Clinical trial NCT02927457
Conditions: Lupus Erythematosus, Cutaneous
Keywords: Cutaneous Lupus Erythematosus-CLE Spleen Tyrosine Kinase-SYK Photoprovocation-PV GSK2646264
Sponsor: GlaxoSmithKline
Start date: 2017-01-13; Completion date: 2018-06-12
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to examine safety, tolerability, pharmacokinetics, pharmacodynamics and clinical effect of repeat dosing of GSK2646264 in patients with subacute and chronic cutaneous lupus erythematosus (CLE) lesions and in acute CLE like lesions induced by photoprovocation (PV).

Current study is two group study. In Group A, Patients with fewer than two active lesions will be enrolled and exposed to photoprovocation (PV) for 3 consecutive days. Patients that develop PV lesions at any time during this period, as determined by the local investigative team, will receive 1% strength GSK2646264 on 1 lesion and placebo on 1 lesion daily and either 1% strength GSK2646264 or placebo on an area of uninvolved skin, for skin pharmacokinetic (PK) of study drug, for 28 days.

In Group B, Patients that have a minimum of 2 active existing CLE lesions as determined by the investigators will be enrolled into group B and have one lesion treated with 1% GSK2646264 and 1 lesion with placebo.

A completed patient will be defined as a subject who receives at least 25 days of study drug and completes the end of treatment biopsy (at day 28) and assessment. Thereafter patients will be followed for 28 days in Group A only or until complete resolution of induced PV lesions, as determined by the investigator.

Detailed description:

Arms: arm 1: Skin areas A to E in group A are identified skin areas across the back of the subject. Subjects will be receiving GSK2646264 1% (A) for Area A- PV lesion, Placebo (P) for Area C- PV lesion and GSK2646264 1% for Area D- uninvolved skin once daily for 28 days according to randomisation. Skin areas B- PV lesion and E- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy. arm 2: Skin areas A to E in group A are identified skin areas across the back of the subject. Subjects will be receiving GSK2646264 1% for Area A- PV lesion, Placebo for Area C- PV lesion and Placebo for Area D- uninvolved skin once daily for 28 days according to randomisation. Skin areas B- PV lesion and E- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy. arm 3: Skin areas A to E in group A are identified skin areas across the back of the subject. Subjects will be receiving Placebo for Area A- PV lesion, GSK2646264 1% for Area C- PV lesion and GSK2646264 1% for Area D- uninvolved skin once daily for 28 days according to randomisation. Skin areas B- PV lesion and E- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy. arm 4: Skin areas A to E in group A are identified skin areas across the back of the subject. Subjects will be receiving Placebo for Area A- PV lesion, GSK2646264 1% for Area C- PV lesion and Placebo for Area D- uninvolved skin once daily for 28 days according to randomisation. Skin areas B- PV lesion and E- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy. arm 5: In group B, two chosen lesions will be labeled F and G based on size (F \>G). Subjects will be receiving GSK2646264 1% for lesion F and Placebo for lesion G once daily for 28 days according to randomisation. Skin area H- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy. arm 6: In group B, two chosen skin lesions will be labeled F and G based on size (F \>G). Subjects will be receiving Placebo for lesion F and GSK2646264 1% for lesion G once daily for 28 days according to randomisation. Skin area H- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy.
Interventions: intervention 1: GSK2646264 1% intervention 2: Placebo
Intervention descriptions: intervention 1: A cream for topical application with a concentration of 1% GSK2646264. intervention 2: Subjects will receive matching Placebo topically.

Protocol documents:
Prot_001.pdf: 
2015N246677_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
204860
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A double-blind (sponsor unblinded) study to investigate safety, 
tolerability, pharmacokinetics, pharmacodynamics and clinical 
effect of repeat dosing of GSK2646264 in cutaneous lupus 
erythematosus patients
Compound Number:
GSK2646264
Development Phase:
I
Effective Date:
14-DEC-2017
Protocol Amendment Number:  03
Author (s):
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2015N246677_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
204860
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N246677_00
2016-MAY-18
Original
2015N246677_01
2016-JUN-13
Amendment No. 1
Update to Time and Events Table Section 7.1.1 Group A and Section 7.1.3 Group B
2015N246677_02
2016-JUN-21
Republished
There was an error regarding the phase of the study. It should be phase I, not phase III.
2015N246677_03
2016-AUG-04
Amendment No. 2
Changes were required following a response from BfArM and ethics.  Specifically, to 
clarify the dose of GSK2646264 applied; Clarification of which groups the 
inclusion/exclusion/withdrawal criteria apply to; Addition of an exclusion criteria related 
to subjects with SLE and/or significant disease in other organs; Clarification related to 
abnormalities observed and withdrawal of subjects who take prohibited medications; 
Addition of HIV test at screening; Addition of withdrawal criteria for Group A subjects 
receiving photoprovocation; Clarification of dose in UV exposure in photoprovocation
2015N246677_04
2017-DEC-14
Amendment No. 3
Clarification of text in Objectives and Endpoints; Clarification of Treatment Groups with 
respect to LET patients and number of lesions they can present with; Update to number 
of patients to be recruited into each group; Update to Risk Assessment Table and 
Summary of Data/Mitigation Strategy; Alteration to Inclusion Criteria with respect to 
BMI; Inclusion of additional medication in Permitted Medications within Inclusion 
Criteria; Update to T&E table with respect to frequency of pregnancy testing for Group A 
and Group B; Revised Sample Size Considerations and Assumptions; Addition of in-
stream review of data


P P D
P P D


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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 
Numbe
r
Site 
Address
Primary 
Medical 
Monitor 
n/a
Medicines 
Research 
Centre, 
Gunnels 
Wood 
Road, 
Stevenage
, Herts, 
SG1 2NY
Secondary 
Medical 
Monitor
n/a
Medicines 
Research 
Centre, 
Gunnels 
Wood 
Road, 
Stevenage
, Herts, 
SG1 2NY
SAE 
contact  
informatio
n 
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):  2016-000277-20
PPD
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204860
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 204860........................................................9
1.1.
Rationale ......................................................................................................9
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................13
4.
STUDY DESIGN ....................................................................................................14
4.1.
Overall Design ............................................................................................14
4.2.
Study Overview Schematic .........................................................................15
4.3.
Type and Number of Subjects.....................................................................17
4.4.
Design Justification.....................................................................................18
4.5.
Dose Justification........................................................................................18
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.........................................................................................24
5.2.
Exclusion Criteria........................................................................................27
5.3.
Screening/Baseline Failures .......................................................................29
5.4.
Withdrawal/Stopping Criteria.......................................................................30
5.4.1.
Safety Related Stopping Criteria for an Individual Subject ...........30
5.4.2.
Local Tolerability..........................................................................32
5.4.3.
Safety Related Study Specific Dose Adjustment Criteria..............32
5.4.4.
Liver Chemistry Stopping Criteria ................................................33
5.4.4.1.
Study Treatment Restart or Rechallenge....................33
5.4.5.
QTc Stopping Criteria ..................................................................34
5.5.
Subject and Study Completion....................................................................34
6.
STUDY TREATMENT ............................................................................................34
6.1.
Treatment Assignment................................................................................35
6.2.
Blinding.......................................................................................................37
6.3.
Packaging and Labeling..............................................................................37
6.4.
Preparation/Handling/Storage/Accountability..............................................38
6.5.
Compliance with Study Treatment Administration.......................................38
6.6.
Treatment of Study Treatment Overdose....................................................38
6.7.
Treatment after the End of the Study ..........................................................39
6.8.
Lifestyle and/or Dietary Restrictions............................................................39
6.8.1.
Contraception Requirements .......................................................39
6.8.2.
Meals and Dietary Restrictions ....................................................39
6.8.3.
Caffeine, Alcohol, and Tobacco ...................................................39
6.8.4.
Activity .........................................................................................39
6.9.
Concomitant Medications and Non-Drug Therapies....................................39
6.9.1.
Permitted Medications and Non-Drug Therapies..........................39


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6.9.2.
Prohibited Medications and Non-Drug Therapies.........................40
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................40
7.1.
Time and Events Tables .............................................................................41
7.1.1.
Group A.......................................................................................41
7.1.2.
Group A PV non-responders........................................................45
7.1.3.
Group B.......................................................................................46
7.2.
Screening and Critical Baseline Assessments ............................................49
7.3.
RCLASI (Clinical Score)..............................................................................49
7.4.
Safety .........................................................................................................50
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........50
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................50
7.4.1.2.
Method of Detecting AEs and SAEs ...........................51
7.4.1.3.
Follow-up of AEs and SAEs........................................51
7.4.1.4.
Cardiovascular and Death Events ..............................51
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................52
7.4.1.6.
Regulatory Reporting Requirements for SAEs............52
7.4.2.
Pregnancy ...................................................................................53
7.4.3.
Physical Exams ...........................................................................53
7.4.4.
Vital Signs....................................................................................53
7.4.5.
Electrocardiogram (ECG).............................................................53
7.4.6.
Photo-provocation model.............................................................53
7.4.7.
Clinical Safety Laboratory Assessments ......................................54
7.5.
Pharmacokinetics .......................................................................................55
7.5.1.
Blood Sample Collection..............................................................55
7.5.2.
Biopsy Sample Collection ............................................................55
7.5.3.
Sample Analysis ..........................................................................56
7.6.
Biomarker(s)/Pharmacodynamic Markers ...................................................56
7.6.1.
Biomarker(s)/Pharmacodynamic measurements in Skin 
Biopsies.......................................................................................56
7.6.2.
Novel Biomarkers ........................................................................57
8.
DATA MANAGEMENT ...........................................................................................57
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................58
9.1.
Hypotheses.................................................................................................58
9.2.
Sample Size Considerations.......................................................................58
9.2.1.
Sample Size Assumptions ...........................................................58
9.2.2.
Sample Size Re-estimation or Adjustment...................................60
9.3.
Data Analysis Considerations .....................................................................61
9.3.1.
Analysis Populations....................................................................61
9.3.2.
Interim Analysis ...........................................................................61
9.4.
Key Elements of Analysis Plan ...................................................................61
9.4.1.
Primary Analyses.........................................................................61
9.4.2.
Secondary Analyses ....................................................................61
9.4.3.
Exploratory Analyses ...................................................................62
10. STUDY GOVERNANCE CONSIDERATIONS........................................................63
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............63


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10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................63
10.3.
Quality Control (Study Monitoring) ..............................................................64
10.4.
Quality Assurance.......................................................................................64
10.5.
Study and Site Closure ...............................................................................64
10.6.
Records Retention......................................................................................65
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................66
10.8.
Safety Reivew Team (SRT) ........................................................................66
11. REFERENCES.......................................................................................................67
12. APPENDICES........................................................................................................69
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................69
12.2.
Appendix 2: Liver Safety – Study Treatment Restart...................................71
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................74
12.3.1.
Definition of Adverse Events........................................................74
12.3.2.
Definition of Serious Adverse Events...........................................75
12.3.3.
Definition of Cardiovascular Events .............................................77
12.3.4.
Recording of AEs and SAEs ........................................................77
12.3.5.
Evaluating AEs and SAEs............................................................78
12.3.6.
Reporting of SAEs to GSK...........................................................79
12.4.
Appendix 4: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) .............................81
12.4.1.
Collection of Pregnancy Information ............................................81
12.5.
Appendix 5 - Country Specific Requirements..............................................83
12.6.
Appendix 6 Protocol Changes.....................................................................84
12.6.1.
Protocol changes for Amendment 3 from the Amendment 
2 ..................................................................................................84
12.6.2.
Protocol changes for Amendment 2 (04-Aug-2016) from 
the Protocol amendment 1 (13-June-2016)................................102
12.6.3.
Protocol changes for Amendment 1 (13-June-2016) from 
the Original Protocol (18-May-2016) ..........................................112


2015N246677_04
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1.
PROTOCOL SYNOPSIS FOR STUDY 204860
1.1.
Rationale
The autoimmune disease lupus erythematosus is associated with a broad range of 
cutaneous pathology which can be induced or exacerbated by  exposure to sunlight. Key 
opinion leaders and patients have highlighted the need for a new and effective topical 
formulation, suitable for long term use on exposed areas, with a favourable safety and 
tolerability profile. GSK2646264 is a potent, selective small molecule inhibitor of spleen 
tyrosine kinase (SYK), a 72 kDa non-receptor tyrosine kinase, with suitable physical-
chemical properties for dermal application. SYK mediates signalling through immuno-
receptors notably the B-cell receptor (BCR), IgG receptors (FcRI and III) and Fc epsilon 
receptors (FcR1). Thus, SYK plays a crucial role in the regulation of immune responses, 
in both adaptive and innate immune recognition in a variety of cell types including 
macrophages, plasmacytoid dendritic cells, T and B cells. Initiation of the lesional 
inflammation in lupus erythematosus is thought to be driven through the activation of 
interferon (IFN) via the innate pathway. SYK mRNA is expressed in both subacute and 
chronic subtypes of lupus and is coexpressed with a large number of genes known to be 
stimulated by the IFN pathway. In addition, phosphorylation of the SYK protein is 
increased in CLE and expressed not only by infiltrating lymphocytes, but also by 
keratinocytes in inflamed areas. SYK inhibition in vitro with GSK143 a selective SYK 
inhibitor has been shown to inhibit production of key IFN responsive genes implicated in 
the lesional pro-inflammatory vicious circle in CLE [Liddle, 2011], [Braegelmann, 2016]. 
This 
study 
is 
designed 
to 
examine 
safety, 
tolerability, 
pharmacokinetics, 
pharmacodynamics and clinical effect of repeat dosing of GSK2646264 in patients with 
subacute and chronic CLE lesions and in acute CLE like lesions induced by 
photoprovocation (PV).


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Objectives
Endpoints
Primary

To evaluate the safety and 
tolerability of repeat doses of a 
cream formulation of GSK 
2646264 in patients with CLE

Safety and tolerability by laboratory tests, 
vital signs, 12-lead ECG, and AE reporting.
Secondary

To determine the effect of 
GSK2646264 on the reduction in 
clinical activity score from 
baseline in treated PV and 
existing CLE lesions

To evaluate the plasma 
concentrations of GSK2646264 in 
patients with CLE

To determine the effect of 
GSK2646264 on expression of 
IFN mRNA signature in skin 
biopsies in treated PV and 
existing CLE lesions

Change from baseline of components of a 
modified RCLASI- composite clinical 
activity score at day 14 and day 28 in PV and 
existing lesions in erythema, oedema, 
dyspigmentation  (and scaling in existing 
CLE lesions only)

PK parameters will be summarised  

Change from baseline in IFN mRNA 
signature in skin biopsies at day 28 in PV 
and existing CLE lesions
Overall Design
This is a double blind (sponsor unblinded) Phase Ib two group study to investigate repeat 
doses of GSK2646264, a spleen tyrosine kinase (SYK) inhibitor administered via topical 
delivery, on safety, pharmacodynamic effect and clinical efficacy in active CLE lesions 
and in acute CLE like lesions induced by an established protocol of PV. The study 
population will be adult subjects (at least 18 years of age) that have been diagnosed with 
either subacute or chronic CLE.
Treatment Groups and Duration
Subjects with CLE that meet the entry criteria at the time of screening will be enrolled 
into two treatment arms dependent on the number of active lesions they present with. 
Group A: Patients with fewer than 2 active lesions will be enrolled into group A and 
exposed to PV for 3 consecutive days.  Patients with Lupus Erythematosus Tumidus 
(LET) can be enrolled into Group A only, and can present with any number of lesions, so 
long as the existing lesions are not in the areas designated for photoprovocation. Patients 
will be assessed for the development of lesions up to 14 days from the first PV. Patients 
that develop PV lesions at any time during this period, as determined by the local 
investigative team, will receive 1% strength GSK2646264 on 1 lesion and placebo on 1 
lesion daily and either 1% strength GSK2646264 or placebo on an area of uninvolved 
skin, for skin PK of study drug, for 28 days.


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Group B: Patients that have a minimum of 2 active existing CLE lesions as determined 
by the investigators will be enrolled into group B and have one lesion treated with 1% 
GSK2646264 and 1 lesion with placebo. 
A completed patient will be defined as a subject who receives at least 25 days of study 
drug and completes the end of treatment biopsy (at day 28) and assessment. Thereafter 
patients will be followed for 28 days or until complete resolution of induced PV lesions, 
as determined by the investigator. 
Type and Number of Subjects
The study population will be adults (at least 18 years of age). We aim to recruit 
approximately 25 patients into the study with the aim to randomise approximately 20
patients that have been evaluated by the investigators and diagnosed with subacute or 
chronic cutaneous lupus erythematosus. Approximately 10 patients will undergo PV in 
group A. PV response rates are estimated at 50% and we expect up to 5 PV positive 
patients to be randomised into the study. We aim to enroll approximately 15 patients into 
group B. We will include females of reproductive potential (FRP) in both groups of this 
study given the age and gender distribution (9:1-Female:Male preponderance) of the 
disease. Exclusion of FRP would significantly impair recruitment into the study and may 
affect the relevance of the data generated as the predominant patient population would be 
excluded.
Early termination of the study may occur due to feasibility of recruitment and/or 
individual subjects reaching safety stopping criteria.
Analysis
All data will be listed and summarised. 
Safety data will be presented in tabular and/or graphical format and summarised 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
Change from baseline in each clinical activity assessment will be analysed by study part;
part A will be summarised descriptively and part B will be analysed using a repeated 
measures mixed model including visit, treatment and lesion position as fixed effects and 
subject as a random effect. Estimates of the treatment means and differences will be 
presented with the associated 95% confidence intervals. 
Change from baseline in each IFN mRNA signature endpoints will be analysed by study 
part; part A will be summarised descriptively and part B will be analysed using a mixed 
model including treatment and lesion position as fixed effects and subject as a random 
effect. Estimates of the treatment means and differences will be presented with the 
associated 95% confidence intervals. If the data is not normally distributed a 
transformation may be applied to the data.  
Full details will be provided in the reporting and analysis plan. 


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In this sponsor-unblinded bilateral design study, 1 or more unblinded data reviews, using 
all available data to date, may be carried out by senior managers (not involved in the 
study conduct) and/or study team members (involved in the study conduct) to aid in 
portfolio and budget decisions.  These administrative reviews will have no impact on the 
ongoing study.  Full details will be provided in the reporting and analysis plan prior to the 
first administrative review.
2.
INTRODUCTION
2.1.
Study Rationale
GSK2646264 is a potent, selective small molecule inhibitor of  SYK, a 72 kDa non-
receptor tyrosine kinase, with suitable physical-chemical properties for dermal 
application  being developed for once daily treatment of skin lesions in CLE.
SYK is an intracellular protein tyrosine kinase that is expressed in many cell types and 
involved in a variety of receptor-mediated signal-transduction pathways notably through 
the BCR, IgG receptors (FcγRI and III) and Fc epsilon receptors (FcεR1). Systemic 
administration of small-molecule inhibitors of SYK activity suppress a number of 
inflammatory disease models such as skin injury and kidney damage in MRL/lpr mice as 
well as established skin lesions in such mice. In addition, inhibition of SYK can result in 
the disappearance of established skin lesions in BAK–/–BAX–/– double-knockout mice, 
which spontaneously develop inflammatory skin lesions [Deng, 2010].
Initiation of the lesional inflammation in CLE is thought to be driven through the 
activation of IFN via the innate pathway. The expression pattern of IFN-inducible 
antiviral proteins (e.g. MxA) and chemokines (e.g. CXCL9, CXCL10) reflects the 
characteristic inflammatory pattern found in different subtypes of CLE and in acute CLE 
lesions induced by photoprovocation. SYK mRNA is expressed in both subacute and 
chronic subtypes of lupus and is co-expressed with a large number of genes, such as MxA 
and CXCL10, known to be stimulated by the IFN pathway [Braegelmann, 2016]. In 
addition, phosphorylated SYK protein is expressed not only by infiltrating lymphocytes, 
but also by keratinocytes in inflamed areas. SYK inhibition in vitro with the selective 
inhibitor GSK143 has been shown to inhibit the production of key IFN responsive genes 
implicated in the lesional pro-inflammatory vicious circle in CLE [Liddle, 2011], 
[Braegelmann, 2016]. These results have been confirmed by gene expression analysis of 
lesional discoid lupus erythematosus skin biopsies, revealing a strong “type I IFN mRNA 
signature” including expression of IFN-inducible genes, such as IRF1, MxA and others. 
Moreover, this data provided evidence that type I IFNs and potentially autoreactive 
cytotoxic lymphocytes targeting adnexal structures are associated with scarring CLE 
lesions and might be responsible for their disfiguring character. 
2.2.
Brief Background
The autoimmune disease lupus erythematosus predominantly affects FRP and is 
associated with a broad range of cutaneous pathology. Current topical treatments for CLE 
include tacrolimus, retinoid and steroid based regimes are only partially effective and 
limited in their use by long term side effects. 


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Key opinion leaders and patients have highlighted the need for a new and effective 
topical formulation, suitable for long term use on exposed areas, with a favourable safety 
and tolerability profile in comparison to topical steroids and immunosuppressants. In 
particular, a reduction in the extent of scarring caused by lesions in exposed areas such as 
the face and scalp is urgently required and would greatly impact on the quality of life 
(QoL) in patients with CLE.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To evaluate the safety and 
tolerability of repeat doses of a 
cream formulation of GSK 
2646264 in patients with CLE

Safety and tolerability by laboratory tests, 
vital signs, 12-lead ECG, and AE reporting.
Secondary

To determine the effect of 
GSK2646264 on the reduction in 
clinical activity score from 
baseline in treated PV and 
existing CLE lesions

To evaluate the plasma 
concentrations of GSK2646264 in 
patients with CLE

To determine the effect of 
GSK2646264 on expression of 
IFN mRNA signature in skin 
biopsies in treated PV and 
existing CLE lesions

Change from baseline of components of a 
modified RCLASI- composite clinical 
activity score at day 14 and day 28 in PV and 
existing lesions in erythema, oedema, 
dyspigmentation  and (scaling in existing 
CLE lesions only)

PK parameters will be summarised

Change from baseline in IFN mRNA 
signature in skin biopsies at day 28 in PV 
and existing CLE lesions
Exploratory

To determine the effect of
GSK2646264 on expression of 
IFN protein markers in skin 
biopsies in treated PV and 
existing CLE lesions

To determine the effect of
GSK2646264 on expression of 
pSYK and SYK protein in skin 
biopsies in treated PV and 
existing CLE lesions 

To determine the effect of

Change from baseline in IFN proteins (eg 
MxA, CXCL10) in skin biopsies at day 28 in 
PV and existing CLE lesions

Change from baseline in pSYK and SYK 
protein in skin biopsies at day 28 in PV and 
existing CLE lesions

Change from baseline in immune cell 


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Objectives
Endpoints
GSK2646264 on immune cell 
markers in skin biopsies in treated 
PV and existing CLE lesions

To determine the effect of 
GSK2646264 on the histological 
disease activity in PV and existing
CLE lesions

To evaluate the skin 
concentrations of GSK2646264 in 
patients with CLE
proteins (eg CD3, CD20, CD11c, CD123, 
CD68) in skin biopsies at day 28 in PV and 
existing CLE lesions

Change from baseline in histopathology 
score (including parakeratosis, 
balloning/hydropic degeneration, epidermal 
cell-death, junctional and dermal 
inflammation) in skin biopsies at day 28 in 
PV and existing CLE lesions

Skin biopsy concentrations and derived 
pharmacokinetic parameters of GSK2646264
4.
STUDY DESIGN
4.1.
Overall Design
This is a double blind (sponsor unblinded) Phase Ib study to investigate repeat topical 
doses of GSK2646264 over 28 days on safety, pharmacodynamic effect, clinical efficacy 
and tolerability in active CLE and in lesions induced by a well established protocol of 
PV. The study population will be adult subjects (at least 18 years of age) that have been 
evaluated by the investigative site team and been diagnosed with either subacute or 
chronic CLE. Patients with Lupus Erythematosus Tumidus (LET) are allowed in group A 
only. The study has a 28 day maximum screening period and subjects who meet the entry 
criteria will be entered into one of two treatment groups dependent on the number of 
active lesions at the time of screening. Approximately 10 patients with fewer than 2 
active lesions at the time of screening will be enrolled into group A and will undergo 
photo-testing followed by PV for up to 3 consecutive days on 3 (7cm by 5cm) areas on 
their back. Patients with LET can be enrolled into Group A only, and can present with 
any number of lesions, so long as the existing lesions are not in the areas designated for 
photoprovocation Patients will be assessed at least twice weekly for up to 14 days from 
the first day of PV. Up to 5 patients that develop PV lesions at all three sites at any time
during this period, as determined by the local investigative team, will have a biopsy of 
one PV lesion (B) and one area of uninvolved skin (E) on their back close to the PV 
lesions (see Section 4.2 schematic and Figure 1 for visual representation). The two non-
biopsied PV lesions (A,C) will be randomised to receive 1% GSK2646264 on one lesion 
and placebo on the other once daily for 28 days. A biopsy will be obtained post-treatment 
from each of these treated lesions. An additional separate area of uninvolved skin on the 
back (D) will be randomised 4:1 to receive either GSK2646264 or placebo and a biopsy 
on day 28 (post-dose) will be taken for skin pharmacokinetics assessment. Patients that 
have not developed PV lesions by day 14 (expected to be approximately 50% of the 
subjects), as determined by the investigative team, will not be included in the study. A 
small percentage of patients will develop PV lesions more than 14 days after PV (defined 
in this study as a ‘non-responder’) and these patients will not be included in the study but 
will be followed up until PV lesion resolution, as determined by the investigator (see 
Section 7.1.2). 


