3), at the time points specified in the Time and 
Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 4.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 4.
7.3.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.

2015N251765_02
CONFIDENTIAL
203167
47
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.3.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects
will be collected after the start of dosing and until 30 days after the last dose.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 5.
7.3.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
head, eyes, ears, nose, throat, skin, thyroid, joint, lymph nodes, cardiovascular, 
respiratory, gastrointestinal and neurological systems. Height and weight will also 
be measured and recorded. 

A brief physical examination will include, at a minimum assessments of the skin,
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.

2015N251765_02
CONFIDENTIAL
203167
48
7.3.4.
Vital Signs

Vital signs will be measured in a supine or semi-supine position after 5 minutes 
rest and will include temperature, systolic and diastolic blood pressure, pulse rate 
and respiratory rate. 
7.3.5.
Electrocardiogram (ECG)

Triplicate ECGs will be obtained at screening and single 12-lead ECGs will be 
obtained at every other time point during the study using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc (F or 
B) intervals.  Refer to Section 5.4.4 for QTc withdrawal criteria and additional 
QTc readings that may be necessary.

ECG is to be measured in a supine or semi supine position after 5 minutes rest.
7.3.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 3, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the laboratory manual for appropriate processing and handling of samples to 
avoid duplicate and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory.
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in times for either a treatment and/or response evaluation to be 
performed.  If a local sample is required it is important that the sample for central 
analysis is obtained at the same time. Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
CRF.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 

2015N251765_02
CONFIDENTIAL
203167
49
Table 3
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 2
Calcium
Alkaline 
phosphatise
Albumin
Triglycerides 2
Total 
Cholesterol2
HDL cholesterol 2
LDL cholesterol 2
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

HIV

Hepatitis B surface antigen (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis C (Hep C antibody)

QuantiFeron Gold test

T-spot (if QuantiFeron is indeterminant)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 3.  

Serum hCG (as needed for women of child bearing potential) to be 
done at screening and if urine test positive at other timepoints in 
study.

Estimated glomerular filtrate rate (eGFR) will be calculated using 
the CKD-EPIformula.
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 5.4.3 and 
Appendix 2.
2.
No fasting required.  Any abnormal result for glucose or lipids (non-fasted) may be 
repeated at the discretion of the investigator.
3.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.

2015N251765_02
CONFIDENTIAL
203167
50
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.
7.3.7.
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 PsO.  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.   
Families and caregivers of subjects being treated with GSK2982772 should be alerted 
about the need to monitor subjects 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.
Subjects being treated with GSK2982772 should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. All subjects who 
experience signs of suicidal ideation or behaviour must immediately be discontinued 
from study medication.
At Screening and baseline (pre-dose Day 1), the ‘Baseline/Screening CSSRS’ (Columbia 
Suicide Severity Rating Scale) will be completed.  At Days 43 (week 6) and Day 85 
(week 12), the ‘Since Last Visit CSSRS’ will be completed.  GSK Version 4.1 of both 
rating scales will be used.
Subjects who answer ‘yes’ to any suicidal behaviour or ‘yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their GP or appropriate psychiatric care.  The medical 
monitor will be notified.  If appropriate, an AE or SAE should be reported (see 
Section 7.3.1 - AE and SAE).  In addition, the investigator should complete a Possible 
Suicidality Related Adverse Event (PSRAE) form to collect detailed information on the 
circumstances of the reported AEs which, in the investigator’s opinion, are possibly 
suicidality-related.  These may include, but are not limited to, an event involving suicidal 
ideation, a preparatory act toward imminent suicidal behaviour, a suicide attempt, or a 
completed suicide.
7.4.
Efficacy
7.4.1.
Patient Reported Outcomes
Note: Patient Reported Outcomes questionnaires should be completed by subjects before 
any other assessments at a clinic visit.

2015N251765_02
CONFIDENTIAL
203167
51
7.4.1.1.
Itch Visual Analogue Scale
The subject will be asked to rate the intensity of itch over the past week by marking a line 
on a 10 cm VAS with anchors “0” (no noticeable itching) to “10” (maximum itching 
sensation).
7.4.1.2.
Dermatology Life Quality Index
The DLQI [Finlay, 1994] will be used to assess quality of life.  The subject will complete 
the questionnaire to evaluate how their psoriasis has affected their life over the previous 
week before the assessment occurs.  Each question will be scored out of 0-3 or 0-2, as 
follows.
0 = Not at all
1 = A little
2 = A lot
3 = Very much
The questionnaire comprises of 10 questions (see SRM for full details). 
7.4.2.
Clinical Disease Assessments
7.4.2.1.
Body Surface Area (BSA)
The BSA affected with psoriasis will be evaluated at Screening and baseline (pre-dose 
Day 1) and on Day 85 by the investigator or suitably trained delegate.  In order to be 
eligible for the study, BSA must be 3%.  As a reference, the area of the whole palm is 
counted as 1% BSA.
7.4.2.2.
Selection of Psoriasis Plaques and Plaque Lesion Severity Scoring 
(PLSS)
Two plaques of at least 3 cm by 3 cm in area will be selected during the Screening 
period, one for clinical assessment (clinical efficacy skin lesion) and one for skin biopsy 
(punch biopsies). If at baseline on Day 1, prior to dosing, another lesion appears more 
suitable, the selected lesion can be changed. Once the lesions have been selected at 
baseline on Day 1, they must not change.
At a minimum, each plaque will have an induration score of 2 (moderate or above) and 
a score of 1 in erythema and scaling.  The PLSS is the sum of the erythema, scaling and 
plaque thickness scores.  Each lesion must have a PLSS score of 5.
Ideally, the biopsy skin lesion should be the most severe plaque of the two.
Selected lesions should be located on areas (trunk or extremities) that can be shielded to 
reduce natural exposure to UV light and should not include scalp, inguinal, genital 
lesions, or the palmar surfaces of the hands and/or feet. Preferably, symmetrical lesions 
will be chosen, but this is not an absolute requirement.

2015N251765_02
CONFIDENTIAL
203167
52
During the study, the PLSS will be recorded for the clinical efficacy skin lesion (the 
biopsy lesion is only for biopsy).
7.4.2.3.
Psoriasis Area Severity Index (PASI)
The PASI scoring system is a widely-used standard clinical tool for assessing the severity 
of psoriasis that takes into account the overall severity of erythema (redness), thickness 
(induration), and scaling, as well as the extent of BSA affected with psoriasis 
[Fredriksson, 1978].  Erythema, induration, and scale are each graded on a 5-point scale 
(0-4), and the % BSA affected is scored on a 7-point scale (0-6) for each of the 4 
specified body regions (head, upper extremities, trunk, and lower extremities). The body 
region scores are each multiplied by a weighted factor; and the sum of the region scores 
give the overall PASI score.  Higher scores indicate more severe disease.  PASI is a static 
measurement made without reference to a previous score (see SRM for full details).
The PASI assessment will be performed by the investigator or suitably trained delegate, 
and whenever possible, the PASI assessments for an individual subject will be completed 
by the same assessor at all time points.
7.4.2.4.
Digital Photography
Photographs will be taken by the investigator or designee to illustrate any visible changes 
in psoriasis target lesions selected on Day 1.  For each subject, the investigator or 
delegate will take photographs of the same area of the body at each time point (i.e., same 
background, same illuminations, and same distance from the body).  Photographs will be 
taken of the area(s) of the body where the selected lesions are present and should be taken 
prior to performing the biopsy.  Photographs of the face will not be taken.  Photographs 
will be stored electronically, labelled, and collected centrally as explained in the Image 
Acquisition Guidelines.  Photographs will be used to document visual changes in lesions. 
Date, time and location of the photographs will be captured in the CRF.
Further details are contained in the Image Acquisition Guidelines.
7.4.2.5.
Physician’s Global Assessment of Disease Activity
The investigator or physician designee only will complete a global assessment of disease 
activity using the physician global assessment item. A 6-point scoring system will be 
used to measure the severity of psoriatic lesions over the entire body at the time of 
evaluation (see SRM for full details).
Note:

The investigator or physician designee should complete the physician’s global 
assessment independently of the subject.

Ideally, the same investigator or physician designee should perform all global 
assessments for each subject for the duration of the study.

2015N251765_02
CONFIDENTIAL
203167
53
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of GSK2982772 will be collected at 
the time points indicated in Section 7.1, Time and Events Table.  The actual date and 
time of each blood sample collection will be recorded.  The timing of PK samples may be 
altered and/or PK samples may be obtained at additional time points to ensure thorough 
PK monitoring.  
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the laboratory manual. 
7.5.2.
Sample Analysis
Plasma analysis will be performed at a bioanalytical site (to be detailed in the SRM) 
under the control of Platform Technologies and Science In vitro/ In vivo Translation
(PTS IVIVT) and Third Party Resource, GlaxoSmithKline. Concentrations of 
GSK2982772 will be determined in plasma samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed 
in the SRM). Once the plasma has been analyzed for GSK2982772 any remaining plasma 
may be analyzed for other compound-related material and the results reported under a 
separate PTS-IVIVT, GlaxoSmithKline protocol.
7.5.3.
Punch Skin Biopsy for Pharmacokinetic Assay
See Section 7.6.1 for more details on punch skin biopsies. A punch skin biopsy will be 
taken at baseline (pre-dose Day 1) and Day 43 (Week 6) to measure the concentration of 
GSK2982772 in the skin (taken from the outer third of the target lesion).  Information on 
processing the biopsies for the skin pharmacokinetic assay will be provided in the SRM.
Once the skin extract has been analyzed for GSK2982772, any remaining skin extract 
may be analyzed for other compound-related material and the results reported under a 
separate PTS-IVIVT, GlaxoSmithKline protocol.
7.5.4.
Sample Analysis
Skin biopsy sample analysis will be performed under the control of PTS-IVIVT, 
GlaxoSmithKline.  An exploratory analysis of concentrations of GSK2982772 in skin 
will be conducted.
7.6.
Biomarker(s)/Pharmacodynamic Markers
7.6.1.
Skin Lesion Biopsy
At baseline (pre-dose Day 1), a target lesion for biopsy will be identified (3 cm by 3 cm) 
on the trunk or extremities. The same target lesion will be used for both the baseline 
lesion biopsy and at Day 43 (Week 6) even if the lesion has cleared. Lesions on palmar 

2015N251765_02
CONFIDENTIAL
203167
54
surfaces of the hands and feet, scalp, knees, elbows and intertriginous areas will not be 
used as the target lesion site.

