Clinical trial NCT03004846
Conditions: Psoriasis
Keywords: Vehicle- controlled GSK2981278 Plaque psoriasis
Sponsor: GlaxoSmithKline
Start date: 2017-02-13; Completion date: 2017-05-05
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
GSK2981278 is an inverse agonist of retinoic acid receptor-related orphan receptor (ROR) gamma. The aim of this study is to evaluate the safety, tolerability, clinical effect, and systemic exposure potential of topically applied GSK2981278 ointment in subjects with plaque psoriasis by treating all plaques on the body for 8 weeks. This single-center study will be conducted in two parts. Part A will be an open-label, single arm study and part B will be a double-blind, randomized, 2-arm, parallel-group, vehicle-controlled study. In Part A, 8 adult subjects and in Part B, 18 adult subjects with chronic stable plaque psoriasis will be enrolled. Total duration of study will be approximately 14 weeks. The results of this study will provide preliminary information about safety and efficacy of the drug and will help in providing the guidance for further development strategy.

Detailed description:

Arms: arm 1: Subjects will receive topical application of GSK2981278 4% ointment twice daily for 8 weeks. Based on new safety information, the concentration of GSK2981278 may be lowered to 2% or 0.8%. arm 2: In Part B, subjects will receive topical application of GSK2981278 4 % ointment or vehicle ointment twice daily for 8 weeks. Based on new safety information, the concentration of GSK2981278 may be lowered to 2% or 0.8%.
Interventions: intervention 1: GSK2981278 ointment intervention 2: Vehicle ointment
Intervention descriptions: intervention 1: GSK2981278 ointment will be applied topically twice daily for 8 weeks to all subjects in Part A and to randomized subjects in Part B. GSK2981278 will be a white to off-white ointment and a thin layer will be applied to all affected areas for given timeframe.

GSK2981278 is available as white to off-white ointment in unit strength 4% (w/w), 2% (w/w) and 0.8% (w/w), for topical application for application as thin layer to all affected areas . intervention 2: It will be supplied as white to off-white vehicle ointment for topical application.

Protocol documents:
Prot_000.pdf: 
2016N275350_01
CONFIDENTIAL
The GlaxoSmithKline group of companies
203820
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A two-part trial to evaluate the safety, tolerability, clinical effect 
and systemic exposure potential of topically applied 
GSK2981278 ointment in subjects with plaque psoriasis
Compound Number:
GSK2981278
Development Phase:
IIa
Effective Date:
13-Dec-2016
Protocol Amendment Number:  01
Author (s):
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N275350_00
2016-SEP-12
Original
2016N275350_01
2016-DEC-13
Amendment No. 1
1. Psoriasis Symptom Diary revised to the original published version
2. Clarification of intent for urine sample analysis, minor text changes to Part A and B 
Time and Events tables to ensure consistency, and more comprehensive information on 
the allergic reaction risk
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved.  Una  
uthorised copying or use of this information is prohibited.
PPD


PPD
PPD
PPD


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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 
1250 South 
Collegeville Rd, 
Collegeville, PA 
19426 (UP1410)
USA
Secondary 
Medical 
Monitor
Burchardstr. 17, 
22095 Hamburg, 
Germany
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.  
Regulatory Agency Identifying Number(s):  EudraCT number 2016-002671-10
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 203820
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


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 203820........................................................8
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................14
4.
STUDY DESIGN ....................................................................................................15
4.1.
Overall Design ............................................................................................15
4.2.
Treatment Arms and Duration.....................................................................15
4.3.
Type and Number of Subjects.....................................................................16
4.4.
Design Justification.....................................................................................16
4.5.
Dose Justification........................................................................................17
4.6.
Benefit:Risk Assessment ............................................................................19
4.6.1.
Risk Assessment .........................................................................20
4.6.2.
Benefit Assessment.....................................................................23
4.6.3.
Overall Benefit:Risk Conclusion...................................................23
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............23
5.1.
Inclusion Criteria.........................................................................................23
5.2.
Exclusion Criteria........................................................................................25
5.3.
Screening/Baseline/Run-in Failures............................................................27
5.4.
Withdrawal/Stopping Criteria.......................................................................27
5.4.1.
Liver Chemistry Stopping Criteria ................................................28
5.4.1.1.
Study Treatment Restart or Rechallenge....................29
5.4.2.
QTc Stopping Criteria ..................................................................29
5.4.3.
Topical Application Site Tolerability Stopping Criteria ..................30
5.5.
Subject and Study Completion....................................................................30
6.
STUDY TREATMENT ............................................................................................31
6.1.
Investigational Product and Other Study Treatment....................................31
6.2.
Treatment Assignment................................................................................31
6.3.
Treatment Administration............................................................................31
6.4.
Planned Dose Adjustments.........................................................................32
6.5.
Blinding.......................................................................................................33
6.6.
Packaging and Labeling..............................................................................33
6.7.
Preparation/Handling/Storage/Accountability..............................................34
6.8.
Compliance with Study Treatment Administration.......................................34
6.9.
Treatment of Study Treatment Overdose....................................................35
6.10.
Treatment after the End of the Study ..........................................................35
6.11.
Lifestyle and/or Dietary Restrictions............................................................35
6.11.1.
Dietary Restrictions......................................................................35
6.11.2.
Alcohol and Tobacco ...................................................................36
6.11.3.
Activity .........................................................................................36
6.12.
Concomitant Medications and Non-Drug Therapies....................................36
6.12.1.
Permitted Medications and Non-Drug Therapies..........................36
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................37


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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................38
7.1.
Time and Events Table for Part A...............................................................40
7.2.
Time and Events table for Part B ................................................................44
7.3.
Screening and Critical Baseline Assessments ............................................47
7.4.
Efficacy.......................................................................................................47
7.4.1.
Target Plaque Severity Score (TPSS)..........................................48
7.4.2.
Physician Global Assessment (PGA)...........................................48
7.4.3.
Psoriasis Area and Severity Index (PASI)....................................48
7.4.4.
Body surface Area (BSA).............................................................48
7.5.
Safety .........................................................................................................48
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........49
7.5.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................49
7.5.1.2.
Method of Detecting AEs and SAEs ...........................49
7.5.1.3.
Follow-up of AEs and SAEs........................................50
7.5.1.4.
Cardiovascular and Death Events ..............................50
7.5.1.5.
Regulatory Reporting Requirements for SAEs............50
7.5.2.
Pregnancy ...................................................................................50
7.5.3.
Physical Exams ...........................................................................51
7.5.4.
Electrocardiogram (ECG).............................................................51
7.5.5.
Vital Signs....................................................................................51
7.5.6.
Clinical Safety Laboratory Assessments ......................................51
7.5.7.
Application Site Tolerability..........................................................53
7.6.
Pharmacokinetics .......................................................................................53
7.6.1.
Blood Sample Collection..............................................................53
7.6.2.
Urine Sample Collection ..............................................................53
7.6.3.
Skin Sample Collection................................................................54
7.6.4.
Sample Analysis ..........................................................................54
7.7.
Biomarker(s)/Pharmacodynamic Markers ...................................................54
7.7.1.
Novel Biomarkers ........................................................................54
7.7.1.1.
RNA Transcriptome Research....................................55
7.7.1.2.
RNA Expression Research of a Subset of RNA 
Species ......................................................................55
7.8.
Genetics .....................................................................................................55
7.9.
Value Evidence and Outcomes...................................................................55
7.9.1.
Psoriasis Symptom Diary.............................................................55
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
9.2.2.
Sample Size Re-estimation or Adjustment...................................57
9.3.
Data Analysis Considerations .....................................................................57
9.3.1.
Analysis Populations....................................................................57
9.3.2.
Interim Analysis ...........................................................................58
9.4.
Key Elements of Analysis Plan ...................................................................58
9.4.1.
Primary Analyses.........................................................................58
9.4.2.
Secondary Analyses ....................................................................59
9.4.3.
Other Analyses ............................................................................59


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10. STUDY GOVERNANCE CONSIDERATIONS........................................................60
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............60
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
10.3.
Quality Control (Study Monitoring) ..............................................................60
10.4.
Quality Assurance.......................................................................................61
10.5.
Study and Site Closure ...............................................................................61
10.6.
Records Retention......................................................................................62
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................62
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................66
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................66
12.2.
Appendix 2: Body Surface Area..................................................................68
12.2.1.
Reference....................................................................................68
12.3.
Appendix 3: Physician Global Assessment (PGA) ......................................69
12.3.1.
References ..................................................................................69
12.4.
Appendix 4: Target Plaque Severity Score (TPSS).....................................70
12.4.1.
References ..................................................................................70
12.5.
Appendix 5: Psoriasis Symptom Diary ........................................................71
12.5.1.
References ..................................................................................73
12.6.
Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments ..............................................................................................74
12.6.1.
Reference....................................................................................76
12.7.
Appendix 7: Psoriasis Area and Severity Index (PASI) ...............................77
12.7.1.
Reference....................................................................................77
12.8.
Appendix 8: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................78
12.8.1.
Definition of Adverse Events........................................................78
12.8.2.
Definition of Serious Adverse Events...........................................79
12.8.3.
Definition of Cardiovascular Events .............................................80
12.8.4.
Recording of AEs and SAEs ........................................................81
12.8.5.
Evaluating AEs and SAEs............................................................81
12.8.6.
Reporting of SAEs to GSK...........................................................83
12.9.
Appendix 9: Collection of Pregnancy Information........................................84
12.10. Appendix 10 - Genetic Research ................................................................85
12.10.1. References ..................................................................................87
12.11. Appendix 11-Protocol Changes ..................................................................88


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1.
PROTOCOL SYNOPSIS FOR STUDY 203820
Rationale
In the first clinical trial of GSK2981278, once daily treatment of GSK2981278 ointment 
(at 0.03%, 0.1%, 0.8%, and 4%) on small test fields (1.13 cm2) of stable plaque(s) over 
19 days appeared to be well tolerated but did not show reduction in psoriatic infiltrate 
thickness.  It is unclear whether the apparent lack of effect on infiltrate thickness in the 
first-time-in-human (FTIH) study was due to the very small surface area treated, the 
relatively short duration of exposure, or both. Therefore the present study will evaluate 
the safety, tolerability, clinical effect, and systemic exposure potential of topically 
applied GSK2981278 ointment in subjects with plaque psoriasis by treating all plaques 
on the body wholly for 8 weeks. The results of this study will provide preliminary 
information on the safety, tolerability, and effect of the GSK2981278 ointment on plaque 
psoriasis at the highest safe and feasible concentration to guide subsequent development 
strategy.


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Objective(s)/Endpoint(s)
Part A
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
topically applied GSK2981278 in subjects 
with plaque psoriasis

Incidence and nature of adverse events 
(AEs) and serious adverse events (SAEs)

Application site tolerability assessment score

Change in clinical laboratory parameters, vital 
signs, and electrocardiogram (ECG) from 
baseline

To evaluate the systemic exposure of 
GSK2981278 following topical application 
in subjects with plaque psoriasis

Plasma concentrations of GSK2981278 
Secondary

To evaluate the clinical effect following 
topical application of GSK2981278 in 
subjects with plaque psoriasis

Mean percent change in Target Plaque 
Severity Score (TPSS) from baseline to 
Week 8 

Mean percent change in Physician’s Global 
Assessment (PGA) score from baseline to 
Week 8

Mean percent change in Psoriasis Area and 
Severity Index (PASI) from baseline to Week 
8
Exploratory

To evaluate the effect of GSK2981278 
ointment on relevant gene expression

Fold change in messenger ribonucleic acid 
(mRNA) biomarkers from baseline to Week 8 
in skin biopsy samples

To investigate the delivery profile of 
GSK2981278 into the psoriatic skin 
following repeat topical applications

Quantification of GSK2981278 in the skin 
biopsy using Matrix Assisted Laser 
Desorption Ionization (MALDI) imaging mass 
spectrometry or High-performance liquid 
chromatography-mass spectrometry (HPLC-
MS) at Week 8

To evaluate the effect of GSK2981278 
ointment on subject-reported outcomes

Mean percent change in Psoriasis Symptom 
Diary score from baseline to each study visit

To evaluate the potential metabolites of 
GSK2981278 in plasma, urine, and skin 
from biopsies in pooled subject samples, 
as data allow

Identification of any compound-derived 
metabolite(s) from plasma and urine and if 
possible estimation of relative amounts of 
drug related material

Quantification of  GSK2981278-derived 
metabolite(s) in the skin biopsy using MALDI 
imaging mass spectrometry or HPLC-MS at 
Week 8


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Part B
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
topically applied GSK2981278 and its 
vehicle in subjects with plaque psoriasis

Incidence and nature of AEs and SAEs

Application site tolerability assessment score

Change in clinical laboratory parameters, vital 
signs, and ECG from baseline

To evaluate the clinical effect of topically 
applied GSK2981278 relative to vehicle 
control in subjects with plaque psoriasis

Mean percent change in TPSS from baseline 
to Week 8 

Mean percent change in PGA score from 
baseline to Week 8

Mean percent change in PASI from baseline 
to Week 8
Exploratory

To explore exposure-response 
relationship of sparse systemic exposures 
with the clinical endpoints (by performing 
population Pharmacokinetic 
(PK)/Pharmacodynamic (PD) analysis, if 
required), as data allows

Plasma concentrations of GSK2981278 and 
clinical endpoints assessed to determine the 
clinical effect (e.g. TPSS, PGA, and PASI) 

To evaluate the effect of GSK2981278 
ointment on subject-reported outcomes

Mean percent change in Psoriasis Symptom 
Diary score from baseline to each study visit
Overall Design
This is a single-center, 2-part Phase I/IIa study to evaluate the safety, tolerability, clinical 
effect and systemic exposure potential of topically applied GSK2981278 ointment in 
subjects with plaque psoriasis. Drug delivery into the skin and changes in the relevant 
biomarkers will be explored using skin punch biopsies as well. 

Part A: open label, single arm study

Part B: double-blind, randomized, 2-arm, parallel-group, vehicle-controlled study
After completion of Week 4 assessments and Week 8 assessments in Part A, the Sponsor 
will review the safety, tolerability, PK and clinical effect data. If data demonstrates a 
mean percent reduction of 40% or greater in TPSS and systemic exposure levels below 
the no observed adverse effect level (NOAEL) determined in the pre-clinical toxicity 
studies without significant safety or tolerability issues at either time point, the study will 
proceed to Part B. 
Treatment Arms and Duration
Each part of this study will consist of 3 periods: the screening period of up to 4 weeks, 
the treatment period of 8 weeks, and the follow-up period of 2 weeks. Study visits will 
occur at Screening; Baseline; Weeks 1, 4, and 8 during the treatment period; and Week 
10 for follow-up, which will be 2 weeks after the last application of study treatment. 
Additional visits may occur, as needed, for early withdrawal or to follow-up on any skin 


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reactions or ongoing AEs. A subject’s total duration of study participation will be 
approximately 14 weeks.
In Part A, subjects will receive topical application of GSK2981278 4% ointment to all 
affected areas of the body twice daily for 8 weeks.
In Part B, subjects will receive topical application of either GKS2981278 4% ointment 
or the vehicle ointment, according to the randomization, to all affected areas of the body 
twice daily for 8 weeks. 
The concentration of GSK2981278 may be lowered to 2% or 0.8% in Part A and/or Part 
B based on the newly available safety and tolerability data. 
Type and Number of Subjects
In Part A, eight adult subjects with chronic stable plaque psoriasis will be enrolled. If 
subjects prematurely discontinue the study treatment, additional replacement subjects 
may be recruited at the discretion of the Sponsor in consultation with the investigator.
In Part B, approximately 18 adult subjects with chronic stable plaque psoriasis will be 
randomized with an allocation ratio of 2:1 to GSK2981278 4% ointment or vehicle 
ointment to have at least 15 evaluable subjects who comply closely with the protocol (e.g. 
have sufficient exposure and critical assessments completed). Subjects who were enrolled 
in Part A will not be eligible to participate in Part B.
If the concentration of GSK2981278 is lowered in either part of the study, additional 
subjects may be enrolled to have the minimum evaluable subjects in that part treated with 
the lower concentration of study treatment.
Analysis
No formal hypothesis tests are planned. Descriptive statistics will be used to assess the 
key objectives of this study.


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2.
INTRODUCTION
GSK2981278 is an inverse agonist of retinoic acid receptor-related orphan receptor 
gamma (ROR) that is being developed for topical treatment of plaque psoriasis.
2.1.
Study Rationale
In the first clinical trial of GSK2981278, once daily treatment of GSK2981278 ointment 
(at 0.03%, 0.1%, 0.8%, and 4%) on small test fields (1.13 cm2) of stable plaque(s) over 
19 days appeared to be well tolerated but did not show reduction in psoriatic infiltrate 
thickness.  It is unclear whether the apparent lack of effect on infiltrate thickness in the 
FTIH study was due to the very small surface area treated, the relatively short duration of 
exposure, or both. Therefore the present study will evaluate the safety, tolerability, 
clinical effect, and systemic exposure potential of topically applied GSK2981278 
ointment in subjects with plaque psoriasis by treating all plaques on the body wholly for 
8 weeks. The results of this study will provide preliminary information on the safety, 
tolerability, and effect of the GSK2981278 ointment on plaque psoriasis at the highest 
safe and feasible concentration to guide subsequent development strategy.  
2.2.
Brief Background
Psoriasis is a chronic inflammatory skin disorder affecting 0.7 to 2.9% of the population 
in Europe and the United States [Parisi, 2013]. Plaque type psoriasis is characterized by 
raised, well-demarcated, erythematous oval plaques with adherent silvery scales [Nestle, 
2009] and affects approximately 85 to 90% of all psoriasis patients [Griffiths, 2007]. 
There is substantial impairment of physical and psychological quality of life associated 
with the disease [DeKorte, 2004].
The primary goal of treatment for psoriasis is to improve the signs and symptoms as there 
is no curative treatment. Approximately 80% of psoriasis patients have mild to moderate 
disease, which is typically managed with topical agents. In patients with more severe 
disease, topical agents are often used adjunctively with either phototherapy or systemic 
medications. Topical corticosteroids are the mainstay of topical therapy and provide 
relatively high efficacy. However, local safety issues such as skin atrophy, telangiectasia, 
and striae distensae as well as systemic safety concerns such as hypothalamic-pituitary-
adrenal (HPA) axis suppression limit their long-term use and use in sensitive areas 
[Menter, 2009]. Other topical agents such as vitamin D analogues and topical retinoids 
are available to complement the corticosteroid therapy. There is a need for an effective 
novel topical agent without the safety concerns associated with corticosteroids.  
Although the pathophysiology of psoriasis is not fully understood, current evidence 
suggests that a combination of genetic, immunologic and environmental factors 
contributes to the disease. Growing understanding of the involvement of the immune 
system in the psoriasis pathophysiology indicates that Type 17 helper T-cell (Th 17) cells 
and their signature proinflammatory cytokine Interleukin-17 (IL-17) plays a critical role 
[Malakouti, 2015]. IL-17A is known to drive inflammatory pathways inherent in 
psoriasis pathogenesis by stimulating keratinocyte expression of multiple chemokines 
and increasing the expression of antimicrobial peptides and contributing to epidermal 


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hyperproliferation and skin barrier disruption.  Increased numbers of IL-17 positive T 
cells and higher IL-17A messenger Ribonucleic acid (RNA) expression in psoriatic 
lesions compared with normal skin have been reported as well [Lynde, 2014]. In addition, 
the involvement of IL-17 cytokines was recently validated with monoclonal antibody 
(mAb) treatment. Three biologic therapies that inhibit the IL-17 cytokines have been 
shown to control the signs and symptoms of plaque-type psoriasis. Phase III study results 
have shown that a greater proportion of patients administered these agents  have a higher 
PASI75 and PASI100 response compared to patients administered existing biologics that 
have different mechanisms of action (e.g., Tumor necrosis alfa (TNF-α) inhibitors and T-
cell inhibitors) [Langley, 2014; Sandoval, 2015; Lebwohl, 2015; Gordon, 2015].  
RORt, a truncated isoform of ROR, is a transcription factor involved in Th17 cell 
differentiation and Th17 cytokine expression. It is expressed in a few distinct types of 
immune cells and is described as the master regulator of Th17 cytokine expression 
[Ivanov, 2006]. 
RORis widely expressed throughout the body and has identical ligand-binding domains 
as RORt [He , 1998]. Compounds targeting RORare expected to modulate the activity 
of RORt as well. Therefore, local delivery of the selective RORinverse agonist 
GSK2981278 to lesional skin of psoriasis patients via topical application is expected to 
block the transcriptional activity of RORt leading to the local suppression of cytokine 
expression from skin-resident T cells and ultimately to improvement in psoriasis, with no 
or minimal systemic effects. 
Pre-clinical data show that GSK2981278 significantly inhibits production of the Th17 
signature cytokines in multiple in vitro and human tissue-based assays, including human 
peripheral T cells and ex vivo human skin [GlaxoSmithKline Document Number 
2016N286376_00 GSK2981278 Investigator’s Brochure (IB)].