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Group B will commence in parallel and recruit approximately 15 patients with a 
minimum of 2 active CLE lesions within the same anatomical area. At the day-5 to day -3 
visit the two chosen lesions will be labelled based on size F (the larger) and G (the 
smaller). Pre-dose biopsies will be taken from both of the lesions (F+G) and an additional 
biopsy (H) from uninvolved skin from the same anatomical area will also be taken. The 
patients will be randomised 2-4 days later to allow for healing of the biopsies  (F+G) and 
one lesion will then be treated with 1% GSK2646264 and the other with placebo once 
daily for 28 days. Biopsies will be obtained post-treatment from both treated CLE lesion 
(F+G). A completed patient will be defined as a patient who receives at least 25 days of 
study drug and completes the end of treatment biopsy (day 28) and assessment.
4.2.
Study Overview Schematic


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Treatment Groups and Duration
In group A subjects will receive both active treatment and placebo-to-match treatment 
which will be randomly assigned to 2 PV lesions (A+C). The skin site from which the 
biopsy to quantify concentration of drug in the skin in group A is taken (site D) will be 
randomised 4:1 to receive either active treatment or placebo.
All subjects in group B will receive both active treatment and placebo to match treatment 
which will be randomly assigned to the two chosen natural lesions (F+G).
The total duration of the study for group A is anticipated to be approximately 14 weeks, 
consisting of the following: Screening period (up-to 28 days); photoprovocation and 
lesion development (3 to 15 days); study treatment period (28 days); follow-up period (28 
days) or until resolution of PV lesions (whichever is the latter). 
The total duration for group B is anticipated to be approximately 12 weeks, consisting of 
the following: Screening period (up-to 28 days); biopsies followed by 2-4 day healing 
period; study treatment period (28 days); follow-up period (28 days).
The duration of study treatment will be 28 days of once-daily cream application to a 
defined skin lesion area not more than 0.5% body surface area (~90cm2).
4.3.
Type and Number of Subjects
We will recruit approximately 25 patients with CLE into the study with the aim to 
randomise approximately 20 patients. Based on past clinical experience approximately 
50% of patients recruited into group A will develop PV lesions and up to 5 PV positive 


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patients will be randomised. We aim to randomise approximately 15 patients into group
B of the study. 
If subjects prematurely discontinue the study, additional replacement subjects may be 
enrolled at the discretion of the Sponsor in consultation with the investigator. 
Early termination of the study may occur due to feasibility of recruitment and/or 
individual subjects reaching safety stopping criteria.
4.4.
Design Justification
This study is designed to investigate repeat topical doses of 1% GSK2646264 over 28 
days on clinical safety, tolerability, pharmacokinetics, efficacy and pharmacodynamic 
effect in CLE and in CLE like lesions induced by PV. 
The study population will include approximately 20 evaluable subjects with subacute 
CLE (SCLE), chronic CLE (CCLE) including LET (group A only). In group A the study 
comprises of a 28 day treatment period and patients will be followed thereafter for 28 
days or until resolution of induced PV lesions as determined by the investigators. 
Endpoint assessments will be conducted at the end of the 28 day treatment period. The 
provoked PV lesions offers the advantage to study acute CLE like lesions that exhibit the 
characteristic IFN signature of CLE lesions but show no features of chronicity and 
scarring. 
In group B outcomes will be assessed in existing CLE lesions of patients with SCLE or 
CCLE but not LET which in the context of a chronic autoimmune disease represent 
multiple stages of lesion development and activity and are heterogenous in nature.
The study is designed to deliver data on safety and tolerability and will inform future 
studies.
4.5.
Dose Justification
GSK2646264 will be administered topically as a cream at 1% (w/w) strength.The 
maximum topically applied dose to any subject at any time point will be 10mg/cm2 of 
cream over 90 cm2 (maximum of ~0.5% Body Surface Area as determined by Du Bois, 
1916). This equates to a maximum of 900mg of cream and therefore 9 mg of 
GSK2646264. A corresponding placebo will also be applied.  Cream will be weighed 
both before and after application. 
In part A of the first time in human study in healthy subjects (study 200196, 
NCT02424799, GlaxoSmithKline Document Number 2013N167482) GSK2646264 was 
given for up to 4 days as a cream of 1% strength (w/w) covering 5.2% BSA for 2 days 
followed by 10.2% BSA for 2 days. Preliminary data from the FTIH study suggests that 
GSK2646264 penetrates through the skin and reaches the systemic circulation.
A Population pharmacokinetics model was developed using clinical data from study 
200196 part A (N=17 healthy volunteers) and 3 cold urticaria subjects from part B. This 
model predicted, for GSK2646264 administered topically as a cream of 1% strength 
(w/w) on 0.5% of BSA, a Cmax of 0.780 ng/mL and an AUC (0-24) at steady state of 


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17.2. ng.h/mL. Those exposures are well within safety margins as described in the 
Investigator 
Brochure 
and 
supplement 
[GlaxoSmithKline 
Document 
Number 
2013N182566_02, GlaxoSmithKline Document Number 2015N268236_01 (Supplement 
1) and GlaxoSmithKline Document Number 2016N281634_00 (Supplement 2]
Preclinically, when GSK2646264 was administered into ex-vivo human healthy skin via a 
microdialysis tube a dose-dependent inhibition of IgE-stimulated histamine release from 
dermal mast cells was observed. The concentration of GSK2646264 required to inhibit 
90% histamine release in anti IgE-stimulated skin ex vivo is achievable by the topical 
route when administered at the 1% strength see GSK2646264 Investigator Brochure.
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2646264 can be found in the Investigator’s Brochure. The following section outlines 
the risk assessment and mitigation strategy for this protocol:


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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Pregnancy & Lactation
Fetal malformations were seen after IV dosing to 
pregnant Dutch belted rabbits with a NOAEL that 
is expected to exceed the highest expected 
human exposure by 13 and 214 fold cover 
compared to the predicted AUC (220 ng.hr/mL) 
and Cmax (167 ng/ml) respectively at the 
NOAEL.
In a subsequent study in the New Zealand White
rabbits, neither cardiovascular nor skeletal 
abnormalities were detected by any route and 
dose at maternal plasma exposures similar to or 
higher than exposures achieved in Dutch Belted 
rabbit. Based on these new fetal and TK data, 
the abnormalities in the Dutch Belted rabbit study 
were unlikely to be test article-related because 
no fetal abnormalities were detected in the New 
Zealand White rabbit with a similar Cmax (bolus 
route compared) or at a 4.5-fold higher AUC 
(bolus vs 24-hr continuous infusion compared).
The higher number of specific cardiovascular 
and skeletal abnormalities observed in the Dutch 
Belted rabbit Embryofoetal Development (EFD)
study is likely related to the known higher 
spontaneous background incidence of these 
findings in Dutch Belted relative to New Zealand 
White fetal rabbits based on Test Facility 
Women who are pregnant, lactating or are 
planning on becoming pregnant during the study 
are not eligible to participate.
Female subjects of reproductive potential will 
undergo regular pregnancy testing (at screening, 
Day 1, Day 14, and at follow-up) and treatment 
will be stopped immediately if a subject is found 
to be pregnant during the study, see Section 7.1
for exact timings. Subjects will also be required 
to be using an appropriate contraceptive (failure 
rate <1%) prior to the start and during the study 
as outlined in the protocol Section 5.1, Inclusion 
criteria.  Females of reproductive potential must 
be on established contraceptives 28 days before 
dosing begins.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
historical control data and this is also supported 
in literature (Posobiec, 2016)
No similar changes were seen in the rat after 
substantially higher exposure.
There is no data available on the effect of 
GSK2646264 in pregnancy and lactation in 
humans.
Thyroid follicular epithelial hypertrophy
Minimal thyroid follicular epithelial hypertrophy 
was observed in all doses following iv 
administration of GSK2646264 in rats for 4 
weeks.  Thyroid hormones (TSH, T3 and T4) at a 
single timepoint 12 hours post last dose were 
within normal range.
No similar changes were seen following dermal 
administration of GSK2646264 in rats for 4 
weeks which resulted in similar AUC values but 
lower Cmax values.
The ongoing clinical study has not identified 
clinical signs or symptoms of thyroid dysfunction 
to date.
The risk of thyroid effect in this study is 
considered not to be significant. 
Subjects with history of Graves’ disease, thyroid 
cancer, or abnormal thyroid function as 
measured by TSH, free T4 and free T3, will be 
excluded from this study.
Monitoring will be based on signs and symptoms, 
and serum markers of thyroid function will be 
measured in patients as outlined in Section 7.1


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Hypersensitivity to formulation
Dose related dermal findings in the rat were 
limited to observations of transient erythema and 
eschar at 1 and 3% (w/w).  Desquamation was 
observed in one control and one treated animal 
at 3% (w/w).  There were no histopathological 
correlates to these observations.  Erythema was 
also a transient observation in the minipig but 
occurred with both vehicle and test article 
formulations without relationship to GSK2646264 
(mesylate salt) dose strength and without 
histopathological correlate.
There may be potential for hypersensitivity 
reactions from the procedures used in the study 
or if subjects are allergic to ingredients in the 
study medications.  
The ongoing FTIH study has not identified any 
significant safety concerns to date, as assessed 
by adverse events.
Subjects will be excluded from the study if they 
are allergic to any ingredient of the study 
medications.
Subjects will undergo regular medical 
assessment and instructed on what action to 
take in the event of an allergic reaction, see 
Section 7.1.
Study Procedures
UV exposure
Risk for development of skin cancer 
PV has been widely used in a number of 
multicenter trials with several thousand patients 
enrolled to date which show no evidence for 
enhanced skin cancer risk. The risk is further 
mitigated by strictly controlled exposure to UV on 
approximately 105cm2 BSA [Kuhn, 2011 ].


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4.6.2.
Benefit Assessment
This study contributes to the development of medicines in an area of unmet need. Key 
opinion leaders and patients have highlighted the need for a new and effective topical 
formulation, suitable for long term use on exposed areas, with a favourable safety and 
tolerability profile in comparison to topical steroids and immunosuppressants. In 
particular, a reduction in the extent of scarring caused by lesions in exposed areas such as 
the face and scalp is urgently required and would greatly impact on the QoL in patients 
with CLE.
All patients in group B of the study will receive study drug on at least one CLE skin 
lesion for up to 28 days. This may improve the treated lesion and may have minor short 
term benefit in terms of appearance of the lesion and associated itch and pain.
4.6.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to mitigate the risk of patients taking part in this 
study, the associated risks are justified by the anticipated long term benefit to patients 
with CLE.
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 Investigator Brochure 
[GlaxoSmithKline Document Number: 2013N182566_02, GlaxoSmithKline Document 
Number 2015N268236_01 (Supplement 1) and GlaxoSmithKline Document Number   
2016N281634_00 (Supplement 2)]
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.  
All inclusion/exclusion criteria and withdrawal criteria apply to subjects in both Part A 
and Part B, unless specifically stated otherwise.


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5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply: 
AGE
1. Between 18 and 70 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Subject values for the following parameters TSH, free T4, and free T3  within the 
normal range. 
3. Subject has confirmed diagnosis of LET (group A only), subacute or chronic CLE as 
determined by the investigators.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range for the 
population being studied may be included: only if the investigator in consultation with 
the Medical Monitor if required agree and document that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures.
WEIGHT
4. Body mass index (BMI) ≥19kg/m2 (inclusive)
SEX
5. Male OR Female
Females: 
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea. In 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 


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required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Section 12.4) from 28 days prior to the first dose 
of study medication and until 12 days after the last dose of study medication and 
completion of the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.


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INFORMED CONSENT
6. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
RELEVANT HABITS
7. All subjects must be free from scarring or skin markings (e.g. tattoos or piercings) 
and open wounds on the defined areas of the body that cream will be applied onto or 
that will be exposed to PV, unless in the opinion of the investigator it will not 
compromise the subjects’ safety and quality of data. 
8. Able to refrain from exposure to extended and direct sunlight during the study period, 
from screening until follow up, especially the area that is under treatment during the 
study.
9. Able to refrain from using self-tanning products on the areas on which the study 
cream will be applied for the duration of the study from screening to follow-up.
10. Able to refrain from shaving and waxing the areas on which the study cream will be 
applied during the duration of the study from screening to follow up.
PERMITTED MEDICATIONS
11. Patient stable on either no treatment or on :

Corticosteroids (≤7.5mg/day prednisone or prednisone equivalent or less) for 
a minimum of 30 days prior to screening and through to Day 28.

and /or hydroxychloroquine (≤400mg daily dose) for a minimum of 60 days 
prior to the initial photoprovocation for group A or Randomisation Visit for 
group B through to day 28. 

Topical steroids applied to the defined areas of the body that are not exposed 
to photoprovocation or  study cream from screening to Day 28.

Topical calcineurin inhibitors and retinoids applied to the defined areas of 
the body that are not exposed to photoprovocation or  study cream from 
screening to Day 28.

Opioids, if required for 
acute and chronic pain management, and
documented in the medical history/records


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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.
ALT >2xULN; 
2.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%)
3.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
4.
QTcF > 450 msec, or QTcF > 480 msec in subjects with Bundle Branch Block
NOTES: 

The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-
read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
5.
History of any past or present benign or malignant skin conditions and disease, 
unless in the opinion of the investigator it will not compromise the subjects safety 
and quality of data.
6.
Subjects with active Systemic Lupus Erythematosus (SLE) and/or significant disease 
in any other organ than the skin, as judged by the Investigator after discussion with 
the medical monitor
7.
Subjects with a history of Graves disease
8.
Subjects with a history of thyroid cancer.
9.
Unable to refrain from vitamins, herbal and dietary supplements (including St John’s 
Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half 
lives (whichever is longer) prior to the screening visit until the completion of the 
follow-up assessments, unless in the opinion of the Investigator, in consultation with 
the GSK Medical Monitor if required, the medication will not interfere with the 
study procedures or compromise subject safety. 
10. Clinically significant abnormality in the hematological, clinical chemistry, or 
urinalysis screen, that in the opinion of the investigator after discussion with the 


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medical monitor, requires further investigation, medical intervention or poses a 
safety risk to the subject to participate in the trial.
11. Subjects who start prohibited medications or therapies at any time during the study 
will be withdrawn from the study.
The following medications and therapies are prohibited at any time during the study:

Use of other investigational agents (biologic or non-biologic; investigational 
applies to any drug not approved for sale in the country in which it is used).

Co-enrolment into another study of an investigational agent or non-drug therapy.

Use of biological agents (e.g., alemtuzumab, rituximab, ATG) during the 
clinical study or within 12 months to first dose of study treatment.

Use of other immunosuppressive drugs commonly used in SLE including 
Azathioprine, Methotrexate, Mycophenolate, Cyclophosphamide within 3 
months to first dose of study treatment.
RELEVANT HABITS
12. History of regular alcohol consumption within 3 months of the study defined as: 
Alcohol will be allowed but limited to an average weekly intake of <21 units for 
males or <14 units for females).   
13. Direct exposure to UV light (e.g. sunbathing) to the testing areas within 2 weeks of 
study entry.
CONTRAINDICATIONS 
14. 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 (refer to the Investigator Brochure for a 
list of excipients).
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
15. 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. 
16. A positive HIV test at screening
17. A positive pre-study drug screen.  
18. Where participation in the study would result in donation of blood or blood products 
in excess of 450 ml within 3 months. 
19. 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 


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study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
20. Exposure to more than 4 investigational medicinal products within 12 months prior 
to the first dosing day.
Country Specific Exclusion criteria wording for Germany:
21. Subjects that are employees of either GlaxoSmithKline (sponsor) or one of the study 
centres (investigators).
22. Subjects who live in detention on court order or on regulatory action, see §40 
subsection 1 sentence 3 no. 4 AMG. (Arzneimittelgesetz).
CONCOMITANT MEDICATIONS
23. Oral Prednisolone 

Greater than 7.5 mg by mouth daily.  

Any increase in dose from screening to Day 28
24. Hydroxychloroquine 

Greater than 400mg oral daily. 

Any increase in dose from screening to Day 28.
  
25. Photosensitizing drugs within 5 half-lives prior to the photoprovocation visit.
5.3.
Screening/Baseline Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomised. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.4.1.6).
Screening assessments that yield initially abberant results (e.g. safety laboratory samples) 
may be repeated by the investigator based on their judgement. Subject re-screening is 
allowed up to a maximum of 2 times. 


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5.4.
Withdrawal/Stopping Criteria
WITHDRAWAL CRITERIA(Specific for Group A ONLY)
1. A subject will be withdrawn from the study, if they demonstrate an excessive or 
adverse reaction to the photoprovocation, as judged by the Investigator after 
discussion with the medical monitor.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. In case a subject withdraws from study they should be 
encouraged to continue contraception for 28 days. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
At the time a subject withdraws, every effort should be made to conduct assessments 
stipulated at the follow-up visit, as per the time & events tables, Section 7.1.
If subjects prematurely discontinue the study, additional replacement subjects may be 
enrolled at the discretion of the Sponsor in consultation with the investigator.
5.4.1.
Safety Related Stopping Criteria for an Individual Subject
A female subject will be withdrawn form the study if a positive pregnancy test is 
obtained during the study.
A subject may be withdrawn from the study if they present dose limiting toxicity. 
Toxicity is defined as dose-limiting toxicity if it meets the following criteria:
- Occurs within 24 hours after any dose.
- and is considered by the Investigator to be possibly or probably related to 
treatment


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- and, for AE or laboratory abnormality, is severe
- and, for tolerability,
is of Grade 3 or higher for “dermal response scoring (i)”, and 
is Grade C, F, G, or H according to the “other effects scoring (ii)” 
(Section 5.4.2 below)
-
and for Thyroid function – TSH to remain within the normal range at Day 14 
If dose limiting toxicity is observed in an individual, the investigator or designee may use 
their medical judgment to stop dosing the individual subject, and is required to 
immediately inform the GSK medical monitor or designee. They will then decide 
whether it is necessary for the Safety Review Team (SRT: See Section 10.8) to be 
convened immediately for review of the data and decision on dose adjustment or 
withdrawal of the individual subject.
The SRT will:

Evaluate and confirm potential dose-limiting toxicities both as data is generated 
(so-called ‘in-stream review’), and at any point during the study when a bulk of 
data review is determined necessary (e.g. this may be conducted once all subjects 
in group A complete all study visits, or at any other point during study conduct).

Pause enrolment and/or request safety-related changes to the trial protocol.
At a minimum (but not limited to), the following data-sets will be reviewed by the SRT:

Clinical laboratory assessments

Vital signs

Adverse (& serious adverse) Events

Local tolerability assessments
Additional data-sets not listed above may also be reviewed as deemed appropriate by the 
SRT. 
A subject may be withdrawn from the study if they present a Serious Adverse Event 
(SAE), regardless of its severity, and reasonably attributable in the opinion of the 
investigator to dosing with GSK2646264.
A subject will be withdrawn if they require concomitant medications as specified and 
listed in Section 5.2.
In the presence of any of the above events, every effort will be made to take a blood 
sample at the time of the event for pharmacokinetics analysis.


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5.4.2.
Local Tolerability
Tolerability will be assessed with the following skin irritation scoring system, where the 
score consists of a numeric score according to the dermal response scoring  i), and a letter 
according to the other effects scoring ii), as follows:
i) Dermal response scoring:
0 = no evidence of irritation
1 = minimal erythema, barely perceptible (pink)
2 = moderate erythema (definite redness), readily visible; minimal edema or 
minimal papular response
3 = strong erythema (intense redness), or erythema and papules
4 = definite edema
5 = erythema, edema, and papules
6 = vesicular eruption
7 = strong reaction spreading beyond test site
ii) Other effects:
Z = no other effect 
A = slight glazed appearance
B = marked glazing
C = glazing with peeling and cracking
F = glazing with fissures
G = film of dried serous exudate covering all or part of the dose site
H = small petechial erosions and/or scabs
5.4.3.
Safety Related Study Specific Dose Adjustment Criteria
If AEs are of severe intensity and are similar across subjects, or if unacceptable 
pharmacological effects, reasonably attributable in the opinion of the investigator to 
dosing with GSK2646264, or if dose limiting toxicity (see Section 5.4.1), are observed in 
at least 2 subjects, relevant reporting and discussion with the GSK medical monitor and 
the SRT will take place.
If a Serious Adverse Event (SAE) occurs in 1 subject and is deemed to be drug related, 
this would be deemed an SAR (Serious Adverse Reaction), and dosing will be halted in 
the individual (Relevant reporting and discussion with the GSK medical monitor and the 
SRT will take place, and halting of dosing will be considered for all study subjects). If 
dosing is halted for the entire study, any resumption of dosing will only take place after 
consideration by the SRT and discussion with the investigators and may necessitate 
approval of a substantial amendment submitted to the Ethics committees and Regulatory 
authorities.


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If average predicted or observed Cmax or AUC(0-24 h after last dose) of GSK264624 is 
greater than 16 ng/mL or 220 ng.hr/mL, respectively, subsequent doses may be adjusted 
based on toxicology cover and this will be agreed by the SRT. 
5.4.4.
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
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 
Section 12.2.
5.4.4.1.
Study Treatment Restart or Rechallenge
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted

Ethics and/or IRB approval is obtained, if required, and


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
Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Section 12.2 for full guidance. 
5.4.5.
QTc Stopping Criteria
A subject that meets either criterion below will be withdrawn from the study. The same 
QT correction formula (e.g QTcF) should be used to determine inclusion and 
discontinuation for any individual subject throughout the study.

QTcF > 500 msec,

Change from baseline: QTcF >60 msec
If a subject has underlying bundle branch block the following withdrawal criteria should 
be used instead:
Baseline 
QTcF 
value 
(with 
underlying bundle branch block)
QTcF withdrawal criteria
<450 msec
>500 msec
450-480 msec
530 msec
Withdrawal of subjects is to be based on an average QTcF value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a brief period 
of time and then use the averaged QTcF values of the 3 ECGs to determine whether the 
subject should be discontinued from the study.
5.5.
Subject and Study Completion
A completed subject will be defined as a subject who receives at least 25 days of study 
drug and completes the end of treatment biopsy and assessment. Patients will be followed 
as per the Time & Events table, Section 7.1 until complete resolution of induced PV 
lesions.
The end of the study is defined as the last subject’s last visit.
6.
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.


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Study Treatment
Product name:
1%
GSK2646264
Placebo
Formulation description:
White to off white aqueous 
cream
White to off white aqueous 
cream
Dosage form:
Topical
Topical
Unit dose strength(s)/Dosage level(s):
1% (w/w)
NA
Route/
Administration/
Duration:
Topical
Topical
Dosing instructions:
Should be applied topically 
as directed.
Should be applied topically as 
directed.
Physical description:
White-to-off-white aqueous 
cream stored in amber 
glass jars
White-to-off-white aqueous 
cream stored in amber glass 
jars
Manufacturer/
source of procurement:
Medpharm Guildford
Medpharm Guildford
6.1.
Treatment Assignment
Subjects will be assigned to treatment in accordance with the randomisation schedule 
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software. 
Skin areas A-C in group A are horizontally distributed across the back of the patient. The 
PV lesions will be labelled A, B, C. Study drug and placebo will be randomly assigned to 
lesions A and C. Lesion B will not be assigned a treatment and will be used for the 
baseline skin biopsy. A further area of uninvolved skin (area D) will also be treated with 
study drug or placebo in a ratio of 4:1. Another area of uninvolved skin (area E) will not 
be treated with either study drug or placebo and will be used solely to take a baseline 
biopsy.
Lesion/Skin Area
Type
Biopsy timing
Receives Drug/Placebo
A
PV lesion
Day 28

B
PV lesion
Baseline
C
PV lesion
Day 28

D
Uninvolved Skin
Day 28

E
Uninvolved Skin
Baseline


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Figure 1
Approximate anatomical representation of UV lesion induction sites 
(A-C) and uninvolved skin (D and E) for Group A
Group A subjects will be assigned to the following regimens:
Skin Sites A/C/D
Assignment ratio
Sequence 1
A/P/A
4
Sequence 2
A/P/P
1
Sequence 3
P/A/A
4
Sequence 4
P/A/P
1
P=Placebo, A= GSK2646264 1%
The nurse administering the treatments may be aware whether a patient is assigned to 
sequences 1/4 or sequences 2/3, however they will remain blinded to treatment. 
In group B, at the day -5 to day -3 visit, prior to pre-dose biopsies being taken, the two 
chosen lesions will be labelled F and G based on size (F >G). The two lesions will be 
randomly assigned placebo or study drug.  An area of uninvolved skin (area H) will not 


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be treated with either study drug or placebo and will be used solely to take a biopsy at 
baseline.  These lesions can be on any part of the body (all 3 lesions must be in the same 
anatomical area), but the subject must consent to be biopsied from the area with the 
lesions.
Lesion/Skin Area
Skin Type
Biopsy timing
Receives Drug/Placebo
F
Natural lesion
Baseline  and Day 28

G
Natural lesion
Baseline  and Day 28

H
Uninvolved Skin
Baseline
Group B subjects will be assigned to one of the following regimens:
Skin Sites F/ G
Assignment ratio
Sequence 1
A/P
1
Sequence 2
P/A
1
P=Placebo, A= GSK2646264 1%
6.2.
Blinding
This will be a double blind (sponsor unblinded) study and the following will apply. 