Two 4-mm tissue biopsies will be taken from the outer third of the selected 
biopsy lesion at baseline (pre-dose Day 1) using standard methodology. The 
second site on the outer third of the same lesion should be at least 1.5 cm from 
the first biopsy. Local anaesthetic will be administered before each biopsy, and 
only suitably experienced personnel, trained in aseptic technique, will obtain the 
biopsies.

At baseline only (pre-dose Day 1), a total of 3 biopsies will be taken, 1 from a 
non-lesional area of skin and 2 biopsies will be taken from the target lesion site.
The target lesion biopsy will be taken from the outer third of the lesion. The 
non-lesional biopsy will be taken from an unaffected area close to the target 
lesion, and cannot include the palmar surfaces of the hands and feet, scalp, 
knees, elbows and intertriginous areas

At Day 43 (Week 6), 2 biopsies will be taken from the same target lesion as 
identified at baseline even if the lesion has cleared. As above, the biopsies will 
be taken from the outer third of the lesion. 
Biopsy tissue taken from the psoriatic skin lesions will be divided accordingly for 
pharmacokinetic, target and pathway engagement, histological and gene expression 
analyses as feasibility dictates. Histologic assessment will include measurement of 
epidermal thickness, total inflammatory infiltrates, keratin expression (e.g., K16) and 
specific cell numbers (which may include by not be limited to) CD3+T-cells, CD11c+ 
myeloid dendritic cells. mRNA may be isolated from skin biopsy tissue, as feasibility
dictates, to determine the effect of placebo and GSK2982772 on markers of inflammation 
and tissue healing (e.g., may include and not be limited to measurement of chemokines, 
cytokines, and extracellular matrix proteases). Examples of technologies that may be 
used for analysis include, but are not limited to quantitative PCR, RNAseq, microarray, 
mass cytometry (CyTOF). See SRM for full details of the division of biopsy tissues. 
The baseline nonlesional skin biopsy will be divided accordingly for histologic and gene 
expression analysis as feasibility dictates.  Histologic assessment will include 
measurement of epidermal thickness, total inflammatory infiltrates, keratin expression 
(e.g., K16) and specific cell numbers (which may include by not be limited to) CD3+T-
cells, CD11c+ myeloid dendritic cells. mRNA expression of inflammatory markers and 
tissue healing will be assessed in baseline nonlesional skin (as above) as feasibility 
dictates, using the same technologies as outlined above.  
7.6.2.
Novel Pharmacodynamic Biomarkers
7.6.2.1.
RIP1 Target Engagement in Blood
Blood samples for RIP1 target engagement will be collected at the time points indicated 
in Section 7.1 to measure levels of free and total RIP1 antibodies.

2015N251765_02
CONFIDENTIAL
203167
55
7.6.2.2.
RIP1 Target Engagement in Tissue
Skin punch biopsy samples for RIP1 target engagement will be collected at the time 
points indicated in Section 7.1 to measure levels of free and drug-bound RIP1 protein if 
sample quantity and data allow.
7.6.2.3.
RIP1 Pathway Markers in Tissue
Skin punch biopsy samples for RIP1 pathway markers will be collected at the time points 
indicated in Section 7.1 to measure total or phosphorylated RIP1, RIP3, MLKL and 
cleaved or total caspase 3 and 8 if sample quantity and data allow.
7.6.3.
Exploratory Novel Biomarkers
With the subject’s consent, tissue, and/or blood sample(s) will be collected during this 
study and may be used for the purposes of measuring novel biomarkers to identify factors 
that may influence disease/condition for study treatment, and/or medically related 
conditions, as well as the biological and clinical responses to GSK2982772.  If relevant, 
this approach will be extended to include the identification of biomarkers associated with 
adverse events.
Samples will be collected at the time points indicated in Section 7.1.  The timing of the 
collections may be adjusted on the basis of emerging pharmacokinetic or PD data from 
this study or other new information in order to ensure optimal evaluation of the PD 
endpoints.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with PsO and/or the action of GSK2982772 may be identified by 
application of:

Gene expression array analysis may be conducted on the blood and/or punch skin 
biopsies using microarray, and/or alternative equivalent technologies such as RNA 
sequencing, which facilitates the simultaneous measurement (and confirmation) of the 
relative abundances of thousands of RNA species resulting in a transcriptome profile 
for each skin sample.

Soluble inflammatory mediators in the blood may be assayed for cytokine and 
inflammatory mediators including, but not limited to, pro-inflammatory and anti-
inflammatory cytokines, chemokines, and acute phase proteins. 

Phosphoprotein detection in skin tissue and blood may be used to validate RIP1 
kinase pathway activation.

High dimensional CyTOF/Helios based immune profiling of peripheral blood cells 
including measurement of immune cell phenotypes, intracellular signalling events and 
key cytokines / chemokines. 
These analyses may be reported under separate protocol following the completion of the 
study. All samples will be retained for a maximum of 15 years after the last subject 
completes the trial. 

2015N251765_02
CONFIDENTIAL
203167
56
7.7.
Genetics
In consenting subjects, a blood sample for pharmacogenetics (PGx) research will be 
drawn on Day 1 (or any time point post randomisation and prior to study completion) to 
better characterize genetic variability that may affect efficacy or safety endpoints.
Information regarding pharmacogenetic (PGx) research is included in Appendix 3.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective of the study is to investigate the safety and tolerability of 
GSK2982772 60 mg BID and 60 mg TID following 12 weeks of treatment.  No formal 
statistical hypotheses will be conducted to assess this objective.
If appropriate, comparisons between the GSK2982772 arms and the placebo arm will be 
made to investigate the secondary inflammatory, mechanistic and efficacy objectives.
Trends over time will be investigated for both treatment arms along with associations 
between each of the parameters.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The study is not powered to detect pre-defined differences.  In Cohort 1, approximately 
30 subjects and up to a maximum of 36, will be randomised into the study to either 
GSK2982772 or placebo in a 2:1 ratio to ensure that approximately 24 evaluable subjects 
complete the study.  

2015N251765_02
CONFIDENTIAL
203167
57
In Cohort 2, approximately 24 subjects and up to a maximum of 32, will be randomised 
into the study to either GSK2982772 or placebo in a 3:1 ratio to ensure that 
approximately 20 evaluable subjects complete the study.
A subject is considered evaluable if they have completed at least one post-treatment 
biopsy.
The primary objective of the study is safety and tolerability, where there will be 20 
subjects randomised to GSK2982772 60 mg BID and 18 subjects randomised to 
GSK2982772 60 mg TID.  Using a Bayesian approach to determine the confidence 
interval around an observed safety event, we would assume a flat Beta (1, 1) prior, and if 
we were to observe one safety event in 20 then the posterior distribution would be Beta 
(2, 20), as outlined below in Figure 4.
Figure 4
One Event in 20 Subjects: Beta (2,20) Distribution
Thus, we can be 95% certain that the true probability of the safety event lies between 
0.01 and 0.24.  Similarly, if we were to observe one safety event in 18 then the posterior 

2015N251765_02
CONFIDENTIAL
203167
58
distribution would be Beta (2, 18), thus we can be 95% certain that the true probability of 
the safety event lies between 0.01 and 0.26.  
For supportive information the properties of the secondary endpoint PLSS have also been 
considered.  Assuming a standard deviation of 25%, it is estimated that the lower and 
upper bounds of the 95% confidence interval for the difference between GSK2982772 60
mg BID (n=20) and placebo (n=10) in percentage change in index lesion PLSS will be 
within approximately 17.1% of the point estimate, and that the lower and upper bounds of 
the 95% confidence interval for the difference between GSK2982772 60 mg TID (n=18) 
and placebo (n=6) in percentage change in index lesion PLSS will be within 
approximately 17.5% of the point estimate.
9.2.2.
Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint to 
investigate the different safety event rates.  If the number of subjects who complete the 
12 weeks is lower than anticipated, then the true incidence rates of safety events that 
could not be ruled out (as outlined in Section 9.2.1) would change.  These changes are 
outlined in Table 4.
Table 4
Sample Size Sensitivity
GSK2982772 subjects 
completing the study
Number of a particular safety 
event observed with 
GSK2982772
Upper limit of exact 95% CI 
indicating that a true 
incidence rate of x% could 
not be ruled out
20
0
16.1%
20
1
23.8%
20
2
30.4%
18
0
17.6%
18
1
26.0%
18
2
33.1%
16
0
19.5%
16
1
28.7%
16
2
36.4%
Similarly, for supportive information a sensitivity analysis of the precision of the 
secondary endpoint percentage change in PLSS has been performed to assess the impact 
of varying variability and numbers of GSK2982772 and placebo subjects Figure 5.

2015N251765_02
CONFIDENTIAL
203167
59
Figure 5
Sample Size Sensitivity for Percentage Change in PLSS
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation or adjustment will be conducted.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All Subjects Population: The ‘All Subjects Population’ is defined as subjects who were 
screened for the study.  This population is used for the summary of selected 
accountability data.
Safety Population: The ‘Safety Population’ is defined as subjects who receive at least 
one dose of study medication. This population is used for the summary of all data 
including demography, safety, efficacy and exploratory data but excluding PK data.