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Part A
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
topically applied GSK2981278 in subjects 
with plaque psoriasis

Incidence and nature of adverse events 
(AEs) and serious adverse events (SAEs)

Application site tolerability assessment score

Change in clinical laboratory parameters, vital 
signs, and electrocardiogram (ECG) from 
baseline

To evaluate the systemic exposure of 
GSK2981278 following topical application 
in subjects with plaque psoriasis

Plasma concentrations of GSK2981278 
Secondary

To evaluate the clinical effect following 
topical application of GSK2981278 in 
subjects with plaque psoriasis

Mean percent change in Target Plaque 
Severity Score (TPSS) from baseline to 
Week 8 

Mean percent change in Physician’s Global 
Assessment (PGA) score from baseline to 
Week 8

Mean percent change in Psoriasis Area and 
Severity Index (PASI) from baseline to Week 
8
Exploratory

To evaluate the effect of GSK2981278 
ointment on relevant gene expression

Fold change in messenger ribonucleic acid 
(mRNA) biomarkers from baseline to Week 8 
in skin biopsy samples

To investigate the delivery profile of 
GSK2981278 into the psoriatic skin 
following repeat topical applications

Quantification of GSK2981278 in the skin 
biopsy using Matrix Assisted Laser 
Desorption Ionization (MALDI) imaging mass 
spectrometry or High-performance liquid 
chromatography mass spectrometry (HPLC-
MS) at Week 8

To evaluate the effect of GSK2981278 
ointment on subject-reported outcomes

Mean percent change in Psoriasis Symptom 
Diary score from baseline to each study visit

To evaluate potential metabolites of 
GSK2981278 in plasma, urine, and skin 
from biopsies in pooled subject samples, 
as data allow

Identification of any compound-derived 
metabolite(s) from plasma and urine and if 
possible estimation of relative amounts of 
drug related material

Identification of GSK2981278-derived 
metabolite(s) in the skin biopsy using MALDI 
imaging mass spectrometry or HPLC-MS at 
Week 8


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Part B
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
topically applied GSK2981278 and its 
vehicle in subjects with plaque psoriasis

Incidence and nature of AEs and SAEs

Application site tolerability assessment score

Change in clinical laboratory parameters, vital 
signs, and ECG from baseline

To evaluate the clinical effect of topically 
applied GSK2981278 relative to vehicle 
control in subjects with plaque psoriasis

Mean percent change in TPSS from baseline 
to Week 8 

Mean percent change in PGA score from 
baseline to Week 8

Mean percent change in PASI from baseline 
to Week 8
Exploratory

To explore exposure-response 
relationship of sparse systemic exposures 
with the clinical endpoints (by performing 
population PK/PD analysis, if required), as 
data allows

Plasma concentrations of GSK2981278 and 
clinical endpoints assessed to determine the 
clinical effect (e.g. TPSS, PGA, and PASI) 

To evaluate the effect of GSK2981278 
ointment on subject-reported outcomes

Mean percent change in Psoriasis Symptom 
Diary score from baseline to each study visit
4.
STUDY DESIGN
4.1.
Overall Design
This is a single-center, 2-part Phase I/IIa study to evaluate the safety, tolerability, clinical 
effect and systemic exposure potential of topically applied GSK2981278 ointment in 
subjects with plaque psoriasis. Drug delivery into the skin and changes in the relevant 
biomarkers will be explored using skin punch biopsies as well. 

Part A: open label, single arm study

Part B: double-blind, randomized, 2-arm, parallel-group, vehicle-controlled study
After completion of Week 4 assessments and Week 8 assessments in Part A, the Sponsor 
will review the safety, tolerability, PK and clinical effect data. If data demonstrates a 
mean percent reduction of 40% or greater in TPSS from baseline and systemic exposure 
levels below the NOAEL determined in the pre-clinical toxicity studies without 
significant safety or tolerability issues at either time point, the study will proceed to Part 
B. 
4.2.
Treatment Arms and Duration
This study will consist of 3 periods: the screening period of up to 4 weeks, the treatment 
period of 8 weeks, and the follow-up period of 2 weeks. Study visits will occur at 


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Screening; Baseline; Weeks 1, 4, and 8 during the treatment period; and Week 10 for 
follow-up, which will be 2 weeks after the last application of study treatment. Additional 
visits may occur, as needed, for early withdrawal or to follow-up on any skin reactions or 
ongoing AEs. A subject’s total duration of study participation will be approximately 14 
weeks.
In Part A, subjects will receive topical application of GSK2981278 4% ointment to all 
affected areas of the body twice daily for 8 weeks.
In Part B, subjects will receive topical application of either GKS2981278 4% ointment 
or the vehicle ointment, according to the randomization, to all affected areas of the body 
twice daily for 8 weeks. 
The concentration of GSK2981278 may be lowered to 2% or 0.8% in Part A and/or Part 
B based on the newly available safety and tolerability data. Refer to Section 6.4 for 
planned dose adjustments.
4.3.
Type and Number of Subjects
In Part A, eight adult subjects with chronic stable plaque psoriasis will be enrolled. If 
subjects prematurely discontinue the study treatment, additional replacement subjects 
may be recruited at the discretion of the Sponsor in consultation with the investigator.
In Part B, approximately 18 adult subjects with chronic stable plaque psoriasis will be 
randomized with an allocation ratio of 2:1 to GSK2981278 4% ointment or vehicle 
ointment to have at least 15 evaluable subjects who comply closely with the protocol (e.g. 
have sufficient exposure and critical assessments completed). Subjects who were enrolled 
in Part A will not be eligible to participate in Part B.
If the concentration of GSK2981278 is lowered in either part of the study, additional 
subjects may be enrolled to have the minimum evaluable subjects in that part treated with 
the lower concentration of study treatment.
4.4.
Design Justification
Single-arm, open-label Part A will allow focused evaluation of safety, tolerability, 
clinical effect, and systemic exposure potential and the exploration of drug delivery to the 
skin and changes in relevant gene expressions following topically applied GSK2981278 
ointment in a small number of subjects without exposing additional subjects to 
unnecessary burdensome assessments. 
Treatment duration of 8 weeks is considered sufficiently long to look for the signal of 
drug effect and determine whether GSK2981278 may be a viable candidate for 
development as a topical treatment for plaque psoriasis.
The number of subjects proposed in this study is expected to provide reasonable 
information on the clinical effect, gene expression changes, and drug delivery into the 
psoriatic skin. 


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If data from Part A demonstrate sufficient signal of drug effect to meet the pre-defined
criteria to proceed to Part B, any clinical effect observed in Part A will be further 
evaluated in a randomized, double-blind, vehicle-controlled fashion in Part B. Inclusion 
of the vehicle group will inform the treatment effect relative to the vehicle effect. 
4.5.
Dose Justification
In this study, the clinical effect of GSK2981278 will be evaluated in patients with 
psoriasis at a 4% w/w dose applied topically to up to 15% of total body surface area for 8 
weeks as an ointment. Data from ex vivo target engagement studies, the first study in 
humans, and repeat dose toxicity studies in rat (oral) and minipig (oral and dermal) were 
considered for the selection of the concentration of GSK2981278 ointment in this study. 
In ex vivo human skin following single dermal application of GSK2981278 with the 
current clinical formulation at concentrations ranging from 0.01 to 4%, a potent dose-
dependent inhibition of Th17 signature cytokines mRNA levels was observed with effect 
reaching plateau after 0.1% concentration (Figure 1). Based on this data, concentrations 
ranging from 0.03% to 4% are being considered in the early phase clinical trials. In this 
study, using a single concentration of GSK2981278 ointment, the highest concentration 
4% is selected to maximize the probability of observing the clinical effect of 
GSK2981278 in patients with psoriasis.
Figure 1
Percent maximum expression of IL-17A transcripts in ex-vivo human 
skin
In the first clinical study (201465), once daily treatment of GSK2981278 at 0.03%, 0.1%, 
0.8% and 4% w/w each applied to a small area of a psoriatic plaque (1.13 cm2) over 
19 days was well tolerated in patients with psoriasis although reduction in the 
inflammatory infiltrate thickness measured by ultrasound was not observed for any of the 
tested concentrations.


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GSK2981278 has been evaluated in repeat dose toxicity studies following oral 
administration for up to 13 weeks in rats and minipigs; following dermal administration 
for up to 13 weeks in minipigs. 
No dose-limiting toxicities were observed in any of the nonclinical toxicity studies, hence 
the NOAELs for systemic effect were established at the highest tested dose levels.
The NOAEL established for systemic effects in the oral 13 week rat study was 
200 mg/kg/day. The end of study area under the concentration-time curve (AUC) and 
maximum plasma concentration (Cmax) values at 200 mg/kg/day in rats were 302 ng.h/mL 
(males) and 4650 ng.h/mL (females) and 79.5 ng/mL (males) and 3390 ng/mL (females), 
respectively.
The NOAEL established for systemic toxicity in the dermal 13 week minipig study using 
the current clinical formulation was 140 mg/kg/day (7%; twice daily (BID); 10% body 
surface area). The end of study AUC and Cmax values at 140 mg/kg/day were 325 
ng.h/mL and 52.4 ng/mL (gender average mean), respectively.
The predicted human AUC at steady state is 58.5 ng.h/mL and Cmax is 2.4 ng/mL 
(4% GSK2981278 [maximum concentration] applied twice daily to 15% body surface 
area [BSA]). Multiples of predicted mean human exposure for AUC and Cmax at the 
NOAEL for systemic findings in the rat (oral) and in the minipig (dermal) are shown in 
Table 1. 
Table 1
Predicted mean human exposures with 90% prediction intervals 
(PIs) for GSK2981278 ointment at 4% (w/w) and calculated mean 
safety covers with 90% PIs.
BSA 
Treated 
(%[cm2]a)
Mean Predicted 
Human Exposureb at 
steady state (PI)
Mean Safety Cover-Fold Difference (PI)
13 Week Rat (Oral –
Males)
13 Week Rat (Oral –
Females)
13 Week Minipig 
(Dermal – Gender 
Averaged)
Cmax 
(ng/mL)
AUC0-24h 
(ng.h/mL)
Cmax 
AUC0-24h 
Cmax 
AUC0-24h 
Cmax 
AUC0-24h 
15 [2595]
2.4 (2.0 –
2.9)
58.5 (47-
70.5)
33 (27 –
41)
5 (4 – 6)
1413 
(1153 –
1730)
79(66 –
99)
21 (17 –
26)
6 (4 – 7)
5 [865)
0.8 (0.7 –
1.0)
19.5 (15.7 
– 23.5)
98 (81 –
122)
15 (13 –
19)
4170 
(3460 –
5189)
238(198 –
297)
64 (51 –
77)
17 (13 -
20)
Key:
a=equivalent area of skin in cm2 for a standard BSA of 1.73 m2
b=calculated using BSA in cm2 for BSA of 1.73m2
The planned twice daily application of GSK2981278 ointment at 4% w/w concentration 
to up to 15% of total BSA in this study provides a safety cover of 5 fold for AUC and 
21 fold for Cmax for systemic effect.


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In a 13-week dermal minipig study, test article-related adverse dermal irritation was 
observed. Dermal irritation included slight to marked erythema and eschar in most 
animals at all dose levels and ulceration, tissue damage, exfoliation and desquamation in 
less than 5 animals. A NOAEL was not established for this effect. However, there was no 
clear dose-response in the incidence and/or severity of clinical and microscopic skin 
findings, and irritation was reversible with treatment discontinuation. These findings 
were not observed with the same formulation in a 4 week dermal study in minipigs. No 
skin irritation findings have been observed in mice, rats or rabbits. In addition, the 
formulation with GSK2981278 was not a contact sensitizer in the mouse local lymph 
node assay, was not classified as an eye irritant in the bovine corneal opacity and 
permeability assay at concentrations up to 7%, and has no potential for phototoxicity in 
nonclinical models
The dermal minipig high dose concentration at 4% of GSK2981278 was equivalent to 
960 µg/cm2. When the minipig dose levels are compared with the clinical dose levels at a 
concentration 4% of GSK2981278, equivalent to 63 µg/cm2, there is a 15 fold 
difference, indicating patients participating in this study will receive a 15 fold lower dose 
on a µg/cm2 basis than minipigs received in the 13 week study due to the difference in the 
volume applied. In addition, even when compared with the lowest dose concentration 
tested in minipigs, 1%, the clinical dose at 4% concentration is almost 4 fold lower on a 
µg/cm2 basis.
Patient’s skin will be monitored for any signs of irritation using the application site 
tolerability scale at Days 1, 15, 29, and 57 in addition to regular AE/SAE monitoring, and 
with phone contact with patients at Days 8 and 43. In the event of skin irritation, study 
treatment will be discontinued according to the stopping criteria (Section 5.4.3). 
Findings from preclinical in vivo pharmacology and toxicology studies with 
GSK2981278 have provided reasonable assurance that there are no undue or unforeseen 
risks for the administration of GSK2981278 to humans at up to 4% concentration twice a 
day to up to 15% BSA in this study (GlaxoSmithKline Document Number
2016N286376_00 GSK2981278 Investigator’s Brochure).
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2981278 can be found in the Investigator’s Brochure (IB).  The following section 
outlines the risk assessment and mitigation strategy for this protocol:  


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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK2981278]
Skin irritation or allergic reaction to 
GSK2981278 or to components of its vehicle.
GSK2981278 was not a contact sensitizer in the 
mouse local lymph node assay and was not classified 
as an eye irritant in the bovine corneal opacity and 
permeability assay at concentrations up to 7%.  
GSK2981278 is a sulphonamide, chemically distinct 
from the antibiotic sulphonamides that are one of the 
most common causes of drug reactions. GSK2981278 
does not contain the arylamine group that is known to 
be associated with allergies and hypersensitivity as the 
antibiotic sulphonamides do. Evidence suggests no 
cross-reactivity between arylamine sulphonamides and 
non-arylamine sulphonamides [Brackett, 2007; Strom, 
2003].
In a 13-week dermal minipig study test article-related 
adverse dermal irritation was observed in a non-dose 
responsive manner and included marked erythema and 
eschar with occasionally ulceration, tissue damage, 
exfoliation and desquamation. A NOAEL was not 
established for this effect, although a systemic NOAEL 
was achieved at 7% concentration BID. There was no 
clear dose-response in the incidence and/or severity of 
clinical and microscopic skin findings, and irritation was 
reversible with treatment discontinuation. These 
findings were not observed with the same formulation 
Potential subjects with a known or suspected 
intolerance to the components of 
GSK2981278 vehicle will be excluded.
Subjects will be informed of the sulphonamide 
nature of the compound via informed consent. 
Subjects will not be excluded from the trial 
solely based on a history of sulphonamide 
allergy.
The skin will be evaluated for any signs of 
allergic reaction or excessive irritation in 
addition to a regular AE/SAE monitoring.
If a subject experiences application site 
reaction, the study treatment may be 
discontinued temporarily or permanently (see 
Section 5.4.3).


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
in a 4 week dermal study in minipigs. No skin irritation 
findings have been observed in mice, rats or rabbits.
In the one and only clinical study conducted to date 
with GSK2981278, study 201465, the physical 
examination of the skin did not show any findings in 
any of the 15 subjects treated with GSK2981278 in 
small areas (1.13 cm2) of the plaque over 19 days.
Systemic reactions including but not limited to 
end organ toxicity. 
No adverse GSK2981278-related systemic findings 
have been observed up to 13 weeks duration in an oral 
rat study, 13 week oral minipig study, or 13 week 
dermal minipig study at doses up to 200 mg/kg/day, 
30 mg/kg/day, or 140 mg/kg/day, respectively.
GSK2981278 did not produce acute cardiovascular 
effects in minipigs or respiratory or neurobehavioural 
effects in rats in safety pharmacology studies at doses 
up to 30 and 200 mg/kg, respectively.  GSK2981278 
inhibited hERG tail current recorded from HEK 293 
cells stably transfected with hERG cDNA, with an IC25 
of 2.2 µM (1.02 g/mL) or 100000 times greater than 
the predicted human free Cmax.
One AE of nasopharyngitis, considered unrelated to 
study treatment, was reported and no SAEs were 
reported in study 201465. No remarkable changes in 
laboratory tests, ECGs or vital signs were reported in 
this study.  
Standard laboratory tests, ECGs and physical 
examinations will be performed and vital signs 
will be reviewed 
Subjects will be monitored for the occurrence 
of AEs/SAEs throughout the study. 
Reproductive and developmental toxicity
GSK2981278 administered to pregnant rats orally up to Only females of non-reproductive potential will 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
200 mg/kg/day or dermal administration in a 
preliminary dose-range finding rabbit study up to 7% 
concentration resulted in no maternal or developmental 
toxicity.
No effects on testes were reported in repeat dose 
toxicity studies.
be enrolled in this study.
In addition, male subjects with female 
partners of child bearing potential will be 
required to use a male condom unless 
vasectomy was done and azoospermia was 
documented.
Study Procedures
Worsening of psoriasis symptoms
Subjects discontinuing their current psoriasis treatment 
may experience a worsening of their psoriasis during 
the washout period before beginning treatment in this 
study.  A worsening of psoriasis may also occur during 
the active treatment period.
Patients did not discontinue the study 201465 due to 
worsening of psoriasis symptoms.
The informed consent for this study will state 
the risk of worsening of the symptoms of 
psoriasis.
Subjects who either choose to withdraw or are 
withdrawn from the study treatment because 
they meet withdrawal/stopping criteria will be 
able to use alternate treatments for their 
psoriasis.
Punch biopsy
Local bleeding and bruising, pain, infection, allergic 
reaction (e.g. to a disinfectant or an anaesthetic agent) 
or damage to the structures beneath the skin (such as 
an artery or nerve) may occur.  Scarring may occur at 
the biopsy site.
Staff performing the procedures will be 
adequately trained and subjects will be 
informed about potential risks.  Local 
anaesthesia will be used prior to obtaining 
biopsies. Proper wound care (e.g. application 
of pressure, bandage, etc.) will be provided as 
needed and subjects will be checked for 
wound healing at the follow-up visit. Pain 
medication (e.g. ibuprofen) will be allowed.


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4.6.2.
Benefit Assessment
Subjects participating in this study may experience improvements, whether it is due to 
GSK2981278 or the vehicle, in their psoriasis lesions during the course of the study. 
Subjects may also benefit from the overall health assessment conducted while 
participating in this study. Subjects participating in the study will also contribute to the 
process of developing a novel agent for the topical treatment of plaque psoriasis.
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 GSK2981278 ointment are 
justified by the anticipated benefits that may eventually be afforded to subjects with 
plaque psoriasis.
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.
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.
The selection of subjects is in accordance with the requirements of §§ 40 and 41 of the 
German drug law (AMG) as well as the recommendations of the currently valid revision 
of the Helsinki Declaration and the International conference on harmonisation of 
technical requirements for registration of pharmaceuticals for human use (ICH)-Good 
Clinical Practice (GCP) guideline.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. 18 years of age and above, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Subjects with clinical diagnosis of stable plaque psoriasis for 6 months, as 
confirmed by the investigator.
3. Body surface area involvement 5% and 15%, excluding face and intertriginous 
areas, at Screening and Baseline (Appendix 2). The area of psoriasis involvement 
may include up to 2% of total BSA on the scalp with only sparse terminal hair and/or 
vellus hair.


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4. A PGA score of 2 at Baseline (Appendix 3)
5. One target plaque located on the trunk or proximal parts of extremities (excluding 
scalp, knees, and elbows) that is at least 9 cm2 in size at Screening and Baseline with 
a Target Plaque Severity Score (TPSS) 5 and induration subscore 2. (Appendix 4)
SEX
6. Male
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 2 weeks after the last dose of study medication.
a. 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.
b. Male condom 
The allowed method of contraception is 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.
7. Female of non-reproductive potential (FNRP)
A FNRP is eligible to participate in this study if she meets at least one of the 
following conditions:
a. Females with one of the following procedures documented and no plans to utilize 
assisted reproductive techniques (e.g., in vitro fertilization or donor embryo 
transfer):
o
Bilateral tubal ligation or salpingectomy
o
Hysteroscopic tubal occlusion procedure with follow-up confirmation of 
bilateral tubal occlusion 
o
Hysterectomy
o
Bilateral Oophorectomy (surgical menopause)
b. Post-menopausal women (including all women over 60 years of age, see below),
Post-Menopause criteria

Females 60 years of age or older

A practical definition accepts menopause after 1 year without menses with an 
appropriate clinical profile, e.g., age appropriate, >45 years, in the absence of 
hormone replacement therapy (HRT) or medical suppression of the menstrual 
cycle (e.g., leuprolide treatment). 
In questionable cases for women <60 years of age, a blood sample with 
simultaneous follicle stimulating hormone and estradiol falling into the 
central laboratory’s post-menopausal reference range is confirmatory (these 


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levels need to be adjusted for specific laboratories/assays) [Kronenberg, 
2008; Strauss, 2004].
Females under 60 years of age, who are on HRT and wish to continue, and 
whose menopausal status is in doubt, should not be enrolled in this study.  
Otherwise, they must discontinue HRT to allow confirmation of post-
menopausal status prior to study enrollment. For most forms of HRT, at 
least 2 to 4 weeks will elapse between the cessation of therapy and the blood 
draw; this interval depends on the type and dosage of HRT.  Following 
confirmation of their post-menopausal status, they can enrol into the study 
and resume use of HRT.
INFORMED CONSENT
8. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.
5.2.
Exclusion Criteria
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.
Psoriasis other than plaque variant (i.e. acute psoriasis guttate, psoriasis punctata, 
psoriasis erythroderma or pustular psoriasis).
2.
Current evidence of another ongoing or any acute cutaneous infection, history of 
repeated or chronic significant skin infections (unless irrelevant in the opinion of the 
investigator, i.e. onychomycosis, labial herpes or other minor diagnosis).
3.
Clinically-relevant skin disease or other skin pathologies, that may, in the opinion of 
the investigator, contraindicate participation or interfere with skin evaluations.
4.
Alanine aminotransferase (ALT) >2xULN and bilirubin >1.5x upper limit of normal 
(ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and 
direct bilirubin <35%).
5.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
6.
QTcB >450 msec or QTcB >480 msec in subjects with Bundle Branch Block. The 
QTcB should be based on single QTcB values of ECG obtained over a brief 
recording period. If QTcB is outside the threshold value, triplicate ECGs may be 
performed with the QTcB values averaged. 
7.
Any condition that, in the judgement of the investigator, would put the subject at 
unacceptable risk for the participation in the trial.  
8.
History of malignancy within 5 years prior to dosing, except adequately treated non-
invasive cancer of the skin (basal or squamous cell).  