The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the  CRF 
A subject may continue in the study if that subject’s treatment assignment is unblinded. 

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.
6.3.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.


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6.4.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK2646264 is 
given below. More details will be available for sites to use in the Study Reference 
Manual (SRM).

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff, which may include a study nurse, 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 which may include a study nurse. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff which may include a study 
nurse.  Adequate precautions to avoid direct eye or skin contact should be taken. 
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.
In the case of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.
6.5.
Compliance with Study Treatment Administration
When subjects are dosed at the site or at their home, they will receive study treatment 
directly from the investigator or designee which may include a study nurse.  The date and 
time of each dose administered in the clinic or at the subjects home will be recorded in 
the source documents.   
6.6.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2646264 that is above the intended dose is considered an 
overdose.
GSK does not recommend specific treatment for an overdose.  The investigator or 
physician in charge of the subject at the time will use clinical judgment to treat any 
overdose.


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6.7.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because 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 patient’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.8.
Lifestyle and/or Dietary Restrictions
6.8.1.
Contraception Requirements
Contraception requirements are presented in detail in Section 12.4
6.8.2.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice 
and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days 
prior to the first dose of study medication until after the final dose.
6.8.3.
Caffeine, Alcohol, and Tobacco

Alcohol will be allowed but limited to an average weekly intake of <21 units for 
males or <14 units for females).   

There are no caffeine or tobacco restrictions.
6.8.4.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests. Subjects may participate in light recreational activities during 
studies.
Subjects should refrain from taking part in water based activities such as swimming and 
use of sauna/steam room for up to 3 hours following application of the study drug.
Showers/bathing should not be taken up to 3 hours following application of the study 
drug.
Use of sunscreen (UVA/UVB protection cream) on any PV lesions or lesions treated with 
study drug or placebo should be avoided.
6.9.
Concomitant Medications and Non-Drug Therapies
6.9.1.
Permitted Medications and Non-Drug Therapies
See Section 5.1 for complete details of permitted medications.


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6.9.2.
Prohibited Medications and Non-Drug Therapies
See Section 5.2 for complete details of prohibited medications
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.
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, 
pharmacokinetic, pharmacodynamic/biomarker or others] assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The IRB/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 450 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

Photographs may be taken of some of the procedures, tests, medical condition or 
reactions which may occur during the study.


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7.1.
Time and Events Tables
7.1.1.
Group A
Procedure
Screening 
(up to Day -
28)
Day 
-15
Day 
-14
Day -
13 to -
1
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 
to Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 29 
to 42
Follow-
upa
a All procedures listed to also be 
conducted if a subject decides to 
prematurely withdraw/discontinue
Informed Consent
X
Inc/Exc criteria 
assessment
X
Demography
X
Pregnancy Test 
(women)
X
X
X
X
Pregnancy testing to be 
performed at Screening, on Day 1 
(pre-dose), Day 14 (pre-dose) and 
once during follow-up, with day 
recorded
TSH, free T4, free 
T3
X
X
X
X
Vital Signs
X
X
X
X
X
Safety Lab Samples 
(clin chem, 
haematol, 
Urinalysis)
X
X
X
X
X
X
X
On days of dosing samples 
should be taken predose.
Sample timepoints during the 
Day-13 to Day-1 period are as 
follows: 
– once weekly during visits to 
assess PV lesion development
Full Physical Exam
X
X


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Procedure
Screening 
(up to Day -
28)
Day 
-15
Day 
-14
Day -
13 to -
1
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 
to Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 29 
to 42
Follow-
upa
a All procedures listed to also be 
conducted if a subject decides to 
prematurely withdraw/discontinue
Brief Physical Exam
X
Assessment to be performed pre-
dose
Sample timepoints during the 
Day-13 to Day-1 period are as 
follows:
– once weekly during visits to 
assess PV lesion development
12-lead ECG
X
X
X
X
On days of dosing assessments 
should be performed predose 
SLE clinical 
assessment
X
X
X
X
On days of dosing assessment as 
defined by the investigator  to be 
performed pre-dose . 
ANA, anti-dsDNA , 
anti-Ro and anti-La 
antibodies, HIV, Hep 
B, Hep C, FSH, 
Drug screen
X
Skin Biopsies
Xb
Xb
bDay 1 biopsies will be taken 
pre-dose. Day 28 biopsies will 
be taken 4 hours post-dose
UV threshold 
testing
X
Photoprovocation
Xc, d
Performed 24 hours after UV 
threshold testing.
cPV occurs once every 24 hours 
for 3 days on Day-14, Day-13 & 
Day-12.
d If PV induced lesions appear at 
all 3 sites after Day -14 or Day -
13, PV treatment can be stopped 
early


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Procedure
Screening 
(up to Day -
28)
Day 
-15
Day 
-14
Day -
13 to -
1
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 
to Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 29 
to 42
Follow-
upa
a All procedures listed to also be 
conducted if a subject decides to 
prematurely withdraw/discontinue
Lesion induction 
assessment
<- ----X------>
Lesion resolution 
assessment
X
X
Clinical score
X
X
X
Components  of the RCLASI as 
defined in Section 7.3
Assessments to be performed 
pre-dose
Local Tolerability
Assessment
X
X
X
X
X
X
X
Assessments to be performed 
pre-dose and up to one hour 
following dosing on days of 
dosing
Dosing
X
X
X
X
X
X
Once daily
Randomisation
X
Pre-dose


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Procedure
Screening 
(up to Day -
28)
Day 
-15
Day 
-14
Day -
13 to -
1
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 
to Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 29 
to 42
Follow-
upa
a All procedures listed to also be 
conducted if a subject decides to 
prematurely withdraw/discontinue
PK blood sample
X
X
X
X
X
X
X
Sampling timepoints:
Day 1 = pre-dose; and 5hrs (1
hr)
Between Day 2 and Day13: one 
pre-dose sample or postdose 
sample with time recorded since 
last dose
Day 14: predose sample 
Between Day 21 and Day27: one 
pre-dose sample or postdose 
sample with time recorded since 
last dose
Day 28: one postdose sample 
with time recorded since last dose
Between Day 29 and Day 42:  
one sample with time recorded 
since last dose
Follow-up visit: one sample with 
sampling day recorded
AE/SAE Review
X
<--------------------------------------------------------------------------X-------------------------------------->
Concomitant 
Medication Review
X
<--------------------------------------------------------------------------X---------------------------------------->


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7.1.2.
Group A PV non-responders
Procedure
Once-weekly up to 28 days after first  
photoprovocation
Final Follow-up visit(s)
(occurs until final PV induced lesion has 
resolved)
Notes
Brief Physical 
Exam
X
X
IMPORTANT: This table is ONLY applicable for 
subjects in group A that do not develop PV induced 
lesions within 14 days of the start of photoprovocation 
Once-weekly assessments will occur from 15 days 
post first photoprovocation up until 28 days post first 
photoprovocation.  Any PV lesion that develops after 
15 days post-photoprovocation will be followed up until 
resolution.
PV Lesion 
assessment (if 
present)
X
X
AE/SAE Review
X
X
Concomitant 
Medication 
Review
X


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7.1.3.
Group B
Procedure
Screening (up 
to Day -28)
Day -5 to 
-3
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 to 
Day 20
Day 21 to 
Day 27
Day 
28
Day 29 
to 42
Follow-up 
(between 
Day 43 to 
Day 56)a
a All procedures listed to also 
be conducted if a subject 
decides to prematurely 
withdraw/discontinue
Informed Consent
X
Inc/Exc criteria 
assessment
X
Demography
X
Pregnancy Test 
(women)
X
X
X
X
Pregnancy testing to be 
performed at Screening, on 
Day 1 (pre-dose), Day 14 (pre-
dose) and once during follow-
up, with day recorded
TSH, free T4, freeT3
X
X
X
X
Vital Signs
X
X
X
X
Safety Lab Samples 
(clin chem ,haematol, 
Urinalysis)
X
X
X
X
x
X
On days of dosing samples 
should be taken predose 
Full Physical Exam
X
X
Brief Physical Exam
X
Assessment to be performed 
pre-dose
12-lead ECG
X
X
X
X
On days of dosing 
assessments should be 
performed predose
SLE clinical 
assessment
X
X
X
X
On days of dosing assessment 
as defined by the investigator 
to be performed pre-dose .
ANA, anti-dsDNA 
antibodies, anti-Ro and 
anti-La antibodies, HIV, 
Hep B, Hep C, FSH, 
Drug screen
X
Lesion selection
X
Refer to Section 4.1 and 


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Procedure
Screening (up 
to Day -28)
Day -5 to 
-3
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 to 
Day 20
Day 21 to 
Day 27
Day 
28
Day 29 
to 42
Follow-up 
(between 
Day 43 to 
Day 56)a
a All procedures listed to also 
be conducted if a subject 
decides to prematurely 
withdraw/discontinue
Section  6.1
Skin Biopsies
Xb
Xb
b2 to 4 days healing time will 
be allowed prior to 
randomisation and the first 
dose.
Day 28 biopsies will be taken 4 
hours post-dose
Clinical score
X
X
X
Local tolerability
Assessment
X
X
X
X
X
X
X
Assessments to be performed 
pre-dose and up to one hour 
following dosing on days of 
dosing
Dosing
X
X
X
X
X
X
Once daily
Randomisation
X
Pre-dose


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Procedure
Screening (up 
to Day -28)
Day -5 to 
-3
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 to 
Day 20
Day 21 to 
Day 27
Day 
28
Day 29 
to 42
Follow-up 
(between 
Day 43 to 
Day 56)a
a All procedures listed to also 
be conducted if a subject 
decides to prematurely 
withdraw/discontinue
PK blood sample
X
X
X
X
X
X
X
Sampling timepoints:
Day 1 = pre-dose; and 5hrs (1
hr) 
Between Day 2 and Day13: 
one pre-dose sample or 
postdose sample with time 
recorded since last dose
Day 14: predose sample 
Between Day 21 and Day27: 
one pre-dose sample or 
postdose sample with time 
recorded since last dose
Day 28:one postdose sample 
with time recorded since last 
dose
Between Day 29 and Day 42:  
one sample with time recorded 
since last dose
Follow-up visit: one sample 
with sampling day recorded
AE/SAE Review
X
Concomitant 
Medication Review
X
Lesion resolution 
assessment
X
X


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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The SLE clinical assessment is an assessment defined by the investigator as per usual 
practice at their site and is used to determine predominant skin disease and no evidence 
of life or organ threatening systemic features.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity. In addition, smoking & alcohol history will be recorded.
Procedures conducted as part of the subject’s routine clinical treatment and obtained prior 
to signing of informed consent may be utilized for screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study.
7.3.
RCLASI (Clinical Score)
The RCLASI (Revised Cutaneous Lupus Erythematosus Disease Area and Severity 
Index) will be used to assess disease activity. RCLASI has been previously described by 
[Kuhn, 2010] as reliable in a multi-centre clinical trial setting for evaluation of CLE 
disease activity and damage to the skin in CLE sub-types.
In this study, components of the RCLASI will be utilised: only activity and 
dyspigmentation part of the damage scores will be recorded for lesions. All other sections 
in the RCLASI (site of involvement, mucous membrane lesions, and alopecia will not be 
used for clinical activity score). 


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Figure 2
RCLASI sub-section
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests [(such as vital signs, physical exams 
and laboratory safety tests)] may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.3.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
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. 
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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
AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.4.1.3), at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 12.3 Appendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.4.1.3.
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 12.3) 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 3.
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 12.3.3 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 
will be required to be completed.
These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 


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The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
7.4.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in subjects with CLE or SLE 
and can be serious/life threatening:

Exacerbation of SLE or transformation of CLE into SLE with organ 
involvement other than the skin 
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of a SAE).  These events will be recorded 
on the DRE page in the subject’s CRF within the appropriate time frame agreed upon by 
the SRT for completion of DRE CRF pages. These DREs will be monitored by the SRT 
(see Section 10.8) on a routine basis.   
NOTE: However, if either of the following conditions apply, then the event must be 
recorded and reported as an SAE (instead of a DRE): 
The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, or
The investigator considers that there is a reasonable possibility that the event was 
related to treatment with the investigational product
7.4.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment  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 Investigator Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.


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7.4.2.
Pregnancy
Any female subject who becomes pregnant while participating

will discontinue study medication immediately.

Please refer to Section 12.4.1 for details of collection of pregnancy information
7.4.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Skin, Cardiovascular, Respiratory, Renal, Gastrointestinal and Neurological 
systems. Height and weight will also be measured and recorded. 

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses
7.4.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse rate and 
respiratory 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. 
7.4.5.
Electrocardiogram (ECG)

Triplicate 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 QTcF intervals. Refer to Section 5.4.5 for QTcF withdrawal
criteria and additional QTcF readings that may be necessary.
7.4.6.
Photo-provocation model
Subjects will undergo UV threshold testing on six 4.5 cm2 areas of the lower back each 
for UVA and UVB irradiation during screening.  The maximum UVA irradiation 
received will be 100 Jcm-2 and the maximum UVB will be 200 mJcm-2 as per the method 
described by Kuhn, (2011). Twenty four hours after day 1 threshold testing, the MTD 
(minimal tanning dose; the lowest dose causing persistent pigment darkening evaluated 
24 hours after irradiation) for UVA and the MED (minimal erythema dose) for UVB will 
be evaluated. The dose intensities used for UVA and UVB irradiation for 
photoprovocation will be customized for each subject by determining his or her 
individual MTD and MED evaluated 24 hours after threshold testing. Thereafter, three
7x5 cm areas of uninvolved skin on the upper back will be irradiated daily for 3 
consecutive days with the MTD for UVA followed by 1.5 MEDs of UVB. All subjects 


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will be prohibited from exposure to direct UV radiation and the use of sunscreen on the 
tested areas.
7.4.7.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 1, 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 Q2 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.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 1. 
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
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)

Drug screen (to include at minimum: amphetamines, barbiturates, 


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Laboratory 
Assessments
Parameters
cocaine, opiates, cannabinoids and benzodiazepines)

Serum  or urine hCG Pregnancy test (as needed for women of child 
bearing potential)

Free T3

Free T4

TSH

ANA, Anti-ds DNA, Anti-Ro and Anti-La antibodies
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 5.4.4 and 
Appendix 2.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline. If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of GSK2646264 will be collected at 
the time points indicated in Section 7.1, Time and Events Tables. 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.  
Approximately 3 mL of blood will be collected into a blood collection tube at time points 
indicated in Section 7.1. 
Detailed sample collection, processing, storage and shipping procedures are provided in 
the Study Reference Manual (SRM).
7.5.2.
Biopsy Sample Collection
Skin punch biopsies, 4 mm in size, will be taken from subjects as detailed in the SRM at 
the timepoints indicated in Section 7.1 Time and Events Table. Biopsies will always be 
taken after the relevant clinical assessments have been completed.
Biopsies for drug concentration and disposition analysis of GSK2646264 will be
collected from subjects in group A only. One biopsy will be obtained at day 28 from 
uninvolved skin (skin area D), treated with either study drug or placebo. 


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The actual date and time of each skin biopsy sample collection will be recorded. Results 
will be reported under a separate Bioimaging protocol.
Details of PK skin biopsy sample processing, storage and shipping procedures are 
provided in the Study Reference Manual (SRM).
7.5.3.
Sample Analysis
Plasma  analysis will be performed under the control of PTS-IVIVT-BIB/TPR/NCGOM, 
GlaxoSmithKline,the details of which will be included in the Study Reference Manual 
(SRM). Concentrations of GSK2646264 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).
Skin biopsy analysis will be performed under the control of Bioimaging, 
GlaxoSmithKline, the details of which will be included in the SRM.  Concentrations of 
GSK2646264 will be determined in skin biopsies using currently approved bioanalytical 
methodology. Drug disposition will be investigated using Matrix Assisted Laser 
Desorption Ionization-Imaging Mass Specrometry (MALDI-IMS), as samples permit.  
Skin biopsy analysis will be completed under a separate protocol and results will be 
reported separately. Once the plasma or skin biopsies have been analyzed for 
GSK2646264 any remaining plasma or skin biopsy may be analyzed for other compound-
related metabolites and the results reported under a separate Mechanistic Safety & 
Disposition/Scinovo, GlaxoSmithKline protocol.
7.6.
Biomarker(s)/Pharmacodynamic Markers
7.6.1.
Biomarker(s)/Pharmacodynamic measurements in Skin Biopsies
For group A, two pre-dose biomarker / PD biopsies will be obtained at day 1, one from 
an uninvolved skin region on the back of the patient (skin area E), and one from PV 
lesion B. At day 28, post-treatment biomarker / PD biopsies will be obtained from the 
two remaining non-biopsied PV lesions A and C, one PV lesion treated with study drug 
and one PV lesion treated with placebo. 
For group B, three pre-dose biomarker / PD biopsies will be obtained at day -5 to -3, one 
from an uninvolved skin region (H) and from both of the existing lesions F and G. 
Ideally, the uninvolved skin region biopsy should be located on the same anatomical 
body area close to the existing lesion biopsy. At day 28, post-treatment biomarker / PD 
biopsies will be obtained from both of the existing lesions F and G, one existing lesion 
treated with study drug and one lesion treated with placebo. 
Details of biomarker / PD skin biopsy sample processing, storage and shipping 
procedures are provided in the Study Reference Manual (SRM).  
Biomarker / PD biopsies will be evaluated histologically and by transcriptomic analysis.
Transcriptomic analysis will determine the effect of placebo and active treatment on IFN 
gene expression. Gene expression will be measured using microarray technology, and/or 


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alternative equivalent technologies, which facilitates the simultaneous measurement of 
the relative abundances of thousands of RNA species resulting in a transcriptome profile 
for a skin biopsy sample. Genes may include but are not restricted to: MX1, MX2, OAS1, 
OAS2, IFI44. The same samples may also be used to confirm findings by application of 
alternative technologies.
Histological assessments of the biopsies will explore changes in pharmacodynamic and 
disease biomarkers. Markers may include (but are not restricted to):
IFN proteins (such as MxA) to assess changes in IFN signalling
SYK protein levels (such as but not restricted to phospho-SYK and total SYK) to assess 
target engagement 
Immune cell and immune cell marker expression (such as CD3+ T cells, CD20+ B cells, 
CD11c+ myeloid dendritic cells and CD68+ macrophages).
Pathological evaluation for general appearance using a histopathological disease activity 
score, scoring on parakeratosis, ballooning, necrosis, junctional inflammation and the 
extent of dermal infiltrate.
7.6.2.
Novel Biomarkers
With the subject’s consent, the same skin biopsy samples described in Section 7.6.1 may 
be used for the purposes of measuring novel biomarkers to identify factors that may 
influence  CLE, and/or medically related conditions, as well as the biological and clinical 
responses to GSK2646264. If relevant, this approach will be extended to include the 
identification of biomarkers associated with adverse events.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with CLE or medically related conditions and/or the action of 
GSK2646264 may be identified by application of transcriptomic and /or histological 
analysis of skin biopsy samples.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial. 
8.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined electronic CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system.  
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.
Adverse events and concomitant medications terms will be coded using MedDRA
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  


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CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent 
to the investigator to maintain as the investigator copy. Subject initials will not be 
collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objectives of the study are to evaluate the safety and tolerability of repeat 
doses of a cream formulation of GSK2646264 in patients with CLE . No formal statistical 
comparisons will be conducted to assess these objectives. If deemed appropriate to assess 
key efficacy and pharamacodynamic endpoints, the following exploratory comparisons 
may be conducted :

GSK2646264 treatment vs. Placebo in PV lesions

GSK2646264 treatment vs. Placebo in natural lesions
9.2.
Sample Size Considerations
There are no formal calculations of power or sample size for this study. The sample sizes
have been chosen based on feasibility, to primarily allow the assessment of safety and 
tolerability of GSK2646264 in patients with CLE.
We will recruit approximately 25 patients with CLE into the study with the aim to 
randomise approximately 20 patients. Approximately 10 patients will undergo PV in 
group A. PV response rates are estimated at 50% and we expect up to 5 PV positive 
patients to be randomised into the study. We aim to randomise approximately 15 patients 
into group B of the study. All patients will be treated with both GSK2646264 and placebo 
on separate lesions (see Section 6.1 for details).
9.2.1.
Sample Size Assumptions
There are no formal calculations of power or sample size for this study. The sample sizes 
have been chosen based on feasibility. 
The primary objective of the study is safety, where a number of safety events are of 
interest. 
For group A, Using a Bayesian approach to determine the confidence interval around an 
observed safety event, we would assume a flat Beta (1,1) prior, and if we were to observe 
1 safety event in 5 then the posterior distribution would be Beta (2, 5), as outlined below:


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0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.5
1.0
1.5
2.0
2.5
x
dbeta(x, 2, 5)
Where we can be 95% certain that the true probability of the safety event lies between 
0.04 and 0.64.
A sample size sensitivity analysis has been conducted on the primary endpoint, to 
investigate different safety event rates with 5 subjects in part A. Additionally, if the 
number of subjects is lower than 5 in group A, then the true incidence rates of safety 
events that could not be ruled out would change.
These changes are outlined in the table below:
N completing the study
Number of particular 
safety events observed 
with active
Upper limit of exact 95% 
CI indicating that a true 
incidence rate of x% could 
not be ruled out
5
0
46%
5
2
78%
4
0
52%
4
1
72%
4
2
85%
For group B, using a Bayesian approach to determine the confidence interval around an 
observed safety event, we would assume a flat Beta (1,1) prior, and if we were to observe 
1 safety event in 15 then the posterior distribution would be Beta (2, 15), as outlined 
below:


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0.0
0.2
0.4
0.6
0.8
1.0
0
1
2
3
4
5
6
x
dbeta(x, 2, 15)
Where we can be 95% certain that the true probability of the safety event lies between 
0.02 and 0.30.
A sample size sensitivity analysis has been conducted on the primary endpoint, to 
investigate different safety event rates with 15 subjects in part B.  Additionally, if the 
number of subjects is lower than 15 in group B, then the true incidence rates of safety 
events that could not be ruled out would change.
These changes are outlined in the table below:
N completing the study
Number of particular 
safety events observed 
with active
Upper limit of exact 95% 
CI indicating that a true 
incidence rate of x% could 
not be ruled out
15
0
21%
15
2
38%
12
0
25%
12
1
36%
12
2
45%
9.2.2.
Sample Size Re-estimation or Adjustment
A sample re-estimation is not planned for this study.