2015N251765_02
CONFIDENTIAL
203167
60
Pharmacokinetic Population: The ‘PK Population' is defined as subjects in the ‘Safety’ 
population who received an active dose and for whom a pharmacokinetic sample was 
obtained and analysed.   This population is used for the summary of PK data only.  Any 
PKPD analyses will be conducted on the Safety population such that subjects receiving 
placebo can be included.
9.3.2.
Interim Analysis
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT) 
which will include members of the GSK2982772 project team, will review blinded safety 
data, including clinical laboratory parameters and adverse events, at appropriate intervals 
during the period of study conduct.
In both cohorts, once an appropriate number of subjects randomised to GSK2982772 
have completed Day 43 (Week 6), the PLSS data will be reviewed in an unblinded 
manner by a Data Review Committee (DRC) consisting of the GSK Project Physician 
Lead (PPL), the study statistician, the study pharmacokineticist, the PRR DPU Head, the 
Early Development Lead (EDL), the Safety Review Team (SRT) leader, or their 
designees on an ongoing basis. A physician external to the GSK2982772 project team 
may also be involved in the data review. Additional inflammatory biomarkers, clinical 
and mechanistic endpoints (e.g., target engagement) may be reviewed if available. No 
other member of the GSK core study team will be unblinded to this data. The primary 
purpose of these reviews will be to monitor PLSS changes for internal decision making 
purposes.  A data review charter will identify the specific GSK individuals involved, 
outline in detail the activities of this review and how the integrity of the study will be 
maintained.  
A formal interim analysis will be conducted after the completion of Cohort 1 and will 
only include those subjects randomised to a BID dosing regimen. The purpose of the 
interim analysis is primarily to provide the project team and key GSK stakeholders with 
an early indication of the safety and efficacy from the trial, and to facilitate decision 
making regarding the subsequent clinical development of GSK2982772.  
9.3.3.
Primary Analyses
All safety evaluations will be based on the Safety population.  Clinical interpretation will 
be based on the review and displays of adverse events, clinical laboratory values, vital 
sign measurements and 12-lead ECG monitoring.
9.3.4.
Secondary Analyses
Comparisons between treatment groups on any changes observed will be conducted for 
the secondary endpoints if deemed appropriate, e.g. changes in the mean target 
engagement, changes in inflammatory markers and percentage change in index lesion 
PLSS be statistically analyzed using a MMRM (repeated measures mixed effects model) 
comparing each GSK2982772 arm with placebo at each time point. If sufficient numbers 
of subjects are enrolled with a BSA >5% then the proportion of subjects achieving PASI 
50/75/90 at Day 85 (12 Weeks), will be statistically analysed using a Generalised 
Estimating Equations (GEE) model comparing each GSK2982772 arm with placebo at 

2015N251765_02
CONFIDENTIAL
203167
61
each time point if appropriate. Similar analyses will be conducted for other secondary 
endpoints if deemed appropriate.
The relationship between each of the mechanistic endpoints and also with the clinical 
endpoints may also be graphically presented and analysed using an appropriate statistical 
model identifying any trends. The model will determine whether the mechanistic effect 
significantly explains or predicts the effect on the other mechanistic or clinical endpoints 
(e.g., index lesion PLSS score). This may be conducted through comparing statistical 
models incorporating different explanatory terms (i.e. mechanistic endpoints) with the 
‘null’ model (no mechanistic endpoints); or if deemed appropriate, multivariate statistical 
methods may also be applied to determine the relationship between the key endpoints. 
The consistency in the changes over time between the endpoints will also be assessed. 
In addition, based on the data that we observe in the study, probabilities of success will 
be determined, where the definition of success will be dependent on the endpoint. For 
example, what is the probability that we would observe a certain percentage change in 
PLSS (i.e., comparatory rate), based on the data that we have observed in the study.
GSK2982772 plasma concentrations will be summarised descriptively by Day and 
nominal time point by dosing regimen. 
Further details regarding the statistical analysis will be outlined in the Reporting and 
Analysis Plan (RAP).
9.3.5.
Other Analyses
9.3.5.1.
Exploratory Analyses
All exploratory endpoints will be descriptively summarized, graphically presented and 
listed appropriately.  Further details can be found in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

2015N251765_02
CONFIDENTIAL
203167
62

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 

2015N251765_02
CONFIDENTIAL
203167
63
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 

2015N251765_02
CONFIDENTIAL
203167
64
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
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.

2015N251765_02
CONFIDENTIAL
203167
65
11.
REFERENCES
Bonnet MC, Preukschat D, Welz P-S, van Loo G, Ermolaeva MA, Bloch W et al.  The 
adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and 
prevents skin inflammation.  Immunity, 2011;35:572-82.
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB. 
Chen T, Guo Z-p, Li L, Wang L, Jia R-z, Cao N et al.  Increased HMGB1 serum levels 
and altered HMGB1 expression in patients with psoriasis vulgaris.  Archives of 
Dermatological Research, 2013;305:263-7.
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C et al.  RIPK3 contributes to 
TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion 
or TAK1 kinase inhibition.  Cell Death and Differentiation, 2013;20:1381-92.
Finlay AY, Khan GK.  Dermatology Life Quality Index (DLQI) – A simple practical 
measure for routine clinical use.  Clin Exp Dermatol, 1994;19:210-216.
Fredriksson T, Pettersson U.  Severe psoriasis – oral therapy with a new retinoid.  
Dermatologica, 1978;157(4):238-44.Finlay AY, Khan GK.  Dermatology Life Quality 
Index (DLQI) – a simple practical measure for routine clinical use.  1978;157:238-44.
GlaxoSmithKline Document Number 2014N204126_01 Investigator's Brochure 
GSK2982772
08-MAR-
2016.
Gorin MB.  Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mo. Aspects Med. 2012; 33:467-486.
Hatcher RA, Trussell J,  Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 
2011: 50.  Table 3 2.
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.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784
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.
U.S. Department of Health and Human Services, Food and Drug Administration (FDA). 
(2012) Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations. Center for Drug Evaluation 
PPD

2015N251765_02
CONFIDENTIAL
203167
66
and Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM292362.pdf
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. 
Cell, 2008; 133(4):693-703.

2015N251765_02
CONFIDENTIAL
203167
67
12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AMD
Age-related macular degeneration
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
BID
Twice a day
BSA
Body Surface Area
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
equation
Cmax
Maximum observed concentration
CNS
Central nervous system
CRF 
Case Report Form
CONSORT
Consolidated Standards of Reporting Trials
CRP
C-Reactive Protein
C-SSRS
Columbia Suicide Severity Rating Scale
CV
Cardiovascular
CYP
Cytochrome P
CyTOF
Mass cytometry
DAMPs
Damage-associated molecular pattern
DRC
Data Review Committee
DLQI
Dermatology Life Quality Index
DMARD
Disease-Modifying Antirheumatic Drugs
DNA
Deoxyribose Nucleic Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDL
Early Development Lead
ETCO2
End-tidal Carbon Dioxide
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTiH
First Time in Human
GCP
Good Clinical Practice
GEE
Generalised Estimating Equations
GFR
Glomerular Filtrate Rate
GSK
GlaxoSmithKline
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
hCG
Human chorionic gonadotropin
HIV
Human Immunodeficiency Virus

2015N251765_02
CONFIDENTIAL
203167
68
IB
Investigator Brochure
IBD
Inflammatory Bowel Disease
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin gamma
IP
Investigational Product
IRB
Institutional Review Board
IRTs
Interactive Response Technology System
Kg
Kilogram
L
Litre
LDH
Lactate Dehydrogenase
MCH
Mean corpuscular haemoglobin
MDMA
3,4-methylenedioxy-methamphetamine
MedDRA
Medical Dictionary for Regulatory Activity
mg
Milligram
mL
Millilitre
MLKL
Mixed lineage kinase domain-like protein
mm
Millimeter
mmol
Millimole
MMRM
Repeated measures mixed effects model
MSDS
Material Safety Data Sheet
NF-B
Nuclear factor kappa-light-chain-enhancer of activated B 
cells
NOAEL
No Adverse Effect Level
NSAID
Non-steroidal Anti-inflammatory Drug
NTI
Narrow therapeutic index
PASI
Psoriasis Area Severity Index
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PGA
Physician Global Assessment
P-gp
P-glycoprotein
PGx
Pharmacogenetics
PI
Principal Investigator
PK
Pharmacokinetic
PLSS 
Psoriasis Lesion Severity Score
PPL
Project Physician Lead
PRO
Patient Reported Outcome
PsO
Psoriasis
PSRAE
Possible Suicidality Related Adverse Event
PTS IVIVT
Platform Technologies and Science In vitro/In vivo 
Translation
PUVA
Psoralen and ultraviolet A
QD
Once a day
QTc
Electrocardiogram QT interval corrected for heart rate
QTcB
Electrocardiogram QT interval corrected for heart rate using 
Bazett’s formula

2015N251765_02
CONFIDENTIAL
203167
69
QTcF
Electrocardiogram QT interval corrected for heart rate using 
Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RIP1
Receptor-interacting protein-1
RIP3
Receptor-interacting protein-3
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SIB
Suicidal Ideation Behaviour
SOP
Standard Operating Procedure
SPF
Sun protection factor
SpO2
Peripheral Capillary Oxygen Saturation
SRM
Study Reference Manual
SRT
Safety Review Team
TB
Tuberculosis
TEAR
Target Engagement Assay RIP1
TID
Three times daily
TLR
Toll-like receptor
TNF
Tumor necrosis factor
UK
United Kingdom
ULN
Upper Limit of Normal
UVB
Ultraviolet B
V
Volume of Distribution
VAS
Visual Analogue Scale
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
QuantiFERON

2015N251765_02
CONFIDENTIAL
203167
70
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 2 days after 
last dose5

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 

2015N251765_02
CONFIDENTIAL
203167
71
treatment and may continue subject in the study 
for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

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, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  

2015N251765_02
CONFIDENTIAL
203167
72
12.3.
Appendix 3 - Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including GSK2982772 or any concomitant medicines;

Psoriasis susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 

2015N251765_02
CONFIDENTIAL
203167
73
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
GSK2982772 has been completed and the study data reviewed. In some cases, the 
samples may not be studied.
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 

2015N251765_02
CONFIDENTIAL
203167
74
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.