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CONCOMITANT MEDICATIONS
9.
Use of prohibited concomitant medications or products within the defined periods 
before the Day 1 visit and during the trial (Table 2).
CONTRAINDICATIONS 
10. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation. 
11. Symptoms of a clinically significant illness that may, in the opinion of the 
investigator, influence the outcome of the trial in the 4 weeks before baseline visit 
and during the trial.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
12. 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. 
13. A positive pre-study drug/alcohol screen.  
14. A positive test for human immunodeficiency virus (HIV) antibody.
15. For Part B only-the subject has participated in Part A of this study.
16. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 4 weeks, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
17. Prolonged exposure to natural or artificial sources of ultraviolet (UV) radiation (e.g., 
exposure to sunlight other than that associated with usual daily activities, use of 
tanning booth, etc.) within 2 weeks prior to the Day 1 visit or intention to have such 
exposure during the study, thought by the investigator likely to modify the subject’s 
psoriasis.
18. In the opinion of the investigator or physician performing the initial examination the 
subject should not participate in the clinical trial, e.g. due to probable 
noncompliance, inability to understand the trial and give adequately informed 
consent, or inability to complete the Psoriasis Symptom Diary (Appendix 5).
19. Close affiliation with the investigator (e.g. a close relative) or persons working at 
bioskin GmbH or subject is an employee of sponsor. 
20. Subject is institutionalized because of legal or regulatory order.


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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 (Section 7.5.1.5).
Subjects who initially do not meet eligibility criteria (e.g., due to use of prohibited 
concomitant medications requiring a longer washout than the specified screening period) 
may be re-screened for the same Part of the study once if their potential eligibility status 
has changed. Eligible subjects may then be enrolled in the study.
A subject who previously failed screening for Part A may be re-screened for Part B if the 
investigator considers that the subject’s potential eligibility status has changed.
5.4.
Withdrawal/Stopping Criteria
Study treatment will be stopped and the subject will complete the Day 57 assessments 
and subsequently enter the follow-up period if any of the following stopping criteria are 
met:

Subject experiences an AE that is severe enough in nature to warrant treatment 
discontinuation in the opinion of the investigator.

Subject presents with a worsening of psoriasis that requires treatment with a 
prohibited concomitant medication in the opinion of the investigator (Table 2).

Additional for Part B: The subject’s randomized treatment assignment is 
unblinded by the investigator.
Reasons for withdrawal from the study may include but are not limited to the following:

Withdrawal of consent. If specified by the subject, the investigator should 
document the reason for withdrawal of consent.

Noncompliance with study procedures

Lost to follow-up

Termination of study by sponsor

Protocol deviation

Investigator discretion
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. 


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
The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow-up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment or the study at any time at his/her own 
request, or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural 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. If the subject has not withdrawn consent to participate in the study, 
then the Week 8 assessments should be performed at the time a subject is prematurely 
withdrawn from the treatment.
If a subject prematurely withdraws prior to enrollment in Part A or randomization in 
Part B, this subject will be classed as a screen failure and will not be counted towards the 
planned enrollment target. The primary reason for withdrawal from the study must be 
recorded in the eCRF.
5.4.1.
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


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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 6. 
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria
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. QTcB will be utilized for this study.
The QTcB should be based on single QTcB values electrocardiograms. If QTcB is 
outside of the threshold value of the stopping criteria shown below, triplicate ECGs will 
be performed over a brief (e.g., 5-10 minute) recording period with the QTcB values 
averaged. 
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTcB > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTcB > 60 msec


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For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTcB with Bundle Branch 
Block
Discontinuation QTcB with Bundle 
Branch Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
5.4.3.
Topical Application Site Tolerability Stopping Criteria
If a subject experiences application site reaction of grade 3 (severe) or 4 (very severe) on 
the topical application site tolerability scale, study treatment will be discontinued 
permanently (Table 5).
If a subject experiences application site reaction of grade 2 (moderate) on the topical 
application site tolerability scale with cracking, study treatment WILL be temporarily 
discontinued and the subject will be put on a dosing holiday until the irritation resolves. If 
a subject experiences application site reaction of grade 2 (moderate) without cracking, 
investigator MAY temporarily discontinue study treatment and put the subject on a 
dosing holiday in consultation with the subject and medical monitor until the irritation 
resolves. No rescue medication will be allowed during a dosing holiday. Investigator in 
consultation with the Medical Monitor may allow the use of emollients during the dosing 
holiday. The dosing holiday will be limited to once in each subject over the course of the 
study and the duration will not exceed 1 week. After the dosing holiday, the subject may 
be retreated with the study treatment if the irritation resolves.
At the time of permanent (grade 3 or 4) or temporary (grade 2) treatment discontinuation 
due to the application site intolerability and at the time of treatment restart (if applicable, 
after a dosing holiday), photographic documentation of a representative area of irritation 
(preferably the target lesion or the vicinity, if affected) will be taken. 
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.


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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.
Study Treatment
Product name:
GSK2981278
Vehicle
Dosage form:
Ointment
Ointment
Unit dose strength(s)/Dosage 
level(s):
4% (w/w)
2% (w/w)
0.8% (w/w)
0% (w/w)
Route of Administration
Topical
Topical
Dosing instructions:
Apply a thin layer to all 
affected areas as 
determined at baseline twice 
daily (morning and evening) 
for 8 weeks.
Apply a thin layer to all 
affected areas as determined 
at baseline twice daily 
(morning and evening) for 8 
weeks.
Physical description:
White to off-white ointment
White to off-white ointment
6.2.
Treatment Assignment
In Part A, all subjects will receive 4% ointment of GSK2981278.
In Part B, subjects will be assigned to 4% ointment of GSK2981278 or the vehicle 
ointment in accordance with the randomization schedule generated by GlaxoSmithKline 
(GSK), prior to the start of the study, using validated internal software.
The concentration of GSK2981278 may be lowered to 2% or 0.8% in Part A and/or Part 
B based on the newly available safety and tolerability data. See Section 6.4 for planned 
dose adjustments.
Once a randomization number has been assigned to a subject, it must not be re-assigned 
to a different subject.
6.3.
Treatment Administration
At the baseline visit, subjects will be instructed on proper application of study treatment. 
The first application will be at the study center under the supervision of study staff. 
Subjects will self-administer study treatment where possible, ensuring that they cover all 
psoriasis lesions identified to be treated at baseline (except on the scalp covered with 
dense terminal hair: sparse terminal hair and/or vellus hair on the scalp are acceptable) 
and approximately 0.5 cm beyond the borders with a thin layer of GSK2981278 ointment 
or vehicle ointment, twice daily (morning and evening). In areas where self-


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administration of study treatment is not possible, study treatment may be applied by 
another person (e.g. site staff during clinic visits, family member or friend outside the 
clinic). The skin should be clean and dry before applying study treatment. Subjects will 
continue to treat all original areas of involvement, even in the event of lesions clearing, 
and to any new areas at the first sign of flaring until the Week 8 visit. Subjects will be 
asked to contact the site if any new lesions are noticed. Subjects must wash hands after 
application, unless treating lesions on the hand(s).
If study treatment is applied to the subject by another person, that person must wear 
protected gloves (e.g. vinyl) and thoroughly wash his/her hands after application.
In the area of the skin where a punch biopsy has been taken and the surrounding areas of 
the skin approximately 1 cm from the edge of the bandage in all direction, study 
treatment will not be applied until the investigator confirms that the wound has healed 
and the bandage is removed.
Subjects should be requested not to take a shower within 15 minutes before or 2 hours 
after treatment application.
6.4.
Planned Dose Adjustments
The concentration of GSK2981278 ointment will be lowered if the tested concentration 
shows tolerability issues as indicated below;

In Part A, if 2 of the first 4 subjects who receive study treatment discontinue the 
study treatment permanently due to application site reaction, the remaining 
subjects in Part A will receive GSK2981278 2% ointment. If GSK2981278 2% 
ointment is used in Part A, Part B will be conducted using the 2% concentration 
rather than the 4%.

In Part B, if 2 of the first 4 subjects who receive study treatment discontinue the 
study treatment permanently due to application site reaction, the remaining 
subjects will receive the next lower concentration GSK2981278 ointment (i.e. if 
4% discontinued, 2%; if 2% discontinued, 0.8%)
The concentration of GSK2981278 ointment for an individual subject will not be changed 
during the study treatment.
Consideration will be also given to decreasing the concentration of the GSK2981278 
ointment for the remaining subjects in the study in the following circumstances:

Adverse events other than the application site reactions, which are of moderate or 
severe intensity and are consistent across subjects in the group, or if unacceptable 
pharmacological effects, reasonably attributable in the opinion of the investigator 
to dosing with study treatment, are observed in more than 2 of the subjects 

The same SAE occurs in more than one subject, reasonably attributable in the 
opinion of the investigator to administration of the study treatment 

In these two circumstances, but not limited to them, dosing will be temporarily 
halted and no further subjects will be dosed until a full safety review of the study 
has taken place. Relevant reporting and discussion with the Medical Monitor, 


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relevant GSK personnel, and with the Ethics Committee will then take place prior 
to any resumption of dosing.
6.5.
Blinding
Part A will be an open-label study. 
Part B will be a double-blind study and the following will apply:

Only the unblinded pharmacist/staff responsible for handling and dispensing of 
the study treatment will have direct access to the subject’s individual study 
treatment. 

The investigator or treating physician may gain access to 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. 

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 case 
report form (CRF) 

A subject will be withdrawn from the study 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.
6.6.
Packaging and Labeling
GSK2981278 ointment and vehicle ointment will be packaged in 30-gram tubes.
The contents of the label will be in accordance with all applicable regulatory 
requirements.


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6.7.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff, as delegated by the principal investigator, 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 Study Reference Manual (SRM). 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact. In the case of unintentional occupational 
exposure notify the monitor, Medical Monitor and/or GSK study contact.

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.
6.8.
Compliance with Study Treatment Administration
Detailed instructions concerning protocol requirements and application of the study 
treatment will be provided to the subject at baseline. Subjects will be instructed to record 
the time of the study treatment application or reason for missed application for each 
planned study treatment administration.  At each post baseline study visit, subjects will 
be asked to provide information from the study diary to study personnel regarding their 
compliance with study product use. Subjects should bring their tube(s) of study treatment 
with them to each visit for study personnel to weigh and document the amount used.
When subjects are dosed at the site, they will self-apply study treatment under the 
direction and supervision of the investigator or designee.  In areas where self-
administration of study treatment is not possible, study treatment may be applied by the 
site staff (Section 6.3). 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. The weight of the tube of 
ointment will be collected before and after the study treatment application at the site. 


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6.9.
Treatment of Study Treatment Overdose
For this study, an overdose may consist of accidental or intentional ingestion of the study 
ointment or excessive application onto the skin (e.g., exposure to larger BSA, using a 
greater quantity, or applying more frequently than instructed).
There is no specific antidote for overdose of GSK2981278 and GSK does not recommend 
specific treatment. Refer to Section 6 of GlaxoSmithKline Document Number 
2016N286376_00 GSK2981278 Investigator’s Brochure for information on overdose.
In the event of an overdose the investigator or treating physician should contact the 
medical monitor to discuss the event and proceed with the following as appropriate for 
the circumstances:
1. In the event of excessive topical application, instruct the subject to wash 
GSK2981278 ointment off the skin and monitor for application-site AEs.
2. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis)
3. Closely monitor the subject for AEs/SAEs and laboratory abnormalities for at least 7 
days or until GSK2981278 can no longer be detected systemically (if plasma level 
was measured per Medical Monitor’s request)
4. Provide appropriate supportive clinical care
Decisions regarding interruptions in application of study treatment will be made by the 
investigator in consultation with the Medical Monitor based on the clinical evaluation of 
the subject and documented in the CRF.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study since the indication being studied is not life threatening or seriously debilitating 
and/or 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.
6.11.
Lifestyle and/or Dietary Restrictions
6.11.1.
Dietary Restrictions
Subjects should refrain from consumption of red wine, oranges, tangerine, tangelo, 
grapefruit, pummelos, other exotic citrus fruits, grapefruit hybrids or juices containing 
these fruits from 7 days prior to the first application of study treatment until after the final 
application.


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6.11.2.
Alcohol and Tobacco

Subjects will be advised to limit alcohol consumption to 2 units/day during the 
treatment period. One unit is equivalent to 8g of alcohol: a half-pint (~240 mL) of 
beer, 1 glass (125 mL) of wine or 1 measure (25 mL) of spirits.

Subjects who use tobacco products should not change their habits of using these 
products during the study treatment.
6.11.3.
Activity
Subjects will abstain from very strenuous exercise (e.g. weight lifting exercise, marathon) 
for at least 1 week prior to each blood collection for clinical laboratory tests.  
Subjects will abstain from sweat inducing physical exercise, bathing, swimming, or the 
use of a sauna before or after study treatment application to minimize any potential effect 
on study drug absorption (2h).
Subjects should be requested not to take a shower within 15 minutes before or 2 hours 
after study treatment application.
Prolonged exposure to natural or artificial sources of UV radiation (e.g., exposure to 
sunlight other than that associated with usual daily activities, use of tanning booth, etc.), 
which is thought by the investigator to potentially impact the subject’s psoriasis, is 
prohibited within 2 weeks prior to the baseline visit and throughout the study until the 
last follow-up visit. 
6.12.
Concomitant Medications and Non-Drug Therapies
All medications and nondrug therapies (including treatments listed in the exclusion
criteria) received by the subject within 4 weeks (28 days) before the Screening visit and 
at any time throughout the study must be recorded in the source documents and eCRF 
with start and end dates, if end dates are available.
6.12.1.
Permitted Medications and Non-Drug Therapies
Medications permitted during the study include contraceptives (for indications other than 
pregnancy prevention), antihistamines, selective leukotriene receptor antagonists (e.g., 
montelukast sodium, zafirlukast), mast cell stabilizers (e.g., cromolyn sodium or 
nedocromil sodium), acetaminophen/paracetamol, ibuprofen, vitamin and mineral 
supplements, medications for regulation of thyroid function, influenza vaccine, and 
medications for AEs, unless specifically prohibited.
Subjects may also use medications for chronic stable concomitant medical conditions 
(e.g, hypertension) that are not expected to affect the study assessments, provided the 
subject is on a stable dose that is not expected to change during the study.
Other concomitant medication may be considered on a case by case basis by the
investigator in consultation with the Medical Monitor if required.


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Medicinal shampoos and other topical treatments for psoriasis lesions on the scalp that 
are not part of assessment in this trial are permitted during the study.
Sunscreen and regular moisturizers (site staff to verify that they are not emollients) may 
be used during the treatment period. However, on the areas to be treated with the study 
treatment, these products must be applied at least 15 minutes after the study treatment if 
applied.  On the scheduled clinic visit days, subjects must not apply these products within 
4 hours of a study visit. 
6.12.2.
Prohibited Medications and Non-Drug Therapies
Use of medications or treatments that would significantly influence or exaggerate 
responses to the test products or that would alter inflammatory or immune response to the 
products is prohibited. Prohibited concomitant medications, products, and procedures 
(Table 2) are not to have been used from the defined periods before the first study 
treatment applications at the Day 1 visit and throughout the study.
In the event a subject takes a prohibited medication, the investigator should consult with 
the Medical Monitor to determine if the subject should be withdrawn from the study.
Table 2
Prohibited Concomitant Medications, Products, and Procedures
Prohibited medications, products, and procedures:
Prohibited 
period before 
Day 1 
Biologic agents: 
(e.g., alefacept 24 weeks; etanercept 12 weeks; ustekinumab 15 weeks)
5 half-lives
Oral retinoids (e.g., acitretin or isotretinoin)
12 weeks
Cyclosporin, interferon, methotrexate, fumaric acid or other systemic 
immunosuppressive or immunomodulating agents (e.g., mycophenolate or 
tacrolimus) 
4 weeks
Other investigational products or procedures
4 weeks or 5 
half-lives, whichever 
is longer
Systemic corticosteroids  or adrenocorticotropic hormone (ACTH) analogs
4 weeks
Systemic anticoagulants (e.g. warfarin, heparin, low molecular weight 
heparin, etc.)
5 half-lives
Immunizations (influenza vaccine will be allowed)
2 weeks
Topical treatments: corticosteroids, immunomodulators, anthralin 
2 weeks


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Prohibited medications, products, and procedures:
Prohibited 
period before 
Day 1 
(dithranol), Vitamin D derivatives, retinoids, coal tar (used on the body).
Drugs known to possibly worsen psoriasis (unless on a stable dose for >12 
weeks), such as, but not limited to: β-blockers (eg, propranolol), lithium, 
iodides, angiotensin-converting enzyme inhibitors, and indomethacin
2 weeks
Any other topical therapy (including emollients) on psoriasis lesions treated 
in this study
Note: Emollients may be used if Investigator, in consultation with the 
Medical Monitor, allows the use during a dosing holiday due to application 
site reaction. (See Section 5.4.3)
1 day
Phototherapy including psoralen plus UVA (PUVA)
2 weeks
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, are essential and required for study conduct.
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 and 
Section 7.2)
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety and 
pharmacokinetic 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 


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relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The Institutional review board (IRB)/ Independent ethics committee (IEC) will 
be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.


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7.1.
Time and Events Table for Part A
Procedure 
Screening
Treatment Period
Follow-up
Notes
Study Days (± specified no. of days)
Day –28 to 
-1
Day 1 
(Basel
ine)
Day 8 
(2 
days) 
Day 
15 
(2 
days)
Day 
29 (3 
days)
Day 
43 (3 
days)
Day 57 
(3 
days)
2 weeks 
post-last 
dose (3 
days)
Subjects who withdraw early from the 
study should complete the Day 57 visit 
assessments and subsequently enter 
follow-up period.
Visits at Day 8 and Day 43 do not need to 
be clinic visits. Indicated information can 
be collected via a phone call with the 
subject.
Screening and Safety assessments
Informed consent
X
Inclusion and exclusion criteria
X
X
Demography
X
Medical history/family history (includes 
substance usage, CV medical history and 
family history of premature CV disease)
X
Substances: Drugs, alcohol and tobacco
Prior and Concomitant Medication review 
(including prior therapy for psoriasis)
X
X
X
X
X
X
Fitzpatrick Skin Type Classification
X
Brief physical exam (including height and 
weight)
X
X
Brief physical exam including weight only 
on Day 57
12-lead Electrocardiogram
X
X
X
X
Triplicate ONLY if first reading is outside 
the eligibility criteria threshold value or 
the stopping criteria threshold value.
Vital sign
X
X
X
X
X
Vital signs include heart rate, blood 
pressure and oral temperature. Ideally, 
heart rate and blood pressure will be 
obtained after the subject has been 
resting in a seated or supine position for 
at least 5 minutes.