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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Safety Population: The safety Population is defined as subjects who receive at least one 
dose of study medication. This population is used for the summary of all data including 
safety, efficacy and pharmacodynamic (PD) data but excluding PK data.
Pharmacokinetic Population: The ‘PK Population’ is defined as subjects in the ‘Safety’ 
population who received an active dose and for whom a pharmacokinetic sample was 
obtained and analysed. This population is used for the summary of PK data only.
9.3.2.
Interim Analysis
In this sponsor-unblinded bilateral design study, 1 or more unblinded data reviews, using 
all available data to date, may be carried out by senior managers (not involved in the 
study conduct) and/or study team members (involved in the study conduct) to aid in 
portfolio and budget decisions.  These administrative reviews will have no impact on the 
ongoing study.  Full details will be provided in the reporting and analysis plan prior to the 
first administrative review.  
9.4.
Key Elements of Analysis Plan
Data will be summarized and analysed according to the GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP. 
Final analysis of groups A and B will be reported together after all subjects in groups A
(up to 5 subjects) and B (approximately 15 subjects) have completed their follow-up visit. 
9.4.1.
Primary Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
9.4.2.
Secondary Analyses
All plasma GSK2646264 concentration data will be graphically represented, descriptively 
summarised and listed appropriately. Plasma GSK2646264 concentration time data will 
be analysed using a population pharmacokinetics (PK) model developed previously 
using data from study 200196 (FTIH of GSK2646264). Population PK parameters 
(Cmax, AUC(0- τ ) and terminal phase half life (t1/2) will be reported. Pharmacokinetic 
data will be presented in graphical and/or tabular form and will be summarized 
descriptively. All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, R&D.
Descriptive statistics of both raw and change from baseline, where appropriate, (i.e. n, 
arithmetic mean, standard deviation, minimum, median and maximum) will be calculated 


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for  erythema, oedema, dyspigmentation  (and scaling in existing lesions only) and 
modified RCLASI and summarized study part. All data will be listed. 
Change from baseline in each clinical activity assessment will be analysed for each lesion 
type using a mixed effects model fitting visit, treatment and lesion location as fixed 
effects and subject as random.  Estimates of the differences between GSK2646264 and 
placebo will be calculated and appropriate statistical inferences based on these results 
will be made.
Descriptive statistics of both raw and change from baseline data, where appropriate, (i.e. 
n, arithmetic mean, standard deviation, minimum, median and maximum) will be 
calculated for the IFN mRNA endpoints and summarized by lesion type (PV and natural 
lesions). All data will be listed.
If data permits, formal statistical analyses of the IFN mRNA endpoints may be 
conducted.
Change from baseline in each IFN mRNA signature endpoints will be analyzed by study 
part using a mixed model including treatment and lesion number as fixed effects and 
subject as a random effect. Estimates of the treatment means and differences will be 
presented with the associated 95% confidence intervals. Distributional assumptions 
underlying the analyses will be assessed as appropriate. If these assumptions are strongly 
violated, appropriate transformations will be investigated and if required alternative 
statistical analyses considered.
Full details will be provided in the RAP.
9.4.3.
Exploratory Analyses
Descriptive statistics of both raw and change from baseline data, where appropriate, (i.e. 
n, arithmetic mean, standard deviation, minimum, median and maximum) will be 
calculated for the exploratory pharmacodynamic endpoints and summarized by study 
part. All data will be listed.
If data permits, formal statistical analyses of the exploratory pharmacodynamic endpoints 
may be conducted, if deemed appropriate and full details will be provided in the RAP. 
Based on the specified statistical analyses, estimates of the differences between 
GSK2646264 and placebo will be calculated and appropriate statistical inferences based 
on these results will be made. Distributional assumptions underlying the analyses will be 
assessed as appropriate. If these assumptions are strongly violated, appropriate 
transformations will be investigated and if required alternative statistical analyses 
considered.
Full details of  the reporting of exploratory endpoints will be provided in the RAP.


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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 favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (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 Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.


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10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
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 


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investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
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.


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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
10.8.
Safety Reivew Team (SRT)
Instream review of unblinded safety data including AE, SAEs, vital signs and laboratory 
data will be conducted by a SRT during the study conduct. The membership of the SRT 
(including members of the central GSK study team) and the proposed frequency of 
review will be documented in the SRT charter.


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11.
REFERENCES
Braegelmann C, Hölzel M, Ludbrook V, Dickson M, Turan N, Ferring-Schmitt S, 
Sternberg S, Bieber T, Kuhn A4, Wenzel J. Spleen tyrosine kinase (SYK) is a potential 
target for the treatment of cutaneous lupus erythematosus patients. Exp Dermatol. 2016. 
DOI: 10.1111/exd.12986.
Deng GM, Liu L, Bahjat FR, Pine PR, Tsokos GC. Suppression of skin and kidney 
disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum. 
2010 Jul;62(7):2086-92
Du Bois D, Du Bois EF, A formula to estimate the approximate surface area if height and 
weight be known. Arch Intern Med, 1916; 17: 863-71
GlaxoSmithKline Document Number 2013N182566_02 GSK2646264 Investigator's 
Brochure 15 Apr 2014.
GlaxoSmithKline Document Number 2015N268236_01 GSK2646264 Investigator's 
Brochure Supplement 1 11-JAN-2016
GlaxoSmithKline Document Number 2016N281634_00 GSK2646264 Investigator's 
Brochure Supplement 2 27-APR-2016
GlaxoSmithKline Document number: 2013N167482. NCT02424799.A randomised 
double blind (sponsor unblinded), single and repeat ascending dose First Time in Human 
study in healthy subjects, cold urticaria and chronic spontaneous urticaria subjects to 
investigate safety, tolerability,  pharmacodynamics and pharmacokinetics of topically 
applied GSK2646264. 11-APR-2016
Hatcher, R., Trussell, J., Nelson, A., et al. Contraceptive Technology 2011 (20th ed.). 
Bridging the Gap Foundation. ISBN 978-1597080057.
ICH, M3 (R2) 2009: ICH guideline M3(R2) on non-clinical safety studies for the conduct 
of human clinical trials and marketing authorisation for pharmaceuticals. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002720.pdf.
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.
Kuhn A, Wozniacka A, Szepietowski JC, Gläser R, Lehmann P, Haust M, Sysa-
Jedrzejowska A, Reich A, Oke V, Hügel R, Calderon C, de Vries DE, Nyberg F. 
Photoprovocation in cutaneous lupus erythematosus: a multicenter study evaluating a 
standardized protocol. J Invest Dermatol. 2011 Aug;131(8):1622-30. doi: 
10.1038/jid.2011.101. Epub 2011 May 19.


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Kuhn et, al. Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index 
(RCLASI): a modiﬁed outcome instrument for cutaneous lupus erythematosus. Br J 
Dermatol. 2010 Jul;163(1):83-92.
Liddle et, al. Discovery of GSK143, a highly potent, selective and orally efficacious 
spleen tyrosine kinase inhibitor. Bioorg Med Chem Lett. 2011 Oct 15;21(20):6188-94.
Posobiec LM, Cox EM, Solomon HM, Lewis EM, Wang K-f and Stanislaus D: A 
Probability Analysis of Historical Pregnancy and Fetal Data from Dutch Belted and New 
Zealand White Rabbit Strains from Embryo-Fetal Development Studies. Birth Defect 
Research (Part B) 2016; 107:76-84.
Sabine Zahn, Medina Graef, Nikolaos Patsinakidis, Aysche Landmann, Christian Surber, 
Joerg Wenzel and Annegret Kuhn. Ultraviolet light protection by a sunscreen prevents 
interferon-driven skin inflammation in cutaneous lupus erythematosus. Experimental 
Dermatology, 2014, 23, 516-518.


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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
BMI
Body Mass Index
BCR
B-cell receptor
CCLE
Chronic Cutaneous Lupus Erythematosus
CLE
Cutaneous Lupus Erythematosus
CONSORT
Consolidated Standards of Reporting Trials 
CRF
Case Report Form
CV
Cardio Vascular
EFD
Embryofoetal development
FcεR1
Fc epsilon receptors
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTIH
First Time in Human
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HIV
Human Immuno-Deficiency Virus
HRT
Hormone Replacement Therapy
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IFN
Interferon
IRB
Institutional Review Board
LET
Lupus Erythematosus Tumidus
MALDI-MS
Matrix Assisted Laser Desorption Ionization-Imaging Mass 
Specrometry
mRNA
Messenger-Ribonucleaic Acid
MSDS
Material Safety Data Sheet
NOAEL
No Observed Adverse Effect Level
PD
Pre-dose
PK
Pharmacokinetics
pSYK
Phosporylated- Spleen Tyrosine Kinase
PV
Photoprovocation
QTcB
QT interval corrected for heart rate according to Bazett’s 
formula 
QTcF
QT interval corrected for heart rate according to Fridericia’s 
formula
QoL
Quality of Life
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SCLE
Sub-acute Cutaneous Lupus Erythematosus


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SD
Standard Deviation
SLE
Systemic Lupus Erythematosus
SRM
Study Reference Manual
SRT
Safety Review Team
SYK
Spleen Tyrosine Kinase
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: Liver Safety – Study Treatment Restart
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 
MONITORING:
For bilirubin or INR criteria:

Viral hepatitis serology4

Blood sample for 
pharmacokinetic (PK) analysis, 
obtained within 24 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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
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 computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  


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Phase II liver chemistry increased monitoring criteria with continued therapy
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, stabilise 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.


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12.3.
Appendix 3: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
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.

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.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes 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 


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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 
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.
12.3.2.
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.


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d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere 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.

Refer to Section 12.2 for the required liver chemistry follow-up instructions


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12.3.3.
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

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4.
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 


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cause-effect relationship to an AE is inappropriate.
12.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure 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 


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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 
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.
12.3.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via PIMS

Facsimile transmission of the following PIMS listings for the corresponding subject 
is the preferred method to transmit SAE information to the Medical Monitor:
SAE listing
Demographic listing
Study treatment listing

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of all required information sent by overnight 
mail.

If the PIMS system is unavailable when the SAE occurs, the site will use the paper 
SAE form and fax that to the Medical Monitor. The site will enter the SAE data into 
PIMS as soon as the system becomes available.


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12.4.
Appendix 4: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
(FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, with combined estrogen and progestogen [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]

Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011].  

Male condom plus partner use of one of the contraceptive options below:
o
Contraceptive subdermal implant 
o
Intrauterine device or intrauterine system 
o
Oral Contraceptive, either combined or progestogen alone Injectable 
progestogen [Hatcher, 2011]
o
Contraceptive vaginal ring [Hatcher, 2011]
o
Percutaneous contraceptive patches [Hatcher, 2011]
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g. male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2)
2009]. 
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
12.4.1.
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 
48 hours of learning of a subject's pregnancy.


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
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 Section 12.3.6. 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 immediately.


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12.5.
Appendix 5 - Country Specific Requirements
No country-specific requirements exist.


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12.6.
Appendix 6 Protocol Changes
12.6.1.
Protocol changes for Amendment 3 from the Amendment 2
Where the Amendment Applies
Amendment 3 applied to all sites
Summary of Amendment Changes with Rationale
Changes have been made to clarify the treatment groups with respect to LET patients, 
update the number of patients to be recruited into each group, update the risk assessment 
table, alter the inclusion criteria with respect to BMI and permitted medications, update 
the T&E table with respect to frequency of pregnancy testing, revise the sample size 
considerations and assumptions, and removal of the interim analysis.
List of Specific Changes
Title Page, Authors
Rationale for change: Author list was updated with new authors
REVISED TEXT:  
Objectives and Endpoints
Rationale for Change: Clarification of CLE versus PV lesions
REVISED TEXT:  

To determine the effect of GSK2646264 on the histological disease activity in PV and 
existing CLE lesions
Section 1 Treatment Groups and Duration
Rationale for Change: Clarification of the number of lesions a patient can present with, 
and to allow LET patients with more than 1 lesion to enter the study
REVISED TEXT:
Subjects with CLE that meet the entry criteria at the time of screening will be enrolled 
into two treatment arms dependent on whether they have a minimum the number of 2 
active lesions they present with.
Group A: Patients with fewer than two2 active lesions will be enrolled into group A and 
exposed to PV for 3 consecutive days.  Patients with Lupus Erythematosus Tumidus 
(LET) can be enrolled into Group A only, and can present with any number of 
PPD


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lesions, so long as the existing lesions are not in the areas designated for 
photoprovocation.
Section 1 Type and Number of Subjects
Rationale for Change:  To amend the total number of subjects to be recruited into the 
study, and incorporate that termination may occur due to feasibility of recruitment of 
subjects reaching stopping criteria
REVISED TEXT
The study population will be adults (at least 18 years of age). We aim to recruit 
approximately 5025 patients into the study with the aim to randomise 40 approximately 
20 patients that have been evaluated by the investigators and diagnosed with subacute or 
chronic cutaneous lupus erythematosus. Approximately 2010 patients will undergo PV in 
group A. PV response rates are estimated at 50% and we expect 10up to 5 PV positive 
patients to be randomised into the study. We aim to enroll up to 30 approximately 15
patients into group B. We will include females of reproductive potential (FRP) in both 
groups of this study given the age and gender distribution (9:1-Female:Male 
preponderance) of the disease. Exclusion of FRP would significantly impair recruitment 
into the study and may affect the relevance of the data generated as the predominant 
patient population would be excluded.
Early termination of the study may occur due to feasibility of recruitment and/or 
individual subjects reaching safety stopping criteria.
Section 1 Analysis
Rationale for Change:  Clarification of statistical analysis to be performed on each group.
REVISED TEXT:
Change from baseline in each clinical activity assessment will be analysed by study part;
part A will be summarised descriptively and part B will be analysed using a repeated 
measures mixed model including visit, treatment and lesion position as fixed effects and 
subject as a random effect. Estimates of the treatment means and differences will be 
presented with the associated 95% confidence intervals. 
Change from baseline in each IFN mRNA signature endpoints will be analysed by study 
part; part A will be summarised descriptively and part B will be analysed using a 
mixed model including treatment and lesion position as fixed effects and subject as a 
random effect. Estimates of the treatment means and differences will be presented with 
the associated 95% confidence intervals. If the data is not normally distributed a 
transformation may be applied to the data.  
In this sponsor-unblinded bilateral design study, 1 or more unblinded data reviews, 
using all available data to date, may be carried out by senior managers (not involved 
in the study conduct) and/or study team members (involved in the study conduct) to 
aid in portfolio and budget decisions. These administrative reviews will have no 


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impact on the ongoing study.  Full details will be provided in the reporting and 
analysis plan prior to the first administrative review.
Section 4.1  Overall Design
Rationale for Change: Clarification of number of lesions that LET patients in Group A 
can present with, and a change to the total number of subjects to be recruited to each 
group of the study.
REVISED TEXT:
.…The study has a 28 day maximum screening period and subjects who meet the entry 
criteria will be entered into one of two treatment groups dependent on whether they have 
a minimumthe number of 2active CLE lesions or not at the time of screening. 
Approximately 2010 patients with fewer than 2 active lesions at the time of screening 
will be enrolled into group A and will undergo photo-testing followed by PV for up to 3 
consecutive days on 3 (7cm by 5cm) areas on their back. Patients with LET can be 
enrolled into Group A only, and can present with any number of lesions, so long as 
the existing lesions are not in the areas designated for photoprovocation Patients 
will be assessed at least twice weekly for up to 14 days from the first day of PV. Patients
Up to 5 patients that develop PV lesions at all three sites at any time during this period, 
as determined by the local investigative team, will have a biopsy of one PV lesion (B) 
and one area of uninvolved skin (E) on their back close to the PV lesions (see Section 4.2
schematic and Figure 1 for visual representation)….
….Group B will commence in parallel and recruit up to 30 patientsapproximately 
15patients with a minimum of 2 active CLE lesions within the same anatomical area(i.e. 
back, chest, head)…..
Section 4.3  Type and Number of Subjects
Rationale for Change:  Amendment to number of subjects to be recruited into each 
group.
REVISED TEXT:
We will recruit approximately 5025 patients with CLE into the study with the aim to 
randomise 40approximately 20 patients. Based on past clinical experience 
approximately 50% of patients recruited into group A will develop PV lesions and 
approximately 50%up to 5 PV positive patients will be non-respondersrandomised. We 
aim to randomise up to 30approximately 15 patients into group B of the study. 
Section 4.4  Design Justification
Rationale for Change:  Amendment to number of subjects to be recruited into each 
group.


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REVISED TEXT: The study population will include approximately 2040 evaluable 
subjects with subacute CLE (SCLE), chronic CLE (CCLE) including LET (group A 
only).
Section 4.6.1  Risk Assessment
Rational for Change:  Update to the Risk Assessment Table due to additional data
REVISED TEXT:
Summary of Data/Rationale for Risk
Mitigation Strategy
Fetal malformations were seen after IV dosing to 
pregnant Dutch belted rabbits with a NOAEL that is 
expected to exceed the highest expected human 
exposure by 13 and 214 fold cover compared to the 
predicted AUC (220 ng.hr/mL) and Cmax (167 ng/ml) 
respectively at the NOAEL.
In a subsequent study in the New Zealand White 
rabbits, neither cardiovascular nor skeletal 
abnormalities were detected by any route and dose 
at maternal plasma exposures similar to or higher 
than exposures achieved in Dutch Belted rabbit.
Based on these new fetal and TK data, the 
abnormalities in the Dutch Belted rabbit study were 
unlikely to be test article-related because no fetal 
abnormalities were detected in the New Zealand 
White rabbit with a similar Cmax (bolus route 
compared) or at a 4.5-fold higher AUC (bolus vs 24-
hr continuous infusion compared). The higher 
number of specific cardiovascular and skeletal 
abnormalities observed in the Dutch Belted rabbit 
Embryofoetal Development (EFD) study is likely 
related to the known higher spontaneous 
background incidence of these findings in Dutch 
Belted relative to New Zealand White fetal rabbits 
based on Test Facility historical control data and this
is also supported in literature (Posobiec, 2016)
Women who are pregnant, lactating or are 
planning on becoming pregnant during the study 
are not eligible to participate.
Female subjects of reproductive potential will 
undergo regular pregnancy testing (at 
screening, Day 1, Day 14, and at follow-up)
and treatment will be stopped immediately if a 
subject is found to be pregnant during the study, 
see Section 7.1 for exact timings. Subjects will 
also be required to be using an appropriate 
contraceptive (failure rate <1%) prior to the start 
and during the study as outlined in the protocol 
Section 5.1, Inclusion criteria.  Females of 
reproductive potential must be on established 
contraceptives 28 days before dosing begins.
Section 5.1   Inclusion Criteria
Rationale for Change: Broaden the inclusion criteria to allow greater range of BMI and 
use of certain medications if documented in medical history
REVISED TEXT:


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Body weight 50 kg and Body mass index (BMI) within the range ≥19.9 – 35 kg/m2
(inclusive)
Opioids, if required for acute and chronic pain management, and documented in the 
medical history/records
Section 6.1  Treatment Assignment
Rationale for Change:  Clarification of where the areas for treatment can be.
REVISED TEXT
These lesions can be on any part of the body (all 3 lesions must be in the same 
anatomical area), but the subject must consent  to be biopsied from the area with 
the lesions
Section 7.1.1  Time and Events Table Group A
Rationale for Change:  Alteration to the frequency of pregnancy testing required 
throughout
REVISED TEXT:
Procedure
Screeni
ng (up 
to Day -
28)
Day 
-15
Da
y -
14
Day 
-13 
to -1
Day 
1
Day 
2 to 
Day 
13
Day 
14
Day 
15 to 
Day 
20
Day 
21 
to 
Day 
27
Day 
28
Day 
29 to 
42
Follow-
upa
a All procedures 
listed should to also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontinu
e
Informed 
Consent
X
Inc/Exc 
criteria 
assessment
X
Demograph
y
X
Pregnancy 
Test 
(women)
X
X
X
X
X
X
X
x
X
Pregnancy testing 
between Day 1 & 
Day 28 should be 
performed once 
every 7 days. to be 
performed at 
Screening, on Day 
1 (pre-dose), Day 
14 (pre-dose) and 
once during 
follow-up, with day 
recordedPregnanc
y test on Day 1 will 
be pre-dose.


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Procedure
Screeni
ng (up 
to Day -
28)
Day 
-15
Da
y -
14
Day 
-13 
to -1
Day 
1
Day 
2 to 
Day 
13
Day 
14
Day 
15 to 
Day 
20
Day 
21 
to 
Day 
27
Day 
28
Day 
29 to 
42
Follow-
upa
a All procedures 
listed should to also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontinu
e
TSH, free 
T4, free T3
X
X
X
X
Vital Signs
X
X
X
X
X
Safety Lab 
Samples 
(clin chem, 
haematol, 
Urinalysis)
X
X
X
X
X
X
X
On days of dosing 
samples should be 
taken predose.
Sample timepoints 
during the Day-13 
to Day-1 period are 
as follows: 
– once weekly 
during visits to 
assess PV lesion 
development
Full 
Physical 
Exam
X
X
Brief 
Physical 
Exam
X
Assessment to be 
performed pre-dose
Sample timepoints 
during the Day-13 
to Day-1 period are 
as follows:
– once weekly 
during visits to 
assess PV lesion 
development
12-lead 
ECG
X
X
X
X
On days of dosing 
assessments 
should be 
performed predose 
SLE clinical 
assessment
X
X
X
X
On days of dosing 
assessment as 
defined by the 
investigator  to be 
performed pre-dose 
. 
ANA, anti-
dsDNA , 
anti-Ro and 
anti-La 
antibodies, 
HIV, Hep B, 
Hep C, 
FSH, Drug 
screen
X


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Procedure
Screeni
ng (up 
to Day -
28)
Day 
-15
Da
y -
14
Day 
-13 
to -1
Day 
1
Day 
2 to 
Day 
13
Day 
14
Day 
15 to 
Day 
20
Day 
21 
to 
Day 
27
Day 
28
Day 
29 to 
42
Follow-
upa
a All procedures 
listed should to also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontinu
e
Skin 
Biopsies
Xb
Xb
bDay 1 biopsies 
will be taken pre-
dose. Day 28 
biopsies will be 
taken 4 hours 
post-dose
UV 
threshold 
testing
X
Photoprovo
cation
Xc,
d
Performed 24 hours 
after UV threshold 
testing.
cPV occurs once 
every 24 hours for 3 
days on Day-14, 
Day-13 & Day-12.     
d If PV induced 
lesions appear at 
all 3 sites after 
Day -14 or Day -13, 
PV treatment can 
be stopped early
Lesion 
induction 
assessment
<- ----X----
-->
Lesion 
resolution 
assessment
X
X
Clinical 
score
X
X
X
Components  of the 
RCLASI as defined 
in Section 7.3
Assessments to be 
performed pre-dose
Local 
Tolerability
Assessment
X
X
X
X
X
X
X
Assessments to be 
performed pre-dose 
and up to one hour 
following dosing on 
days of dosing
Dosing
X
X
X
X
X
X
Once daily
Randomisat
ion
X
Pre-dose


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Procedure
Screeni
ng (up 
to Day -
28)
Day 
-15
Da
y -
14
Day 
-13 
to -1
Day 
1
Day 
2 to 
Day 
13
Day 
14
Day 
15 to 
Day 
20
Day 
21 
to 
Day 
27
Day 
28
Day 
29 to 
42
Follow-
upa
a All procedures 
listed should to also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontinu
e
PK blood 
sample
X
X
X
X
X
X
X
Sampling 
timepoints:
Day 1 = pre-dose; 
and 5hrs (1 hr)
Between Day 2 and 
Day13: one pre-
dose sample or 
postdose sample 
with time recorded 
since last dose
Day 14: predose 
sample 
Between Day 21 
and Day27: one 
pre-dose sample or 
postdose sample 
with time recorded 
since last dose
Day 28: one 
postdose sample 
with time recorded 
since last dose
Between Day 29 
and Day 42:  one 
sample with time 
recorded since last 
dose
Follow-up visit: one 
sample with 
sampling day 
recorded
AE/SAE 
Review
X
<--------------------------------------------------------------------------X-------------------------------------->
Concomitan
t Medication 
Review
X
<--------------------------------------------------------------------------X----------------------------------------
>
Section 7.1.3   Time and Events Table Group B


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Rationale for Change:  Alteration to the frequency of pregnancy testing required 
throughout
REVISED TEXT:
Procedure
Screening (up 
to Day -28)
Day -5 
to -3
D
a
y 
1
Day 
2 to 
Day 
13
Da
y 
14
Day 
15 to 
Day 
20
Day 
21 to 
Day 
27
D
a
y 
2
8
Day 
29 
to
42
Follo
w-up 
(bet
wee
n 
Day 
43 to 
Day 
56)a
a All procedures 
listed should also
to be conducted 
if a subject 
decides to 
prematurely 
withdraw/disconti
nue
Informed 
Consent
X
Inc/Exc 
criteria 
assessment
X
Demography
X
Pregnancy 
Test 
(women)
X
X
X
X
X
X
x
X
Pregnancy 
testing between 
Day 1 & Day 28 
should be 
performed once 
every 7 days. On 
days of dosing, 
test should be 
performed pre-
dose
Pregnancy 
testing to be 
performed at 
Screening, on 
Day 1 (pre-
dose), Day 14 
(pre-dose) and 
once during 
follow-up, with 
day recorded
TSH, free 
T4, freeT3
X
X
X
X
Vital Signs
X
X
X
X
Safety Lab 
Samples 
(clin chem 
,haematol, 
Urinalysis)
X
X
X
X
x
X
On days of 
dosing samples 
should be taken 
predose 
Full Physical 
Exam
X
X
Brief 
Physical 
Exam
X
Assessment to 
be performed 
pre-dose
12-lead ECG
X
X
X
X
On days of 
dosing 