2015N251765_02
CONFIDENTIAL
203167
75
12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 

2015N251765_02
CONFIDENTIAL
203167
76
Events NOT meeting definition of an AE include:
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a. Results in death
b. Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 

2015N251765_02
CONFIDENTIAL
203167
77
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
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 reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

2015N251765_02
CONFIDENTIAL
203167
78
Cardiovascular Events (CV) Definition:

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed PRO questionnaires and the collection of AE data are 
independent components of the study.

Responses to each question in the PRO questionnaire will be treated in accordance 
with standard scoring and statistical procedures detailed by the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.

2015N251765_02
CONFIDENTIAL
203167
79
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

2015N251765_02
CONFIDENTIAL
203167
80
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) 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 subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

2015N251765_02
CONFIDENTIAL
203167
81
12.5.
Appendix 5: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.5.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1. Contraceptive subdermal implant
2. Intrauterine device or intrauterine system
3. Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
4. Injectable progestogen [Hatcher, 2011]
5. Contraceptive vaginal ring [Hatcher, 2011]
6. Percutaneous contraceptive patches [Hatcher, 2011]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable):
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until 90 days after the last dose of study medication.
1.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
2.
Male condom plus partner use of one of the contraceptive options below that meets 
the SOP effectiveness criteria including a <1% rate of failure per year, as stated in 
the product label:

Contraceptive subdermal implant

Intrauterine device or intrauterine system

2015N251765_02
CONFIDENTIAL
203167
82

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.5.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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 fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating

Will be withdrawn from the study.

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks 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. 

2015N251765_02
CONFIDENTIAL
203167
83

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.

2015N251765_02
CONFIDENTIAL
203167
84
12.6.
Appendix 6: Protocol Changes
12.6.1.
Protocol Amendment 01
Where the amendment applies
This protocol amendment applies to all countries.
Summary of amendment changes and rationale
Regulatory feedback led to a requirement for additional concomitant medication 
restrictions. In addition, some administrative clarifications have been made.
List of specific changes (bold indicates text added and strikethrough indicates text 
removed)
Authors
Author (s):
 
Section 1 Protocol synopsis for study 203167
An ongoing review of available efficacy, pharmacodynamic and mechanistic endpoints 
will be conducted during the study by a Data Review Committee (DRC), consisting of a 
limited number of GSK individuals, some of whom are also members of the GSK study 
team who are not involved in the day-to-day running of the study.
Section 4.5 Dose justification
It is anticipated that a human dose of 60 mg BID will produce AUC(0-24) and Cmax values 
of approximately 9 ug.h/mL and 1 ug/mL, respectively, which are approximately 1/6th  
and 1/12th of the gender-averaged AUC (48.4 ug.h/mL) and Cmax (12.3 ug/mL) achieved 
in the 13 week monkey study at the NOAEL dose of 30 mg/kg/day.
PPD

2015N251765_02
CONFIDENTIAL
203167
85
Section 4.6.1 Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Investigational Product (IP) GSK2982772
Drug Interaction
Non-clinical data:
In vitro studies with GSK2982772 
assessing potential drug-drug 
interactions with Cytochrome P450 3A4 
(CYP3A4) substrates and P-glycoprotein
(Pgp) inhibitors 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 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 GSK2982772 IB 
[GlaxoSmithKline Document Number 
2014N204126_01].
Subject Selections:

Subjects who are taking 
concomitant medications known 
to inhibit Pgp or are CYP3A4 
narrow therapeutic index (NTI) 
substrates will be excluded from 
the study.  See Section 6.11.2 for 
a comprehensive list of 
medications.
Subject Monitoring:

Subjects’ concomitant medication 
usage will be reviewed prior to 
inclusion and monitored 
throughout the study.
Subjects should be monitored 
throughout the study for potential 
effects of interaction between 
GSK2982772 and other concomitant 
medications.
Section 6.4 Blinding
This will be a double blind (sponsor unblind) study and the following will apply. 

Sponsor unblinded refers only to the Data Review Committee (DRC) consisting 
of the GSK study physician, the study statistician, the study pharmacokineticist, 
Pattern Recognition Receptor (PRR) Discovery Performance Unit (DPU) 
Head, the Early Development Leader (EDL), the Safety Review Team (SRT) 
leader, or their designees on an ongoing basis. A physician external to the 
GSK2982772 project team may also be involved in the data review.  A data 
review charter will identify the specific GSK individuals involved; outline in 
detail the activities of this review, and how the integrity of the study will be 
maintained. The rest of the core GSK study team will remain blinded.

2015N251765_02
CONFIDENTIAL
203167
86
Section 6.11.2 Prohibited Medications and Non-Drug Therapies
Prohibited Medications
Therapy
Time period 
P-glycoprotein (Pgp) inhibitors including 
but not limited to amiodarone, azithromycin, 
captopril, carvedilol, clarithromycin, 
conivaptan, cyclosporine, diltiazem, 
dronedarone, erythromycin, felodipine, 
itraconazole, ketoconazole, lopinavir, 
ritonavir, quercetin, quinidine, ranolazine, 
ticagrelor, verapamil [FDA, 2012].
4 weeks prior to first dose until after the 
follow up visit (Day 112).
Narrow therapeutic index (NTI) CYP3A4 
substrates including but not limited to 
alfentanil, astemizole, cisapride, 
cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine [FDA, 
2012].
4 weeks prior to the first dose until after 
the follow up visit (Day 112).

2015N251765_02
CONFIDENTIAL
203167
87
Section 7.1 Time and Events Table
Procedures
Screening
Treatment Period
Early Withdrawal 14
Follow Up
Notes
Day 1 
Day 8 
Day 15
Day 22
Day 29
Day 36
Day 43
(week 6)
Day 50
Day 57
Day 64
Day 71
Day 78
Day 85
(week 12)
Visit windows
Screening: up to 30d before Day 1.
Treatment Period (except Day 1 & 85): 
3d. Day 1 NA; Day 85 2d.
Early Withdrawal: NA
Follow Up: 28d after last dose 3d
Screening Procedures
Screening procedures in addition to those listed below are (outpatient visit): informed consent; inclusion/ exclusion criteria; demography; medical history (includes past and 
current conditions, medication history, and family history of premature CV disease); HIV, Hep B and Hep C screen; serum pregnancy test (WCBP only).
Site Visit
X
X
X
X
X
X
X
X
X
X
X
1. Full physical exam: height/weight at 
Screening, height not required at later 
timepoints.
2. Vitals: BP, HR, RR, temperature. 
ECG triplicate at Screening only.
3. Urinalysis not required on Days 29, 
57 and 71. 
4. If urine test is positive, confirmatory 
serum test must be performed.
5. Pre-dose
6. Subjects must take study medication 
twice a day approx. 12h apart. Exact 
time of dosing to be recorded in diary 
cards. On Days 43 and 85, subjects 
must not take medication at home in the 
morning. Subjects will complete pre-
dose assessments and then will be 
administered their morning dose of 
medication at site on Day 43 only. On 
Day 85, subjects no longer dosed.
7. Diary card checked by site staff and 
new diary card dispensed at every 
study visit.
Phone call
X
X
X
X
X
Safety Assessments
Full physical exam1
X
X
X
X
Brief physical exam
X5
X
X
X5
X
X
12-lead ECG, vital signs2
X
X5
X
X
X
X5
X
X
X
X
X
Columbia Suicide Severity 
Rating Scale (C-SSRS)
X
X5
X5
X
X
Hematology, chemistry, 
urinalysis 
X
X5
X
X
X3
X5
X3
X3
X
X
X
FSH & estradiol  (if 
applicable)
X
Serum pregnancy 
(WCBP)
X
Urine pregnancy test 
(WCBP only)4
X5
X
X
X
X5
X
X
X
X
X
Study Treatment
Randomisation
X
Study medication (twice 
daily)6
X
X-------------------------------------------------------------------------------------------------X
Dispensing of study 
medication
X
X
X
Dispensing of diary cards7
X
X
X
X
X
X
X