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Procedure 
Screening
Treatment Period
Follow-up
Notes
Study Days (± specified no. of days)
Day –28 to 
-1
Day 1 
(Basel
ine)
Day 8 
(2 
days) 
Day 
15 
(2 
days)
Day 
29 (3 
days)
Day 
43 (3 
days)
Day 57 
(3 
days)
2 weeks 
post-last 
dose (3 
days)
Subjects who withdraw early from the 
study should complete the Day 57 visit 
assessments and subsequently enter 
follow-up period.
Visits at Day 8 and Day 43 do not need to 
be clinic visits. Indicated information can 
be collected via a phone call with the 
subject.
HIV, Hep B and Hep C screen
X
If test otherwise performed within 3 
months prior to first dose of study 
treatment, testing at screening is not 
required
Urine pregnancy test (FNRP)
X
Laboratory assessments (include liver 
chemistries) and urinalysis
X
X
X
X
X
Urinalysis: On Days 1, 29, and 57, urine 
PK sample can be used.
AE/SAE review
X
X
X
X
X
X
X
Visits at Day 8 and Day 43 do not need to 
be office visits. This information may be 
collected via a phone call with the 
subject. On these days subject will be 
asked about application site tolerability 
also.  
Application site tolerability
X
X
X
X
See Section 7.5.7.
Enrollment to study
Identify and mark target lesion for TPSS
X
Identify and mark area for biopsy collection
X
Dispense tubes of study treatment
X
X
X
Study treatment application
---------------------------------------------------
On clinic visit days, the morning 
application will be done in the clinic
Review compliance diary
X
X
X
X
X
Subjects will use a diary to record daily 
applications of study treatment and 
reasons for any missed applications
On Day 8 and Day 43, subjects will be 
asked about compliance via phone. 
Collect and weigh tubes of study treatment
X
X
X
X
Efficacy assessments


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Procedure 
Screening
Treatment Period
Follow-up
Notes
Study Days (± specified no. of days)
Day –28 to 
-1
Day 1 
(Basel
ine)
Day 8 
(2 
days) 
Day 
15 
(2 
days)
Day 
29 (3 
days)
Day 
43 (3 
days)
Day 57 
(3 
days)
2 weeks 
post-last 
dose (3 
days)
Subjects who withdraw early from the 
study should complete the Day 57 visit 
assessments and subsequently enter 
follow-up period.
Visits at Day 8 and Day 43 do not need to 
be clinic visits. Indicated information can 
be collected via a phone call with the 
subject.
Psoriasis Symptom Diary
X
X
X
X
X
To be completed by subject before any 
other assessments at a clinic visit
Target Plaque Severity Score (TPSS)
X
X
X
X
X
Physician Global Assessment (PGA)
X
X
X
X
X
Psoriasis Area Severity Index (PASI)
X
X
X
X
%BSA affected
X
X
X
X
X
%BSA treated
X
X
X
X
Pharmacokinetics
Plasma sample for GSK2981278
X
X
X
X
Day 1, Day 29, and Day 57: pre-dose, 
and 1h, 2h, 4h, 6h, 8h, and 10h post 
morning dose
Day 15: pre-dose and 2h post morning 
dose
Plasma sample for metabolite(s)
X
X
Pre-dose, and 1h, 2h, 4h, 6h, 8h, and 
10h post morning dose.
Urine sample for metabolite(s)
X
X
Pre-dose urine on Day 1, 0-10h pool
Two aliquots to be made for metabolite 
analysis and urinalysis. See Section 7.6.2
Other assessments
Skin punch biopsy
X
X
4 mm biopsy before study treatment 
application.
2 at Baseline (1 from non-lesional skin;1 
from lesional skin-both for gene 
expression analyses)
2 at Day 57 (1 from lesions skin for gene 
expression analyses;1 from lesional skin  
for drug level)


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Procedure 
Screening
Treatment Period
Follow-up
Notes
Study Days (± specified no. of days)
Day –28 to 
-1
Day 1 
(Basel
ine)
Day 8 
(2 
days) 
Day 
15 
(2 
days)
Day 
29 (3 
days)
Day 
43 (3 
days)
Day 57 
(3 
days)
2 weeks 
post-last 
dose (3 
days)
Subjects who withdraw early from the 
study should complete the Day 57 visit 
assessments and subsequently enter 
follow-up period.
Visits at Day 8 and Day 43 do not need to 
be clinic visits. Indicated information can 
be collected via a phone call with the 
subject.
Biopsy wound assessment
X
X
Photograph of target lesion
X
X


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7.2.
Time and Events table for Part B
Procedure 
Screening
Treatment Period
Follow-up
Notes
Study Days (± specified no. of days)
Day –28 
to -1
Day 1 
(Baseline)
Day 8 
(2 
days)
Day 15 
(2 
days)
Day 
29
(3 
days)
Day 
43 
(3 
days)
Day 
57 
(3 
days)
2 weeks post-
last dose (3 
days)
Subjects who withdraw early from the 
study should complete the Day 57 visit 
assessments and subsequently enter 
follow-up period.
Visits at Day 8 and Day 43 do not 
need to be clinic visits. Indicated 
information can be collected via a 
phone call with the subject.
Screening and Safety assessments
Informed consent
X
Inclusion and exclusion criteria
X
X
Will be assessed prior to 
randomization
Demography
X
Medical history/family history (includes 
substance usage, CV medical history and 
family history of premature CV disease)
X
Substances: Drugs, alcohol and 
tobacco
Prior and Concomitant Medication review
(including prior therapy for psoriasis)
X
X
X
X
X
X
Fitzpatrick Skin Type Classification
X
Brief physical exam (including height and 
weight)
X
X
Brief physical exam including weight 
on D57
12-lead Electrocardiogram
X
X
X
X
Vital sign
X
X
X
X
X
Vital signs include heart rate, blood 
pressure and oral temperature. Ideally, 
heart rate and blood pressure will be 
obtained after the subject has been 
resting in a seated or supine position 
for at least 5 minutes.
HIV, Hep B and Hep C screen
X
If test otherwise performed within 3 
months prior to first dose of study 
treatment, testing at screening is not 
required


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Procedure 
Screening
Treatment Period
Follow-up
Notes
Study Days (± specified no. of days)
Day –28 
to -1
Day 1 
(Baseline)
Day 8 
(2 
days)
Day 15 
(2 
days)
Day 
29
(3 
days)
Day 
43 
(3 
days)
Day 
57 
(3 
days)
2 weeks post-
last dose (3 
days)
Subjects who withdraw early from the 
study should complete the Day 57 visit 
assessments and subsequently enter 
follow-up period.
Visits at Day 8 and Day 43 do not 
need to be clinic visits. Indicated 
information can be collected via a 
phone call with the subject.
Urine pregnancy test (FNRP) 
X
Laboratory assessments (include liver 
chemistries) and urinalysis
X
X
X
X
X
Genetic sample 
X
Informed consent for optional,genetic 
research must be obtained before 
collecting a sample.
Pre-dose & post-randomisation
AE/SAE review
X
X
X
X
X
X
X
Visits at Day 8 and Day 43 do not 
need to be office visits.  This 
information may be collected via a 
phone call with the subject. On these 
days subject will also be asked about 
application site tolerability.  
Application site tolerability
X
X
X
X
See Section 7.5.7.
Enrollment to study
Identify and mark target lesion for TPSS
X
Randomisation
X
Dispense tubes of study treatment
X
X
X
Study treatment application
---------------------------------------------------
On clinic visit days, the morning 
application will be done in the clinic
Review compliance diary
X
X
X
X
X
Subjects will use a diary to record daily 
applications of study treatment and 
reasons for any missed applications.
On Day 8 and Day 43, subjects will be 
asked about compliance via phone or 
text message.
Collect and weigh tubes of study treatment
X
X
X
X


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Procedure 
Screening
Treatment Period
Follow-up
Notes
Study Days (± specified no. of days)
Day –28 
to -1
Day 1 
(Baseline)
Day 8 
(2 
days)
Day 15 
(2 
days)
Day 
29
(3 
days)
Day 
43 
(3 
days)
Day 
57 
(3 
days)
2 weeks post-
last dose (3 
days)
Subjects who withdraw early from the 
study should complete the Day 57 visit 
assessments and subsequently enter 
follow-up period.
Visits at Day 8 and Day 43 do not 
need to be clinic visits. Indicated 
information can be collected via a 
phone call with the subject.
Efficacy assessments
Psoriasis Symptom Diary
X
X
X
X
X
To be completed by subject before any 
other assessments at a clinic visit
Target Plaque Severity Score (TPSS)
X
X
X
X
X
Physician Global Assessment (PGA)
X
X
X
X
X
Psoriasis Area Severity Index (PASI)
X
X
X
X
%BSA affected
X
X
X
X
X
%BSA treated
X
X
X
X
Pharmacokinetics
Plasma sample for GSK2981278
X
X
X
X
Day 1: between 3 and 12h post 
morning dose
Day 15: pre-dose
Days 29 and 57: within 12 h of 
morning dose
Other assessments
Photograph of target lesion
X
X


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7.3.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
The subject’s Fitzpatrick skin type (Table 3) will be documented.
Table 3
Fitzpatrick Skin Type Classification
Type 
Constitutive Skin Color (Unexposed) and 
Typical Characteristics 
Response to Ultraviolet Light 
Exposure 
I 
White; very fair; red or blond hair; blue eyes; 
freckles 
Always burns, never tans 
II 
White; fair; red, blond, or brown hair; hazel or 
green eyes 
Usually burns, tans with 
difficulty 
III 
White; any eye or hair color; very common 
Sometimes mild burn, gradually 
tans 
IV 
White or light brown; typical Mediterranean 
Caucasian skin 
Rarely burns, tans with ease 
V 
Brown; mid-eastern skin types 
Very rarely burns, tans very 
easily 
VI 
Black 
Never burns, tans very easily 
Source: Based on the characteristics originally described in Fitzpatrick, 1988
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5. Known drug allergies will be captured in the eCRF. 
Screening procedures should not commence until after all relevant study approvals have 
been obtained and until after the informed consent has been signed. The investigator must 
maintain a subject screening log to document identification of subjects who signed the 
informed consent document.
Psoriasis Symptom Diary should be completed by subjects before any other assessment at 
a clinic visit, in the order specified (Appendix 5). 
Photographic documentation of the target lesion will be collected at baseline and Day 57. 
Information on the photographic procedure is available in the SRM.
7.4.
Efficacy
All efficacy assessments should be performed by the same investigator or designated 
evaluator for an individual subject. In the event the same evaluator is not available for the 
duration of the study, another investigator or designated evaluator with comparable 
training will perform the assessments.


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7.4.1.
Target Plaque Severity Score (TPSS)
A target lesion of at least 9 cm2 with a TPSS 5 and an induration subscore 2 will be 
selected at baseline. The severity of erythema, scaling, and induration (plaque thickness) 
will be assessed by the investigator on a 5-point scale ranging from 0=none to 4=very 
marked (Appendix 4). A total score will be calculated by adding the individual scores 
(13-point scale; maximum score 12). TPSS is the primary measure of clinical effect for 
this study.
7.4.2.
Physician Global Assessment (PGA)
The PGA is a clinical tool for assessing the current state/severity of a subject’s psoriasis 
(Appendix 3). It is a static 5-point morphological assessment of overall disease severity, 
as determined by the investigator, using the clinical characteristics of erythema, plaque 
thickness, and scaling as guidelines. At each specified time point, the PGA is made 
without reference to previous scores. Variations of the PGA are frequently used in 
clinical studies because it is a simple assessment that is more similar to the assessments 
actually used in clinical practice [Feldman, 2005]. PGA will be assessed on the entire 
treated area (i.e. including the scalp lesion, if applicable).
7.4.3.
Psoriasis Area and 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 scale, as well as the extent of BSA affected with psoriasis [Feldman, 
2005] [Appendix 7]. The 3 clinical signs are each graded on a 5-point scale (0 to 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 individual scores are 
multiplied by a weighted factor for each body region; the sum of these scores gives the 
overall PASI score. Higher scores indicate more severe disease. PASI is a static 
assessment made without reference to previous scores.
7.4.4.
Body surface Area (BSA)
The extent of BSA affected by psoriasis is a general indicator of disease severity and will 
be measured throughout the study. The extent of BSA to which study treatment is applied 
will also be recorded. It is suggested, for the purpose of approximate clinical estimation, 
the total palmar surface area of the palm plus five digits be assumed to be approximately 
equivalent to 1% BSA. See Appendix 2.
7.5.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1 and Section 7.2).  Additional time points for safety tests may be added 
during the course of the study based on newly available data to ensure appropriate safety 
monitoring.


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Safety will be assessed by the monitoring and recording of all AEs and SAEs; evaluation 
of application site tolerability; monitoring of hematology, clinical chemistry, urinalysis 
and vital signs; and the performance of ECGs and physical examinations.
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 8
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.5.1.1.
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. 

AEs will be collected from the start of study treatment until the follow-up contact 
(Section 7.5.1.3), at the timepoints specified in the Time and Events Table 
(Section 7.1 and Section 7.2).

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 8.

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 8
7.5.1.2.
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?” 


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7.5.1.3.
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 8.
7.5.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 8 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular 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.
This information should be recorded in the specific Cardiovascular or Death section of 
the CRF within 1 week of when the AE/SAE(s) or Death is first reported.
7.5.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee 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.
7.5.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until 2 weeks post-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 9. 


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7.5.3.
Physical Exams

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen) and a measurement 
of weight. Height will be also measured and recorded at Screening.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses
7.5.4.
Electrocardiogram (ECG)
Single 12-lead ECGs will be obtained at each timepoint during the study using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  QTcB will be utilized for this study. If QTcB is outside the threshold value of 
the eligibility criteria or stopping criteria, triplicate ECGs will be performed over a brief 
(e.g. 5 to 10 minutes) recording period with the QTcB values averaged. Refer to Section 
5.4.2 for QTc stopping criteria.
7.5.5.
Vital Signs

Vital signs will be measured in seated or supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure and pulse rate. 

Three readings of blood pressure and pulse rate will be taken

First reading should be rejected

Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
7.5.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 4, 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 SRM OR 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 SRM 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 local laboratory, apart 
from liver events monitoring which will be performed by the central laboratory. The 
results of each test must be entered or electronically transferred into the eCRF.


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Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 4. 
Table 4
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
Blood Urea 
Nitrogen 
(BUN)
Potassium
Aspartate amino-
transferase (AST) 
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
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 (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Urine hCG Pregnancy test (at Screening for women of non-child 
bearing potential) 
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 5.4.1 and 
Appendix 6.
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.


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7.5.7.
Application Site Tolerability
The investigator or designated evaluator will assess application site tolerability focusing 
on the treated non-lesional skin surrounding the plaques at each visit using the 5-point 
tolerability assessment scale presented in Table 5. Refer to Section 5.4.3 for topical 
application site tolerability stopping criteria.
Table 5
Topical Application Site Tolerability Assessment Scale
Grade
Severity
Description
0
None
No evidence of local intolerance
1
Mild
Minimal erythema and/or edema, slight glazed appearance
2
Moderate
Definite erythema and/or edema with peeling and/or 
cracking
3
Severe-To be reported 
as an AE
Erythema, edema glazing with fissures, few vesicles or 
papules: Remove and discontinue study treatment
4
Very Severe-To be 
reported as an AE
Strong reaction spreading beyond the treated area, bullous 
reaction, erosion: Remove and discontinue study treatment
7.6.
Pharmacokinetics
7.6.1.
Blood Sample Collection
Blood samples for PK analysis of GSK2981278 and related metabolite(s) will be 
collected at the time points indicated in Section 7.1 and Section 7.2, 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.  
Blood samples will be collected into 2 EDTA tubes, each containing 3 mL of blood: one 
for GSK2981278 and another for related metabolite(s).
Details of PK blood sample collection, processing, storage and shipping procedures are 
provided in the SRM. 
7.6.2.
Urine Sample Collection
Urine samples for analysis of GSK2981278 and related metabolite(s) will be collected at 
the timepoints listed in Section 7.1, Time and Events Table.  The timing of urine samples 
may be altered and/or samples may be obtained at additional time points to ensure 
thorough PK monitoring.
Total urine voided will be collected over the period of collection as specified in Section 
7.1.
Details of PK urine sample collection, processing, storage and shipping procedures are 
provided in the SRM.


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7.6.3.
Skin Sample Collection
Skin samples for evaluation of drug delivery will be collected at Day 57 by taking a 
4 mm punch biopsy from the area of psoriatic plaque identified for skin biopsies at 
baseline.
Details of PK skin sample processing, storage and shipping procedures are provided in 
the SRM.
Additional skin samples will be collected for gene expression analyses. See Section 7.7.1
for details.
7.6.4.
Sample Analysis
Plasma analysis will be performed under the control of PTS-IVIVT-BIB/TPR, 
GlaxoSmithKline, the details of which will be included in the SRM. Concentrations of 
GSK2981278 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).
Plasma will also be analyzed for other compound-related metabolites and the results 
reported under a separate PTS-PDS-ASD, GlaxoSmithKline protocol. Raw data will be 
archived at the GlaxoSmithKline.
Analysis of urine sample analysis will be performed under the control of PTS-PDS-ASD, 
GlaxoSmithKline.  Urine will be analyzed for GSK2981278 and other compound-related 
metabolites and the results will be reported under a separate PTS-PDS-ASD, 
GlaxoSmithKline protocol. Raw data will be archived at GlaxoSmithKline.
Skin biopsy samples analysis will be performed under the control of PTS-IVIVT-
Bioimaging, GlaxoSmithKline.  Skin biopsy samples may be analyzed for concentrations 
of GSK2981278 and compound-related metabolites using MALDI imaging or HPLC-MS 
and the results will be reported under a separate PTS-IVIVT-Bioimaging, GSK protocol.  
Raw data will be archived at GSK.
7.7.
Biomarker(s)/Pharmacodynamic Markers
7.7.1.
Novel Biomarkers
Skin samples for biomarker analyses will be collected at Baseline and Day 57.
With the subject’s consent, a total of 3 4-mm punch skin biopsies will be taken from each 
subject for biomarker analyses in Part A of this study: 1 from non-lesional skin at 
baseline, 1 from lesional skin at baseline and 1 at Day 57 from the treated skin of the 
same plaque where the baseline biopsy was taken.  Skin sample(s) may be used for the 
purposes of measuring novel biomarkers to identify factors that may influence psoriasis 
as well as the biological and clinical responses to GSK2981278.  
Samples will be collected at the timepoints indicated in Section 7.1.


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Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with psoriasis and/or the action of GSK2981278 may be identified by 
application of:

RNA transcriptome analysis of skin samples.

Measurement of the levels of mRNA in skin samples.
Details of skin sample storage are provided in the SRM.
7.7.1.1.
RNA Transcriptome Research
Transcriptome studies will be conducted using microarray, which facilitates the 
simultaneous measurement of the relative abundances of thousands of RNA species 
resulting in a transcriptome profile for each skin sample.  This will enable the evaluation 
of changes in transcriptome profiles that may correlate with biological response relating 
to psoriasis or the action of GSK2981278.
The same samples may also be used to confirm findings by application of alternative 
technologies.
7.7.1.2.
RNA Expression Research of a Subset of RNA Species
RNA expression studies will be conducted using quantitative RT-PCR technologies. The 
RNAs assayed will be those expected to be modulated by GSK2981278.  These 
biomarkers include IL-17A, IL-17F, DEFB4A, IL-19, IL-36, CCL20, S100A7a, IL-8, IL-
22, RORC and Krt6A. This will enable the evaluation of changes in RNA expression 
profiles that may correlate with biological response relating to psoriasis or the action of 
GSK2981278.
7.8.
Genetics
Information regarding genetic research is included in Appendix 10
7.9.
Value Evidence and Outcomes
7.9.1.
Psoriasis Symptom Diary
The Psoriasis Symptom Diary was developed to assess daily self-reports of psoriasis 
symptoms and the functional impact related to the underlying pathophysiology of the 
disease [Strober, 2013]. Questions about how severe and how bothersome various signs 
and symptoms are to the subject are answered using an 11-point numerical rating scale 
(Appendix 5). In this study, subjects will be asked to complete the Psoriasis Symptom 
Diary questionnaire at the clinic during the scheduled visits.


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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK/bioskin defined eCRFs, 
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.  

eCRFs (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
Refer to the reporting and analysis plan (RAP)/statistical analysis plan (SAP) for 
additional details regarding data analyses. Reporting will be performed in accordance 
with applicable GSK and/or contract research organization (CRO) standards.
9.1.
Hypotheses
No formal hypothesis tests are planned. Descriptive statistics will be used to assess the 
key objectives of this study: evaluation of safety, tolerability, systemic exposure and 
clinical effect of topically applied GSK2981278 ointment in subjects with plaque 
psoriasis.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Sample size is based on feasibility and the estimated number of subjects expected to 
provide reasonable information on the key objectives of the study.
For Part A:
Summary statistics, such as mean % of reduction in TPSS, mean % reduction in PGA and 
mean % of reduction in PASI will be estimated. With 8 evaluable subjects, precisions on 
these estimates are assessed as below.


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Endpoint
Assumptions
Sample Size
95%CI estimate
Mean % reduction in 
TPSS
50% reduction with 20% standard 
deviation will be observed
N=8
33.3% - 66.7% 
Mean % reduction in 
PGA
50% reduction with 30% standard 
deviation will be observed
N=8
24.9%-75.1%
Mean % reduction in 
PASI
50% reduction with 25% standard 
deviation will be observed
N=8
29.1% -70.9%
For Part B:
With 15 subjects (10 in GSK2981278 arm and 5 in the Vehicle arm), the power to detect 
difference between GSK2981278 arm and the vehicle arm in terms of TPSS reduction, 
and PASI reduction are assessed below:
Endpoint
Assumptions
Sample Size 
(API:Vehicle)
Power to reject* 
H0: API=Vehicle 
(Alpha=5%)
Mean % 
reduction in 
TPSS
50% reduction in GSK arm and 20% 
reduction in Vehicle with 20% standard 
deviation will be observed
N=10:5
71.7% 
Mean % 
reduction in 
PASI
50% reduction in GSK arm and 10% in 
Vehicle with 20% standard deviation 
will be observed
N=10:5
92.1%
*2-sample t test
API- Active Pharmaceutical Ingredient
9.2.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation or adjustment is planned.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Per Protocol (PP) analysis set will include all randomized subjects who comply closely
with the protocol (e.g. have sufficient exposure). PP analysis set details will be defined in
the RAP/SAP. The PP analysis set will be the primary set for efficacy analyses. 
Safety analysis set will include all subjects exposed to at least 1 application of study 
product. The safety analysis set will be the primary set for safety analyses. 
Pharmacokinetic (PK) analysis set will include subjects with at least one sample collected 
and analyzed for plasma drug concentration. The PK analysis set will be the primary set 
for PK analyses.