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Procedure
Screening (up 
to Day -28)
Day -5 
to -3
D
a
y 
1
Day 
2 to 
Day 
13
Da
y 
14
Day 
15 to 
Day 
20
Day 
21 to 
Day 
27
D
a
y 
2
8
Day 
29 
to
42
Follo
w-up 
(bet
wee
n 
Day 
43 to 
Day 
56)a
a All procedures 
listed should also
to be conducted 
if a subject 
decides to 
prematurely 
withdraw/disconti
nue
assessments 
should be 
performed 
predose
SLE clinical 
assessment
X
X
X
X
On days of 
dosing 
assessment as 
defined by the 
investigator to be 
performed pre-
dose .
ANA, anti-
dsDNA 
antibodies, 
anti-Ro and 
anti-La 
antibodies, 
HIV, Hep B, 
Hep C, FSH, 
Drug screen
X
Lesion 
selection
X
Refer to Section 
4.1 and Section  
6.1
Skin 
Biopsies
Xb
X
b
b2 to 4 days
healing time will 
be allowed prior 
to randomisation 
and the first 
dose.
Day 28 biopsies 
will be taken 4 
hours post-dose
Clinical 
score
X
X
X
Local 
tolerability
Assessment
X
X
X
X
X
X
X
Assessments to 
be performed 
pre-dose and up 
to one hour 
following 
dosing on days of 
dosing
Dosing
X
X
X
X
X
X
Once daily
Randomisati
on
X
Pre-dose


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Procedure
Screening (up 
to Day -28)
Day -5 
to -3
D
a
y 
1
Day 
2 to 
Day 
13
Da
y 
14
Day 
15 to 
Day 
20
Day 
21 to 
Day 
27
D
a
y 
2
8
Day 
29 
to
42
Follo
w-up 
(bet
wee
n 
Day 
43 to 
Day 
56)a
a All procedures 
listed should also
to be conducted 
if a subject 
decides to 
prematurely 
withdraw/disconti
nue
PK blood 
sample
X
X
X
X
X
X
X
Sampling 
timepoints:
Day 1 = pre-
dose; and 5hrs 
(1 hr) 
Between Day 2 
and Day13: one 
pre-dose sample 
or postdose 
sample with time 
recorded since 
last dose
Day 14: predose 
sample 
Between Day 21 
and Day27: one 
pre-dose sample 
or postdose 
sample with time 
recorded since 
last dose
Day 28:one 
postdose sample 
with time 
recorded since 
last dose
Between Day 29 
and Day 42:  one 
sample with time 
recorded since 
last dose
Follow-up visit: 
one sample with 
sampling day 
recorded
AE/SAE 
Review
X
Concomitant 
Medication 
Review
X
Lesion 
X
X


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Procedure
Screening (up 
to Day -28)
Day -5 
to -3
D
a
y 
1
Day 
2 to 
Day 
13
Da
y 
14
Day 
15 to 
Day 
20
Day 
21 to 
Day 
27
D
a
y 
2
8
Day 
29 
to
42
Follo
w-up 
(bet
wee
n 
Day 
43 to 
Day 
56)a
a All procedures 
listed should also
to be conducted 
if a subject 
decides to 
prematurely 
withdraw/disconti
nue
resolution 
assessment
Section 7.4.7  Clinical Safety Laboratory Assessments
Rationale for Change:  Removal of non-required footnote number
REVISED TEXT:

Serum  or urine hCG Pregnancy test (as needed for women of child bearing potential) 
2
Section 9.2  Sample Size Considerations
Rationale for Change:  Amendment to the total number of subjects to be recruited to the 
study and sample size assumptions.
REVISED TEXT:
We will recruit approximately 5025 patients with CLE into the study with the aim to 
randomise approximately 20 40 patients. Approximately 20 10 patients will undergo PV 
in group A. PV response rates are estimated at 50% and we expect 10 up to 5 PV positive 
patients to be randomised into the study. We aim to randomise up to 30 approximately 
15 patients into group B of the study. All patients will be treated with both GSK2646264 
and placebo on separate lesions (see Section 6.1 for details).
…..For group A, Using a Bayesian approach to determine the confidence interval around 
an observed safety event, we would assume a flat Beta (1,1) prior, and if we were to 
observe 1 safety event in 10 5 then the posterior distribution would be Beta (2, 5 10), as 
outlined below:…..


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0.0
0.2
0.4
0.6
0.8
1.0
0
1
2
3
4
x
dbeta(x, 2, 10)
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.5
1.0
1.5
2.0
2.5
x
dbeta(x, 2, 5)
Where we can be 95% certain that the true probability of the safety event lies between 
0.04 0.02 and 0.64 0.41.
A sample size sensitivity analysis has been conducted on the primary endpoint, to 
investigate different safety event rates with 5 subjects in part A. Additionally, iIf the 
number of subjects is lower than 5 10 in group A, then the true incidence rates of safety 
events that could not be ruled out would change.


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N completing the study
Number of particular 
safety events observed 
with active
Upper limit of exact 95% 
CI indicating that a true 
incidence rate of x% could 
not be ruled out
510
0
4629%
510
2
7852%
48
0
5234%
48
1
7248%
48
2
8560%
For group B, using a Bayesian approach to determine the confidence interval around an 
observed safety event, we would assume a flat Beta (1,1) prior, and if we were to observe 
1 safety event in 15 30 then the posterior distribution would be Beta (2, 15 30), as 
outlined below:
0.0
0.2
0.4
0.6
0.8
1.0
0
2
4
6
8
10
x
dbeta(x, 2, 30)


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0.0
0.2
0.4
0.6
0.8
1.0
0
1
2
3
4
5
6
x
dbeta(x, 2, 15)
Where we can be 95% certain that the true probability of the safety event lies between 
0.02 0.01 and 0.30 0.17.
A sample size sensitivity analysis has been conducted on the primary endpoint, to 
investigate different safety event rates with 15 subjects in part B.  Additionally, i If the 
number of subjects is lower than 15 30 in group B, then the true incidence rates of safety 
events that could not be ruled out would change.
N completing the study
Number of particular
safety events observed 
with active
Upper limit of exact 95% 
CI indicating that a true 
incidence rate of x% could 
not be ruled out
1530
0
2111%
1530
2
3821%
1228
0
2512%
1228
1
3618%
1228
2
4523%
A key secondary endpoint is to determine the effect of GSK2646264 on expression of 
IFN mRNA signature in skin biopsies in treated PV and existing CLE lesions.  The 
estimate of standard deviation comes from existing data on subjects with CDLE 
[Braegelmann, 2016].
Variable
Gene 
Sd 
Estimated 
10 subjects
30 subjects


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Name
log 2 
scale
within SD
Estimated 
width of 
95% CI of 
treatment 
difference 
on the log 
2 scale
95% CI of 
the treatment 
ratio (if ratio 
is 1)
Estimated 
width of 
95% CI of 
treatment 
difference 
on the log 
2 scale
95% CI of 
the treatment 
ratio (if ratio 
is 1).
A_23_P6263
MX2
0.43
0.28
±0.465
(0.72, 1.38)
±0.243
(0.84, 1.18)
A_33_P32782
00
MX2
0.60
0.39
±0.647
(0.64, 1.57)
±0.338
(0.79, 1.26)
A_23_P20408
7
OAS2
0.42
0.27
±0.448
(0.73, 1.36)
±0.234
(0.85, 1.18)
A_23_P17663
MX1
0.40
0.26
±0.432
(0.74, 1.35)
±0.225
(0.86, 1.17)
A_23_P23074
IFI44
0.43
0.28
±0.465
(0.72, 1.38)
±0.243
(0.84, 1.18)
A_24_P30309
1
CXCL1
0
0.98
0.64
±1.063
(0.48, 2.09)
±0.555
(0.68, 1.47)
A_33_P33431
75
CXCL1
0
0.84
0.55
±0.913
(0.53, 1.88)
±0.477
(0.72, 1.39)
The following precision estimates are based on variability estimates from existing data on 
subjects with SCLE.
Variable
Gene 
Name
Sd 
log 2 
scale
Estimated 
within SD
10 subjects
30 subjects
Estimated 
width of 
95% CI of 
treatment 
difference 
on the log 
2 scale
95% CI of
the treatment 
ratio (if ratio 
is 1)
Estimated 
width of 
95% CI of 
treatment 
difference 
on the log 
2 scale
95% CI of 
the treatment 
ratio (if ratio 
is 1).
A_23_P6263
MX2
0.89
0.58
±0.963
(0.51, 1.95)
±0.503
(0.71, 1.42)
A_33_P32782
00
MX2
0.87
0.57
±0.946
(0.52, 1.93)
±0.494
(0.71, 1.41)
A_23_P20408
7
OAS2
0.57
0.37
±0.614
(0.65, 1.53)
±0.321
(0.80, 1.25)
A_23_P17663
MX1
0.66
0.43
±0.714
(0.61, 1.64)
±0.373
(0.77, 1.30)
A_23_P23074
IFI44
0.12
0.08
±0.133
(0.91, 1.10)
±0.069
(0.95, 1.05)
A_24_P30309
1
CXCL1
0
1.43
0.94
±1.561
(0.34, 2.95)
±0.815
(0.57, 1.76)
A_33_P33431
75
CXCL1
0
1.50
0.98
±1.627
(0.32, 3.09)
±0.85
(0.55, 1.80)


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An exploratory endpoint of this study is to determine the effect of GSK2646264 on the 
extent of histological disease activity in PV and existing CLE lesions. Data presented in 
[Zahn, 2014] for parakeratosis, ballooning, necrosis, junctional inflammation and dermal 
infiltrate show a between subject standard deviation of between 0.44 and 0.67. Based on 
10 subjects in group A it is estimated that the 95% confidence interval will be within 0.98 
of the estimate of the treatment difference where the within subject SD is assumed to be 
0.59. Based on 30 subjects in group B it is estimated that the 95% confidence interval 
will be within 0.51 of the estimate of the treatment difference where the within subject 
SD is assumed to be 0.59.
Between Subject 
standard deviation
Within subject SD 
approximation
10 Subjects. 
Estimated width of 
95% CI
30 subjects. 
Estimated width of 
95% CI
0.447
0.29
±0.481
±0.251
0.670
0.44
±0.731
±0.382
0.894
0.59
±0.980
±0.512
Section 9.3.2  Interim Analysis
Rationale for Change:  Introduction of in-stream review of data
REVISED TEXT:
In this sponsor-unblinded bilateral design study, 1 or more unblinded data reviews, 
using all available data to date, may be carried out by senior managers (not involved 
in the study conduct) and/or study team members (involved in the study conduct) to 
aid in portfolio and budget decisions.  These administrative reviews will have no 
impact on the ongoing study.  Full details will be provided in the reporting and 
analysis plan prior to the first administrative review.  
Section 9.4  Key Elements of Analysis Plan
Rationale for Change
REVISED TEXT:
Final analysis of groups A and B will be reported after all subjects in groups A and B 
respectively have completed their follow-up visit; this may be at the same time or 
different times depending on the relative rates of recruitment. Final analysis for group B 
will be reported after all subjects in group B have completed their follow up visit. Final 
analysis of groups A and B will be reported together after all subjects in groups A 
(up to 5 subjects) and B (approximately 15 subjects) have completed their follow-up 
visit.


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Section References
Rationale for Change:  Additional reference added
REVISED TEXT:
Posobiec LM, Cox EM, Solomon HM, Lewis EM, Wang K-f and Stanislaus D: A 
Probability Analysis of Historical Pregnancy and Fetal Data from Dutch Belted and 
New Zealand White Rabbit Strains from Embryo-Fetal Development Studies. Birth 
Defect Research (Part B) 2016; 107:76-84.


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12.6.2.
Protocol changes for Amendment 2 (04-Aug-2016) from the 
Protocol amendment 1 (13-June-2016)
Where the Amendment Applies
Amendment 2 applies to all site
Summary of Amendment Changes with Rationale
Changes have been made following review from BfArM and ethics, primarily to 
inclusion/exclusion criteria, and clarification of dose.  
List of Specific Changes
Title Page, Authors
Rationale for change: Author’s name was added.
REVISED TEXT
 (II TAU),
 (PCPS), 
 (DMPK), 
 (QSci), 
 (CPSSO), 
 (II TAU), 
 (II TAU), 
 
 (GCSP), 
 (CUC), 
 (CPMS)
Section 4.5 Dose Justification
1st Paragraph 
Rationale for change: Dose to be applied was clarified to include details on total 
cream to be applied and to weigh cream to ensure amount of dose applied.
REVISED TEXT
GSK2646264 will be administered topically as a cream at 1% (w/w) strength.The 
maximum topically applied dose to any subject at any time point will be 10mg/cm2 of 
cream over 90 cm2 (maximum of ~0.5% Body Surface Area as determined by Du 
Bois, 1916 ). This equates to a maximum of 900mg of cream and therefore 9 mg of 
GSK2646264. A corresponding placebo will also be applied.  Cream will be weighed 
both before and after application.
Section 5  Selection of Study Population and Withdrawal Criteria
2nd Paragraph
Rationale for change: Section was updated to specify groups to which
inclusion/exclusion/withdrawal criteria apply.
REVISED TEXT
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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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 Investigator Brochure 
[GlaxoSmithKline Document Number: 2013N182566_02, GlaxoSmithKline Document 
Number 2015N268236_01 (Supplement 1) and GlaxoSmithKline Document Number   
2016N281634_00 (Supplement 2)]
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.
All inclusion/exclusion criteria and withdrawal criteria apply to subjects in both 
Part A and Part B, unless specifically stated otherwise.
Section 5.2 Exclusion criteria
Rationale for change: Conditions for medical history and diagnostic test, were 
updated to add more details for subjects to be excluded, disease condition, withdrawal 
from study and inclusion of HIV test. 
REVISED TEXT
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.
ALT >2xULN; 
2.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%)
3.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
4.
QTcF > 450 msec, or QTcF > 480 msec in subjects with Bundle Branch Block
NOTES: 

The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-
read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).


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5.
History of any past or present benign or malignant skin conditions and disease, 
unless in the opinion of the investigator it will not compromise the subjects safety 
and quality of data.
6.
Subjects with active Systemic Lupus Erythematosus (SLE) and/or significant 
disease in any other organ than the skin, as judged by the Investigator after 
discussion with the medical monitor
7.
Subjects with a history of Graves disease
8.
Subjects with a history of thyroid cancer.
9.
Unable to refrain from vitamins, herbal and dietary supplements (including St John’s 
Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half 
lives (whichever is longer) prior to the screening visit until the completion of the 
follow-up assessments, unless in the opinion of the Investigator, in consultation with 
the GSK Medical Monitor if required, the medication will not interfere with the 
study procedures or compromise subject safety. 
10. Clinically significant abnormality in the hematological, clinical chemistry, or 
urinalysis screen, that in the opinion of the investigator after discussion with the 
medical monitor, requires further investigation, medical intervention or poses a 
risk to the subject to participate in the trial.
11. Subjects who start prohibited medications or therapies at any time during the study 
will may be withdrawn from the study.  Subjects who start prohibited medications or 
therapies may remain in the study only with the approval of the Medical Monitor and 
at the discretion of the Sponsor.
The following medications and therapies are prohibited at any time during the study:

Use of other investigational agents (biologic or non-biologic; investigational 
applies to any drug not approved for sale in the country in which it is used).

Co-enrolment into another study of an investigational agent or non-drug therapy.

Use of biological agents (e.g., alemtuzumab, rituximab, ATG) during the 
clinical study or within 12 months to first dose of study treatment.
Use of other immunosuppressive drugs commonly used in SLE including 
Azathioprine, Methotrexate, Mycophenolate, Cyclophosphamide within 3 months to 
first dose of study treatment.
REVISED TEXT


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DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
15. 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. 
16. A positive HIV test at screening
17. A positive pre-study drug screen.  
18. Where participation in the study would result in donation of blood or blood products 
in excess of 450 ml within 3 months. 
19. 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: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
20. Exposure to more than 4 investigational medicinal products within 12 months prior 
to the first dosing day.
Country Specific Exclusion criteria wording for Germany:
21. Subjects that are employees of either GlaxoSmithKline (sponsor) or one of the study 
centres (investigators).
22. Subjects who live in detention on court order or on regulatory action, see §40 
subsection 1 sentence 3 no. 4 AMG. (Arzneimittelgesetz).


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Section 5.4 Withdrawal/Stopping Criteria
Rationale for change: Withdrawal criteria specific for group A added and typo error 
was corrected.
REVISED TEXT
WITHDRAWAL (Specific for Group A ONLY)
1. A subject will be withdrawn from the study, if they demonstrate an excessive 
or adverse reaction to the photoprovocation, as judged by the Investigator 
after discussion with the medical monitor.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. In case a subject withdraws from study they should be 
encouraged to continue contraception for 28 days. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural or administrative reasons. A subject 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.


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Section 5.4.3 Safety Related Study Specific Dose Adjustment Criteria
Rationale for change: Criteria for reporting AE of severe intensity was updated. 
1st paragraph
REVISED TEXT
If AEs are of severe intensity and are similar across subjects, or if unacceptable 
pharmacological effects, reasonably attributable in the opinion of the investigator to 
dosing with GSK2646264, or if dose limiting toxicity (see Section 5.4.1), are observed in
2 or more subjects at least 2 subjects, relevant reporting and discussion with the GSK 
medical monitor and the SRT will take place.
Section 7. Study Assessments and Procedures
Rationale for change: Laboratory test to be done at screening updated to make it 
consistent with the change done in Exclusion criteria.
REVISED TEXT
There is addition of HIV, Hep B, Hep C, FSH, Drug screen tests in Section 7.1.1, 
Group A


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Procedure
Screening (up 
to Day -28)
Day 
-15
Day 
-14
Day -
13 to -
1
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 
to Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 29 
to 42
Follow-upa
a All procedures listed should also 
be conducted if a subject decides 
to prematurely 
withdraw/discontinue
12-lead ECG
X
X
X
X
On days of dosing assessments 
should be performed predose 
SLE clinical 
assessment
X
X
X
X
On days of dosing assessment as 
defined by the investigator  to be 
performed pre-dose . 
ANA, anti-dsDNA , 
anti-Ro and anti-La 
antibodies, HIV, 
Hep B, Hep C, FSH, 
Drug screen
X
There is addition of HIV, Hep B, Hep C, FSH, Drug screen tests in Section 7.1.3, Group B
Procedure
Screening (up 
to Day -28)
Day -5 to -
3
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 to 
Day 20
Day 21 to 
Day 27
Day 
28
Day 29 
to 42
Follow-up 
(between 
Day 43 to 
Day 56)a
a All procedures listed should 
also be conducted if a subject 
decides to prematurely 
withdraw/discontinue
12-lead ECG
X
X
X
X
On days of dosing 
assessments should be 
performed predose
SLE clinical 
assessment
X
X
X
X
On days of dosing assessment 
as defined by the investigator 
to be performed pre-dose .
ANA, anti-dsDNA 
antibodies, anti-Ro and 
anti-La antibodies, HIV, 
Hep B, Hep C, FSH, 
Drug screen
X


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Section 7.4.6 Photo-provocation model
Rationale for change: Section was updated to include details on maximum UVA & 
UVB irradiation to be received
REVISED TEXT
Subjects will undergo UV threshold testing on six 4.5 cm2 areas of the lower back each 
for UVA and UVB irradiation during screening.  The maximum UVA irradiation 
received will be 100 Jcm-2 and the maximum UVB will be 200 mJcm-2 as per the 
method described by Kuhn (2011).
Section 7.4.7 Clinial Safety Laboratory Assessments
Rationale for change: Laboratory test to be done was updated to make it consistent 
with the update done in Exclusion criteria and Time & Events Table.
Table 1
REVISED TEXT
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
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)

Drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)

Serum  or urine hCG Pregnancy test (as needed for women of child 
bearing potential) 2

Free T3


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Laboratory 
Assessments
Parameters

Free T4

TSH

ANA, Anti-ds DNA, Anti-Ro and Anti-La antibodies
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 5.4.4 and 
Appendix 2.
Section 11 References
Rationale for Change: Reference updated due to addition of references in  Section 
4.5.
REVISED TEXT
Du Bois D, Du Bois EF, A formula to estimate the approximate surface area if 
height and weight be known. Arch Intern Med, 1916; 17: 863-71
Section 12.1. Appendix 1-Abbreviation and Trademarks
Rational for change: There is an updation in abbreviation list
REVISED TEXT
AE
Adverse Event
BMI
Body Mass Index
BCR
B-cell receptor
CCLE
Chronic Cutaneous Lupus Erythematosus
CLE
Cutaneous Lupus Erythematosus
CONSORT
Consolidated Standards of Reporting Trials 
CRF
Case Report Form
CV
Cardio Vascular
FcεR1
Fc epsilon receptors
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTIH
First Time in Human
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HIV
Human Immuno-Deficiency Virus
HRT
Hormone Replacement Therapy
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee


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IFN
Interferon
IRB
Institutional Review Board
LET
Lupus Erythematosus Tumidus
MALDI-MS
Matrix Assisted Laser Desorption Ionization-Imaging 
Mass Specrometry
mRNA
Messenger-Ribonucleaic Acid
MSDS
Material Safety Data Sheet
NOAEL
No Observed Adverse Effect Level
PD
Pre-dose
PK
Pharmacokinetics
pSYK
Phosporylated- Spleen Tyrosine Kinase
PV
Photoprovocation
QTcB
QT interval corrected for heart rate according to 
Bazett’s formula 
QTcF
QT interval corrected for heart rate according to 
Fridericia’s formula
QoL
Quality of Life
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SCLE
Sub-acute Cutaneous Lupus Erythematosus
SD
Standard Deviation
SLE
Systemic Lupus Erythematosus
SRM
Study Reference Manual
SRT
Safety Review Team
SYK
Spleen Tyrosine Kinase


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12.6.3.
Protocol changes for Amendment 1 (13-June-2016) from the 
Original Protocol (18-May-2016)
Summary of Amendment Changes with Rationale
Changes have been made to the Time and events table to add another column day 15 to 
day 20 to highlight any study procedures being taken. 
List of Specific Changes
Section 7.1.1 Group A 
Rationale for change: Changes have been made to the Time and events table to add 
another column day 15 to day 20 . 