2015N251765_02
CONFIDENTIAL
203167
88
Procedures
Screening
Treatment Period
Early Withdrawal 14
Follow Up
Notes
Day 1 
Day 8 
Day 15
Day 22
Day 29
Day 36
Day 43
(week 6)
Day 50
Day 57
Day 64
Day 71
Day 78
Day 85
(week 12)
Visit windows
Screening: up to 30d before Day 1.
Treatment Period (except Day 1 & 85): 
3d. Day 1 NA; Day 85 2d.
Early Withdrawal: NA
Follow Up: 28d after last dose 3d
PROs/ Disease Assessments
8.  Blood samples for inflammatory 
biomarkers and mRNA taken pre-dose
on Day 1, Day 43 and Day 85. 
9. PK blood samples taken pre-dose on 
Day 43. Post-dose serial PK samples 
taken on Day 1 and Day 43 at 1, 2, 4, 
and 6 hours post-dose.
10. Pre-dose Day 1 one biopsy taken 
from non-lesional skin and two biopsies 
taken from biopsy target lesion.
11. On Day 43, two biopsies taken from 
the same target lesion that was 
selected at Day 1. Punch biopsies on 
Day 43 are to be taken pre-dose.
12. Biopsy only required at Early 
Withdrawal visit if completed at least 14 
days of treatment and prior to Day 43.
13. PGx sample collected at Day 1, 
after randomization and separate
informed consent. If sample not 
collected at Day 1, can be collected at 
any time post-randomization. 
14. If subject withdraws early, every 
effort will be made for the subject to 
complete an Early Withdrawal visit prior 
to Follow Up. 
Psoriatic Body Surface 
Area
X
X5
X
X
PASI, PGA, PLSS, Itch
X
X5
X
X
X5
X
X
X
X
DLQI
X
X5
X5
X
X
Photograph of lesions
X5
X5
X
X
Other Assessments and Procedures
Blood sample for 
inflammatory biomarkers8
X5
X5
X
X
Blood sample for mRNA 
analysis8
X5
X5
X
X
Blood sample for Target 
Engagement
X5
X5
X
X
PK blood samples9
X
X5
X
X
Skin punch biopsies for 
PK, inflammatory 
biomarkers, mRNA, target 
engagement & pathway 
engagement
X5,10
X11
X12
Pharmacogenetic sample 
(PGx)
X13
Con med review & AE/SAE 
reporting
X-------------------------------------------------------------------------------------------------------------------------X

2015N251765_02
CONFIDENTIAL
203167
89
Section 7.2 Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors and smoking history (as detailed in the 
CRF) will be assessed at screening. 
Section 7.3.4 Vital Signs
Vital signs will be measured in a supine or semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, pulse rate and respiratory 
rate
Section 7.5.2 Sample Analysis
Plasma analysis will be performed at a bioanalytical site (to be detailed in the SRM) 
under the control of Platform Technologies and Science In vivo In vitro Technology In 
vitro/ In vivo Translation (PTS IVIVT) and Third Party Resource, GlaxoSmithKline.
Section 9.3.2 Interim Analysis
Once an appropriate number of subjects randomised to GSK2982772 have completed 
Day 43 (Week 6), the PLSS data will be reviewed in an unblinded manner by a Data 
Review Committee (DRC) consisting of the GSK study physician, the study statistician, 
the study pharmacokineticist, the PRR DPU Head, the Early Development Lead (EDL), 
the Safety Review Team (SRT) leader, or their designees on an ongoing basis.
12.6.2.
Protocol Amendment 2
Where the amendment applies
This protocol amendment applies to all countries.
Summary of amendment changes and rationale
An additional cohort of subjects is being included in the study in order to evaluate a 60
mg TID dosing regimen.  Because of the short half-life, a modified release formulation is 
now being developed in attempt to increase the Ctrough and decrease the peak to trough 
ratio using a once or twice daily dosing regimen. This is considered desirable for 
improving safety and tolerability and will aid in reduction of PK variability with the 
current IR formulation. It is believed that by increasing the frequency of dosing to three 
times daily (TID) with the current formulation, this will closely simulate the PK profile 
of a preferred modified release formulation.
List of specific changes (bold indicates text added and strikethrough indicates text 
removed)
Authors
PPD

2015N251765_02
CONFIDENTIAL
203167
90
Medical Monitor Page
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor 
Tel       
Email   
Mobile  
Tel: 
Mobile: 
Email:
Mobile  
 
 
Mobile:
N/A
Stockley Park 
West, 1-3 
Ironbridge 
Road, 
Uxbridge, 
Middlesex, 
UB11 1BT, 
United 
Kingdom
Pattern
Recognition
Receptor DPU,
UP4440
1250 S
Collegeville, PA
19426
Secondary 
Medical 
Monitor
Mobile:
Email 
Tel: 
Mobile: 
Email:
Mobile:
Mobile: 
1250S 
Collegeville 
Rd.
Collegeville PA 
19426, USA
Cytokine
Chemokine
DPU, GSK,
Gunnels Wood
Road,
Stevenage,
SG1 2NY, UK
SAE 
contact  
information 
Medical 
Monitor as 
above
Synopsis Rationale
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg twice daily and 60 mg three times daily for 84 days). In 
addition a number of experimental and clinical endpoints will be employed to obtain 
information on the pharmacokinetics, pharmacodynamics, and efficacy in subjects with 
active plaque-type psoriasis (PsO).  
PPD
PP
D
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
D
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
D

2015N251765_02
CONFIDENTIAL
203167
91
Synopsis Objectives and Endpoints
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 60 
mg twice daily doses and 60 mg three times 
daily doses of GSK2982772 in subjects with 
active plaque-type psoriasis.

Adverse events

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, heart 
rate, respiratory rate and body temperature)

12-Lead ECG monitoring
Secondary

To investigate the pharmacokinetics of 
GSK2982772 in blood following 60 mg twice 
daily doses and 60 mg three times daily
doses of GSK2982772 in subjects with active 
plaque-type psoriasis.

Pre-dose plasma concentrations of 
GSK2982772 at Days 43 (Week 6) and 85 
(Week 12).

Post-dose plasma concentrations of 
GSK2982772 on Days 1 and 43 (Week 6) at 1, 
2, 4 and 6 hours post dose.

To investigate the effect of 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772 on inflammatory biomarkers in 
skin biopsies from psoriatic skin lesions in 
subjects with active plaque-type psoriasis.

Change from baseline in histopathological 
scoring of psoriatic lesional biopsies which 
may include, but are not limited to the following 
as data permit:  K16, CD3/CD11c, CD161, 
elastase positive dermal cells and epidermal 
thickness.  

mRNA expression of inflammatory gene 
transcripts which may include, but are not 
limited to the following as data permit:  IL-4, IL-
10, IL-17, IL-21, IL-22, IL-23, TNF and IFNγ on 
Days 1 (Week 0) and 43 (Week 6).

To investigate the effect of 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772 on disease activity in subjects 
with active plaque-type psoriasis

Percentage change from baseline and actual 
Psoriatic Lesion Severity Sum (PLSS) scores 
in the index lesion.
Exploratory

To investigate the effect of 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772 on disease activity in subjects 
with active plaque-type psoriasis

Change from baseline in Psoriasis Area 
Severity Index (PASI) scores.

The proportion of subjects who achieve PASI ≥ 
50%, 75%, and 90% improvement from 
baseline score.

Change from baseline and actual Physician 
Global Assessment (PGA).

The proportion of subjects who achieve “clear” 
(0) or “almost clear” (1) on (PGA).

Change from baseline in body surface area 
(BSA).

To investigate the effect of 60 mg twice daily 

Change from baseline in blood inflammatory 

2015N251765_02
CONFIDENTIAL
203167
92
Objectives
Endpoints
doses and 60 mg three times daily doses of 
GSK2982772 on inflammatory biomarkers in 
the blood of subjects with active plaque-type 
psoriasis.
markers which may include, but are not limited 
to the following as data permit:  CRP, VEGF, 
S100A8, S100A9, IL-17, IL-22, and TNF.

To investigate the effect of 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772 on transcriptome profiling of both 
blood and skin of subjects with active plaque-
type psoriasis.

Transcriptomic analysis of mRNA isolated from 
blood and skin at Day 1 (Week 0) and Day 43 
(Week 6).

To investigate pathway and target engagement 
following 60 mg twice daily doses and 60 mg 
three times daily doses of GSK2982772 in 
blood and skin biopsy tissue in subjects with 
active plaque-type psoriasis.

Pharmacology biomarker endpoints may 
include, but are not limited to the following 
Days 1 (Week 0), 43 (Week 6) and 85 (Week 
12),  as data permit:
o
Target Engagement Assay RiP1 
(TEAR1) in blood and skin.
o
Total or phosphorylated RIP1, 
MLKL, and RIP3, cleaved and 
total caspase 3 and caspase 8 
signatures in skin.

To investigate the concentration of 
GSK2982772 in the skin of subjects with active 
plaque-type psoriasis after 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772.

Pre-dose GSK2982772 concentrations in skin 
biopsies at Days 1 (Week 0) and 43 (Week 6), 
as data permit.

To investigate the effect of 60 mg twice daily
doses and 60 mg three times daily doses of 
GSK2982772 on the patient reported 
outcomes (PROs) of subjects with active 
plaque-type psoriasis.

Change from baseline in Dermatology Life 
Quality Index (DLQI) score.

Change from baseline and actual Visual 
Analogue Scale (VAS) itch score.
Synopsis Overall Design
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled, 
repeat dose study to investigate the safety and tolerability, PK, PD, and preliminary 
efficacy of GSK2982772 in subjects with active plaque-type psoriasis.  The study design 
schematic is depicted in Figure 1 below.  There will be two cohorts of subjects.  
Cohort 1 will receive either GSK2982772 60 mg or placebo orally twice daily and 
Cohort 2 will receive either GSK2982772 60 mg or placebo orally three times daily.