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9.3.2.
Interim Analysis
No interim analysis is planned.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
Safety and tolerability analyses:
Extent of exposure will be summarized. A by-subject listing of data on subject exposure 
to study drug will be produced. AEs will be tabulated according to the current version of 
MedDRA. Frequencies and percentages will be presented overall, for each system organ 
class, and for each preferred term. Summaries of treatment-emergent AEs, treatment-
related AEs, AEs leading to discontinuation of study product applications, and SAEs will 
be completed. AE onset, severity, relationship to study product, action taken, and 
outcome will be listed by subject.
Each quantitative laboratory test will be summarized at every scheduled time point. The 
number of subjects with abnormal values based on values relative to the laboratory 
normal ranges will be summarized for each assessed time point. A listing of laboratory 
data for subjects with values out of the laboratory normal range will be provided.
Vital sign value and change from baseline at Week 8 for each vital sign parameter will be 
summarized using descriptive statistics. A listing of vital signs and a listing of change 
from baseline for vital signs will be provided. 
ECG value and change from baseline at every scheduled time point for each ECG 
parameter will be summarized using descriptive statistics. The ECG will be evaluated by 
the investigator as “Normal”, “Abnormal, not clinically significant”, and “Abnormal, 
clinically significant”. A summary of ECG findings will be provided. Also, a listing of 
ECG values and a listing of ECG findings will be generated. 
If applicable, liver event data will be listed.
Systemic exposure/Pharmacokinetic Analyses (Part A):
Plasma concentrations of GSK2981278 will be determined. For Part A, if the 
concentration data permits, the following PK parameters will be calculated: AUC(0-t),  
AUC(0-), Cmax, tmax, and half-life (t1/2), steady state assessments such as Cand R0.  
Clinical effect analyses (Part B):
Mean percentage change in TPSS, PGA and PASI scores from baseline to each study 
visit will be summarized based on the per protocol analysis set. 
The data may also be summarized using the following measures as needed:


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
proportion of subjects who achieve a PGA score of 0 or 1 and a minimum 2-grade 
improvement from baseline to each study visit

proportion of subjects with ≥50% improvement in PASI from baseline to each 
study visit

change in PASI from baseline to each study visit
In addition, statistical comparisons may be made as necessary between GSK arm and the 
Vehicle arm for mean percentage change from baseline to Week 8 in terms of TPSS, 
PGA and PASI score. 
9.4.2.
Secondary Analyses
Secondary analyses will be the clinical effect analyses for Part A. Clinical effect data 
will be summarized using both the Observed Cases (OC) approach and the last 
observation carried forward (LOCF) approach if there are missing values.
Mean percentage change in TPSS, PGA and PASI scores from baseline to each study 
visit will be summarized based on the per protocol analysis set.
The data may also be summarized using the following measures as needed:

proportion of subjects who achieve a PGA score of 0 or 1 and a minimum 2-grade 
improvement from baseline to each study visit 

proportion of subjects with ≥75% improvement in PASI from baseline to each 
study visit 

proportion of subjects with ≥50% improvement in PASI from baseline to each 
study visit 

change in PASI from baseline to each study visit 
9.4.3.
Other Analyses
Additional analyses may be performed as described in the RAP/SAP.


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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
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH GCP and 
applicable country-specific regulatory requirements.
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 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:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

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 


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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 
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 


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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, 
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.


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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 Part B 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.


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11.
REFERENCES
Brackett, C. Sulfonamide allergy and cross-reactivity. Curr Allergy Asthma Rep
2007;7:41-48.
DeKorte J, Sprangers MA, Mombers FM, Bos JD. Quality of life in patients with 
psoriasis:a systematic literature review. J Investig Dermatol Symp Proc. 2004;9:140-147. 
Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 
2005;64:65-68. 
Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through IV. Arch 
Dermatol. 1988;124(6):869-871. 
GlaxoSmithKline Document Number 2016N286376_00. Investigator's Brochure. Report 
Date 16-Jul-2016. 
Gordon K.  Ixekizumab for Treatment of Moderate-to-Severe Plaque Psoriasis: 60-week 
Results from a Double-Blind Phase 3 Induction and Randomized Withdrawal Study 
(UNCOVER-1). AAD 2015 Late-breaking abstract F010.
Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet
2007;370:263-71.
He YW, Deftos ML, Ojala EW, Bevan MJ. RORt, a novel isoform of an orphan 
receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. 
Immunity1998;9(6):797-806.
Ivanov II. The orphan nuclear receptor RORt directs the differentiation program of 
proinflammatory IL-17+ T helper cell. Cell 2006;126(6):1121-1133.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Langley RG. Secukinumab in plaque psoriasis-Results of two phase 3 trials. N Engl J 
Med 2014;371(4):326-338.
Lebwohl, M. AMAGINE-2: A Randomized, Double-blind, Phase 3 Efficacy and Safety 
Study of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe 
Plaque Psoriasis Patients.  AAD 2015 Late-breaking abstract F010.
Lynde CW. Interleukin 17A: Toward a new understanding of psoriasis pathogenesis. J 
Am Acad Dermatol 2014;71:141-150.
Malakouti M. The role of IL-17 in psoriasis. J Dermatolog Treat 2015;26 (1):41-44.
Menter A. Guidelines of care for the management of psoriasis and psoriatic arthritis. J
Am Acad Dermatol 2009;60:643-59.


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Nestle FO. Psoriasis. N Engl J Med 2009;361(5):496-509.
Parisi R Global epidemiology of psoriasis: a systematic review of incidence and 
prevalence. J Invest Dermatol 2013;133:377-385.
Sandoval LF, Williams B, Feldman SR. Clinical potential of brodalumab in the 
management of psoriasis: the evidence to date. Psoriasis: Targets and Therapy. 
2015;5:35-41.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.
Strober BE, Nyirady J, Mallya UG, Guettner A, Papavassilis C, Gottlieb AB. Item-level 
psychometric properties for a new patient reported Psoriasis Symptom Diary. Value 
Health. 2013;16:1014-1022
Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between 
sulphonamide antibiotics and sulphonamide nonantibiotics. N Engl J Med
2003;346:1628-35.


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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
API
Active pharmaceutical ingredient
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BID
Twice daily
BSA
Body surface area
BUN
Blood urea nitrogen
cm2
Centimeter squared
Cmax
Maximum plasma concentration
CRF
Case report form
CV
Cardiovascular
ECGs
Electrocardiograms
eCRF
Electronic case report form
FNRP
Females of non-reproductive potential
FRP
Females of reproductive potential
FTIH
First time in humans
GCP
Good clinical practice
GSK
GlaxoSmithKline
h
Hour
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
hERG
Human ether-a-go-go related gene
HIV
Human immunodeficiency virus
HPA
Hypothalamic-Pituitary-Adrenal
HRT
Hormone replacement therapy
IB
Investigator’s brochure
ICH
International conference on harmonisation of technical 
requirements for registration of pharmaceuticals for human 
use
IEC
Independent ethics committee
IFN-
Interferon-gamma
INR
International normalized ratio
IRB
Institutional review board
kg
kilogram
m2
meter squared
mAb
Monoclonal antibody
MALDI
Matrix Assisted Laser Desorption Ionization
Max
Maximum
MCH
Mean corpuscular hemoglobin


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MCV
Mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
mg
milligram
Min
minimum
mL
milliliter
mRNA
Messenger ribonucleic acid
msec
millisecond
ng
nanogram
NOAEL
No observed adverse effect level
PASI
Psoriasis area and severity index
PD
Pharmacodynamic
PGA
Physician’s global assessment of improvement
PI
Prediction interval
PK
Pharmacokinetic
PP
Per protocol
PTS
Platform technology and science
QTc
Corrected QT interval
QTcB
Corrected QT interval using Bazett’s formula
RAP
Reporting and analysis plan
RBC
Red blood cell
ROR
Retinoic acid receptor-related orphan receptor gamma
SAE
Serious adverse event
SAP
Statistical analysis plan
SRM
Study reference manual
Th-17
Type 17 helper T-cell
TPSS
Target plaque severity score
g
microgram
ULN
Upper limit of normal
M
micromolar
UV
Ultraviolet
WBC
White blood cell
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None


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12.2.
Appendix 2: Body Surface Area
Assessment of body surface area with Psoriasis will be performed separately for four 
body surface regions: the head (h), the upper extremities (u), the trunk (t), and the lower 
extremities (l), corresponding to 10, 20, 30, and 40% of the total body area, respectively.
Body Region
Surface Area of Body Region
head (h)
10%
upper extremities (u)
20%
trunk (t)
30%
lower extremities (l)
40%
12.2.1.
Reference
Finlay A.Y., Current Severe Psoriasis and the Rule of Tens. British J. of Dermatology. 
2005;152:861-867.


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12.3.
Appendix 3: Physician Global Assessment (PGA)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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12.4.
Appendix 4: Target Plaque Severity Score (TPSS)
Score
Scaling 
Erythema 
Induration 
0
None
No evidence of scaling 
No evidence of erythema; 
hyperpigmentation may be 
present 
No elevation over normal 
skin 
1
Slight
Occasional fine scale 
over less than 5% of 
the lesion 
Faint erythema 
Possible but difficult to 
ascertain whether there is 
a slight elevation above 
normal skin 
2
Moderate
Fine scales 
predominate 
Light red coloration 
Slight but definite 
elevation, typically edges 
are indistinct or sloped 
3
Marked
Coarse scales 
predominate 
Moderate red coloration 
Moderate elevation with 
rough or sloped edges 
4
Very marked
Very thick tenacious 
scale predominates 
Dusky to deep red 
coloration 
Very marked elevation 
typically with hard sharp 
edges
12.4.1.
References
Menter A, Papp KA, Tna H, Tyring S, Wolk R, Buonanno M. Efficacy of tofacitinib, an 
oral janus kinase inhibitor, on clinical signs of moderate-to-severe plaque psoriasis in 
different body regions. J Drugs Dermatol 2014;13(3):252-256.
Ports WC, Khan S, Lan S, Lamba M, Bolduc C, Bissonnette R, Papp K. A randomized 
phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitiib in the 
treatment of chronic plaque psoriasis. Br J Dermatol 2013;169:137-145.


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12.5.
Appendix 5: Psoriasis Symptom Diary
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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12.6.
Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments
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 
treatment and may continue subject in the study 
for any protocol specified follow-up 
assessments 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 12 hours 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 
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


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Liver Chemistry Stopping Criteria – Liver Stopping Event
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
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]). Liver imaging 
(ultrasound, magnetic resonance, or 
computerized 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.
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.  


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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
12.6.1.
Reference
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.7.
Appendix 7: Psoriasis Area and Severity Index (PASI)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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12.8.
Appendix 8: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.8.1.
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 


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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.
12.8.2.
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 
normal life functions.


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
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.
12.8.3.
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

Valvulopathy

Pulmonary hypertension


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
Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.8.4.
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 Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes 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
12.8.5.
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.


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
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.
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 


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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.
12.8.6.
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 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.


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12.9.
Appendix 9: 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 8. 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 discontinue study 
medication or 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. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.


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12.10.
Appendix 10 - 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 GSK2981278 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 


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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). 
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 
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. 


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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.
12.10.1.
References
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. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.


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12.11.  Appendix 11-Protocol Changes 
Protocol Amendment 1: 13 December 2016 
App
l
icab
le to a
l
l sub
jects. 
 
Sect
ion  
Or
ig
ina
l Text 
Changes 
Rat
iona
le 
Med
ica
l 
Mon
itor/Sponsor 
Informat
ion 
Page 
 
 
1250 South Co
l
legev
i
l
le Rd, 
Co
l
legev
i
l
le, PA 19426 
(UP4300) 
 
 
1250 South Co
l
legev
i
l
le Rd, 
Co
l
legev
i
l
le, PA 19426 
(UP1410), USA 
Updated pr
imary 
med
ica
l mon
itor
’s 
fax number and 
address 
1 and 3 
 
 
 
 
 
 
Ident
if
icat
ion of any compound-
der
ived metabo
l
ite(s) from 
p
lasma and ur
ine  
 
 
 
 
To eva
luate the ur
inary 
e
l
im
inat
ion of GSK2981278 
after top
ica
l app
l
icat
ion 
in 
subjects w
ith p
laque 
psor
ias
is/Ur
ine concentrat
ion 
of GSK2981278 
Ident
if
icat
ion of any compound-
der
ived metabo
l
ite(s) from 
p
lasma and ur
ine and if 
possible estimation of relative 
amounts of drug related 
material 
 
Removed the exp
loratory ur
inary 
e
l
im
inat
ion eva
luat
ion ob
ject
ive 
and correspond
ing endpo
int from 
Part A Ob
ject
ive(s) and 
Endpo
int(s) 
C
lar
if
icat
ion that 
ur
ine samp
le 
is 
co
l
lected for ana
lys
is 
of metabo
l
ites and 
GSK2981278 for 
structure e
luc
idat
ion 
and not for abso
lute 
measurement of 
GSK2981278 
in 
ur
ine 
7.1 
 
Pharmacok
inet
ics  
Ur
ine samp
le  
 
 
0-10h poo
l 
Three a
l
iquots to be made for 
parent drug ana
lys
is, 
metabo
l
ite ana
lys
is and 
ur
ina
lys
is. See Sect
ion 7.6.2. 
 
N/A 
Pharmacok
inet
ic 
Ur
ine samp
le for metabolite 
analysis  
 
Pre-dose urine on Day 1, 0-10h 
poo
l 
Two a
l
iquots to be made for 
metabo
l
ite ana
lys
is and 
ur
ina
lys
is. See Sect
ion 7.6.2 
 
Removed ur
ine PK samp
le 
co
l
lect
ion at Day 29 
7.6.2  
Ur
ine samp
les for PK ana
lys
is 
of GSK2981278 and re
lated 
metabo
l
ite(s) 
Ur
ine samp
les for ana
lys
is of 
GSK2981278 and re
lated 
metabo
l
ite(s) 
4.1 
... reduct
ion of 40% or greater 
in TPSS and ... 
... reduct
ion of 40% or greater 
in 
TPSS from baseline and ... 
C
lar
if
icat
ion 
PPD
PPD
PPD
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Section
Original Text
Changes
Rationale
4.6.1
N/A
Added additional information 
related to the risk of ‘Skin 
irritation or allergic reaction to 
GSK2981278 or to components 
of its vehicle’: Line 6-line 13 
added to Summary of 
Data/Rational for Risk and line 5-
line 9 to Mitigation Strategy.
More complete risk 
assessment of 
GSK2981278
7.1
Screening 
Day -27 to 0
Screening
Day -28 to -1
Consistency with 
Part B Time and 
Events Table
7.2
N/A
Added vital signs assessment at 
the Screening Visit
Aligned with other 
safety assessments 
(ECG, labs, etc.)
7.2
N/A
Added “(including prior therapy 
for psoriasis)” to Prior and 
Concomitant Medication Review 
description
Consistency with 
Time and Events 
Table Part A 
description
7.5.5
...in supine or semi-supine
position...
...in seated or supine position...
Consistency with 
description in Time 
and Events Table
7.7.1
All samples will be retained for 
a maximum of 15 years after 
the last subject completes the 
trial.
Added “Details of skin sample 
storage are provided in the 
SRM.”
Correction and more 
appropriate placing 
of information
7.9.1
In addition to the 16 questions 
in the published instrument, 6 
questions have been added to 
assess the severity and bother 
of skin flaking, dryness and 
bleeding. 
Reference to 6 additional 
questions in Psoriasis Symptom 
Diary removed
Novartis did not 
approve modified 
PSD
12.5  Appendix 
5
N/A
Removed questions 17-22 from 
the Psoriasis Symptom Diary
9.2.1
Fisher’s Exact Test
2-sample t test
Correction
Throughout the 
protocol
Correction of 
typographical errors

SAP_001.pdf: 
1.1 
 
Statistical Analysis Plan 
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203820 SAP Version 1.0, October 12, 2017 
SOP ST/05, Template from 20120906 
 
Statistical Analysis Plan 
 
 
 
A two-part trial to evaluate the safety, tolerability, 
clinical effect and systemic exposure potential of 
topically applied GSK2981278 ointment in subjects 
with plaque psoriasis 
 
 
 
This statistical analysis plan is the property of bioskin GmbH. It may not be reproduced, distributed or otherwise used. The rights to the information in 
this analysis plan and the resulting trial first become the property of the sponsor when the contract stipulations have been fulfilled on the side of bioskin 
GmbH and the sponsor. 
 
bioskin GmbH  •  Burchardstrasse 17  •  20095 Hamburg  •  Germany 
 
Confidential 


1.1 
 
Statistical Analysis Plan 
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SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 _
___________________________________________  
Manager, Clinical Pharmacology, GlaxoSmithKline 
 
 
 
 
 
 ______________________________________________________________  
Senior Director, Clinical Statistics, GlaxoSmithKline 
 
 
 
 
 
 
____________________________________________________  
Manager, Clinical Programming, GlaxoSmithKline 
 
 
 
 
 
 ______________________________________________________________  
PhD 
Principal Statistician, Clinical Statistics, GlaxoSmithKline 
 
 
 
 
 
 ______________________________________________________________  
PhD 
Senior Clinical Trial Manager, bioskin GmbH 
 
 
 
 
 
 
_________________________________________  
Head Biostatistics, bioskin GmbH 
. 
PPD
PPD
PPD
PPD
PPD
PPD


1.1 
 
Statistical Analysis Plan 
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Table of contents 
1 
OVERVIEW ................................................................................................................. 7 
1.1 
Background / rationale ................................................................................................. 7 
1.2 
Objectives .................................................................................................................... 8 
1.3 
Modifications from the statistical section in the protocol ............................................... 9 
2 
INVESTIGATIONAL PLAN .......................................................................................... 9 
2.1 
Study design and randomization .................................................................................. 9 
2.2 
Sample size justification ............................................................................................. 11 
2.3 
Study plan .................................................................................................................. 13 
2.3.1 
Time and events table for Part A ................................................................................ 13 
2.3.2 
Time and events table for Part B ................................................................................ 16 
3 
STATISTICAL AND ANALYTICAL PROCEDURES ................................................. 19 
3.1 
Definitions .................................................................................................................. 19 
3.2 
Analysis variables ...................................................................................................... 24 
3.2.1 
Pharmacokinetic variables ......................................................................................... 24 
3.2.2 
Pharmacodynamic variables ...................................................................................... 24 
3.2.3 
Efficacy variable(s) ..................................................................................................... 25 
3.2.4 
Safety variables ......................................................................................................... 30 
3.3 
Analysis populations .................................................................................................. 33 
3.3.1 
Efficacy population ..................................................................................................... 33 
3.3.2 
Safety population ....................................................................................................... 34 
3.3.3 
Pharmacokinetic population ....................................................................................... 34 
3.3.4 
Other populations ...................................................................................................... 34 
3.4 
Statistical methods ..................................................................................................... 34 
3.4.1 
Discontinuations, dropouts and analysis populations ................................................. 35 
3.4.2 
Demographics and baseline characteristics ............................................................... 35 
3.4.3 
Treatment compliance ............................................................................................... 35 
3.4.4 
Efficacy analyses ....................................................................................................... 36 
3.4.4.1 
Hypotheses ............................................................................................................ 36 
3.4.4.2 
Statistical analyses ................................................................................................. 36 
3.4.5 
Safety analyses ......................................................................................................... 36 
3.4.5.1 
Extent of exposure to study drug ............................................................................ 36 
3.4.5.2 
Adverse events....................................................................................................... 37 
3.4.5.3 
Laboratory analyses ............................................................................................... 37 
3.4.5.4 
ECG analyses ........................................................................................................ 37 
3.4.5.5 
Tolerability analyses ............................................................................................... 37 
3.4.5.6 
Other safety analyses ............................................................................................. 37 
(continued) 


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Table of contents (continued) 
3.4.6 
Pharmacokinetic analyses ......................................................................................... 38 
3.4.6.1 
Overview of planned pharmacokinetic analyses ..................................................... 38 
3.4.6.2 
Drug Concentration Measures ................................................................................ 38 
3.4.6.3 
Pharmacokinetic Parameters .................................................................................. 38 
3.5 
Data handling conventions ......................................................................................... 39 
3.5.1 
Missing data............................................................................................................... 39 
3.5.2 
Window for time points ............................................................................................... 40 
3.5.3 
Unscheduled visits ..................................................................................................... 40 
3.5.4 
Pooling of centers for statistical analyses ................................................................... 40 
3.5.5 
Statistical technical issues ......................................................................................... 40 
3.5.6 
Database related issues ............................................................................................ 40 
4 
INTERIM ANALYSIS ................................................................................................. 40 
5 
SOFTWARE DOCUMENTATION .............................................................................. 40 
6 
REFERENCES .......................................................................................................... 40 
 
 
 
 