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REVISED TEXT
Procedure
Screen
ing (up 
to Day 
-28)
Day 
-15
Day 
-14
Da
y -
13 
to -
1
D
a
y 
1
D
a
y 
2 
to 
D
a
y 
1
3
D
a
y 
1
4
Da
y 
15 
to 
Da
y 
20
Day 
21 
to 
Day 
27
Da
y 
28
Day 
29 
to 
42
Follow-
upa
a All procedures 
listed should also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontin
ue
Informed 
Consent
X
Inc/Exc 
criteria 
assessme
nt
X
Demograp
hy
X
Pregnanc
y Test 
(women)
X
X
X
X
X
X
X
x
X
Pregnancy testing 
between Day 1 & 
Day 28 should be 
performed once 
every 7 days. 
Pregnancy test on 
Day 1 will be pre-
dose.
TSH, free 
T4, ,free 
T3
X
X
X
X
Vital 
Signs
X
X
X
X
X
Safety 
Lab 
Samples 
(clin 
chem, 
haematol, 
Urinalysis)
X
X
X
X
X
X
X
On days of dosing 
samples should be 
taken predose.
Sample timepoints 
during the Day-13 
to Day-1 period are 
as follows: 
– once weekly 
during visits to 
assess PV lesion 
development
Full 
Physical 
Exam
X
X
Brief 
Physical 
Exam
X
Assessment to be 
performed pre-
dose
Sample timepoints 
during the Day-13 
to Day-1 period are 
as follows:
– once weekly 


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Procedure
Screen
ing (up 
to Day 
-28)
Day 
-15
Day 
-14
Da
y -
13 
to -
1
D
a
y 
1
D
a
y 
2 
to 
D
a
y 
1
3
D
a
y 
1
4
Da
y 
15 
to 
Da
y 
20
Day 
21 
to 
Day 
27
Da
y 
28
Day 
29 
to 
42
Follow-
upa
a All procedures 
listed should also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontin
ue
during visits to 
assess PV lesion 
development
12-lead 
ECG
X
X
X
X
On days of dosing 
assessments 
should be 
performed predose 
SLE 
clinical 
assessme
nt
X
X
X
X
On days of dosing 
assessment as 
defined by the 
investigator  to be 
performed pre-
dose . 
ANA, anti-
dsDNA , 
anti-Ro 
and anti-
La 
antibodies
X
Skin 
Biopsies
X
b
Xb
bDay 1 biopsies 
will be taken pre-
dose. Day 28 
biopsies will be 
taken 4 hours 
post-dose
UV 
threshold 
testing
X
Photoprov
ocation
Xc
Performed 24 
hours after UV 
threshold testing.
cPV occurs once 
every 24 hours for 
3 days on Day-14, 
Day-13 & Day-12.
Lesion 
induction 
assessme
nt
<- ----X-----
->
Lesion 
resolution 
assessme
nt
X
X
Clinical 
score
X
X
X
Components  of 
the RCLASI as 
defined in Section 


2015N246677_04
CONFIDENTIAL
204860
115
Procedure
Screen
ing (up 
to Day 
-28)
Day 
-15
Day 
-14
Da
y -
13 
to -
1
D
a
y 
1
D
a
y 
2 
to 
D
a
y 
1
3
D
a
y 
1
4
Da
y 
15 
to 
Da
y 
20
Day 
21 
to 
Day 
27
Da
y 
28
Day 
29 
to 
42
Follow-
upa
a All procedures 
listed should also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontin
ue
7.3 Assessments 
to be performed 
pre-dose
Local 
Tolerabilit
y
Assessme
nt
X
X
X
X
X
X
X
Assessments to be 
performed pre-
dose and up to one 
hour following 
dosing on days of 
dosing
Dosing
X
X
X
X
X
X
Once daily
Randomis
ation
X
Pre-dose
PK blood 
sample
X
X
X
X
X
X
X
Sampling 
timepoints:
Day 1 = pre-dose; 
and 5hrs (1 hr)
Between Day 2 
and Day13: one 
pre-dose sample or 
postdose sample 
with time recorded 
since last dose
Day 14: predose 
sample 
Between Day 21 
and Day27: one 
pre-dose sample or 
postdose sample 
with time recorded 
since last dose
Day 28: one 
postdose sample 
with time recorded 
since last dose
Between Day 29 
and Day 42:  one 
sample with time 
recorded since last 
dose
Follow-up visit: one 
sample with 


2015N246677_04
CONFIDENTIAL
204860
116
Procedure
Screen
ing (up 
to Day 
-28)
Day 
-15
Day 
-14
Da
y -
13 
to -
1
D
a
y 
1
D
a
y 
2 
to 
D
a
y 
1
3
D
a
y 
1
4
Da
y 
15 
to 
Da
y 
20
Day 
21 
to 
Day 
27
Da
y 
28
Day 
29 
to 
42
Follow-
upa
a All procedures 
listed should also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontin
ue
sampling day 
recorded
AE/SAE 
Review
X
<--------------------------------------------------------------------------X----
------------------------------------------->
Concomita
nt 
Medicatio
n Review
X
<--------------------------------------------------------------------------X----
------------------------------------------>
Section 7.1.3 Group B
Rationale for change: Changes have been made to the Time and events table to add 
another column day 15 to day 20. 
REVISED TEXT


2015N246677_04
CONFIDENTIAL
204860
117
Procedure
Screen
ing (up 
to Day 
-28)
Day 
-5 to 
-3
Da
y 1
Day 2 
to 
Day 
13
Da
y 
14
Day 
15 to 
Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 
29 
to 
42
Follow
-up 
(betwe
en Day 
43 to 
Day 
56)a
a All procedures 
listed should also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontin
ue
Informed 
Consent
X
Inc/Exc 
criteria 
assessment
X
Demography
X
Pregnancy 
Test 
(women)
X
X
X
X
X
X
x
X
Pregnancy testing 
between Day 1 & 
Day 28 should be 
performed once 
every 7 days. On 
days of dosing, test 
should be 
performed pre-
dose
TSH, free 
T4, freeT3
X
X
X
X
Vital Signs
X
X
X
X
Safety Lab 
Samples 
(clin chem 
,haematol, 
Urinalysis)
X
X
X
X
x
X
On days of dosing 
samples should be 
taken predose 
Full Physical 
Exam
X
X
Brief 
Physical 
Exam
X
Assessment to be 
performed pre-
dose
12-lead ECG
X
X
X
X
On days of dosing 
assessments 
should be 
performed predose
SLE clinical 
assessment
X
X
X
X
On days of dosing 
assessment as 
defined by the 
investigator to be 
performed pre-
dose .
ANA, anti-
dsDNA 
antibodies, 
anti-Ro and 
anti-La 
antibodies
X
Lesion 
selection
X
Refer to Section 
4.1 and Section 6.1 
Skin 
Biopsies
Xb
Xb
b2 to 4 days 
healing time will be 
allowed prior to 


2015N246677_04
CONFIDENTIAL
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Procedure
Screen
ing (up 
to Day 
-28)
Day 
-5 to 
-3
Da
y 1
Day 2 
to 
Day 
13
Da
y 
14
Day 
15 to 
Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 
29 
to 
42
Follow
-up 
(betwe
en Day 
43 to 
Day 
56)a
a All procedures 
listed should also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontin
ue
randomisation and 
the first dose.
Day 28 biopsies 
will be taken 4 
hours post-dose
Clinical 
score
X
X
X
Local 
tolerability
Assessment
X
X
X
X
X
X
X
Assessments to be 
performed pre-
dose and up to one 
hour following 
dosing on days of 
dosing
Dosing
X
X
X
X
X
X
Once daily
Randomisati
on
X
Pre-dose


2015N246677_04
CONFIDENTIAL
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119
Procedure
Screen
ing (up 
to Day 
-28)
Day 
-5 to 
-3
Da
y 1
Day 2 
to 
Day 
13
Da
y 
14
Day 
15 to 
Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 
29 
to 
42
Follow
-up 
(betwe
en Day 
43 to 
Day 
56)a
a All procedures 
listed should also 
be conducted if a 
subject decides to 
prematurely 
withdraw/discontin
ue
PK blood 
sample
X
X
X
X
X
X
X
Sampling 
timepoints:
Day 1 = pre-dose; 
and 5hrs (1 hr) 
Between Day 2 
and Day13: one 
pre-dose sample or 
postdose sample 
with time recorded 
since last dose
Day 14: predose 
sample 
Between Day 21 
and Day27: one 
pre-dose sample or 
postdose sample 
with time recorded 
since last dose
Day 28:one 
postdose sample 
with time recorded 
since last dose
Between Day 29 
and Day 42:  one 
sample with time 
recorded since last 
dose
Follow-up visit: one 
sample with 
sampling day 
recorded
AE/SAE 
Review
X
Concomitant 
Medication 
Review
X
Lesion 
resolution 
assessment
X
X

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204860
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a double-blind (sponsor 
unblinded) study to investigate safety, tolerability, 
pharmacokinetics, pharmacodynamics and clinical effect of 
repeat dosing of GSK2646264 in cutaneous lupus 
erythematosus patients 
Compound Number 
:
GSK2646264
Effective Date 
:
28-JUN-2018
Description :

This RAP is intended to describe the safety, tolerability, pharmacokinetics, 
pharmacodynamics and clinical efficacy analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the
final Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
05-Oct-2016
(Critical 
Components)
Manager, Clinical Statistics
22-JUN-2018
Principal Statistician, Clinical Statistics
22-JUN-2018
Manager, Clinical Pharmacology
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
204860
2
Approved by: 
19-Sep-2016
(Critical 
Components)
Director, Statistics & Programming, Clinical Statistics
28-Jun-2018
(eTMF)
Director, Clinical Statistics
27-Jun-2018
(eTMF)
Director Programming, Clinical Programming & Governance 
26-Jun-2018 
(email)
Principal Programmer 
26-Jun-2018
(eTMF)
Manager, Clinical Pharmacology
 
25-Jun-2018
(eTMF)
Clinical Development Manager
 
13-Jun-2016 
(email)
Clinical Development Director
 
22-Jun-2018
(eTMF)
Principal, Clinical Data Management 
25-Jun-2018
(eTMF)
Investigator, Biology, EMU DPU
27-Jun-2018
(eTMF)
Principal Clinical Research Scientist 
25-Jun-2018
(eTMF)
SERM Director 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
204860
3
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses.................................................................................12
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Analyses ...................................................................15
7.
PRIMARY STATISTICAL ANALYSES....................................................................16
7.1.
Safety Analyses..........................................................................................16
7.1.1.
Overview of Planned Adverse Events Analyses...........................16
7.1.2.
Overview of Planned Clinical Laboratory Analyses ......................17
7.1.3.
Overview of Planned Other Safety Analyses................................17
8.
SECONDARY STATISTICAL ANALYSES .............................................................19
8.1.
Efficacy Analyses........................................................................................19
8.1.1.
Overview of Planned Efficacy Analyses .......................................19
8.1.2.
Planned Efficacy Statistical Analyses...........................................19
8.2.
Pharmacokinetic Analyses..........................................................................20
8.2.1.
Overview of Planned Pharmacokinetic Analyses .........................20
8.2.2.
Drug Concentration Measures .....................................................20
8.2.3.
Pharmacokinetics from Skin biopsy .............................................21
8.3.
Pharmacodynamic and Biomarker Analyses...............................................22
8.3.1.
Overview of Planned Pharmacodynamic and Biomarker 
Analyses......................................................................................22
8.3.2.
Planned Pharmacodynamic and Biomarker Statistical 
Analyses......................................................................................22
9.
OTHER STATISTICAL ANALYSES .......................................................................25
9.1.
Exploratory Pharmacodynamic and Biomarker Analyses............................25
9.1.1.
Overview of Planned Exploratory Pharmacodynamic and 
Biomarker Analyses.....................................................................25
10. REFERENCES.......................................................................................................26
11. APPENDICES........................................................................................................27


CONFIDENTIAL
204860
4
11.1.
Appendix 1: Time & Events.........................................................................28
11.1.1.
Protocol Defined Time & Events ..................................................28
11.1.2.
Group A.......................................................................................28
11.1.3.
Group A PV non-responders........................................................32
11.1.4.
Group B.......................................................................................33
11.2.
Appendix 2: Data Display Standards & Handling Conventions....................36
11.2.1.
Study Treatment & Sub-group Display Descriptors......................36
11.2.2.
Baseline Definition & Derivations .................................................38
11.2.2.1.
Baseline Definitions....................................................38
11.2.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................40
11.2.3.
Reporting Process & Standards...................................................40
11.3.
Appendix 3: Derived and Transformed Data ...............................................42
11.3.1.
General........................................................................................42
11.3.2.
Study Population..........................................................................42
11.3.3.
Safety ..........................................................................................43
11.3.4.
Efficacy........................................................................................44
11.3.5.
Biomarker ....................................................................................45
11.4.
Appendix 4: Premature Withdrawals & Handling of Missing Data ...............48
11.4.1.
Premature Withdrawals................................................................48
11.4.2.
Handling of Missing Data.............................................................48
11.4.2.1.
Handling of Missing Dates..........................................48
11.4.2.2.
Handling of Partial Dates............................................49
11.5.
Appendix 5: Values of Potential Clinical Importance ...................................50
11.5.1.
Laboratory Values........................................................................50
11.5.2.
ECG.............................................................................................51
11.5.3.
Vital Signs....................................................................................51
11.6.
Appendix 6: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................52
11.6.1.
Statistical Analysis Assumptions..................................................52
11.7.
Appendix 7 – Abbreviations & Trade Marks ................................................53
11.7.1.
Abbreviations...............................................................................53
11.7.2.
Trademarks .................................................................................54
11.8.
Appendix 8: List of Data Displays ...............................................................55
11.8.1.
Data Display Numbering..............................................................55
11.8.2.
Mock Example Shell Referencing ................................................55
11.8.3.
Deliverable [Priority].....................................................................55
11.8.4.
Study Population Tables..............................................................56
11.8.5.
Safety Tables...............................................................................58
11.8.6.
Efficacy Tables ............................................................................61
11.8.7.
Efficacy Figures ...........................................................................62
11.8.8.
Pharmacokinetic Tables...............................................................63
11.8.9.
Pharmacokinetic Figures .............................................................64
11.8.10. Pharmacodynamic Tables ...........................................................65
11.8.11. Pharmacodynamic Figures ..........................................................67
11.8.12. ICH Listings .................................................................................70
11.8.13. Non-ICH Listings..........................................................................74
11.9.
Appendix 9: Example Mock Shells for Data Displays ..................................76


CONFIDENTIAL
204860
5
1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this reporting and analysis plan (RAP) is to describe the 
planned analyses and outputs for the final reporting of group A and group B.
Protocol

This RAP is based on the protocol amendment 3 [(Dated: 14/DEC/2017) of 
study GSK204860 (GSK Document No.: 2015N246677_04] and eCRF Version 
(Version 1).
Primary 
Objective

To evaluate the safety and tolerability of repeat doses of a cream formulation of 
GSK2646264 in patients with CLE
Primary 
Endpoint

Safety and tolerability by laboratory tests, vital signs, 12 lead ECG and AE 
reporting
Study 
Design

This is a double blind (sponsor unblinded) Phase Ib two group study to 
investigate repeat doses of GSK2646264, a spleen tyrosine kinase (SYK) 
inhibitor administered via topical delivery, on safety, pharmacodynamic effect 
and clinical efficacy in active CLE lesions and in acute CLE like lesions induced 
by an established protocol of Photoprovocation (PV). 

The study population will be adult subjects (at least 18 years of age) that have 
been diagnosed with either subacute or chronic CLE.

Group A: Patients with fewer than two active lesions will be enrolled into group A 
and exposed to PV for 3 consecutive days.  (Patients with LET, presenting with 
any number of lesions can enrol into Group A). Patients will be assessed for the 
development of lesions up to 14 days from the first PV. Patients that develop PV 
lesions at any time during this period, as determined by the local investigative 
team, will receive 1% strength GSK2646264 on 1 lesion and placebo on 1 lesion 
daily and either 1% strength GSK2646264 or placebo on an area of uninvolved 
skin, for skin PK of study drug, for 28 days.

Group B: Patients that have a minimum of 2 active existing CLE lesions as 
determined by the investigators will be enrolled into group B and have one lesion 
treated with 1% GSK2646264 and 1 lesion with placebo.
Planned 
Analyses

Final analysis of groups A and B will be reported together after all subjects in 
groups A (up to 5 subjects) and B (approximately 15 subjects) have completed 
their follow-up visit.
Analysis 
Populations

Safety Population: The ‘Safety Population’ is defined as subjects who receive 
at least one dose of study medication. This population is used for the summary 
of all data including safety, efficacy and pharmacodynamic (PD) data but 
excluding PK data. 

Pharmacokinetic Population: The ‘PK Population’ is defined as subjects in the 
‘Safety’ population who received an active dose and for whom a 
pharmacokinetic sample was obtained and analysed. This population is used for 
the summary of PK data only.

PV failures: The ’PV Failures Population’ is defined as subjects who enrolled 
into Group A but were not randomised to a treatment. This population is used to 
present concomitant medications and Adverse event information for these 
subjects.


CONFIDENTIAL
204860
6
Overview
Key Elements of the RAP

All Screened: The ‘All Screened Population’ comprises of all subjects who have 
entered the study and will be used for the listing and summary of screen failures. 
Hypothesis

The primary objective of the study is to evaluate the safety and tolerability of 
repeat doses of a cream formulation of GSK2646264 in patients with CLE. 

No formal statistical comparisons will be conducted to assess this primary 
objective. 

If deemed appropriate to assess key efficacy and pharmacodynamic endpoints, 
the following exploratory comparisons may be conducted:
GSK2646264 treatment vs. Placebo in PV lesions
GSK2646264 treatment vs. Placebo in natural CLE lesions
Primary 
Analyses

Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) 
standards.
Secondary 
Analyses

All plasma GSK2646264 concentration data will be graphically represented, 
descriptively summarised and listed appropriately. Plasma GSK2646264 
concentration time data will be analysed using a Non-compartmental Analysis 
(NCA), if data permit. Pharmacokinetic data will be presented in graphical and/or 
tabular form and will be summarized descriptively. 

Descriptive statistics of both raw and change from baseline, where appropriate
will be calculated for erythema, oedema, dyspigmentation (and scaling in 
existing lesions only) and modified RCLASI. Change from baseline in each 
clinical activity assessment will be analysed using a repeated measures mixed 
effects model with subject random effect and treatment and baseline activity 
score as the fixed effect. 

IFN mRNA data will be normalised, back transformed and log2 transformed 
mRNA intensity data in each IFN mRNA signature endpoints will be analysed
using a mixed model with subject random effect and treatment and baseline 
intensity as the fixed effect. Fold changes will be derived form the back-
transformed estimate of the difference between adjusted means.
Exploratory 
Analyses

Descriptive statistics of both raw and change from baseline will be calculated for 
exploratory Pharmacodynamic/Biomarker endpoints. Change from baseline in
these endpoints may be analysed using a mixed model with subject random 
effect and treatment and baseline activity score as the fixed effect. If data 
permits, endpoints may be analysed using a mixed model with subject random 
effect and skin type as the fixed effect to study the difference due to skin type. 


CONFIDENTIAL
204860
7
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
The following changes were made to the originally planned statistical analysis specified 
in the protocol amendment 3 [(Dated: 14/DEC/2017)]:

The secondary endpoint for the plasma concentration of GSK2646264 is clarified in 
the RAP:
Secondary Objectives
Secondary Endpoints

To evaluate the plasma
concentrations of GSK2646264 in
patients with CLE

PK parameters, including but not limited to AUC, 
Cmax, tmax, half-life (t1/2) if data permits.
Since no subjects were randomised into Group A, no outputs will be generated for this 
part. Listings will be produced for the enrolled (PV failure) subjects in Group A who 
were not randomised.
In the protocol Section 9.4.2, it states that ‘Change from baseline in each clinical activity 
assessment will be analysed for each lesions type’. Due to the small number of patients in 
the study, no formal statistical analysis will be conducted for the RCLASI scores. 
Descriptive summary for raw and change baseline scores will be calculated and 
presented.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the safety and
tolerability of repeat doses of a
cream formulation of GSK2646264 
in patients with CLE

Safety and tolerability by laboratory tests, vital signs, 
12-lead ECG, and AE reporting.
Secondary Objectives
Secondary Endpoints

To determine the effect of
GSK2646264 on the reduction in
clinical activity score from baseline 
in treated PV and existing CLE 
lesions

Change from baseline of components of a modified 
RCLASI- composite clinical activity score at day 14 
and day 28 in PV and existing lesions in erythema, 
oedema, dyspigmentation and (scaling in existing
CLE lesions only)

To evaluate the plasma
concentrations of GSK2646264 in
patients with CLE

PK parameters, including but not limited to AUC, 
Cmax, tmax, half-life (t1/2) if data permits.

To determine the effect of
GSK2646264 on expression of IFN 
mRNA signature in skin biopsies in 
treated PV and existing CLE 

Change from baseline in IFN mRNA signature in skin 
biopsies at day 28 in PV and existing CLE lesions


CONFIDENTIAL
204860
8
Objectives
Endpoints
lesions
Exploratory Objectives
Exploratory Endpoints

To determine the effect of 
GSK2646264 on expression of IFN 
protein markers in skin biopsies in 
treated PV and existing CLE 
lesions

Change from baseline in IFN proteins (e.g. MxA, 
CXCL10) in skin biopsies at day 28 in PV and 
existing CLE lesions

To determine the effect of
GSK2646264 on expression of
pSYK and SYK protein in skin
biopsies in treated PV and existing 
CLE lesions

Change from baseline in pSYK and SYK protein in 
skin biopsies at day 28 in PV and existing CLE 
lesions

To determine the effect of
GSK2646264 on immune cell
markers in skin biopsies in treated 
PV and existing CLE lesions

Change from baseline in immune cell proteins (e.g.
CD3, CD20, CD11c, CD123, CD68) in skin biopsies 
at day 28 in PV and existing CLE lesions

To determine the effect of
GSK2646264 on the histological
disease activity in PV and existing
CLE lesions

Change from baseline in histopathology score 
(including parakeratosis, ballooning/hydropic 
degeneration, epidermal cell-death, junctional and 
dermal inflammation) in skin biopsies at day 28 in PV 
and existing CLE lesions

To evaluate the skin
concentrations of GSK2646264 in
patients with CLE

Skin biopsy concentrations and derived
pharmacokinetic parameters of GSK2646264


CONFIDENTIAL
204860
9
2.3.
Study Design
Overview of Study Design and Key Features


CONFIDENTIAL
204860
10
Overview of Study Design and Key Features
Design
Features

This is a double blind (sponsor unblinded) Phase Ib two group study to 
investigate repeat doses of GSK2646264, a spleen tyrosine kinase (SYK)
inhibitor administered via topical delivery, on safety, pharmacodynamic 
effect and clinical efficacy in active CLE lesions and in acute CLE like 
lesions induced by an established protocol of PV. The study population will 
be adult subjects (at least 18 years of age) that have been diagnosed with 
either subacute or chronic CLE. Patients with Lupus Erythematosus 
Tumidus (LET) are allowed in group A only.

Group A: Patients with fewer than two active lesions will be enrolled into 
group A and exposed to PV for 3 consecutive days (Patients with LET 
presenting with any number of lesions can also be enrolled into Part A).
Patients will be assessed for the development of lesions up to 14 days 


CONFIDENTIAL
204860
11
Overview of Study Design and Key Features
from the first PV. Patients that develop PV lesions at any time during this
period, as determined by the local investigative team, will receive 1% 
strength GSK2646264 on 1 lesion and placebo on 1 lesion daily and either 
1% strength GSK2646264 or placebo on an area of uninvolved skin, for 
skin PK of study drug, for 28 days.

Group B: Patients that have a minimum of 2 active existing CLE lesions as 
determined by the investigators will be enrolled into group B and have one 
lesion treated with 1% GSK2646264 and 1 lesion with placebo.
Dosing

Topical application daily for 28 days
Treatment 
Assignment

Group A Subjects will be assigned the following regimens:
Skin Sites A/C/D
Sequence 
assignment ratio
Sequence 1
A/P/A
4
Sequence 2
A/P/P
1
Sequence 3
P/A/A
4
Sequence 4
P/A/P
1
P=Placebo, A= GSK2646264 1%
Where sites are highlighted below:


CONFIDENTIAL
204860
12
Overview of Study Design and Key Features
PV lesion and area uninvolved skin (area B and E respectively) will be used 
solely to take biopsy.

Group B Subjects will be assigned the following regimens:
Skin Sites F/ G
Sequence assignment 
ratio
Sequence 1
A/P
1
Sequence 2
P/A
1
P=Placebo, A= GSK2646264 1%
Where skin sites F and G will be chosen, lesions F> in size than G, and an 
area of uninvolved skin (area H) will be used solely to take biopsy. 
Final analysis

Final analysis of groups A and B will be reported together after all subjects 
in groups A (up to 5 subjects) and B (approximately 15 subjects) have 
completed their follow-up visit.
2.4.
Statistical Hypotheses
The primary objective of the study is to evaluate the safety and tolerability of repeat
doses of a cream formulation of GSK2646264 in patients with CLE. No formal statistical
comparisons will be conducted to assess this objective. If deemed appropriate to assess
key efficacy and pharmacodynamic endpoints, the following exploratory comparisons
may be conducted:

Group B
o
GSK2646264 treatment vs. Placebo in natural CLE lesions
If deemed appropriate the following exploratory comparisons may be conducted for 
pharmacodynamic markers from the skin biopsies:

Group B
o
Baseline GSK2646264 lesion vs uninvolved skin (skin area H)
o
Baseline Placebo lesion vs uninvolved skin (skin area H) 
o
GSK2646264 lesion at Day 28 vs uninvolved skin (skin area H)
o
Placebo lesion at Day 28 vs uninvolved skin (skin area H)
3.
PLANNED ANALYSES
3.1.
Final Analyses
The final planned analyses will be performed after the completion of the following 
sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 


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4.
Randomisation codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Safety

Comprise of all subjects who receive at least 
one dose of study treatment.

This population will be based on the treatment 
the subject actually received.

Study Population

Safety

Efficacy

Pharmacodynamic
Pharmacokinetic

Subjects in the ‘Safety’ population for whom a 
pharmacokinetic sample was obtained and 
analysed.

PK
PV Failures

Subjects who enrolled into Group A but were 
not randomised to a treatment.

AEs relating to PV

Concomitant 
medications
All Screened

Comprises of all subjects who have entered 
the study

Screen failures
NOTES : 

Please refer to Appendix 8: List of Data Displays which details the population to be used for each display being 
generated.
4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Time & Events
11.2
Appendix 2: Data Display Standards & Handling Conventions
11.3
Appendix 3: Derived and Transformed Data
11.4
Appendix 4: Premature Withdrawals & Handling of Missing Data
11.5
Appendix 5: Values of Potential Clinical Importance
11.6
Appendix 6: Model Checking and Diagnostics for Statistical Analyses.