2015N251765_02
CONFIDENTIAL
203167
93
Schematic added:
Cohort 2
Synopsis Treatment Arms and Duration
In Cohort 1 subjects who have completed screening assessments and are eligible will be 
randomised in a 2:1 ratio (active to placebo) to one of the following treatments:
60 mg GSK2982772 twice daily (BID) 
Placebo twice daily (BID) 
In Cohort 2 subjects who have completed screening assessments and are eligible will 
be randomised in a 3:1 ratio (active to placebo) to one of the following treatments:
60 mg GSK2982772 three times daily (TID) 
Placebo three times daily (TID) 
Synopsis Type and Number of Subjects
In Cohort 1, a sufficient number of subjects will be screened so that approximately 30 
subjects with active PsO are randomised.  Additional or replacement subjects may be 
randomised (up to a maximum of 36) into the study at the discretion of the Sponsor, to 
ensure that approximately 24 evaluable subjects complete the study.
In Cohort 2, a sufficient number of subjects will be screened so that approximately 
24 subjects with active PsO are randomised.  Additional or replacement subjects 
may be randomised (up to a maximum of 32) into the study at the discretion of the 
Sponsor, to ensure that approximately 20 evaluable subjects complete the study. 
For both cohorts, a subject is considered evaluable if they have completed at least one 
post-treatment biopsy.
Synopsis Analysis
An ongoing review of available efficacy, pharmacodynamic and mechanistic endpoints 
will be conducted during the study by a Data Review Committee (DRC), consisting of a 
limited number of GSK individuals, some of whom are also members of the GSK study 

2015N251765_02
CONFIDENTIAL
203167
94
team who are not involved in the day-to-day running of the study.  The primary purpose 
of these reviews will be to monitor target engagement, inflammatory markers and the 
index lesion PLSS for internal decision making. A data review charter will outline in 
detail the activities of this review and how the integrity of the study will be maintained.  
An interim analysis will be conducted after the completion of Cohort 1.
Comparisons between treatment groups on any changes observed will be conducted for 
the secondary endpoints if deemed appropriate, e.g. changes in the mean target 
engagement, changes in inflammatory markers and percentage change in index lesion 
PLSS will be statistically analyzed using a repeated measures mixed effects model 
(MMRM) comparing each GSK2982772 arm with placebo at each time point.  
Section 2.1 Study Rationale
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg twice daily and 60 mg three times daily for 84 days). In 
addition, a number of experimental and clinical endpoints will be employed to obtain 
information on the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary 
efficacy in subjects with active PsO
Section 3 Objectives and Endpoints
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 60 
mg twice daily doses and 60 mg three times 
daily doses of GSK2982772 in subjects with 
active plaque-type psoriasis.

Adverse events

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis)

Vital sign measurements (blood pressure, heart 
rate, respiratory rate and body temperature)

12-Lead ECG monitoring
Secondary

To investigate the pharmacokinetics of 
GSK2982772 in blood following 60 mg twice 
daily doses and 60 mg three times daily
doses of GSK2982772 in subjects with active 
plaque-type psoriasis.

Pre-dose plasma concentrations of 
GSK2982772 at Days 43 (Week 6) and 85 
(Week 12).

Post-dose plasma concentrations of 
GSK2982772 on Days 1 and 43 (Week 6) at 1, 
2, 4 and 6 hours post dose.

To investigate the effect of 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772 on inflammatory biomarkers in 
skin biopsies from psoriatic skin lesions in 
subjects with active plaque-type psoriasis.

Change from baseline in histopathological 
scoring of psoriatic lesional biopsies which 
may include, but are not limited to the following 
as data permit:  K16, CD3/CD11c, CD161, 
elastase positive dermal cells and epidermal 
thickness.  

mRNA expression of inflammatory gene 
transcripts which may include, but are not 
limited to the following as data permit:  IL-4, IL-
10, IL-17, IL-21, IL-22, IL-23, TNF and IFNγ on 
Days 1 (Week 0) and 43 (Week 6).

2015N251765_02
CONFIDENTIAL
203167
95
Objectives
Endpoints

To investigate the effect of 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772 on disease activity in subjects 
with active plaque-type psoriasis

Percentage change from baseline and actual 
Psoriatic Lesion Severity Sum (PLSS) scores 
in the index lesion.
Exploratory

To investigate the effect of 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772 on disease activity in subjects 
with active plaque-type psoriasis

Change from baseline in Psoriasis Area 
Severity Index (PASI) scores.

The proportion of subjects who achieve PASI ≥ 
50%, 75%, and 90% improvement from 
baseline score.

Change from baseline and actual Physician 
Global Assessment (PGA).

The proportion of subjects who achieve “clear” 
(0) or “almost clear” (1) on (PGA).

Change from baseline in body surface area 
(BSA).

To investigate the effect of 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772 on inflammatory biomarkers in 
the blood of subjects with active plaque-type 
psoriasis.

Change from baseline in blood inflammatory 
markers which may include, but are not limited 
to the following as data permit:  CRP, VEGF, 
S100A8, S100A9, IL-17, IL-22, and TNF.

To investigate the effect of 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772 on transcriptome profiling of both 
blood and skin of subjects with active plaque-
type psoriasis.

Transcriptomic analysis of mRNA isolated from 
blood and skin at Day 1 (Week 0) and Day 43 
(Week 6).

To investigate pathway and target engagement 
following 60 mg twice daily doses and 60 mg 
three times daily doses of GSK2982772 in 
blood and skin biopsy tissue in subjects with 
active plaque-type psoriasis.

Pharmacology biomarker endpoints may 
include, but are not limited to the following 
Days 1 (Week 0), 43 (Week 6) and 85 (Week 
12),  as data permit:
o
Target Engagement Assay RiP1 
(TEAR1) in blood and skin.
o
Total or phosphorylated RIP1, 
MLKL, and RIP3, cleaved and 
total caspase 3 and caspase 8 
signatures in skin.

To investigate the concentration of 
GSK2982772 in the skin of subjects with active 
plaque-type psoriasis after 60 mg twice daily 
doses and 60 mg three times daily doses of 
GSK2982772.

Pre-dose GSK2982772 concentrations in skin 
biopsies at Days 1 (Week 0) and 43 (Week 6), 
as data permit.

To investigate the effect of 60 mg twice daily
doses and 60 mg three times daily doses of 
GSK2982772 on the patient reported 

Change from baseline in Dermatology Life 
Quality Index (DLQI) score.

2015N251765_02
CONFIDENTIAL
203167
96
Objectives
Endpoints
outcomes (PROs) of subjects with active 
plaque-type psoriasis.

Change from baseline and actual Visual 
Analogue Scale (VAS) itch score.
Section 4.1 Overall Design
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled, 
repeat dose study to investigate the safety and tolerability, PK, PD, and preliminary 
efficacy of GSK2982772 in subjects with active plaque-type psoriasis.  The study design 
schematic is depicted in Figure 2 below.  There will be two cohorts of subjects.  
Cohort 1 will receive either GSK2982772 60 mg or placebo orally twice daily and 
Cohort 2 will receive either GSK2982772 60 mg or placebo orally three times daily.
Schematic added:
Cohort 2
Section 4.2.2 Treatment Period
In Cohort 1, subjects will be randomly assigned to either GSK2982772 60mg or placebo 
orally twice daily (approximately 12 hours apart) for 84 days.  In Cohort 2 subjects will 
be randomly assigned to either GSK2982772 60 mg or placebo orally three times 
daily (approximately 8 hours apart) for 84 days.  
Section 4.3 Type and Number of Subjects
In Cohort 1, a sufficient number of subjects will be screened so that approximately 30 
subjects with active PsO are randomised.  Additional or replacement subjects may be 
randomised (up to a maximum of 36) into the study at the discretion of the Sponsor, to 
ensure that approximately 24 evaluable subjects complete the study.
In Cohort 2, a sufficient number of subjects will be screened so that approximately 
24 subjects with active PsO are randomised.  Additional or replacement subjects 
may be randomised (up to a maximum of 32) into the study at the discretion of the 
Sponsor, to ensure that approximately 20 evaluable subjects complete the study. 
For both cohorts, a subject is considered evaluable if they have completed at least one 
post-treatment biopsy

2015N251765_02 
CONFIDENTIAL 
 
 
 
203167 
 
97 
 
Section 4.4 Design Justification 
In Cohort 1 the subjects will be randomised in a 2:1 ratio to GSK2982772 60mg BID 
and placebo respectively.  In Cohort 2 the subjects will be randomised in a 3:1 ratio 
to GSK2982772 60 mg TID and placebo respectively. The primary objective of this 
study is safety and tolerability and assessment of this is most valuable in a placebo 
controlled, blinded study. The placebo group was deemed necessary as autoimmune 
diseases naturally fluctuate in severity.  However, the size of the placebo group has been 
kept to a minimum.  Subjects will not be allowed to continue standard of care therapy 
including topical (not permitted on biopsy areas), oral and biologic therapy.  A washout 
period of specific therapies can be found in Section 6.11 
Section 4.5 Dose Justification 
The initial selection of the 60 mg BID dose to be being tested in this study is based on 
the safety, PK, and PD data from the GSK2982772 First Time in Human (FTiH) study, 
200975. GSK2982772 administered at 60 mg BID for 14 days was well tolerated and no 
safety concerns were identified. A BID dosing regimen was initially selected over a QD 
dosing regimen due to the short half-life of GSK2982772 in humans (~2 hours). Based on 
preliminary PK/PD modelling of ex-vivo RIP1 target engagement and GSK2982772 
concentrations from the multiple dose ascending part of Study 200975, a 60 mg BID dose 
is was predicted to have on average 95% RIP1 target engagement in blood and 
approximately 90% of subjects are predicted to have >90% RIP1 target engagement in 
blood at Cmin using a novel in-house ex-vivo PD/target engagement assay based 
solely on the TNF pathway which is believed to be a key component of the RIP1 
pathway. Assuming a skin: blood ratio of 0.4 (as observed in the rat), the average RIP1 
target engagement in skin is predicted to be 92%. At Cmin, 44% of subjects are predicted 
to have >90% RIP1 target engagement in the skin and 90% of subjects are predicted to 
have >80% RIP1 target engagement in the skin. 
However, based on final PK/PD modelling from the full repeat dose part of the 
Study 200975 (up to 120 mg BID), a 60 mg BID dose is now predicted to have on 
average 99.3% RIP1 target engagement in blood and approximately 90% of 
subjects will have  >96.3% target engagement at Cmin.  In skin, assuming the same 
skin: blood ratio of 0.4 as noted above, the average RIP target engagement at 60 mg 
TID in skin in predicted to be 96%.  At Cmin, 43% of subjects are predicted to have 
>90% RIP1 target engagement in the skin and 90% of subjects are predicted to 
have >70% RIP1 target engagement in the skin.    
In review of this final FTiH data, it is believed that the Cmin target exposure may not 
be achieved with a 60mg BID dosing regimen.  The Cmin values at 60 mg TID are 
predicted to be approximately 3.5 fold higher than for 60 mg BID.  Therefore, a 60 
mg TID cohort is now being proposed.   
 