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Abbreviations and definitions 
%CVb 
between subject coefficient of variation 
ACTH 
adrenocorticotropic hormone 
AE 
adverse events 
ALT 
alanine transaminase 
API 
active pharmaceutical ingredient  
AST 
aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
BMI 
body mass index 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CPMS 
Clinical Pharmacology Modelling and Simulation 
CRF 
case report form 
CTP  
clinical trial protocol 
CV 
cardiovascular 
D 
day 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FNRP 
female of non-reproductive potential 
g 
gram 
GI 
giga 
GSK 
GlaxoSmithKline 
H 
hour 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
Hep 
hepatitis  
HIV 
human immunodeficiency virus 
 
HPLC-MS 
High-performance liquid chromatography-mass spectrometry 
IMP 
investigational medicinal product 
L 
liter 
LLN 
lower limit of normal 
LOCF 
last observation carried forward 
msec 
millisecond 
MALDI 
matrix assisted laser desorption ionization 
Max 
maximum 
MedDRA 
medical dictionary for regulatory activities 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
Min 
minimum 
mmHg 
millimeter of mercury 
mol 
mole 


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mRNA 
messenger ribonucleic acid 
n 
non-missing observations  
NOAEL 
no observed adverse effect level 
OC 
observed cases 
PASI 
psoriasis area and severity index 
PCI 
potential clinical importance 
PD 
pharmacodynamic 
PDF 
portable document format 
PGA 
physician’s global assessment 
PK 
pharmacokinetic  
PP 
per protocol 
RBC 
red blood cells 
RNA 
ribonucleic acid 
RTF 
rich text format 
SAE 
serious adverse events 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
sec 
seconds 
ss 
steady state 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamate-pyruvate transaminase 
TEAE 
treatment emergent adverse event 
TPSS 
target plaque severity score 
ULN 
upper limit of normal 
U 
unit 
UV 
ultraviolet 
WBC 
white blood cells 
 
 
 


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Statistical Analysis Plan 
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1 Overview 
This Statistical Analysis Plan (SAP) is issued to provide a comprehensive and detailed 
description of strategy, rationale, and statistical technique that will be used to evaluate the 
safety, tolerability and systemic exposure of topically applied GSK2981278 in subjects with 
plaque psoriasis. 
The credibility of the study findings will be ensured by pre-specifying the statistical approaches 
to the analysis of the study data prior to unblinding of the randomization schedule. This SAP is 
based on the clinical trial protocol number 203820 (GSK document number 2016N275350_01), 
dated December 13, 2016. 
1.1 
Background / rationale 
In the first clinical trial of GSK2981278, once daily treatment of GSK2981278 ointment (at 
0.03%, 0.1%, 0.8%, and 4%) on small test fields (1.13 cm2) of stable plaque(s) over 19 days 
appeared to be well tolerated but did not show reduction in psoriatic infiltrate thickness.  It is 
unclear whether the apparent lack of effect on infiltrate thickness in the first-time-in-human study 
was due to the very small surface area treated, the relatively short duration of exposure, or both, 
therefore, the present study will evaluate the safety, tolerability, clinical effect, and systemic 
exposure potential of topically applied GSK2981278 ointment in subjects with plaque psoriasis 
by treating all plaques on the body wholly for 8 weeks.  The results of this study will provide 
preliminary information on the safety, tolerability, and effect of the GSK2981278 ointment on 
plaque psoriasis at the highest safe and feasible concentration to guide subsequent 
development strategy. 


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1.2 
Objectives 
Part A 
Objectives 
Endpoints 
Primary 
 To evaluate the safety and tolerability of 
topically applied GSK2981278 in subjects with 
plaque psoriasis 
 
 
 Incidence and nature of adverse events (AEs) 
and serious adverse events (SAEs) 
 Application site tolerability assessment score 
 Change in clinical laboratory parameters, vital 
signs, and electrocardiogram (ECG) from 
baseline 
 To evaluate the systemic exposure of 
GSK2981278 following topical application in 
subjects with plaque psoriasis 
 Plasma concentrations of GSK2981278  
 
Secondary 
 To evaluate the clinical effect following topical 
application of GSK2981278 in subjects with 
plaque psoriasis 
 Mean percent change in Target Plaque Severity 
Score (TPSS) from baseline to Week 8  
 Mean percent change in Physician’s Global 
Assessment (PGA) score from baseline to Week 
8 
 Mean percent change in Psoriasis Area and 
Severity Index (PASI) from baseline to Week 8 
Exploratory 
 To evaluate the effect of GSK2981278 
ointment on relevant gene expression 
 
 Fold change in messenger ribonucleic acid 
(mRNA) biomarkers from baseline to Week 8 in 
skin biopsy samples 
 To investigate the delivery profile of 
GSK2981278 into the psoriatic skin following 
repeat topical applications 
 Quantification of GSK2981278 in the skin biopsy 
using Matrix Assisted Laser Desorption Ionization 
(MALDI) imaging mass spectrometry or High-
performance liquid chromatography-mass 
spectrometry (HPLC-MS) at Week 8 
 To evaluate the effect of GSK2981278 
ointment on subject-reported outcomes 
 Mean percent change in Psoriasis Symptom 
Diary score from baseline to each study visit 
 To evaluate the potential metabolites of 
GSK2981278 in plasma, urine, and skin from 
biopsies in pooled subject samples, as data 
allow 
 Identification of any compound-derived 
metabolite(s) from plasma and urine and if 
possible estimation of relative amounts of drug 
related material 
 Quantification of GSK2981278-derived 
metabolite(s) in the skin biopsy using MALDI 
imaging mass spectrometry or HPLC-MS at Week 
8 


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Part B 
Objectives 
Endpoints 
Primary 
 To evaluate the safety and tolerability of 
topically applied GSK2981278 and its vehicle 
in subjects with plaque psoriasis 
 
 
 Incidence and nature of AEs and SAEs 
 Application site tolerability assessment score 
 Change in clinical laboratory parameters, vital 
signs, and ECG from baseline 
 To evaluate the clinical effect of topically 
applied GSK2981278 relative to vehicle 
control in subjects with plaque psoriasis 
 Mean percent change in TPSS from baseline to 
Week 8  
 Mean percent change in PGA score from baseline 
to Week 8 
 Mean percent change in PASI from baseline to 
Week 8 
Exploratory 
  To explore exposure-response relationship of 
sparse systemic exposures with the clinical 
endpoints (by performing population 
Pharmacokinetic (PK)/Pharmacodynamic (PD) 
analysis, if required), as data allows 
 Plasma concentrations of GSK2981278 and 
clinical endpoints assessed to determine the 
clinical effect (e.g. TPSS, PGA, and PASI)  
 To evaluate the effect of GSK2981278 
ointment on subject-reported outcomes 
 Mean percent change in Psoriasis Symptom 
Diary score from baseline to each study visit 
 
1.3 
Modifications from the statistical section in the protocol 
Not applicable. 
2 Investigational plan 
2.1 
Study design and randomization 
Overall design 
This is a single-center, 2-part Phase I/IIa study to evaluate the safety, tolerability, clinical effect 
and systemic exposure potential of topically applied GSK2981278 ointment in subjects with 
plaque psoriasis. Drug delivery into the skin and changes in the relevant biomarkers will be 
explored using skin punch biopsies as well.  
 
Part A: open label, single arm study 
 
Part B: double-blind, randomized, 2-arm, parallel-group, vehicle-controlled study 
After completion of Week 4 assessments and Week 8 assessments in Part A, the Sponsor will 
review the safety, tolerability, PK and clinical effect data. If data demonstrates a mean percent 
reduction of 40% or greater in TPSS and systemic exposure levels below the no observed 
adverse effect level (NOAEL) determined in the pre-clinical toxicity studies without significant 
safety or tolerability issues at either time point, the study will proceed to Part B.  
After the Sponsor’s review of Week 8 data in Part A against the pre-defined criteria, the Sponsor 
decided not to proceed to Part B of the trial, as the threshold level of reduction in TPSS was not 


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reached. In the following the trial design and planned analytical methods for Part A and Part B 
will be given, while detailed analyses will be provided for Part A only. 
Treatment arms and duration 
Each part of this study will consist of 3 periods: the screening period of up to 4 weeks, the 
treatment period of 8 weeks, and the follow-up period of 2 weeks. Study visits will occur at 
Screening; Baseline; Weeks 1, 4, and 8 during the treatment period; and Week 10 for follow-up, 
which will be 2 weeks after the last application of study treatment. Additional visits may occur, 
as needed, for early withdrawal or to follow-up on any skin reactions or ongoing AEs. A 
subject’s total duration of study participation will be approximately 14 weeks. 
In Part A, subjects will receive topical application of GSK2981278 4% ointment to all affected 
areas of the body twice daily for 8 weeks 
In Part B, subjects will receive topical application of either GKS2981278 ointment or the vehicle 
ointment, according to the randomization, to all affected areas of the body twice daily for 8 
weeks. The starting concentration of GSK2981278 in Part B will be determined based on Part A 
data review. 
In both Parts, the subjects will receive 113 applications during the 8 weeks (Day 1 to Day 57) of 
treatment period. 
The concentration of GSK2981278 may be lowered to 2% or 0.8% in Part A and/or Part B 
based on the newly available safety and tolerability data. See clinical trial protocol (CTP), 
section 6.4 for planned dose adjustments. 
Treatment assignment 
In Part A, all subjects will receive 4% ointment of GSK2981278. 
In Part B, subjects will be assigned to ointment of GSK2981278 or the vehicle ointment in 
accordance with the randomization schedule generated by GlaxoSmithKline (GSK), prior to the 
start of the study, using validated internal software. The starting concentration of GSK2981278 
in Part B will be determined based on Part A data review. 
Once a randomization number has been assigned to a subject, it must not be re-assigned to a 
different subject. 
The concentration of GSK2981278 may be lowered to 2% or 0.8% in Part A and/or Part B 
based on the newly available safety and tolerability data. See CTP, section 6.4 for planned dose 
adjustments. 
Blinding 
Part A will be an open-label study.  
Part B will be a double-blind study (see CTP, section 6.5 for details). 
Type and number of subjects 
In Part A, eight adult subjects with chronic stable plaque psoriasis will be enrolled. If subjects 
prematurely discontinue the study treatment, additional replacement subjects may be recruited 
at the discretion of the Sponsor in consultation with the investigator. 
In Part B, approximately 18 adult subjects with chronic stable plaque psoriasis will be 
randomized with an allocation ratio of 2:1 to GSK2981278 ointment or vehicle ointment to have 
at least 15 evaluable subjects who comply closely with the protocol (e.g. have sufficient 
exposure and critical assessments completed). The starting concentration of GSK2981278 in 


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Part B will be determined based on Part A data review. Subjects who were enrolled in Part A will 
not be eligible to participate in Part B. 
If the concentration of GSK2981278 is lowered in either part of the study, additional subjects 
may be enrolled to have the minimum evaluable subjects in that part treated with the lower 
concentration of study treatment. 
Compliance with study treatment administration 
Subjects will be instructed to record the time of the study treatment application or reason for 
missed application for each planned study treatment administration.  At each post baseline 
study visit, subjects will be asked to provide information from the study diary to study personnel 
regarding their compliance with study product use. Subjects should bring their tube(s) of study 
treatment with them to each visit for study personnel to weigh and document the amount used. 
When subjects are dosed at the site, they will self-apply study treatment under the direction and 
supervision of the investigator or designee. The date and time of each dose administered in the 
clinic will be recorded in the source documents. The weight of the tube of ointment will be 
collected before and after the study treatment application at the site. 
Analysis 
No formal hypothesis tests are planned. Descriptive statistics will be used to assess the key 
objectives of this study. 
2.2 
Sample size justification 
Sample size is based on feasibility and the estimated number of subjects expected to provide 
reasonable information on the key objectives of the study. 
For Part A: 
Summary statistics, such as mean % of reduction in TPSS, mean % reduction in PGA and 
mean % of reduction in PASI will be estimated. With 8 evaluable subjects, precisions on these 
estimates are assessed as below. 
 
Endpoint 
Assumptions 
Sample Size 
95%CI estimate 
Mean % reduction in 
TPSS 
50% reduction with 20% standard 
deviation will be observed 
N=8 
33.3% - 66.7%  
Mean % reduction in 
PGA 
50% reduction with 30% standard 
deviation will be observed 
N=8 
24.9%-75.1% 
Mean % reduction in 
PASI 
50% reduction with 25% standard 
deviation will be observed 
N=8 
29.1% -70.9% 
 
For Part B: 
With 15 subjects (10 in GSK2981278 arm and 5 in the Vehicle arm), the power to detect 
difference between GSK2981278 arm and the vehicle arm in terms of TPSS reduction, and 
PASI reduction are assessed below: 
 


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Endpoint 
Assumptions 
Sample Size 
(API:Vehicle) 
Power to reject* 
H0: API=Vehicle 
(Alpha=5%) 
Mean % 
reduction in 
TPSS 
50% reduction in GSK arm and 20% 
reduction in Vehicle with 20% standard 
deviation will be observed 
N=10:5 
71.7%  
Mean % 
reduction in 
PASI 
50% reduction in GSK arm and 10% in 
Vehicle with 20% standard deviation 
will be observed 
N=10:5 
92.1% 
*2-sample t test 
API- Active Pharmaceutical Ingredient 


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2.3 
Study plan 
2.3.1 Time and events table for Part A 
Procedure  
Screening 
Treatment Period 
Follow-up 
Notes 
Study Days (± specified no. of days) 
Day –28 to -
1 
Day 1 
(Baseli
ne) 
Day 8 
(2 
days)  
Day 
15 
(2 
days) 
Day 29 
(3 
days) 
Day 43 
(3 
days) 
Day 57 
(3 
days) 
2 weeks post-
last dose (3 
days) 
Subjects who withdraw early from the study 
should complete the Day 57 visit 
assessments and subsequently enter follow-
up period. 
Visits at Day 8 and Day 43 do not need to be 
clinic visits. Indicated information can be 
collected via a phone call with the subject. 
Screening and Safety assessments 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical history/family history (includes 
substance usage, CV medical history and 
family history of premature CV disease) 
X 
 
 
 
 
 
 
 
Substances: Drugs, alcohol and tobacco 
Prior and Concomitant Medication review 
(including prior therapy for psoriasis) 
X 
X 
 
X 
X 
 
X 
X 
 
Fitzpatrick Skin Type Classification 
X 
 
 
 
 
 
 
 
 
Brief physical exam (including height and weight) 
X 
 
 
 
 
 
X 
 
Brief physical exam including weight only on 
Day 57 
12-lead Electrocardiogram 
X 
X 
 
 
X 
 
X 
 
Triplicate ONLY if first reading is outside the 
eligibility criteria threshold value or the 
stopping criteria threshold value. 
Vital sign 
X 
X 
 
X 
X 
 
X 
 
Vital signs include heart rate, blood pressure 
and oral temperature. Ideally, heart rate and 
blood pressure will be obtained after the 
subject has been resting in a seated or 
supine position for at least 5 minutes. 


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Procedure  
Screening 
Treatment Period 
Follow-up 
Notes 
Study Days (± specified no. of days) 
Day –28 to -
1 
Day 1 
(Baseli
ne) 
Day 8 
(2 
days)  
Day 
15 
(2 
days) 
Day 29 
(3 
days) 
Day 43 
(3 
days) 
Day 57 
(3 
days) 
2 weeks post-
last dose (3 
days) 
Subjects who withdraw early from the study 
should complete the Day 57 visit 
assessments and subsequently enter follow-
up period. 
Visits at Day 8 and Day 43 do not need to be 
clinic visits. Indicated information can be 
collected via a phone call with the subject. 
HIV, Hep B and Hep C screen 
X 
 
 
 
 
 
 
 
If test otherwise performed within 3 months 
prior to first dose of study treatment, testing 
at screening is not required 
Urine pregnancy test (FNRP) 
X 
 
 
 
 
 
 
 
 
Laboratory assessments (include liver 
chemistries) and urinalysis 
X 
X 
 
X 
X 
 
X 
 
Urinalysis: On Days 1, 29, and 57, urine PK 
sample can be used. 
AE/SAE review 
 
X 
X 
X 
X 
X 
X 
X 
Visits at Day 8 and Day 43 do not need to be 
office visits. This information may be 
collected via a phone call with the subject. 
On these days subject will be asked about 
application site tolerability also.   
Application site tolerability 
 
X 
 
X 
X 
 
X 
 
See CTP, section 7.5.7 
Enrollment to study 
 
 
 
 
 
 
 
 
 
Identify and mark target lesion for TPSS 
 
X 
 
 
 
 
 
 
 
Identify and mark area for biopsy collection 
 
X 
 
 
 
 
 
 
 
Dispense tubes of study treatment 
 
X 
 
X 
X 
 
 
 
 
Study treatment application 
 
--------------------------------------------------- 
 
On clinic visit days, the morning application 
will be done in the clinic 
Review compliance diary 
 
 
X 
X 
X 
X 
X 
 
Subjects will use a diary to record daily 
applications of study treatment and reasons 
for any missed applications 
On Day 8 and Day 43, subjects will be asked 
about compliance via phone.  
Collect and weigh tubes of study treatment 
 
X 
 
X 
X 
 
X 
 
 
Efficacy assessments 
 
 
 
 
 
 
 
 
 
Psoriasis Symptom Diary 
X 
X 
 
X 
X 
 
X 
 
To be completed by subject before any other 
assessments at a clinic visit 
Target Plaque Severity Score (TPSS) 
X 
X 
 
X 
X 
 
X 
 
 
Physician Global Assessment (PGA) 
X 
X 
 
X 
X 
 
X 
 
 


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Procedure  
Screening 
Treatment Period 
Follow-up 
Notes 
Study Days (± specified no. of days) 
Day –28 to -
1 
Day 1 
(Baseli
ne) 
Day 8 
(2 
days)  
Day 
15 
(2 
days) 
Day 29 
(3 
days) 
Day 43 
(3 
days) 
Day 57 
(3 
days) 
2 weeks post-
last dose (3 
days) 
Subjects who withdraw early from the study 
should complete the Day 57 visit 
assessments and subsequently enter follow-
up period. 
Visits at Day 8 and Day 43 do not need to be 
clinic visits. Indicated information can be 
collected via a phone call with the subject. 
Psoriasis Area Severity Index (PASI) 
 
X 
 
X 
X 
 
X 
 
 
%BSA affected 
X 
X 
 
X 
X 
 
X 
 
 
%BSA treated 
 
X 
 
X 
X 
 
X 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
Plasma sample for GSK2981278 
 
X 
 
X 
X 
 
X 
 
Day 1, Day 29, and Day 57: pre-dose, and 
1h, 2h, 4h, 6h, 8h, and 10h post morning 
dose 
Day 15: pre-dose and 2h post morning dose 
Plasma sample for metabolite(s) 
 
X 
 
 
 
 
X 
 
Pre-dose, and 1h, 2h, 4h, 6h, 8h, and 10h 
post morning dose. 
Urine sample for metabolite(s) 
 
X 
 
 
  
 
X 
 
Pre-dose urine on Day 1, 0-10h pool 
Two aliquots to be made for metabolite 
analysis and urinalysis. See CTP, section 
7.6.2 
Other assessments 
 
 
 
 
 
 
 
 
 
Skin punch biopsy 
 
X 
 
 
 
 
X 
 
4 mm biopsy before study treatment 
application. 
2 at Baseline (1 from non-lesional skin;1 from 
lesional skin-both for gene expression 
analyses) 
 2 at Day 57 (1 from lesions skin for gene 
expression analyses;1 from lesional skin  for 
drug level) 
Biopsy wound assessment 
 
 
 
X 
 
 
 
X 
 
Photograph of target lesion 
 
X 
 
 
 
 
X 
 
 


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2.3.2 Time and events table for Part B 
Procedure  
Screening 
Treatment Period 
Follow-up 
Notes 
Study Days (± specified no. of days) 
Day –28 to 
-1 
Day 1 
(Baseline) 
Day 8 
( 2 
days) 
Day 15 
( 2 
days) 
Day 29 
(3 
days) 
Day 43 
(3 
days) 
Day 57 
(3 
days) 
2 weeks post-
last dose (3 
days) 
Subjects who withdraw early from the 
study should complete the Day 57 visit 
assessments and subsequently enter 
follow-up period. 
 Visits at Day 8 and Day 43 do not need to 
be clinic visits. Indicated information can 
be collected via a phone call with the 
subject. 
Screening and Safety assessments 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
Will be assessed prior to randomization 
Demography 
X 
 
 
 
 
 
 
 
 
Medical history/family history (includes 
substance usage, CV medical history 
and family history of premature CV 
disease) 
X 
 
 
 
 
 
 
 
Substances: Drugs, alcohol and tobacco  
Prior and Concomitant Medication review 
(including prior therapy for psoriasis) 
X 
X 
 
X 
X 
 
X 
X 
 
Fitzpatrick Skin Type Classification 
X 
 
 
 
 
 
 
 
 
Brief physical exam (including height and weight) 
X 
 
 
 
 
 
X 
 
Brief physical exam including weight on 
D57 
12-lead Electrocardiogram 
X 
X 
 
 
X 
 
X 
 
 
Vital sign 
X 
X 
 
X 
X 
 
X 
 
Vital signs include heart rate, blood 
pressure and oral temperature. Ideally, 
heart rate and blood pressure will be 
obtained after the subject has been 
resting in a seated or supine position for 
at least 5 minutes. 
HIV, Hep B and Hep C screen 
X 
 