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the Safety population, unless otherwise 
specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 8: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Endpoint / Parameter / Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition
Y
Reasons for Screen Failure
Y
Y
Subjects by Country and Centre
Y
Reasons for Subject Withdrawal
Y
Subjects for Whom the Treatment Blind was Broken
Y
Planned and Actual Treatments
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Subjects with Inclusion/Exclusion Criteria Deviations
Y [1]
Populations Analysed
Study Populations and Exclusions
Y
Subjects Excluded from Any Population
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Race and Racial Combinations
Y
Y [2]
Race and Racial Combination Details
Y
Prior and Concomitant Medications
Current/Past Medical Conditions
Y
Y
Concomitant Medications
Y
Y
Type of CLE
Y
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Y
Y
NOTES :

Y = Yes display generated.
[1] Listing also includes analysis population exclusions.
[2] Listing of race.


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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Safety Analyses
7.1.1.
Overview of Planned Adverse Events Analyses
The safety analyses will be based on the Safety population, unless otherwise specified.
Table 3 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 8: List of Data Displays.
Table 3
Overview of Planned Adverse Events Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AEs by SOC 
Y
Y
All Drug-Related AEs by SOC
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT & Verbatim Text
Y
Serious and Other Significant AEs
Non-Fatal Serious AEs
Y
Serious AEs by SOC
Y
Reasons for Considering as a Serious AE
Y
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study 
Treatment by Overall Frequency
Y
Y
[1] Plot of common AEs and relative risk will be generated.


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7.1.2.
Overview of Planned Clinical Laboratory Analyses
The safety analyses will be based on the safety population, unless otherwise specified.
Table 4 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 8: List of Data Displays.
Table 4
Overview of Planned Clinical Laboratory Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
L
T
L
Chemistry
Chemistry Changes from Baseline 
Y
Emergent Chemistry Results Relative to Normal Range 
Y
Hematology
Hematology Changes from Baseline
Y
Emergent Hematology Results Relative to Normal Range 
Y
Urinalysis
Urine Concentration Changes from Baseline
Y
Emergent Urinalysis Dipstick Results
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Hepatobiliary Laboratory Abnormalities
Y
Medical Conditions for Subjects with Liver Stopping 
Events
Y
Substance Use for Subjects with Liver Stopping Events
Y
All Laboratory
Laboratory Data for Subjects with Abnormalities of 
Potential Clinical Concern
Y
Y
Laboratory Data Abnormalities of Potential Clinical 
Importance
Y
Y
NOTES:

T = Table, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance, BL = Baseline

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.
7.1.3.
Overview of Planned Other Safety Analyses
The safety analyses will be based on the Safety population, unless otherwise specified.
Table 5 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 8: List of Data Displays.


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Table 5
Overview of Planned Other Safety Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
L
T
L
ECG
ECG Findings 
Y
Maximum Emergent QTc Values by Category
Y
Change from Baseline in ECG Values by Visit
Y
Maximum Change from Baseline in QTc Values by 
Category
Y
All ECG Values for Subjects with a Value of PCI
Y
Y
ECG Values of PCI
Y
Y
Abnormal ECG Findings
Y
Vital Signs
Change From Baseline in Vital Signs by Visit
Y
Emergent Vital Signs Results by Grade Relative to 
Normal Range by PCI Criteria
Y
All Vital Signs for Subjects with Values of PCI
Y
Y
Local Tolerability
Skin Irritation Score1
Y2
Y2
Y2
Y2
Dermal Response and Other Dermal Effects 
Y
Y
NOTES:

T = Table, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance, BL = Baseline

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

[1]: See Section 11.3.3 for more details.

[2]: Absolute and change from baseline will be displayed on the same output.


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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Efficacy Analyses
8.1.1.
Overview of Planned Efficacy Analyses
The secondary efficacy analyses will be based on the safety population, unless otherwise
specified and will be based on Group B subjects only.
Table 6 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 8: List of Data Displays.
Table 6
Overview of Planned Efficacy Analyses
Endpoint 
Absolute
Summary
Individual
T
F
F
L
Clinical Score
RCLASI and 
Components
Y1,2
Y2
Y2
Y1
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

[1]: Include both absolute and change from baseline 

[2]: By Disease Characteristics (Chronic CLE, Acute CLE, Sub-acute CLE, LET and All).
8.1.2.
Planned Efficacy Statistical Analyses
Due to the small number of patients in the study, no formal statistical analysis will be 
conducted.


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8.2.
Pharmacokinetic Analyses
8.2.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the Pharmacokinetic population, 
unless otherwise specified and will be based on Group B subjects only.
The pharmacokinetic analyses will be performed by, or under the direct auspices of 
Clinical Pharmacokinetic Modelling Simulation (CPMS), GlaxoSmithKline.
Table 7 provides an overview of the planned analyses, with full details being presented in 
Appendix 8: List of Data Displays. 
Table 7
Overview of Planned Pharmacokinetic Analyses
Endpoint 
Untransformed
Log-Transformed
Summary
Individual
Summary
T
F
F
L
T
Plasma
Plasma concentrations
Y
Y[1,2]
Y[1]
Y
Plasma PK 
Parameters[3]
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.    

[1] Linear and Semi-log plots will be created on the same display

[2] Separate Mean (±SD) and Median (range) plots will be generated

[3] if data permit
8.2.2.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 11.2.3
Reporting Process & Standards).
8.2.3. Pharmacokinetic Parameters
8.2.3.1. Deriving Pharmacokinetic Parameters

Refer to Appendix 5: Data Display Standards & Handling Conventions 
(Section 11.2.3 Reporting Process & Standards).

The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using WinNonLin, if data permit.

All calculations of non-compartmental parameters will be based on actual sampling 
times.


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Table 8
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) will be calculated using the linear trapezoidal rule 
for each incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid.
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC = AUC(0-t) + C(t) / lambda_z
%AUCex
The percentage of AUC (0-∞) obtained by extrapolation (%AUCex) will be 
calculated as:
[AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100
Cmax
Maximum observed concentration, determined directly from the concentration-time 
data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / lambda_z
NOTES:

Additional parameters may be included as required.

Lambda_z is the terminal phase rate constant.
8.2.3.
Pharmacokinetics from Skin biopsy
The PK analysis of the skin biopsy was from Group A in the study. Since no subjects 
were randomised in this group, there were no skin biopsies for the PK analysis and 
therefore no outputs will be generated.


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8.3.
Pharmacodynamic and Biomarker Analyses
8.3.1.
Overview of Planned Pharmacodynamic and Biomarker Analyses
The pharmacodynamic analyses will be based on the Safety population, unless otherwise 
specified and will be based on Group B subjects only.
The transcriptomic data handling, qc and normalisation will be performed by, or under 
the direct auspices of Target Sciences (TSci) Statistics, GlaxoSmithKline.
Table 9 provides an overview of the planned pharmacodynamic and Biomarker analyses,
with full details of data displays being presented in Appendix 8: List of Data Displays.
Table 9
Overview of Planned Pharmacodynamic and Biomarker Analyses
Endpoint 
Absolute
Fold change
Summary
Individual
Stats Analysis
T
F
F
L
T
F
L
IFN mRNA signature 
in skin biopsies2
Y1
Y1
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

[1]: By Disease Characteristics (Chronic CLE, Acute CLE, Sub-acute CLE, LET and All).

[2]: List of genes and probesets are given in Section 11.3.5
RNA will be extracted and hybridised using a balanced batch design. An appropriate 
microarray platform will be determined at the time of hybridisation, to allow for 
improvements in technology. The quality of the data will be assessed and then normalised 
using appropriate methodologies and software.
Microarray mRNA data will be normalised using gcRMA or RMA in Array Studio v5.0 
or later. After normalisation, the data will be quality assessed and any samples deemed as 
QC fails will be excluded from any further analysis. This quality assessment will involve 
looking for outlying signals in both the normalised expression data and the MAS5 QC 
metrics generated from each sample. If any samples are excluded, the remaining data 
will be re-normalised. The output from the normalisation will be log2 transformed mRNA 
intensity data (measured in arbitrary units).
8.3.2.
Planned Pharmacodynamic and Biomarker Statistical Analyses
Planned Statistical Analyses
Endpoint(s)

IFN mRNA signatures
Model Specification
Microarray mRNA data have been collected from the skin biopsy in both GSK2646264 and placebo 


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Planned Statistical Analyses
treated lesions on Day -5 to -3 (Baseline) and Day 28.
To compare the expression value for each probe set, the following mixed- effects model will be 
fitted to each probe set, with mRNA intensity (log2 scale) as the response variable. 
Baseline is defined as the measurement taken pre-dose at baseline of each treated lesions (i.e 
lesion-specific baseline). 
The baseline observation will be defined as an additional response measured on the same subject 
prior to application of the treatment. Then this observation is not affected by any of the effects 
included in the basic model for the response.
Visit
Trt
XTrt
Baseline
GSK2646264
NA
Baseline
Placebo
NA
Day 28
GSK2646264
GSK2646264
Day 28
Placebo
Placebo
The model will include:

Fixed terms: Treatment (Xtrt: Placebo, GSK2646264, NA), Visit, Visit and Treatment (Xtrt) 
interaction 

Random: Subject (in sas Random intercept /subject=subjid)

Repeated: Visit (in SAS Repeated visit / subject=subjid type=un)
For each probe set analysed adjusted means with corresponding 95% CI and fold changes with 
corresponding 95% CI’s will be outputted. The fold change is derived from the ratio of the back-
transformed estimate of the difference (GSK2646264 – Placebo) between adjusted means.
Since the data will be log2 transformed prior to the analysis the treatment effects will be expressed 
as ratios after back transformation. These ratios can be converted from treatment ratios to fold 
change values as follows:  

If ratio ≥ 1 then fold change = ratio

If ratio < 1 then fold change = -1/ratio
Model Checking

Refer to Appendix 6 : Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Back transformed baseline-adjusted means along with 95% CIs will be calculated for each
treatment group. Additionally, fold changes between active and placebo in change from 


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Planned Statistical Analyses
baseline intensity will be calculated, along with 95% CI.
Endpoint(s)

IFN mRNA signatures
Model Specification
Microarray mRNA data have been collected from the skin biopsy in from different lesions on Day -5 
to -3 (Baseline) and Day 28.
To compare the expression value for each probe set, the following mixed- effects model will be 
fitted to each probe set, with mRNA intensity (log2 scale) as the response variable. 
The model will include:

Fixed terms: Skin Type

Random: Subject (in sas Random intercept /subject=subjid)
Notes Group B: Skin type refers to uninvolved skin, baseline GSK2646264 lesion, baseline 
Placebo lesion, GSK2646264 lesion at day 28 and Placebo lesion at day 28
For each probe set analysed adjusted means with corresponding 95% CI and fold changes with 
corresponding 95% CI’s will be outputted. The fold change is derived from the ratio of the back-
transformed estimate of the difference (GSK2646264 – Placebo) between adjusted means.
Since the data will be log2 transformed prior to the analysis the lesion effects will be expressed as 
ratios after back transformation. These ratios can be converted from treatment ratios to fold change 
values as follows:  

If ratio ≥ 1 then fold change = ratio

If ratio < 1 then fold change = -1/ratio
Model Checking

Refer to Appendix 6: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
Back transformed baseline-adjusted means along with 95% CIs will be calculated for each skin 
type group. Additionally, following fold changes with 95% CI will also be presented:
-
GSK2646264 lesion at day 28 – Uninvolved Skin (skin area H)
-
Placebo lesion at day 28 – Uninvolved Skin (skin area H)
-
Baseline GSK2646264 lesion – Uninvolved Skin (skin area H)
-
Baseline Placebo lesion – Uninvolved Skin (skin area H)


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9.
OTHER STATISTICAL ANALYSES
9.1.
Exploratory Pharmacodynamic and Biomarker Analyses
9.1.1.
Overview of Planned Exploratory Pharmacodynamic and 
Biomarker Analyses
The pharmacodynamic analyses will be based on the Safety population, unless otherwise 
specified.
Table 9 provides an overview of the planned pharmacodynamic and Biomarker analyses, 
with full details of data displays being presented in Appendix 8: List of Data Displays.
Table 10
Overview of Planned Exploratory Pharmacodynamic and Biomarker 
Analyses
Endpoint
Untransformed
Absolute
Summary
Individual
T
F
L
F
Skin Biopsy
IFN proteins (e.g. 
MxA, CXCL10) in 
skin biopsies 
Y2,3
Y3
Y2
Y3
Immune cell proteins 
(e.g. CD3, CD20, 
CD11c, CD123, 
CD68) in skin 
biopsies 
Y2,3
Y3
Y2
Y3
Histopathology score 
in skin biopsies [1]
Y2,3
Y3
Y2
Y3
pSYK and SYK 
protein in skin 
biopsies
Y2,3
Y3
Y2
Y3
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

[1] component scores; parakeratosis, ballooning/hydropic degeneration, epidermal cell-death, junctional and 
dermal inflammation will not be statistically analysed. 

[2] Include both absolute and change from baseline

[3]: By Disease Characteristics (Chronic CLE, Acute CLE, Sub-acute CLE, LET and All).


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10.
REFERENCES
GlaxoSmithKline Document Number 2015N246677_04: A double-blind (sponsor 
unblinded) study to investigate safety, tolerability, pharmacokinetics, pharmacodynamics 
and clinical effect of repeat dosing of GSK2646264 in cutaneous lupus erythematosus 
patients Effective date: 14-DEC-2017


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11.
APPENDICES
Section
Appendix
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 11.1
Appendix 1: Time and Events
Section 11.2
Appendix 2: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 11.3
Appendix 3: Derived and Transformed Data

General, Study Population & Safety

Efficacy

Pharmacodynamic and or Biomarkers
Section 11.4
Appendix 4: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 11.5
Appendix 5: Values of Potential Clinical Importance
Section 11.6
Appendix 6: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 11.7
Appendix 7: Abbreviations & Trade Marks
Section 11.8
Appendix 8: List of Data Displays
Section 11.9
Appendix 9: Example Mock Shells for Data Displays


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11.1.
Appendix 1: Time & Events
11.1.1.
Protocol Defined Time & Events
11.1.2.
Group A
Procedure
Screening 
(up to Day -
28)
Day 
-15
Day 
-14
Day -
13 to -
1
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 
to Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 29 
to 42
Follow-
upa
a All procedures listed to also be 
conducted if a subject decides to 
prematurely withdraw/discontinue
Informed Consent
X
Inc/Exc criteria 
assessment
X
Demography
X
Pregnancy Test 
(women)
X
X
X
X
Pregnancy testing to be 
performed at Screening, on Day 1 
(pre-dose), Day 14 (pre-dose) and 
once during follow-up, with day 
recorded
TSH, free T4, free 
T3
X
X
X
X
Vital Signs
X
X
X
X
X
Safety Lab Samples 
(clin chem, 
haematol, 
Urinalysis)
X
X
X
X
X
X
X
On days of dosing samples 
should be taken predose.
Sample timepoints during the 
Day-13 to Day-1 period are as 
follows: 
– once weekly during visits to 
assess PV lesion development
Full Physical Exam
X
X


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Procedure
Screening 
(up to Day -
28)
Day 
-15
Day 
-14
Day -
13 to -
1
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 
to Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 29 
to 42
Follow-
upa
a All procedures listed to also be 
conducted if a subject decides to 
prematurely withdraw/discontinue
Brief Physical Exam
X
Assessment to be performed pre-
dose
Sample timepoints during the 
Day-13 to Day-1 period are as 
follows:
– once weekly during visits to 
assess PV lesion development
12-lead ECG
X
X
X
X
On days of dosing assessments 
should be performed predose 
SLE clinical 
assessment
X
X
X
X
On days of dosing assessment as 
defined by the investigator to be 
performed pre-dose . 
ANA, anti-dsDNA , 
anti-Ro and anti-La 
antibodies, HIV, Hep 
B, Hep C, FSH, 
Drug screen
X
Skin Biopsies
Xb
Xb
bDay 1 biopsies will be taken 
pre-dose. Day 28 biopsies will 
be taken 4 hours post-dose
UV threshold 
testing
X
Photoprovocation
Xc, d
Performed 24 hours after UV 
threshold testing.
cPV occurs once every 24 hours 
for 3 days on Day-14, Day-13 & 
Day-12.
d If PV induced lesions appear at 
all 3 sites after Day -14 or Day -
13, PV treatment can be stopped 
early


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Procedure
Screening 
(up to Day -
28)
Day 
-15
Day 
-14
Day -
13 to -
1
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 
to Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 29 
to 42
Follow-
upa
a All procedures listed to also be 
conducted if a subject decides to 
prematurely withdraw/discontinue
Lesion induction 
assessment
<- ----X------>
Lesion resolution 
assessment
X
X
Clinical score
X
X
X
Components  of the RCLASI as 
defined in Section 11.3.4
Assessments to be performed 
pre-dose
Local Tolerability
Assessment
X
X
X
X
X
X
X
Assessments to be performed 
pre-dose and up to one hour 
following dosing on days of 
dosing
Dosing
X
X
X
X
X
X
Once daily
Randomisation
X
Pre-dose


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Procedure
Screening 
(up to Day -
28)
Day 
-15
Day 
-14
Day -
13 to -
1
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 
to Day 
20
Day 
21 to 
Day 
27
Day 
28
Day 29 
to 42
Follow-
upa
a All procedures listed to also be 
conducted if a subject decides to 
prematurely withdraw/discontinue
PK blood sample
X
X
X
X
X
X
X
Sampling timepoints:
Day 1 = pre-dose; and 5hrs (1
hr)
Between Day 2 and Day13: one 
pre-dose sample or postdose 
sample with time recorded since 
last dose
Day 14: predose sample 
Between Day 21 and Day27: one 
pre-dose sample or postdose 
sample with time recorded since 
last dose
Day 28: one postdose sample 
with time recorded since last dose
Between Day 29 and Day 42:  
one sample with time recorded 
since last dose
Follow-up visit: one sample with 
sampling day recorded
AE/SAE Review
X
<--------------------------------------------------------------------------X-------------------------------------->
Concomitant 
Medication Review
X
<--------------------------------------------------------------------------X---------------------------------------->


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11.1.3.
Group A PV non-responders
Procedure
Once-weekly up to 28 days after first  
photoprovocation
Final Follow-up visit(s)
(occurs until final PV induced lesion has 
resolved)
Notes
Brief Physical 
Exam
X
X
IMPORTANT: This table is ONLY applicable for 
subjects in group A that do not develop PV induced 
lesions within 14 days of the start of photoprovocation 
Once-weekly assessments will occur from 15 days 
post first photoprovocation up until 28 days post first 
photoprovocation.  Any PV lesion that develops after 
15 days post-photoprovocation will be followed up until 
resolution.
PV Lesion 
assessment (if 
present)
X
X
AE/SAE Review
X
X
Concomitant 
Medication 
Review
X


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11.1.4.
Group B
Procedure
Screening (up 
to Day -28)
Day -5 to 
-3
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 to 
Day 20
Day 21 to 
Day 27
Day 
28
Day 29 
to 42
Follow-up 
(between 
Day 43 to 
Day 56)a
a All procedures listed to also 
be conducted if a subject 
decides to prematurely 
withdraw/discontinue
Informed Consent
X
Inc/Exc criteria 
assessment
X
Demography
X
Pregnancy Test 
(women)
X
X
X
X
Pregnancy testing to be 
performed at Screening, on 
Day 1 (pre-dose), Day 14 (pre-
dose) and once during follow-
up, with day recorded
TSH, free T4, freeT3
X
X
X
X
Vital Signs
X
X
X
X
Safety Lab Samples 
(clin chem ,haematol, 
Urinalysis)
X
X
X
X
x
X
On days of dosing samples 
should be taken predose 
Full Physical Exam
X
X
Brief Physical Exam
X
Assessment to be performed 
pre-dose
12-lead ECG
X
X
X
X
On days of dosing 
assessments should be 
performed predose
SLE clinical 
assessment
X
X
X
X
On days of dosing assessment 
as defined by the investigator 
to be performed pre-dose .
ANA, anti-dsDNA 
antibodies, anti-Ro and 
anti-La antibodies, HIV, 
Hep B, Hep C, FSH, 
Drug screen
X
Lesion selection
X


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Procedure
Screening (up 
to Day -28)
Day -5 to 
-3
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 to 
Day 20
Day 21 to 
Day 27
Day 
28
Day 29 
to 42
Follow-up 
(between 
Day 43 to 
Day 56)a
a All procedures listed to also 
be conducted if a subject 
decides to prematurely 
withdraw/discontinue
Skin Biopsies
Xb
Xb
b2 to 4 days healing time will 
be allowed prior to 
randomisation and the first 
dose.
Day 28 biopsies will be taken 4 
hours post-dose
Clinical score
X
X
X
Local tolerability
Assessment
X
X
X
X
X
X
X
Assessments to be performed 
pre-dose and up to one hour 
following dosing on days of 
dosing
Dosing
X
X
X
X
X
X
Once daily
Randomisation
X
Pre-dose


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Procedure
Screening (up 
to Day -28)
Day -5 to 
-3
Day 
1
Day 2 to 
Day 13
Day 
14
Day 15 to 
Day 20
Day 21 to 
Day 27
Day 
28
Day 29 
to 42
Follow-up 
(between 
Day 43 to 
Day 56)a
a All procedures listed to also 
be conducted if a subject 
decides to prematurely 
withdraw/discontinue
PK blood sample
X
X
X
X
X
X
X
Sampling timepoints:
Day 1 = pre-dose; and 5hrs (1
hr) 
Between Day 2 and Day13: 
one pre-dose sample or 
postdose sample with time 
recorded since last dose
Day 14: predose sample 
Between Day 21 and Day27: 
one pre-dose sample or 
postdose sample with time 
recorded since last dose
Day 28:one postdose sample 
with time recorded since last 
dose
Between Day 29 and Day 42:  
one sample with time recorded 
since last dose
Follow-up visit: one sample 
with sampling day recorded
AE/SAE Review
X
Concomitant 
Medication Review
X
Lesion resolution 
assessment
X
X


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11.2.
Appendix 2: Data Display Standards & Handling 
Conventions
11.2.1.
Study Treatment & Sub-group Display Descriptors
Study population and Safety displays will be presented by sequence. Treatment will not 
be used to summarise these endpoints as all subjects will receive both active and placebo 
concurrently. 
Study Group Descriptions
RandAll NG 
Data Displays for Reporting 
Strata 
Code
Description
Description
Order [1]
A
Group A - Fewer than 2 active 
lesions (PV)
Group A - (PV lesions)
1
B
Group B - At least 2 active CLE
lesions
Group B – (CLE lesions)
2
Group A sequence descriptions:
Sequence Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
AA/PC/AD
GSK2646264 skin site A/ 
Placebo skin site C/ 
GSK2646264 skin site D
GSK2646264 skin area A/ 
Placebo skin area C/ 
GSK2646264 skin area D
1
AA/PC/PD
GSK2646264 skin site A/
Placebo skin site C/
Placebo skin site D
GSK2646264 skin area A/  
Placebo skin area C/
Placebo skin area D
2
     PA/AC/AD
Placebo skin site A/ 
GSK2646264 skin site C/
GSK2646264 skin site D
Placebo skin area A/ 
GSK2646264 skin area C/
GSK2646264 skin area D
3
PA/AC/PD
Placebo skin site A /
GSK2646264 skin site C/
Placebo skin site D
Placebo skin area A/
GSK2646264 skin area C/
Placebo skin area D
4
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
2.
Present code as well as description in displays


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Group B sequence descriptions:
Sequence Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
AF/PG
GSK2646264 skin site F/ Placebo 
skin site G
GSK2646264 skin area F/
Placebo skin area G
1
PF/AG
Placebo skin site F/ GSK2646264 
skin site G
Placebo skin area F/
GSK2646264 skin area G
2
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
2.
Present code as well as description in displays.
Based on the randomisation schedule, treatments/descriptions will be programmatically 
assigned to each skin site area. Local tolerability, Efficacy and Pharmacodynamic 
endpoints are measured at a skin site level and therefore the following treatments will be 
used:
Group A
Treatment group descriptions
Skin area
Data Displays for Reporting
Code
Type
Description
Order
A
PV lesion
GSK2646264 or Placebo [2]
1 or 2
B
PV lesion
Baseline lesion 
3
C
PV lesion
GSK2646264 or Placebo [2]
1 or 2
D
Uninvolved Skin
GSK2646264 or Placebo [2]
1 or 2
E
Uninvolved Skin
Uninvolved skin
4
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
2.
Based on randomisation schedule
3.
GSK2646264 will have a code of 1, Placebo will have a code of 2


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Group B
Treatment group descriptions
Skin area
Data Displays for Reporting
Code
Type
Description
Order
F
Natural Lesion
GSK2646264 or Placebo [2]
1 or 2
G
Natural Lesion
GSK2646264 or Placebo [2]
1 or 2
H
Uninvolved Skin
Uninvolved skin
4
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
2.
Based on randomisation schedule
3.
GSK2646264 will have a code of 1, Placebo will have a code of 2
11.2.2.
Baseline Definition & Derivations
11.2.2.1.
Baseline Definitions
Group A:
Study Assessments Considered as Baseline
Baseline 
Used in 
Data 
Display
Screening
Day -15
Day -13 
to Day -1
Day 1 (Pre-Dose)
Safety
Vital Signs
X
X
X
Day 1 [1]
Safety Lab Samples
X
X
X
Day 1
12-lead ECG
X
X
Day 1
Pharmacodynamic
Skin Biopsy (IFN, 
mRNA, IFN proteins, 
pSYK and SYK 
proteins, immune cell 
proteins)
X
Day 1
(Lesion B 
will be used 
as 
baseline)
Efficacy
RCLASI and 
components
X
Day 1
Pharmacokinetic
Plasma PK
X
Day 1
NOTES :

[1] Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value 
for that time point.