 

2015N251765_02
CONFIDENTIAL
203167
98
Using the final PK/PD, a 60 mg TID dose is predicted to have on average 99% RIP1 
target engagement in blood and approximately 90% of subjects will have > 96% 
target engagement at Cmin.  In skin, the average RIP target engagement at 60 mg 
TID is predicted to be 98%.  At Cmin, 91% of subjects are predicted to have >90% 
RIP1 target engagement in the skin and 90% of subjects are predicted to have 
>91% RIP1 target engagement in the skin.  
In addition, because of the short half-life, a modified release formulation is now 
being developed with the aim to provide a once daily dosing regimen.  By increasing 
the frequency of dosing to three times daily (TID) with the current immediate 
release formulation, this will more closely match the PK, safety and efficacy profile 
of a preferred once daily modified release formulation.
Therefore, it is predicted that a dose of GSK2982772 60 mg BID may be clinically 
efficacious in subjects with active PsO.
It is anticipated that a human dose of 60 mg BID will produce AUC(0-24) and Cmax 
values of approximately 9 ug.h/mL and 1 ug/mL, respectively, which are approximately 
1/6th and 1/12th of the gender-averaged AUC (48.4 ug.h/mL) and Cmax (12.3 ug/mL) 
achieved in the 13 week monkey study at the NOAEL dose of 30 mg/kg/day.
The safety of increasing the dose frequency to 60 mg TID is justified based on 
nonclinical safety findings to date with GSK2982772. It is anticipated that a human 
dose of 60 mg TID (180 mg/day) will produce AUC(0-24) and Cmax values of 
approximately 9.9 ug.h/mL and 0.8 ug/mL, respectively, which are approximately 
1/5th and 1/15th of the gender-averaged AUC (48.4 ug.h/mL) and Cmax (12.3 ug/mL) 
achieved in the 13 week monkey study at the no adverse effect level (NOAEL) dose 
of 30 mg/kg/day. Please see GSK2982772 IB [GlaxoSmithKline Document Number 
2014N204126_01].
Up to 03 Apr 2017, a total of approximately 93 subjects across 4 clinical studies have 
been randomised to receive GSK2982772. In Study 200975, GSK2982772 
administered up to 120 mg BID for 14 days and was well tolerated and no safety 
concerns were identified. A total of 9 subjects had received 120 mg BID in that 
study.  Please see GSK2982772 IB [GlaxoSmithKline Document Number 
2014N204126_01]. In this current study, 203167, approximately 22 of 33 subjects 
have been randomised to GSK2982772 60 mg BID. In other Phase 2a studies in 
Rheumatoid Arthritis [(RA); Study 203168] and Ulcerative Colitis [(UC); Study 
202152], a total of 4 subjects have been randomised to GSK2982772 60 mg BID.
GSK2982772 was well tolerated and no drug-related SAEs have been reported.  
There was a death of a 19 year old male subject in this current study due to an 
accidental overdose with 3,4-methylenedioxy-methamphetamine (MDMA) that was 
not considered drug related by the Principal Investigator (PI).
The proposed 60 mg TID dose regimen is predicted to have mean Cmax (0.80 µg/mL) 
and AUC(0-24) (9.9 µg.hr/mL ) that are approximately 10% and 50% higher, 
respectively than for 60 mg BID (0.70 µg/mL and 6.6 µg.hr/mL).  This exposure is 
well within the observed Cmax and AUC(0-24) values at 120 mg BID in Study 200975.

2015N251765_02
CONFIDENTIAL
203167
99
Section 5.1 Inclusion Criteria
For both cohorts, a subject will be eligible for inclusion in this study only if all of the 
following criteria apply:
Section 5.2 Exclusion Criteria
For both cohorts, a subject will not be eligible for inclusion in this study only if all of 
the following criteria apply:
20.  The subject has participated in a clinical trial and has received an investigational 
product within 30 days or 5 half-lives, whichever is longer before the first dose of study 
medication, or plans to take part in another clinical trial at the same time as participating 
in this clinical trial. Subjects who were randomized into Cohort 1 are not eligible to 
be re-randomized into Cohort 2.
21.  Haemoglobin <11 g/dL; haematocrit <30%, white blood cell count ≤3000/mm3 (≤3.0 
x 109/L); or ≥14,000/mm3 (≥14 x 109/L); platelet count ≤ 100,000/µL (≤100 x 109/L); 
absolute neutrophil count ≤1.5 3 x 109/L lymphocyte count <1 x 109/L at the screening 
visit.
Section 5.3 Screening / Baseline / Run-in Failures
Subjects who do not qualify to participate in the study due to a screening laboratory value 
or ECG abnormality can repeat the test once within the original screening time window, 
if the Investigator believes there is a reasonable possibility that the subject would be 
eligible if re-tested. 
Subjects can be re-screened only on approval of the GSK Medical Monitor and only 
once. Re-screening is allowed when a subject failed inclusion/exclusion criteria or 
some other screening condition initially, but the Investigator believes there is a 
reasonable probability that the subject would be eligible if re-screened.
Section 5.4.1 Individual Safety Stopping Rules
Study medication will be discontinued in the event of any of the following:

If a subject experiences a serious or severe clinically significant AE that in the 
clinical judgement of the investigator, after consultation with the medical monitor, 
there is a reasonable possibility that the AE is related to investigational product.

The subject becomes pregnant.

The subject initiates treatment with any prohibited medication for the treatment of 
PsO as listed in Section 6.11.2.

The subject develops a serious opportunistic or atypical infection.

2015N251765_02
CONFIDENTIAL
203167
100

If the liver chemistry stopping criteria (Section 5.4.3), QTc stopping criteria 
(Section 5.4.4), or haematologic stopping criteria (Section 5.4.5) are met.

The subject experiences any signs of suicidal ideation or behaviour (Section 
7.3.7).
Section 5.4.5 Haematologic Stopping Criteria
Study treatment will be stopped for a subject if any of the following haematological 
stopping criteria is met:

Haemoglobin <9 g/dL or an absolute decrease of ≥3 g/dL from baseline (pre-dose 
Day 1)

Neutrophils <1 x 109/L

Lymphocytes <0.5 × 109/L

Platelets <50 × 109/L
Section 6.1 Investigation Product and Other Study Treatment
Study Treatment
Product name:
GSK2982772
Placebo
Dosage form:
Tablet
Tablet
Unit dose strength(s)/Dosage 
level(s):
30 mg
NA
Route of Administration 
For oral use only
For oral use only
Dosing instructions for Cohort 1:
Take TWO tablets in the 
MORNING and TWO tablets in the 
EVENING as directed
Take TWO tablets in the 
MORNING and TWO tablets in the 
EVENING as directed
Dosing instructions for Cohort 
2:
Take TWO tablets THREE times 
daily as directed by your 
physician
Take TWO tablets THREE times 
daily as directed by your 
physician
Physical description
White to almost white, round, film 
coated tablet
White to almost white, round film 
coated tablet
Source of procurement
Study medication is supplied by 
GlaxoSmithKline
Placebo is supplied by 
GlaxoSmithKline
Section 6.2 Treatment Assignment
In Cohort 1, subjects will take study medication every day, twice a day, approximately 
12 hours apart.   Subjects will be randomised to receive either GSK2982772 or placebo in 
a 2:1 ratio. In Cohort 2, subjects will take study medication every day, three times a 
day, with approximately 8 hours between each dose.  Subjects will be randomised to 
receive either GSK2982772 or placebo in a 3:1 ratio.
Section 6.4 Blinding
This will be a double blind (sponsor unblind) study and the following will apply. 

2015N251765_02
CONFIDENTIAL
203167
101
Sponsor unblinded refers only to the Data Review Committee (DRC) consisting of the 
GSK study physician Project Physician Lead (PPL), the study statistician, the study 
pharmacokineticist, Pattern Recognition Receptor (PRR) Discovery Performance Unit 
(DPU) Head, the Early Development Leader (EDL), the Safety Review Team (SRT) 
leader, or their designees on an ongoing basis.
Section 6.8 Treatment of Study Treatment Overdose
For this study, any dose of GSK2982772 >120 mg daily will be considered an overdose 
in Cohort 1 and any dose of GSK2982772 >180 mg daily will be considered an 
overdose in Cohort 2.  GSK does not recommend specific treatment for an overdose.  
The investigator will use clinical judgement to treat any overdose as and when they are 
made aware of this.