 
 
 
 
 
 
If test otherwise performed within 3 
months prior to first dose of study 
treatment, testing at screening is not 
required 
Urine pregnancy test (FNRP)  
X 
 
 
 
 
 
 
 
 


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Procedure  
Screening 
Treatment Period 
Follow-up 
Notes 
Study Days (± specified no. of days) 
Day –28 to 
-1 
Day 1 
(Baseline) 
Day 8 
( 2 
days) 
Day 15 
( 2 
days) 
Day 29 
(3 
days) 
Day 43 
(3 
days) 
Day 57 
(3 
days) 
2 weeks post-
last dose (3 
days) 
Subjects who withdraw early from the 
study should complete the Day 57 visit 
assessments and subsequently enter 
follow-up period. 
 Visits at Day 8 and Day 43 do not need to 
be clinic visits. Indicated information can 
be collected via a phone call with the 
subject. 
Laboratory assessments (include liver 
chemistries) and urinalysis 
X 
X 
 
X 
X 
 
X 
 
 
Genetic sample  
 
X 
 
 
 
 
 
 
Informed consent for optional,genetic 
research must be obtained before 
collecting a sample. 
Pre-dose & post-randomisation 
AE/SAE review 
 
X 
X 
X 
X 
X 
X 
X 
Visits at Day 8 and Day 43 do not need to 
be office visits.  This information may be 
collected via a phone call with the subject. 
On these days subject will also be asked 
about application site tolerability.   
Application site tolerability 
 
X 
 
X 
X 
 
X 
 
See CTP, section 7.5.7 
Enrollment to study 
 
 
 
 
 
 
 
 
 
Identify and mark target lesion for TPSS 
 
X 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
Dispense tubes of study treatment 
 
X 
 
X 
X 
 
 
 
 
Study treatment application 
 
--------------------------------------------------- 
 
On clinic visit days, the morning 
application will be done in the clinic 
Review compliance diary 
 
 
X 
X 
X 
X 
X 
 
Subjects will use a diary to record daily 
applications of study treatment and 
reasons for any missed applications. 
On Day 8 and Day 43, subjects will be 
asked about compliance via phone or text 
message. 
Collect and weigh tubes of study treatment 
 
X 
 
X 
X 
 
X 
 
 
Efficacy assessments 
 
 
 
 
 
 
 
 
 
Psoriasis Symptom Diary 
X 
X 
 
X 
X 
 
X 
 
To be completed by subject before any 
other assessments at a clinic visit 
Target Plaque Severity Score (TPSS) 
X 
X 
 
X 
X 
 
X 
 
 


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Procedure  
Screening 
Treatment Period 
Follow-up 
Notes 
Study Days (± specified no. of days) 
Day –28 to 
-1 
Day 1 
(Baseline) 
Day 8 
( 2 
days) 
Day 15 
( 2 
days) 
Day 29 
(3 
days) 
Day 43 
(3 
days) 
Day 57 
(3 
days) 
2 weeks post-
last dose (3 
days) 
Subjects who withdraw early from the 
study should complete the Day 57 visit 
assessments and subsequently enter 
follow-up period. 
 Visits at Day 8 and Day 43 do not need to 
be clinic visits. Indicated information can 
be collected via a phone call with the 
subject. 
Physician Global Assessment (PGA) 
X 
X 
 
X 
X 
 
X 
 
 
Psoriasis Area Severity Index (PASI) 
 
X 
 
X 
X 
 
X 
 
 
%BSA affected 
X 
X 
 
X 
X 
 
X 
 
 
%BSA treated 
 
X 
 
X 
X 
 
X 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
Plasma sample for GSK2981278 
 
X 
 
X 
X 
 
X 
 
Day 1: between 3 and 12h post morning 
dose 
Day 15: pre-dose 
Days 29 and 57: within 12 h of morning 
dose 
Other assessments 
 
 
 
 
 
 
 
 
 
Photograph of target lesion 
 
X 
 
 
 
 
X 
 
 
 


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3 Statistical and analytical procedures 
3.1 
Definitions 
The following definitions apply: 
Screen failure 
A subject who signs the informed consent but is not enrolled into the study. See ‘Enrolled 
analysis set’ in section 3.3.4 for the definition of enrollment.  
Study day 
The number of days from date of the Day 1 visit: 
study day = missing,  
If date of assessment or event is missing 
study day = date of assessment or event - date of the Day 1 visit,  
If date of assessment or event < date of the Day 1 visit,  
study day = date of assessment or event - date of the Day 1 visit + 1,  
If date of assessment or event ≥ date of the Day 1 visit  
Study treatment 
Any combination of products received by the subject as per the protocol design 
On-treatment phase 
The on-treatment phase will be defined as the period starting with the first application of study 
treatment and ending with the last application of study treatment. 
Completed subject  
A completed subject is one who has completed all phases of the study including the follow-up 
visit. 
Past medical conditions 
Medical conditions resolved (not on-going) prior to the start date of the study treatment , i.e. with 
medical condition start date missing or before study treatment start date and a not completely 
missing stop date before study treatment start date. 
Current medical conditions 
Medical conditions unresolved (on-going) at the study treatment start, i.e. if any of the following 
conditions hold: 
 
Medical condition start date is before study treatment start date and stop date is on or 
after study treatment start date or completely missing.  
 
Medical condition start date is completely missing and stop date is on or after study 
treatment start date. 


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 
Both, start date and stop date for a medical condition are completely missing. 
 
Prohibited medications and non-drug therapies 
Prohibited concomitant medications, products, and procedures (Table 1) are not to have been 
used from the defined periods before the first study treatment applications at the Day 1 visit and 
throughout the study. 
 
Table 1 
Prohibited concomitant medications, products, and procedures 
Prohibited medications, products, and procedures:  
Prohibited period 
before Day 1  
Biologic agents:  
(e.g., alefacept 24 weeks; etanercept 12 weeks; ustekinumab 15 weeks) 
5 half-lives 
Oral retinoids (e.g., acitretin or isotretinoin) 
12 weeks 
Cyclosporin, interferon, methotrexate, fumaric acid or other systemic 
immunosuppressive or immunomodulating agents (e.g., mycophenolate 
or tacrolimus)  
4 weeks 
Other investigational products or procedures 
4 weeks or 5 
half-lives, 
whichever is longer 
Systemic corticosteroids or adrenocorticotropic hormone (ACTH) analogs 
4 weeks 
Systemic anticoagulants (e.g. warfarin, heparin, low molecular weight 
heparin, etc.) 
5 half-lives 
Immunizations (influenza vaccine will be allowed) 
2 weeks 
Topical treatments: corticosteroids, immunomodulators, anthralin 
(dithranol), Vitamin D derivatives, retinoids, coal tar (used on the body). 
2 weeks 
Drugs known to possibly worsen psoriasis (unless on a stable dose for 
>12 weeks), such as, but not limited to: β-blockers (eg, propranolol), 
lithium, iodides, angiotensin-converting enzyme inhibitors, and 
indomethacin 
2 weeks 
Any other topical therapy (including emollients) on psoriasis lesions 
treated in this study 
Note: Emollients may be used if Investigator, in consultation with the 
Medical Monitor, allows the use during a dosing holiday due to application 
site reaction. (See Topical Application Site Tolerability Stopping Criteria, 
below) 
1 day 
Phototherapy including psoralen plus UVA (PUVA) 
2 weeks 


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Prior medication or therapies 
Medication or therapy with start date missing or before study treatment start date and a not 
completely missing stop date before study treatment start date . 
Concomitant medications or therapies 
Medication or therapy occurring during the treatment period or follow-up, i.e. if any of the 
following conditions hold: 
 
Medication or therapy start date is before study treatment start date and stop date is on 
or after study treatment start date or completely missing.  
 
Medication or therapy start date is on or after study treatment start date and on or before 
last visit date. 
 
Medication or therapy start date is missing and stop date is on or after study treatment 
start date. 
 
Both, start date and stop date for a medication or therapy are completely missing. 
 
Potential clinical importance (PCI) ranges 
 
 
Table 2 
Haematology analytes: Potential clinical importance (PCI) ranges 
Lab test 
Low 
High 
WBC (GI/L) 
≤ 0.67 x LLN 
≥ 1.82 x ULN 
Neutrophil (GI/L) 
≤ 0.83 x LLN 
Hemoglobin (G/L) 
male 
 
≥ 1.03 x ULN 
female 
 
≥ 1.13 x ULN 
Hematocrit (Fraction of 1) 
male 
 
≥ 1.02 x ULN 
female 
 
≥ 1.17 x ULN 
Platelet count (GI/L) 
≤ 0.67 x LLN 
≥ 1.57 x ULN 
Lymphocytes (GI/L) 
≤ 0.81 x LLN 
 
Table 3 
Chemistry analytes: Potential clinical importance (PCI) ranges 
Lab test 
Low 
High 
Albumin (mmol/L) 
≤ 0.86 x LLN 
Calcium (mmol/L) 
≤ 0.91 x LLN 
≥ 1.06 x ULN 
Glucose (mmol/L) 
≤ 0.71 x LLN 
≥ 1.41 x ULN 
Potassium (mmol/L) 
≤ 0.86 x LLN 
≥ 1.10 x ULN 
Sodium (mmol/L) 
≤ 0.96 x LLN 
≥ 1.03 x ULN 
 
Table 4 
Liver function test analytes: Potential clinical importance (PCI) ranges 
Lab test 
High 
ALT/SGPT (U/L) 
≥ 2 x ULN 
AST/SGOT (U/L) 
≥ 2 x ULN 
Alkaline phosphatase (U/L) 
≥ 2 x ULN 


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Lab test 
High 
Total Bilirubin (µmol/L) 
≥ 1.5 x ULN 
Total Bilirubin (µmol/L) and ALT (U/L) 
≥ 1.5 x ULN Total Bilirubin and ≥ 2 x ULN ALT 
 
Table 5 
ECG: Potential clinical importance (PCI) ranges 
ECG Parameter* 
Low 
High 
Absolute QTc interval (msec) 
 
> 450 
Increase from baseline QTc (msec) 
 
> 60 
PR interval (msec) 
< 110 
> 220 
QRS interval (msec) 
< 75 
> 110 
* for specifications of QTc see section on QTc stopping criteria below 
 
Table 6 
Vital signs: Potential clinical importance (PCI) ranges 
VS Parameter 
Low 
High 
Systolic Blood Pressure (mmHg) 
< 85 
> 160 
Diastolic Blood Pressure (mmHg) 
< 45 
> 100 
Heart Rate (bpm) 
< 40 
> 110 
 
Phase II liver chemistry stopping criteria 
Liver safety required actions and follow-up assessments can be found in CTP, Appendix 6.  
QTc stopping criteria 
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. QTcB will be utilized for this study. 
The QTcB should be based on single QTcB values electrocardiograms. If QTcB is outside of the 
threshold value of the stopping criteria shown below, triplicate ECGs will be performed over a 
brief (e.g., 5-10 minute) recording period with the QTcB values averaged.  
A subject who meets either of the bulleted criteria below will be withdrawn from the study: 
 
QTcB > 500 msec OR Uncorrected QT > 600 msec 
 
Change from baseline of QTcB > 60 msec 
For patients with underlying bundle branch block, follow the discontinuation criteria listed below: 
 
Table 7 
QTc stopping criteria for patients with underlying bundle branch block 
Baseline QTcB with Bundle Branch 
Block 
Discontinuation 
QTcB 
with 
Bundle 
Branch Block 
<450 msec 
>500 msec 
450 – 480 msec 
≥530 msec 
 


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Topical application site tolerability stopping criteria 
If a subject experiences application site reaction of grade 3 (severe) or 4 (very severe) on the 
topical application site tolerability scale (Table 14), study treatment will be discontinued 
permanently. 
If a subject experiences application site reaction of grade 2 (moderate) on the topical application 
site tolerability scale with cracking, study treatment WILL be temporarily discontinued and the 
subject will be put on a dosing holiday until the irritation resolves. If a subject experiences 
application site reaction of grade 2 (moderate) without cracking, investigator MAY temporarily 
discontinue study treatment and put the subject on a dosing holiday in consultation with the 
subject and medical monitor until the irritation resolves. No rescue medication will be allowed 
during a dosing holiday. Investigator in consultation with the Medical Monitor may allow the use 
of emollients during the dosing holiday. The dosing holiday will be limited to once in each 
subject over the course of the study and the duration will not exceed 1 week. After the dosing 
holiday, the subject may be retreated with the study treatment if the irritation resolves. 
At the time of permanent (grade 3 or 4) or temporary (grade 2) treatment discontinuation due to 
the application site intolerability and at the time of treatment restart (if applicable, after a dosing 
holiday), photographic documentation of a representative area of irritation (preferably the target 
lesion or the vicinity, if affected) will be taken. 
Treatment emergent adverse events (TEAEs) 
AEs occurred or worsened within the window of the first application of study treatment and 
15 hours after the last application of study treatment, if any of the following conditions hold:  
 
AE onset date is on or after study treatment start date and on or before 15 hours after 
the last application of study treatment. 
 
AE onset date is completely missing and AE stop date is on or after study treatment start 
date. 
 
date of the last application is missing and AE stop date or AE onset date is after study 
treatment start date. 
 
both AE onset date and stop date are completely missing. 
The 15 hours comes from the roughly predicted value of 5 times half-life of GSK2981278 in 
animal studies.  
Baseline 
Last observation collected prior to the first application of study treatment. 
Last observation carried forward (LOCF) 
The last observed value (either scheduled or unscheduled) carried forward and used for all 
subsequent scheduled points where the data is missing. Only efficacy data up to Day 57 visit 
will be imputed. No imputation for the Follow-up visit will be carried out. 
Change from baseline  
Change from baseline will be calculated by the post-baseline assessment value minus the 
baseline assessment value. 


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% Change from baseline  
% Change from baseline will be calculated by the formula: (change from baseline / the baseline 
assessment value) * 100. 
 
3.2 
Analysis variables 
3.2.1 Pharmacokinetic variables 
The planned Pharmacokinetic variables are described below. Analysis of compound-related 
metabolites in plasma, GSK2981278 and related metabolites in urine and GSK2981278 and 
compound-related metabolites in skin, if conducted, will be reported under separate protocols 
and will be outside the scope of this statistical analysis plan.  
Blood sample collection 
Blood samples for PK analysis of GSK2981278 and related metabolite(s) will be collected at the 
time points indicated in section 2.3.1 and section 2.3.2, 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.   
Plasma concentrations of GSK2981278 will be determined.  
For Part A, if the concentration data permits, the following PK parameters will be calculated: 
AUC(0-t), Cmax, tmax, and steady state assessments such as C and time invariance.   
Urine sample collection 
Urine samples for analysis of GSK2981278 and related metabolite(s) will be collected at the 
timepoints listed in section 2.3.1, Time and events table.  The timing of urine samples may be 
altered and/or samples may be obtained at additional time points to ensure thorough PK 
monitoring. 
Total urine voided will be collected over the period of collection as specified in section 2.3.1. 
Skin sample collection 
Skin samples for evaluation of drug delivery will be collected in Part A, at Day 57 by taking a 4 
mm punch biopsy from the area of psoriatic plaque identified for skin biopsies at baseline. 
Skin biopsy samples for drug and metabolite analysis will be performed under the control of 
PTS-IVIVT-Bioimaging, GlaxoSmithKline. Skin biopsy samples may be analyzed for 
concentrations of GSK2981278 and compound-related metabolites using MALDI imaging or 
HPLC-MS and the results will be reported under a separate PTS-IVIVT-Bioimaging, GSK 
protocol. Raw data will be archived at GSK. 
3.2.2 Pharmacodynamic variables 
Skin samples for biomarker analyses will be collected at Baseline and Day 57 in Part A. 
With the subject’s consent, a total of 3 4-mm punch skin biopsies will be taken from each 
subject for biomarker analyses in Part A of this study: 1 from non-lesional skin at baseline, 1 
from lesional skin at baseline and 1 at Day 57 from the treated skin of the same plaque where 
the baseline biopsy was taken. Skin sample(s) may be used for the purposes of measuring 


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novel biomarkers to identify factors that may influence psoriasis as well as the biological and 
clinical responses to GSK2981278.   
Novel candidate biomarkers and subsequently discovered biomarkers of the biological response 
associated with psoriasis and/or the action of GSK2981278 may be identified by application of: 
 
RNA transcriptome analysis of skin samples. 
 
Measurement of the levels of mRNA in skin samples. 
RNA transcriptome analysis of skin samples 
Transcriptome studies will be conducted using microarray, which facilitates the simultaneous 
measurement of the relative abundances of thousands of RNA species resulting in a 
transcriptome profile for each skin sample.  This will enable the evaluation of changes in 
transcriptome profiles that may correlate with biological response relating to psoriasis or the 
action of GSK2981278. 
Measurement of the levels of mRNA in skin samples 
RNA expression studies will be conducted using quantitative RT-PCR technologies. The RNAs 
assayed will be those expected to be modulated by GSK2981278.  These biomarkers include 
IL-17A, IL-17F, DEFB4A, IL-19, IL-36, CCL20, S100A7a, IL-8, IL-22, RORC and Krt6A. This will 
enable the evaluation of changes in RNA expression profiles that may correlate with biological 
response relating to psoriasis or the action of GSK2981278. 
The evaluation of the effect of GSK2981278 ointment on relevant biomarkers is out of scope of 
this SAP. 
3.2.3 Efficacy variable(s) 
All efficacy assessments should be performed by the same investigator or designated evaluator 
for an individual subject. In the event the same evaluator is not available for the duration of the 
study, another investigator or designated evaluator with comparable training will perform the 
assessments. 
Target plaque severity score (TPSS) 
A target lesion of at least 9 cm2 with a TPSS ≥5 and an induration subscore ≥2 will be selected 
at baseline. The severity of erythema, scaling, and induration (plaque thickness) will be 
assessed by the investigator on a 5-point scale ranging from 0=none to 4=very marked: 
 
Table 8 
TPSS scales 
Score 
Scaling  
Erythema  
Induration  
0 
None 
No evidence of scaling  No evidence of erythema; 
hyperpigmentation may 
be present  
No elevation over normal 
skin  
1 
Slight 
Occasional fine scale 
over less than 5% of 
the lesion  
Faint erythema  
Possible but difficult to 
ascertain whether there is 
a slight elevation above 
normal skin  


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Score 
Scaling  
Erythema  
Induration  
2 
Moderate 
Fine scales 
predominate  
Light red coloration  
Slight but definite 
elevation, typically edges 
are indistinct or sloped  
3 
Marked 
Coarse scales 
predominate  
Moderate red coloration  
Moderate elevation with 
rough or sloped edges  
4 
Very marked 
Very thick tenacious 
scale predominates  
Dusky to deep red 
coloration  
Very marked elevation 
typically with hard sharp 
edges 
 
 A total score will be calculated by adding the individual scores (13-point scale; maximum score 
12). TPSS is the primary measure of clinical effect for this study. 
Physician global assessment (PGA) 
The PGA is a clinical tool for assessing the current state/severity of a subject’s psoriasis. It is a 
static 5-point morphological assessment of overall disease severity, as determined by the 
investigator, using the clinical characteristics of erythema, plaque thickness, and scaling as 
guideline: 
 
Table 9 
PGA scale 
 
At each specified time point, the PGA is made without reference to previous scores. Variations 
of the PGA are frequently used in clinical studies because it is a simple assessment that is more 
similar to the assessments actually used in clinical practice [Feldman, 2005]. PGA will be 
assessed on the entire treated area (i.e. including the scalp lesion, if applicable). 
Psoriasis area and 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 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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(induration), and scale, as well as the extent of BSA affected with psoriasis [Feldman, 2005]. 
The 3 clinical signs are each graded on a 5-point scale (0 to 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).  
 
Table 10 
Elements of the Psoriasis Area and Severity Index 
Note: Items in shaded rows will be calculated from Items 1, 2, 3, and 5. 
 
For Items 1, 2, and 3, generate an average score for erythema, thickness, and scale for each of 
the 4 body areas using the following 5-point scale: 0=None; 1=Slight; 2=Mild; 3=Moderate; 
4=Severe.  For Item 5, enter the area score for percentage of skin covered by psoriasis 
according to the following chart. 
 
Table 11 
Percentage of skin covered with psoriasis for each area 
Area: 
0% 
1 - <10% 
10 - <30% 
30 - <50% 
50 - <70% 
70 - <90% 
90% 
Score: 
0 
1 
2 
3 
4 
5 
6 
 
The individual scores are multiplied by a weighted factor for each body region; the sum of these 
scores gives the overall PASI score. Higher scores indicate more severe disease. PASI is a 
static assessment made without reference to previous scores. 
Body surface area (BSA) 
The extent of BSA affected by psoriasis is a general indicator of disease severity and will be 
measured throughout the study. The extent of BSA to which study treatment is applied will also 
be recorded. It is suggested, for the purpose of approximate clinical estimation, the total palmar 
surface area of the palm plus five digits be assumed to be approximately equivalent to 1% BSA.  
Assessment of body surface area with Psoriasis will be performed separately for four body 
surface regions: the head (h), the upper extremities (u), the trunk (t), and the lower extremities 
(l), corresponding to 10, 20, 30, and 40% of the total body area, respectively. 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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Table 12 
Body region in percent of total body area 
Body Region 
Surface Area of Body Region 
head (h) 
10% 
upper extremities (u) 
20% 
trunk (t) 
30% 
lower extremities (l) 
40% 
Psoriasis Symptom Diary 
The Psoriasis Symptom Diary was developed to assess daily self-reports of psoriasis symptoms 
and the functional impact related to the underlying pathophysiology of the disease [Strober, 
2013]. Questions about how severe and how bothersome various signs and symptoms are to 
the subject are answered using an 11-point numerical rating scale (see below).  In this study, 
subjects will be asked to complete the Psoriasis Symptom Diary questionnaire at the clinic 
during the scheduled visits. 
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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3.2.4 Safety variables 
Planned time points for all safety assessments are listed in the Time and events table (section 
2.3.1 and section 2.3.2).  Additional time points for safety tests may be added during the course 
of the study based on newly available data to ensure appropriate safety monitoring. 
Safety will be assessed by the monitoring and recording of all AEs and SAEs; evaluation of 
application site tolerability; monitoring of hematology, clinical chemistry, urinalysis and vital 
signs; and the performance of ECGs and physical examinations. 
Adverse events 
The definitions of an AE or SAE can be found in CTP, Appendix 8. 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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 
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.  
 
AEs will be collected from the start of study treatment until the follow-up contact (CTP, 
section 7.5.1.3), at the timepoints specified in the Time and Events Table (section 2.3.1 
and section 2.3.2). 
 
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. 
Laboratory variables 
All protocol required laboratory assessments, as defined in Table 13, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.  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. 
All study-required laboratory assessments will be performed by a local laboratory, apart from 
liver events monitoring which will be performed by the central laboratory. The results of each 
test must be entered or electronically transferred into the eCRF. 
Haematology, clinical chemistry, urinalysis and additional parameters are to be tested, as listed 
below. 
 
Table 13 
Laboratory Parameters 
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 
Blood Urea 
Nitrogen 
(BUN) 
Potassium Aspartate amino-
transferase (AST) 
(SGOT) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
ALT (SGPT) 
Total Protein 
Glucose  
Calcium 
Alkaline phosphatise Albumin 


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Laboratory 
Assessments 
Parameters 
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 (HBsAg) 
 
Hepatitis C (Hep C antibody) 
 
FSH and estradiol (as needed in women of non-child bearing potential 
only) 
 
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
 
Urine hCG Pregnancy test (at Screening for women of non-child 
bearing potential)  
NOTES : 
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in CTP, section 5.4.1 and 
CTP, Appendix 6. 
 
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. 
Electrocardiogram (ECG) 
Single 12-lead ECGs will be obtained at each timepoint during the study using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.  
QTcB will be utilized for this study. If QTcB is outside the threshold value of the eligibility criteria 
or stopping criteria, triplicate ECGs will be performed over a brief (e.g. 5 to 10 minutes) 
recording period with the QTcB values averaged. Refer to section 3.1 for QTc stopping criteria. 
Application site tolerability 
The investigator or designated evaluator will assess application site tolerability focusing on the 
treated non-lesional skin surrounding the plaques at each visit using the 5-point tolerability 
assessment scale presented in Table 14. Refer to section 3.1 for topical application site 
tolerability stopping criteria. 
 


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Table 14 
Application site tolerability assessment scale 
Grade 
Severity 
Description 
0 
None 
No evidence of local intolerance 
1 
Mild 
Minimal erythema and/or edema, slight glazed 
appearance 
2 
Moderate 
Definite erythema and/or edema with peeling and/or 
cracking 
3 
Severe-To be reported 
as an AE 
Erythema, edema glazing with fissures, few vesicles 
or papules: Remove and discontinue study treatment 
4 
Very Severe-To be 
reported as an AE 
Strong reaction spreading beyond the treated area, 
bullous reaction, erosion: Remove and discontinue 
study treatment 
Pregnancy 
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of dosing and until 2 weeks post-last dose. 
Physical exams 
A brief physical examination will include, at a minimum assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen) and a measurement of weight. Height 
will be also measured and recorded at Screening. 
Vital signs 
Vital signs will be measured in seated or supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure and pulse rate. Three readings of blood 
pressure and pulse rate will be taken. First reading should be rejected. Second and third 
readings should be averaged to give the measurement to be recorded in the CRF. 
3.3 
Analysis populations 
3.3.1 Efficacy population 
Per Protocol (PP) analysis set will include all randomized subjects (in Part A, all randomized 
subjects refer to all subjects who are eligible for treatment phase as no randomization will take 
place), who comply closely with the protocol (e.g. have sufficient exposure).  
The following deviations from the protocol are considered major for the exclusion of the subjects 
from the PP analysis set: 
 
violation of eligibility criteria; 
 
consumption of forbidden concomitant medication during the study; 
 
application of less than 80% or more than 120% of the planned number of 113 doses 
(see section 2.1); 


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Subjects will not be excluded from the PP, if the reason for the protocol deviation or premature 
treatment or trial discontinuation is due to lack of efficacy or due to an at least possibly 
treatment related adverse event.  
Prior to breaking the blind and/or the data review meeting, other additional criteria may be 
added to the list to accommodate for unforeseen events that occurred during the conduct of the 
trial that result in noteworthy study protocol violations. 
PP analysis set will be the primary set for efficacy analyses.  
3.3.2 Safety population 
Safety analysis set will include all subjects exposed to at least 1 application of study product. 
The safety analysis set will be the primary set for safety analyses.  
3.3.3 Pharmacokinetic population 
Pharmacokinetic (PK) analysis set will include subjects with at least one sample collected and 
analyzed for plasma drug concentration. The PK analysis set will be the primary set for PK 
analyses. 
3.3.4 Other populations 
Screened analysis set will include all subjects who sign informed consent. This set will be used 
for evaluating screen failures, study populations and exclusion of subjects from any population. 
Enrolled analysis set will include all subjects who are eligible for treatment phase, indicated by 
eligibility status eCRF page. This set will be used for evaluating subject disposition, reasons for 
study withdrawal, age ranges, planned and actual treatments. 
3.4 
Statistical methods 
The statistical evaluation will be performed by bioskin using SAS® version 9.3 or higher 
(Statistical Analysis System, SAS Inc., Cary, NC) software package.  
A complete set of raw data listings will be appended to the Statistical Report. All tables, figures 
and listings will be presented in RTF and PDF documents without any manual editing, i.e. they 
will appear unmodified as programmed by means of the statistical package. 
Descriptive summaries will be given by treatment group and/or overall. The number of subjects 
within each treatment group of the analysis set will be given in each table. 
Categorical variables will be summarized with counts (n) and percentages (%), together with the 
number of non-missing values. The number of non-missing values will be used as the 
denominator for the calculation of percentages. Incidence of adverse events will be based on 
the number of subjects in the respective analysis set and treatment group.  
Descriptive statistics for continuous variables will be comprised of the number of non-missing 
observations (n), mean, standard deviation (SD), median, minimum (Min) and maximum (Max), 
if not otherwise stated. 
When applicable, these summaries will be provided by visit. In case of premature withdrawal 
from the trial, efficacy and safety assessments performed at the time point of withdrawal, will be 
summarized, separately to the planned visits.  


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As a rule, mean, and median will be reported to one decimal place more than the observed 
values, SD with two decimal places more than the observed values, Min and Max with the same 
number of decimal places as the observed values.  
3.4.1 Discontinuations, dropouts and analysis populations 
The number and percentage of subjects who entered, completed and withdrew during the whole 
study, as well as at the treatment period (Visit Day 1 to Visit Day 57) and the follow-up/end of 
study period (Follow-up Visit), together with reasons for discontinuation, will be tabulated for the 
enrolled analysis set. Screening status and reasons for screen failures will be tabulated for the 
screened analysis set. The number and percentage of subjects in each analysis set will be 
summarized with the screened analysis set.  
Subjects discontinuing the study will be listed with date of discontinuation, study day of 
discontinuation, and reason for discontinuation. The reasons for screen failures will be listed 
with date of screen failure. 
Important protocol deviations (section 3.3.1) will be listed with date of deviation, study day of 
deviation, as well as protocol deviation category, coded term and descriptions. 
Subjects with inclusion/exclusion criteria deviations will be listed with inclusion/exclusion type 
and criteria descriptions. 
Subjects enrolled but excluded from either PP analysis set, safety analysis set or PK analysis 
set will be listed along with date, study day and category of deviation, the criteria which lead to 
exclusion, as well as exclusion from populations.   
3.4.2 Demographics and baseline characteristics 
Demographic and background data, consisting of age (determined as number of full years of the 
difference between date of informed consent and date of birth, with day of birth set to June 
30th), sex, race and ethnicity assessed at screening will be summarized using descriptive 
statistical methods for the enrolled analysis set. Baseline characteristics such as height [cm], 
and Fitzpatrick skin type will also be included in the summary.  
Baseline assessments of efficacy and safety parameters will be presented in context of the 
evaluation of efficacy/safety parameters, with baseline, defined as the last observation prior to 
the first application of study treatment. Pregnancy tests and screening laboratory assessments 
will only be listed.  
Past and current medical conditions, i.e. general medical history, cardiovascular events and 
history of stable plaque psoriasis, will be listed only. General medical history and cardiovascular 
events will be listed with classification and a flag identifying the condition as past or current, 
according to the definition in section 3.1.  
Concomitant medications or therapies will be presented by GSKDrug Anatomical Therapeutic 
Chemical (ATC) classification level 1 (Body System) and ingredient. In any given category (e.g., 
drug category) a subject will be counted only once. Prior and concomitant medications/therapies 
will be listed. 
Family history, as related to the inclusion/exclusion criteria will be listed only. 
3.4.3 Treatment compliance 
The treatment compliance will be assessed by evaluation of the total number of investigational 
medicinal product (IMP) applications and the % IMP applications.  


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The total number of IMP applications will be calculated by: 
Duration of treatment [days] * 2 – 1 – number of missed applications + number of overdoses, 
with duration of the treatment calculated by: 
Date of last IMP application – Date of first IMP application + 1. 
The % IMP applications will be calculated by (the total number of IMP applications / the planned 
total number of IMP applications) *100, where the planned total number of IMP application is 
113 (see section 2.1).  
The total number of IMP applications and % of IMP applications will be presented using 
descriptive statistics for continuous variables in the safety analysis set.  
3.4.4 Efficacy analyses 
3.4.4.1 Hypotheses 
No formal hypothesis tests are planned. Descriptive statistics will be used to assess the key 
objectives of this study: evaluation of safety, tolerability, systemic exposure and clinical effect of 
topically applied GSK2981278 ointment in subjects with plaque psoriasis. 
3.4.4.2 Statistical analyses 
Clinical effect data will be summarized using both the Observed Cases (OC) approach and the 
last observation carried forward (LOCF) approach if there are missing values. 
Both change and percent change in TPSS, PGA, PASI and Psoriasis Symptom Diary scores, 
and in %BSA affected and treated, from baseline to each study visit will be summarized based 
on the per protocol analysis set. For TPSS, the individual subscore for scaling, erythema and 
induration, as well as the total score will be summarized. For PASI, the item 6 score for each 
body area, as well as the total score will be summarized. For Psoriasis Symptom Diary, the 
score for severity of itching (Question 1), the score for bother of itching (Question 2) and the 
total score, calculated by the sum of scores from each question, will be summarized. The mean 
Total TPSS score will be presented by a line plot.  
3.4.5 Safety analyses 
Safety will be evaluated by extent of exposure to study drug, adverse events (AEs), application 
site tolerability, lab data and vital signs. 
3.4.5.1 Extent of exposure to study drug 
The extent of exposure to study drug will be summarized by the duration of the treatment, the 
total number of IMP applications, the total amount of IMP used [g] and the average amount of 
IMP used per application [g]. For each treatment descriptive statistics will be presented in the 
safety analysis set.   
The duration of the treatment and total number of IMP applications will be calculated, as given 
in section 3.4.3. Total amount of IMP used [g] will be determined from the weights of distributed 
and returned IMP containers and average amount per application [g] will be calculated as the 
total amount of IMP used divided by the total number of IMP applications.  
The exposure to study treatment will be summarized. A by-subject listing of data on subject 
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of the treatment, dose, dose units, dose formulation, dose frequency, the total number of IMP 
applications, the total amount of IMP used [g], the average amount of IMP used per application 
[g], and % of IMP applications. 
3.4.5.2 Adverse events 
AEs will be coded according to version 20.0 of medical dictionary for regulatory activities 
(MedDRA). If data allow, summaries of AE will be provided. Frequencies and percentages will 
be presented overall, for each system organ class, and for each preferred term. Summaries of 
treatment-emergent AEs, treatment-related AEs, AEs leading to discontinuation of study 
treatment, and SAEs will be provided. When appropriate, AE onset date, end date, duration 
[days] (end date – onset date + 1), time since study treatment start date [days] (onset date - 
study treatment start date + 1), seriousness, severity, relationship to study drug, action taken, 
and outcome will be listed by subject together with baseline characteristics including age, race, 
sex, weight and BMI. 
3.4.5.3 Laboratory analyses 
Change from baseline in hematology and chemistry results will be summarized at every 
scheduled time point. Urinalysis dipstick results will be summarized by frequency counts. The 
number of subjects with abnormal values based on values relative to the laboratory normal 
ranges will be summarized for each assessed time point.  
A listing of all laboratory data for subjects with any value of PCI or outside the normal range and 
a listing of laboratory values of PCI or outside the normal range will be provided. A listing of 
laboratory data with character results will be provided. When appropriate, the listing will include 
age, race, sex, the laboratory test name (units), planned visit, date of lab sample, study day of 
lab sample, lab test value, normal value range, abnormal range flag, and PCI flag. 
A listing of urinalysis data for subjects with any value of PCI will be provided. 
3.4.5.4 ECG analyses  
Change from baseline at every scheduled time point for each ECG parameter will be 
summarized using descriptive statistics. The ECG will be evaluated by the investigator as 
“Normal”, “Abnormal, not clinically significant”, and “Abnormal, clinically significant”. A summary 
of ECG findings will be provided. Also, a listing of all ECG data for subjects with any value of 
PCI, a listing of ECG values of PCI and a listing of ECG clinically significant abnormal findings 
will be generated.  
3.4.5.5 Tolerability analyses 
A listing of application site tolerability will be provided. 
3.4.5.6 Other safety analyses 
Change from baseline for each vital sign parameter, including weight [kg] and the body mass 
index (BMI) [kg/m²], determined as weight [kg] / (height [m])2, will be summarized by visit using 
descriptive statistics. A listing of vital signs and a listing of change from baseline for vital signs 
will be provided. A listing of vital signs for subjects with any value of PCI and a listing of vital 
signs of PCI will be provided.  
If applicable, liver event data will be listed. 


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3.4.6 Pharmacokinetic analyses 
3.4.6.1 Overview of planned pharmacokinetic analyses 
The Pharmacokinetic analyses will be based on the “Pharmacokinetic” population, unless 
otherwise specified. Derivation of pharmacokinetic parameters will be performed by, or under 
the direct auspices of, Clinical Pharmacology Modelling and Simulation (CPMS), 
GlaxoSmithKline.  
Table 15 provides an overview of the planned Pharmacokinetic analyses: 
 
Table 15 
Overview of Planned Pharmacokinetic Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.4.6.2 Drug Concentration Measures 
Concentrations of GSK2981278 in plasma will be listed and summarized by visit (Day 1, Day 
15, Day 29, Day 57) and nominal time.  Standard summary statistics will be calculated.  Refer to 
the guidance document, Non-Compartmental Analysis of Pharmacokinetic Data [GUI_51487], 
for more information regarding the treatment of GSK2981278 concentrations below the assay’s 
lower limit of quantification (NQ). 
3.4.6.3 Pharmacokinetic Parameters 
3.4.6.3.1 Deriving Pharmacokinetic Parameters 
 
The pharmacokinetic parameters in plasma will be calculated by standard non-
compartmental analysis according to current working practices and using Phoenix 
WinNonlin v 6.3 or higher.  
 
All calculations of non-compartmental parameters will be based on actual sampling times for 
the final analysis. 
Pharmacokinetic parameters described in  
Table 16 will be determined from the plasma concentration-time data, as data permits. All 
parameters will be calculated for Day 1, 29 and Day 57 as data permits, except where stated 
otherwise for time-invariance. 
 
[Endpoint / 
Parameter/ Display 
Type] 
Untransformed 
Log-Transformed 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
PK Concentrations 
Plasma GSK2981278 
concentrations 
 
 
 
Y 
Y 
Y 
Y 
 
 
 
 
Y 
Y 
 
PK Parameters 
Plasma GSK2981278 
parameters 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
Y 
 
 
NOTES : 
 
T = Table, F = Figure, L = Listings, Y = Display generated. 
 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
 
Individual = Represents FL related to any displays of individual subject observed raw data.     
 
 


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Table 16 
Derived Pharmacokinetic Parameters 
Parameter 
Parameter Description 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
AUC(0-t) 
Area under the concentration-time curve from time zero to the last measured concentration 
[10 hrs] will be calculated using the linear trapezoidal rule for each incremental trapezoid 
and the log trapezoidal rule for each decremental trapezoid. 
Time-
invariance 
Time-invariance estimated as a ratio of AUC(0-t) on Day n (where n=29, 57) to AUC(0-t) on 
Day 1. 
NOTES: 
 
Additional parameters may be included as required. 
3.4.6.3.2 Statistical Analysis of Pharmacokinetic Parameters 
No planned statistical analyses of pharmacokinetic parameters. Pharmacokinetic parameters 
will be summarized descriptively. Log10-transformed data will be summarized by the geometric 
mean, determined as 10 to the power of the mean of log-transformed data, standard deviation 
of log10-transformed data (SD(log)), and the between subject coefficient of variation (%CVb), 
determined as 
√10(SD(log))2 −1 ∗100. 
3.5 
Data handling conventions 
 
For this study subject data will be entered into GSK/bioskin defined eCRFs, 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) Version 20.0 and an internal validated 
medication dictionary, GSKDrug Version 1.3.   
 
eCRFs (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. 
 
3.5.1 Missing data 
A description of missing data will be provided in the clinical study report.  
Clinical effect data will be summarized using both the Observed Cases (OC) approach and the 
last observation carried forward (LOCF) approach if there are missing values. Only efficacy data 
up to Day 57 visit will be imputed. No imputation for the Follow-up visit will be carried out. 
For past and current medical conditions, missing or incomplete (i.e., partial missing) start date 
and/or stop date will not be imputed. If the stop date is not identifiable as prior to date of first 
application of study treatment, the medical condition will be considered as current, and past, 
otherwise (see section 3.1).  


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For prior or concomitant medications or therapies, incomplete (i.e., partial missing) start date 
and/or stop date will not be imputed. If the stop date is not identifiable as prior to date of first 
application of study treatment, the medication or therapy will be considered as concomitant, and 
prior, otherwise (see section 3.1). 
For the assessment of order of events, event A is prior to event B, if year of event A is prior of 
year of event B, or if years are equal, if month of event A is prior to month of event B, or if years 
and months are equal, if day of event A is prior to day of event B.  
3.5.2 Window for time points 
Visit window violations will be documented as protocol deviations and assessed within the blind 
data review meeting. 
Assessments performed out of the planned visit windows will be assigned to the nearest, 
directly preceding or following, planned visit, only, if the visit is missing. If both visits are missing 
and the distances are equal, the assignment is performed to the following one. Otherwise the 
assessments will not be included in the statistical evaluation and will be listed only. 
3.5.3 Unscheduled visits 
If applicable, the reason for unscheduled visit measurements will be given together with the 
results in data listings. For the analysis, the unscheduled assessments will be assigned to a 
planned visit following the procedure in section 3.5.2, above. 
3.5.4 Pooling of centers for statistical analyses 
Not applicable. 
3.5.5 Statistical technical issues 
Not applicable. 
3.5.6 Database related issues 
Not applicable. 
4 Interim analysis 
No formal interim analysis is planned. 
5 Software documentation 
The statistical evaluation will be performed at bioskin using the software package SAS 
(Statistical Analysis System, SAS Inc., Cary, NC). 
6 References 
GlaxoSmithKline Document Number 2016N275350_01 Study ID 203820. A two-part trial to 
evaluate the safety, tolerability, clinical effect and systemic exposure potential of topically 
applied GSK2981278 ointment in subjects with plaque psoriasis. 2016-Dec-13. 


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Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 
2005;64:65-68. 
GlaxoSmithKline Document Number GUI_51487, version 4.0. Non-compartmental analysis of 
pharmacokinetic data. Effective date 2014-Oct-29. 
Lebwohl, M. AMAGINE‐2: A Randomized, Double‐blind, Phase 3 Efficacy and Safety Study of 
Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis 
Patients.  AAD 2015 Late-breaking abstract F010. 
Strober BE, Nyirady J, Mallya UG, Guettner A, Papavassilis C, Gottlieb AB. Item-level 
psychometric properties for a new patient reported Psoriasis Symptom Diary. Value Health. 
2013;16:1014-1022