2015N251765_02
CONFIDENTIAL
203167
102
Section 7.1 Time and Events Table
Procedures
Screening
Treatment Period
Early Withdrawal 14
Follow Up
Notes
Day 1 
Day 8 
Day 15
Day 22
Day 29
Day 36
Day 43
(week 6)
Day 50
Day 57
Day 64
Day 71
Day 78
Day 85
(week 12)
Visit windows
Screening: up to 30d before Day 1.
Treatment Period (except Day 1 & 
85): 3d. Day 1 NA; Day 85 2d.
Early Withdrawal: NA
Follow Up: 28d after last dose 3d
Screening Procedures
Screening procedures in addition to those listed below are (outpatient visit): informed consent; inclusion/ exclusion criteria; demography; medical history (includes past and 
current conditions, medication history, and family history of premature CV disease); HIV, Hep B and Hep C screen; serum pregnancy test (WCBP only).
Site Visit
X
X
X
X
X
X
X
X
X
X
X
1. Full physical exam: height/weight at 
Screening, height not required at later 
timepoints.
2. Vitals: BP, HR, RR, temperature. 
ECG triplicate at Screening only.
3. Urinalysis not required on Days 29, 
57 and 71. 
4. If urine test is positive, confirmatory 
serum test must be performed.
5. Pre-dose
6. In Cohort 1, subjects must take 
study medication twice a day approx. 
12h apart.  In Cohort 2, subjects must 
take study medication three times a 
day approx. 8h apart. Exact time of 
dosing to be recorded in diary cards. 
On Days 43 and 85, subjects must not 
take medication at home in the 
morning. Subjects will complete pre-
dose assessments and then will be 
administered their morning dose of 
medication at site on Day 43 only. On 
Day 85, subjects no longer dosed.
7. Diary card checked by site staff and 
new diary card dispensed at every 
study visit.
Phone call
X
X
X
X
X
Safety Assessments
Full physical exam1
X
X
X
X
Brief physical exam
X5
X
X
X5
X
X
12-lead ECG, vital signs2
X
X5
X
X
X
X5
X
X
X
X
X
Columbia Suicide Severity 
Rating Scale (C-SSRS)
X
X5
X5
X
X
Hematology, chemistry, 
urinalysis 
X
X5
X
X
X3
X5
X3
X3
X
X
X
FSH & estradiol  (if 
applicable)
X
Serum pregnancy (WCBP)
X
Urine pregnancy test 
(WCBP only)4
X5
X
X
X
X5
X
X
X
X
X
Study Treatment
Randomisation
X
Study medication (twice 
daily)6
X
X-------------------------------------------------------------------------------------------------X
Dispensing of study 
medication
X
X
X
Dispensing of diary cards7
X
X
X
X
X
X
X

2015N251765_02
CONFIDENTIAL
203167
103
Procedures
Screening
Treatment Period
Early Withdrawal 14
Follow Up
Notes
Day 1 
Day 8 
Day 15
Day 22
Day 29
Day 36
Day 43
(week 6)
Day 50
Day 57
Day 64
Day 71
Day 78
Day 85
(week 12)
Visit windows
Screening: up to 30d before Day 1.
Treatment Period (except Day 1 & 
85): 3d. Day 1 NA; Day 85 2d.
Early Withdrawal: NA
Follow Up: 28d after last dose 3d
PROs/ Disease Assessments
8.  Blood samples for inflammatory 
biomarkers and mRNA taken pre-dose 
on Day 1, Day 43 and Day 85. 
9. PK blood samples taken pre-dose on 
Day 43. Post-dose serial PK samples 
taken on Day 1 and Day 43 at 1, 2, 4, 
and 6 hours post-dose.
10. Pre-dose Day 1 one biopsy taken 
from non-lesional skin and two biopsies 
taken from biopsy target lesion.
11. On Day 43, two biopsies taken from 
the same target lesion that was 
selected at Day 1. Punch biopsies on 
Day 43 are to be taken pre-dose.
12. Biopsy only required at Early 
Withdrawal visit if completed at least 14 
days of treatment and prior to Day 43.
13. PGx sample collected at Day 1, 
after randomization and separate 
informed consent. If sample not 
collected at Day 1, can be collected at 
any time post-randomization. 
14. If subject withdraws early, every 
effort will be made for the subject to 
complete an Early Withdrawal visit prior 
to Follow Up. 
Psoriatic Body Surface 
Area
X
X5
X
X
PASI, PGA, PLSS, Itch
X
X5
X
X
X5
X
X
X
X
DLQI
X
X5
X5
X
X
Photograph of lesions
X5
X5
X
X
Other Assessments and Procedures
Blood sample for 
inflammatory biomarkers8
X5
X5
X
X
Blood sample for mRNA 
analysis8
X5
X5
X
X
Blood sample for Target 
Engagement
X5
X5
X
X
PK blood samples9
X
X5
X
X
Skin punch biopsies for 
PK, inflammatory 
biomarkers, mRNA, target 
engagement & pathway 
engagement
X5,10
X11
X12
Pharmacogenetic sample 
(PGx)
X13
Con med review & AE/SAE 
reporting
X-------------------------------------------------------------------------------------------------------------------------X

2015N251765_02
CONFIDENTIAL
203167
104
Section 7.3.7 Suicidal Risk Monitoring
Subjects being treated with GSK2982772 should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. Consideration should 
be given to discontinuing GSK2982772 in subjects who experience signs of suicidal 
ideation or behaviour. All subjects who experience signs of suicidal ideation or 
behaviour must immediately be discontinued from study medication.
Section 9.1 Hypotheses
The primary objective of the study is to investigate the safety and tolerability of 
GSK2982772 60 mg BID and 60 mg TID following 12 weeks of treatment.  No formal 
statistical hypotheses will be conducted to assess this objective.
Section 9.2.1 Sample Size Assumptions
The study is not powered to detect pre-defined differences.  In Cohort 1, approximately 
30 subjects and up to a maximum of 36, will be randomised into the study to either 
GSK2982772 or placebo in a 2:1 ratio to ensure that approximately 24 evaluable subjects 
complete the study.  
In Cohort 2, approximately 24 subjects and up to a maximum of 32, will be 
randomised into the study to either GSK2982772 or placebo in a 3:1 ratio to ensure 
that approximately 20 evaluable subjects complete the study.
A subject is considered evaluable if they have completed at least one post-treatment 
biopsy.
The primary objective of the study is safety and tolerability, where there will be 20 
subjects randomised to GSK2982772 60 mg BID and 18 subjects randomised to 
GSK2982772 60 mg TID.  Using a Bayesian approach to determine the confidence 
interval around an observed safety event, we would assume a flat Beta (1, 1) prior, and if 
we were to observe one safety event in 20 then the posterior distribution would be Beta 
(2, 20), as outlined below in Figure 4.
Thus, we can be 95% certain that the true probability of the safety event lies between 
0.01 and 0.24.  Similarly, if we were to observe one safety event in 18 then the 
posterior distribution would be Beta (2, 18), thus we can be 95% certain that the 
true probability of the safety event lies between 0.01 and 0.26.  
For supportive information the properties of the secondary endpoint PLSS have also been 
considered.  Assuming a standard deviation of 25%, it is estimated that the lower and 
upper bounds of the 95% confidence interval for the difference between GSK2982772 60
mg BID (n=20) and placebo (n=10) in percentage change in index lesion PLSS will be 
within approximately 20.3 17.1% of the point estimate, and that the lower and upper 
bounds of the 95% confidence interval for the difference between GSK2982772 60
mg TID (n=18) and placebo (n=6) in percentage change in index lesion PLSS will be 
within approximately 17.5% of the point estimate.

2015N251765_02
CONFIDENTIAL
203167
105
Section 9.2.2 Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint to 
investigate the different safety event rates.  If the number of subjects who complete the 
12 weeks is lower than 20 in the GSK2982772 group anticipated, then the true incidence 
rates of safety events that could not be ruled out (as outlined in Section 9.2.1) would 
change.  These changes are outlined in Table 4.
Figure deleted:
Figure 5
Sample Size Sensitivity for Percentage Change in PLSS

2015N251765_02
CONFIDENTIAL
203167
106
Figure added:
Figure 5
Sample Size Sensitivity for Percentage Change in PLSS
Section 9.3.2 Interim Analysis
In both cohorts, once an appropriate number of subjects randomised to GSK2982772 
have completed Day 43 (Week 6), the PLSS data will be reviewed in an unblinded 
manner by a Data Review Committee (DRC) consisting of the GSK study physician
Project Physician Lead (PPL), the study statistician, the study pharmacokineticist, the 
PRR DPU Head, the Early Development Lead (EDL), the Safety Review Team (SRT) 
leader, or their designees on an ongoing basis.  A physician external to the GSK2982772 
project team may also be involved in the data review. Additional inflammatory 
biomarkers, clinical and mechanistic endpoints (e.g. target engagement) may be reviewed 
if available. No other member of the GSK core study team will be unblinded to this data. 
The primary purpose of these reviews will be to monitor PLSS changes for internal 
decision making purposes.  A data review charter will identify the specific GSK 
individuals involved, outline in detail the activities of this review and how the integrity of 
the study will be maintained.  

2015N251765_02
CONFIDENTIAL
203167
107
A formal interim analysis will be conducted after the completion of Cohort 1 and 
will only include those subjects randomised to a BID dosing regimen. The purpose 
of the interim analysis is primarily to provide the project team and key GSK 
stakeholders with an early indication of the safety and efficacy from the trial, and to 
facilitate decision making regarding the subsequent clinical development of 
GSK2982772.  
Section 9.3.4 Secondary Analyses
Comparisons between treatment groups on any changes observed will be conducted for 
the secondary endpoints if deemed appropriate, e.g. changes in the mean target 
engagement, changes in inflammatory markers and percentage change in index lesion 
PLSS be statistically analyzed using a MMRM (repeated measures mixed effects model) 
comparing each GSK2982772 arm with placebo at each time point. If sufficient numbers 
of subjects are enrolled with a BSA >5% then the proportion of subjects achieving PASI 
50/75/90 at Day 85 (12 Weeks), will be statistically analysed using a Generalised 
Estimating Equations (GEE) model comparing each GSK2982772 arm with placebo at 
each time point if appropriate. Similar analyses will be conducted for other secondary 
endpoints if deemed appropriate.
GSK2982772 plasma concentrations will be summarised descriptively by Day and 
nominal time point by dosing regimen.
Section 12.1. Appendix 1 – Abbreviations and Trademarks
MDMA
3,4-methylenedioxy-methamphetamine
PI
Principal Investigator
PPL
Project Physician Lead
TID
Three times daily