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Group B:
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -5 to Day -3
Day 1 (Pre-
Dose)
Safety
Vital Signs
X
X
Day -5 to Day -3 [1]
Safety Lab Samples
X
X
X
Day 1
12-lead ECG
X
X
Day 1
Pharmacodynamic
Skin Biopsy (IFN, 
mRNA, IFN proteins, 
pSYK and SYK 
proteins, immune cell 
proteins)
X
Day -5 to Day -3
Efficacy
RCLASI and 
components
X
Day 1
Pharmacokinetics
Plasma PK
X
Day 1
NOTES :

Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point.


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11.2.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 11.2.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.
11.2.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used to perform all data analyses and 
generation of displays.
Reporting Area
HARP Server
: us1salx00259
HARP Area
:\us1salx00259\arprod\gsk2646264\mid204860\final_01
QC Spreadsheet
:\us1salx00259\arprod\gsk2646264\mid204860\final_01\document
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards
Generation of RTF Files

RTF files will be generated for listings and tables

PDF flies will be generated for figures
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 


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Reporting Standards
may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD)
of logged data and between geometric coefficient of variation (CVb/w (%))
will be reported.
[1] CVb (%) = √(exp(SD2) - 1) * 100
(SD = SD of log transformed data)
[2] CVw (%) = √ (exp(MSE) - 1) * 100
(MSE = mean square error from mixed effect model of loge-transformed data).
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
   


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11.3.
Appendix 3: Derived and Transformed Data
11.3.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from randomisation date :

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Randomisation Date   → Study Day = Ref Date – Randomisation Date    

Ref Data ≥ Randomisation Date   → Study Day = Ref Date – (Randomisation Date) + 1    
11.3.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / Height (m)2
Extent of Exposure

Number of days of exposure to study cream will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Subjects who were randomised but did not report a treatment start date will be categorised as 
having zero days of exposure. 

Exposure data on a day is recorded in the eCRF in the following manner:

Weight of container and ancillary kit BEFORE application (A)

Weight of container and ancillary kit AFTER application (B)

Location of cream application, where all locations that apply are ticked (C)
This means that the weight of cream that was applied on that day (calculated as B-A) is the total 
dose of cream, with part of the total dose of cream applied to each of all the body locations (C) 
that are ticked.  

The cumulative dose of cream will be based on the formula:


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Extent of Exposure
Cumulative Dose = Sum of (Number of Days x Total Daily Dose of cream)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
11.3.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as : 
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    


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11.3.4.
Efficacy
RCLASI

Modified RCLASI Activity score will be derived by adding together patient’s score for Erythema, 
Scaling/Hyperkeratosis (group B only) and Edema/infiltration. If any one of these components 
are missing, then the modified RCLASI Activity Score will be set to missing.
Modified RCLASI Activity score = Erythema +  Scaling/Hyperkeratosis (group B only) + 
Edema/Infiltration

Overall Modified RCLASI score will be derived by summing the activity and dyspigmentation 
score. If any one of these components is missing, then the overall modified RCLASI Score will 
be set to missing.

Overall Modified RCLASI Score = Modified RCLASI Activity score + Dyspigmentation 
Tolerability score
Tolerability will be assessed with the skin irritation scoring system for Part A and B of study, where 
the score consists of a numeric score according to the dermal response scoring i), and a letter 
according to the other effects scoring ii), as follows:
i) Dermal response scoring:
0 = no evidence of irritation
1 = minimal erythema, barely perceptible (pink)
2 = moderate erythema (definite redness), readily visible; minimal edema or minimal papular 
response
3 = strong erythema (intense redness), or erythema and papules
4 = definite edema
5 = erythema, edema, and papules
6 = vesicular eruption
7 = strong reaction spreading beyond test site
ii) Other effects:
Z = no other effect
A = slight glazed appearance
B = marked glazing
C = glazing with peeling and cracking
F = glazing with fissures
G = film of dried serous exudate covering all or part of the patch site
H = small petechial erosions and/or scabs
For each skin assessment, letter grade will be converted to numeric values as below:
A=0, Z=0, B=1, C=2, F=3, G=3, H=3. 
A combined score for each subject will be calculated by adding all numeric and letter scores
The Skin Irritation Score for will be calculated for each subject at each timepoint and for each body 
part.


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11.3.5.
Biomarker
IFN mRNA signature

Genes to be reported in the descriptive and analysis summary include, but not limited to:
o
CXCL10
o
IFI16
o
IFI44
o
IFI44L
o
IFIH1
o
MX1
o
MX2
o
OAS1
o
OAS2
o
OAS3
o
IFIT1
o
IFIT3
o
OASL
o
ISG15
o
IL1A
o
IL1B
o
IL6
Since each gene has multiple probesets, the following table highlights the probesets which have, 
historically, been of good quality and hence will be used for the analysis in this study. Entrez ID is 
also specified, which is a unique code a gene. These can be used at the programming stage to 
subset from multiple genes and probesets. 
PROBSID
GENESYMB
Entrez_ID
204533_at
CXCL10
3627
206332_s_at
IFI16
3428
208965_s_at
IFI16
3428
208966_x_at
IFI16
3428
214059_at
IFI44
10561
214453_s_at
IFI44
10561
204439_at
IFI44L
10964
1555464_at
IFIH1
64135
216020_at
IFIH1
64135
219209_at
IFIH1
64135
203153_at
IFIT1
3434
204747_at
IFIT3
3437
229450_at
IFIT3
3437
208200_at
IL1A
3552
210118_s_at
IL1A
3552
205067_at
IL1B
3553
39402_at
IL1B
3553
205207_at
IL6
3569


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205483_s_at
ISG15
9636
202086_at
MX1
4599
204994_at
MX2
4600
202869_at
OAS1
4938
205552_s_at
OAS1
4938
204972_at
OAS2
4939
206553_at
OAS2
4939
228607_at
OAS2
4939
218400_at
OAS3
4940
232666_at
OAS3
4940
205660_at
OASL
8638
210797_s_at
OASL
8638
Immunohistochemistry (IHC) biomarkers
Cells in lesional biopsies are measured by IHC. Single stains include but are not limited to; pSyk+, 
tSyk+, MxA+, CD3+, CD20+, CD68+, CD11c+, CD123+, Dual stains include but are not limited to; 
pSyk/tSyk, pSyk/CD11c, pSyk/CD123, in Epidermal, Dermal and combined areas of skin.
Each single/dual stain is assessed at 20x magnification across the whole 1 layer (3.5um slice) of the 
biopsy by automated image analysis and normalised by area (mm2). The regions of interest are the 
epidermis, dermis and glass, however only cells within the epidermis and dermis are analysed, 
which are classified by the automated image analysis software HALO. A manual QC process will be 
conducted on the software assigned regions of interest if necessary at the discretion of the operator, 
including but not limited to removal or addition of incorrectly classified areas within HALO. Other 
artefacts (tissue folding, stain precipitation) will be excluded from the ROI manually at the discretion 
of the operator and confirmation by the pathologist.
The number of positive cells for each marker will be calculated from the single or dual stain where 
appropriate. The reportables will include but are not limited to the total number of cells for each 
marker normalised by area (mm2), total area (mm2), total number of cells per mm2, percentage of 
dual positive cells from total cells and percentage of each marker that is positive for both markers in 
the dual stains where applicable. These values will be provided for both dermis and epidermis 
separately, and combined, and will be derived by the BIB group within GSK prior to data transfer.
Histopathology score

The component scores (patient’s parakeratosis, ballooning\hydropic degeneration, epidermal 
cell-death, junctional inflammation and dermal inflammation scores) are scored twice by two 
independent investigators. Derivation,
Mean component score = (score 1 + score 2)/2
will be used to derive the mean component scores for each patient. This will be used for the 


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descriptive summaries. If one of the scores missing then the other score will be used as the 
mean component score. 

Overall histopathology score will be derived by summing derived mean component scores for 
patient’s parakeratosis, ballooning\hydropic degeneration, epidermal cell-death, junctional 
inflammation and dermal inflammation scores. This will be used for the descriptive summaries. 

Note for listing only: For each score, the overall histopathology score will be derived by 
summing component scores for patient’s parakeratosis, ballooning\hydropic degeneration, 
epidermal cell-death, junctional inflammation and dermal inflammation scores. This will be used 
for the descriptive summaries. 


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11.4.
Appendix 4: Premature Withdrawals & Handling of Missing 
Data
11.4.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as 
subject who receives at least 25 days of study drug and completes the end of 
treatment biopsy and assessment.

Withdrawn subjects may be replaced in the study.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
11.4.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to 
blank fields on the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered 
to be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
IFN mRNA 
signatures 

No imputation methods will be used for missing value.  
IHC 
biomarkers

Change from baseline will be derived for this marker (see Section 11.2.2.2). If 
data is missing at any particular time point, then the change from baseline will
be set to missing.
Histopathology 
score

Change from baseline score will be derived (see Section 11.2.2.2) for 
individual components. If one or more of the components are missing then 
final score will be set to missing. If a score is missing at any particular time 
point, then the change from baseline score will be set to missing. 
Histopathology 
component 
score

Change from baseline score will be derived for individual components for 
each subject. If a score is missing at any particular time point, then the 
change from baseline score will be set to missing. 
11.4.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.


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Element
Reporting Detail
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month may 
be missing. In such a case, the following conventions will be applied for 
calculating the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date 
will be used and hence the event is considered On-treatment 
o
Missing Stop Day: Last day of the month will be used, unless this is after 
the stop date of study treatment; in this case the study treatment stop 
date will be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied.
11.4.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month. 
o
However, if these results in a date prior to Week 1 Day 1 and the event 
could possibly have occurred during treatment from the partial information, 
then the Week 1 Day 1 date will be assumed to be the start date. 
o
The AE will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


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11.5.
Appendix 5: Values of Potential Clinical Importance
11.5.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Red Blood Cell Count (RBC)
x1012/ L
4.2
5.9
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
Monocytes
x109/ L
0.14
1.3
Eosinophils
x109/ L
0.55
Basophils
x109/ L
0.22
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
G/L
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin


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Liver Function
Test Analyte
Units
Category
Clinical Concern Range
+
U/L
2x ULN ALT
11.5.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450
Absolute PR Interval
msec
< 110
> 220 
Absolute QRS Interval
msec
< 75
> 110
Change from Baseline
Increase from Baseline QTc
msec
>30
11.5.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥40
≥ 40
Diastolic Blood Pressure
mmHg
≥20
≥ 20
Heart Rate
bpm
≥30
≥ 30


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11.6.
Appendix 6: Model Checking and Diagnostics for Statistical 
Analyses
11.6.1.
Statistical Analysis Assumptions
Endpoint(s)

IFN mRNA signatures
Analysis

Mixed model

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 

If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data.


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11.7.
Appendix 7 – Abbreviations & Trade Marks
11.7.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
A&R
Analysis and Reporting 
BMI
Body Mass Index
CI
Confidence Interval
CLE
Cutaneous Lupus Erythematosus
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
FRP
Females of Reproductive Potential
FTIH
First Time in Human
GUI
Guidance
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IFN
Interferon
IMMS
International Modules Management System
IP
Investigational Product
LET
Lupus Erythematosus Tumidus
MMRM
Mixed Model Repeated Measures
mRNA
Messenger-Ribonucleaic Acid
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
pSYK
Phosporylated- Spleen Tyrosine Kinase
PV
Photoprovocation
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
RCLASI
Revised Cutaneous Lupus Erythematosus Disease Area and Severity 
Index
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SOP
Standard Operation Procedure


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Abbreviation
Description
SYK
Spleen Tyrosine Kinase
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
GSK
GlaxoSmithKline
11.7.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
WinNonlin


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11.8.
Appendix 8: List of Data Displays
11.8.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.14
Safety
2.1 to 2.20
Efficacy
3.1 
3.1 to 3.2
Pharmacokinetic
4.1 to 4.3
4.1 to 4.3
Pharmacodynamic 
5.1 to 5.5
5.1 to 5.12
Section
Listings
ICH Listings
1 to 33
Other Listings
34 to 44
11.8.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 9: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacodynamic 
PD_Fn
PD_Tn
PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
11.8.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.


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11.8.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
CP_ES1p
Summary of Subject Disposition (Group B-Natural Lesions)
SAC
1.2.
All Screened
ES6
Summary of Reasons for Screen Failure (Group A- PV lesions)
SAC
1.3.
All Screened
ES6
Summary of Reasons for Screen Failure (Group B-Natural 
Lesions)
SAC
1.4.
Safety
NS1
Summary of Number of Subjects by Country and Centre (Group 
B-Natural Lesions)
SAC
Protocol Deviation
1.5.
Safety
DV1
Summary of Important Protocol Deviations (Group B-Natural 
Lesions)
SAC
Population Analysed
1.6.
All 
Screened
SP1
Summary of Study Populations and Exclusions (Group A- PV 
lesions)
SAC
1.7.
All 
Screened
SP1
Summary of Study Populations and Exclusions (Group B-Natural 
Lesions)
SAC


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Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
1.8.
Safety
DM3
Summary of Demographic Characteristics (Group B-Natural 
Lesions)
Include BMI
SAC
1.9.
Safety
DM5
Summary of Race and Racial Combinations (Group B-Natural 
Lesions)
SAC
1.10.
Safety
DM6
Summary of Race and Racial Combination Details (Group B-
Natural Lesions)
SAC
Prior and Concomitant medications
1.11.
Safety
MH1, MH4
Summary of [Current/Past] Medical Conditions (Group B-Natural 
Lesions)
SAC
1.12.
Safety
CM1
Summary of Concomitant Medications (Group B-Natural 
Lesions)
SAC
1.13.
Safety
SAFE_T3
Summary of Type of CLE (Group B-Natural Lesions)
Obtained from medical conditions page 
in eCRF. Under Disease Diagnosis – 2. 
Disease characteristics.
SAC
Exposure and Treatment Compliance
1.14.
Safety
EX1
Summary of Weight of Study Cream Applied (Group B-Natural 
Lesions)
See Section 11.3.2 regarding total daily 
dose of cream; label first row as “Daily 
Weight of Cream (g)” with following 
footnote: “Note: Daily Dose refers to the 
one lesion that either active or placebo 
treatment is applied to; 
Label second row as “Cumulative 
Weight of Cream (g)”.  
SAC


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11.8.5.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
2.1.
Safety
CP_AE1p
Summary of All Adverse Events by System Organ Class (Group 
B-Natural Lesions)
Only Total adverse events will be 
summarised.
SAC
2.2.
Safety
CP_AE1p
Summary All Drug-Related Adverse Events by System Organ 
Class (Group B-Natural Lesions)
Only Total adverse events will be 
summarised.
SAC


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Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
2.3.
Safety
        CP_AE1p
Summary of Serious Adverse Events by System Organ Class
(Group B-Natural Lesions)
Only Total adverse events will be 
summarised.
SAC
2.4.
Safety
CP_AE1p
Summary of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment by Overall 
Frequency (Group B-Natural Lesions)
Only Total adverse events will be 
summarised.
SAC
Laboratory: Chemistry
2.5.
Safety
LB1
Summary of Chemistry Changes from Baseline (Group B-
Natural Lesions)
Treatment column will not be displayed.
SAC
2.6.
Safety
LB3
Summary of Emergent Chemistry Results Relative to Normal 
Range (Group B-Natural Lesions)
Treatment columns will be replaced by 
one ‘Part B’ column
SAC
Laboratory: Hematology
2.7.
Safety
LB1
Summary of Hematology Changes from Baseline (Group B-
Natural Lesions)
Includes baseline values.
Treatment column will not be displayed.
SAC
2.8.
Safety
LB3
Summary of Emergent Hematology Results Relative to Normal 
Range (Group B-Natural Lesions)
As notes for Chemistry T2.12.
SAC
Laboratory: Urinalysis
2.9.
Safety
LB1
Summary of Urine Concentration Changes from Baseline (Group 
B-Natural Lesions)
Includes Baseline values.
Treatment column will not be displayed.
SAC
2.10.
Safety
LB2
Summary of Emergent Urinalysis Dipstick Results (Group B-
Natural Lesions)
As above for Chemistry, using dipstick 
categories.
SAC
Laboratory: Hepatobiliary (Liver)
2.11.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting (Group 
B-Natural Lesions)
Treatment columns will be replaced by 
one ‘Part B’ column
SAC


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Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12.
Safety
LIVER10
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormality Criteria (Group B-Natural Lesions)
Treatment columns will be replaced by 
one ‘Part B’ column
SAC
ECG
2.13.
Safety
EG1
Summary of ECG Findings (Group B-Natural Lesions)
Treatment columns will be replaced by 
one ‘Part B’ column
SAC
2.14.
Safety
CP_EG11
Summary of Maximum Emergent QTc Values by Category 
(Group B-Natural Lesions)
Treatment columns will be replaced by 
one ‘Part B’ column
SAC
2.15.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
(Group B-Natural Lesions)
Note: IDSL shell in development.
Includes Baseline values.
Treatment columns will be replaced by 
one ‘Part B’ column
SAC
2.16.
Safety
CP_EG12
Summary of Maximum Change from Baseline in QTc Values by 
Category (Group B-Natural Lesions)
Treatment columns will be replaced by 
one ‘Part B’ column
SAC
Vital Signs
2.17.
Safety
VS1
Summary of Change from Baseline in Vital Signs by Visit (Group 
B-Natural Lesions)
Treatment column will not be displayed.
SAC
2.18.
Safety
VS3
Summary of Emergent Vital Signs Results Relative to Normal 
Range (Group B-Natural Lesions)
Treatment columns will be replaced by 
one ‘Part B’ column
SAC
Local Tolerability
2.19.
Safety
SAFE_T1
Summary (Absolute and Change from Baseline) of Mean 
irritation score assessment – (Group B-Natural Lesions)
SAC
2.20.
Safety
SAFE_T2
Assessment of Maximum Dermal Reactions and Response
(Group B-Natural Lesions)
SAC


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11.8.6.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
RCLASI
3.1.
Safety
PD_T1
Summary of RCLASI and components (Absolute and Change 
from Baseline) (Group B-Natural Lesions)
Page by score type (e.g. 
component/final) 
Include absolute and change from 
baseline.
First variable for Type of CLE – include 
All.
Include footnote for derivation (see
Section 11.3.4)
SAC


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11.8.7.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
RCLASI
3.1.
Safety
PD_F1
Individual profile plots of RCLASI and components (Group B-
Natural Lesions)
Page by score type (e.g. 
component/final) 
Column panel by treatment group
Symbol by subject Id.
Line pattern by CLE type.
Include footnote for derivation (see
Section 11.3.4)
SAC
3.2.
Safety
PD_F2
Summary of Mean (SE) in RCLASI and components (Group B-
Natural Lesions)
Panel by CLE type (include All).
Include footnote for derivation (see
Section 11.3.4)
SAC


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11.8.8.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK
PKPT1
Summary of Serum GSK2646264 Pharmacokinetic 
concentrations versus time by actual dose (Group B-Natural 
Lesions)
SAC
4.2.
PK
PKPT1
Summary of Derived Serum GSK2646264 Pharmacokinetic 
Parameters by actual dose (Group B-Natural Lesions)
SAC
4.3.
PK
PKPT1
Summary of Log-Transformed Derived Serum GSK2646264 
Pharmacokinetic Parameters by actual dose (Group B-Natural 
Lesions)
SAC


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11.8.9.
Pharmacokinetic Figures
Pharmacokinetic : Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK
PKCF1P
Individual GSK2646264 Plasma Concentration-Time Plot by 
Subject (Linear and Semi-Log) (Group B-Natural Lesions)
Refer Table1 treatment description 
table
1.X-axis display actual relative time
2.Include line for LLQ along with 
footnote defining LLQ value
3.Include values below LLQ
SAC
4.2.
PK
PKCF2
Mean (SD) Plasma GSK2646264 Concentration-Time Plots 
(Linear and Semi-log) (Group B-Natural Lesions)
1.Refer Table 1 treatment 
description table
2. Include the full SD bars i.e.(not 
just the +ve SD) at each time point.
3. X-axis displays planned  relative 
time
4.  Include line for LLQ along with 
footnote defining LLQ value.
SAC
4.3.
PK
PKCF3
Median (Range) Plasma GSK2646264 Concentration-Time Plot 
(Linear and Semi-log) (Group B-Natural Lesions)
1.Refer Table 1 treatment 
description table
2. X-axis displays planned  relative 
time
3.  Include line for LLQ along with 
footnote defining LLQ value.
4. Combine data per dose group; 
i.e. no distinction of ADA status
SAC


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11.8.10.
Pharmacodynamic Tables
Pharmacodynamic (and or Biomarker) : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
IFN mRNA signature
5.1.
Safety
PD2
Summary of mRNA Expression of Inflammatory Gene 
Transcripts in Biopsy (Group B-Natural Lesions)
Summary by treatment group (Placebo, 
GSK2646264 and uninvolved skin)
First variable for Type of CLE – include 
All.
See Section 11.3.5 for list of genes and 
probe-sets to be summarised
SAC
5.2.
Safety
PD_T2
Summary of Adjusted Mean and Fold Changes in mRNA 
Expression of Inflammatory Gene Transcripts in Biopsies (Group 
B-Natural Lesions)
Summary by treatment group (Placebo 
and GSK2646264)
See Section 11.3.5 for list of genes and 
probe-sets to be analysed
Footnote: ‘Comparison to placebo fold 
change’ is the fold change on 
GSK2646264 relative to placebo in log2
intensity at day 28.’
SAC
5.3.
Safety
PD_T3
Summary of Adjusted Mean and Fold Changes in mRNA 
Expression of Inflammatory Gene Transcripts in Biopsies by 
Skin Type (Group B-Natural Lesions)
Summary by skin type
See Section 11.3.5 for list of genes and 
probe-sets to be analysed
Footnote: ‘Comparison to uninvolved 
fold change’ is the fold change on 
GSK2646264 relative to placebo in log2
intensity.’
SAC


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Pharmacodynamic (and or Biomarker) : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Other biomarkers
5.4.
Safety
PD_T1
Summary of Cell Markers from Immunohistochemistry (Absolute 
and Change from baseline) (Group B-Natural Lesions)
Summary by lesion type (Placebo, 
GSK2646264 and uninvolved skin).
Replace treatment title with ‘Lesion 
type’
First variable for Type of CLE – include 
All.
SAC
5.5.
Safety
PD_T1
Summary of Histopathology score and components in skin 
biopsies (Absolute and Change from baseline) (Group B-Natural 
Lesions)
Page by score type – e.g final score 
then component score summaries 
Summary by lesion type (Placebo, 
GSK2646264 and uninvolved skin).
Include change from baseline column  
where applicable.
Replace treatment title with ‘Lesion 
type’
First variable for Type of CLE – include 
All.
SAC


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11.8.11.
Pharmacodynamic Figures
Pharmacodynamic (and or Biomarker) : Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
IFN mRNA signature
5.1.
Safety
PD_F1
Individual Subject Profiles for mRNA Expression of IFN 
Signatures in Skin Biopsies (Group B-Natural Lesions)
Symbol by subject id, column panel by 
treatment group (Placebo and 
GSK2646264)
Symbol by subject Id.
Line pattern by CLE type
See Section 11.3.5 for list of genes and 
probe-sets to be summarised
SAC
5.2.
Safety
PD_F3
Adjusted Mean Intensities (95% CI) for mRNA Expression IFN 
Signatures in Skin Biopsies (Group B-Natural Lesions)
Y xais – log2 scale
By treatment group (Placebo and 
GSK2646264)
Jitter by treatment (i.e. do not overlay 
the mean error bars.)
SAC
5.3.
Safety
PD_F4
Adjusted Mean (95% CI) Fold Change in mRNA Expression of 
IFN Signatures in Skin Biopsies (Group B-Natural Lesions)
Page by Gene ID.
X-axis -  probeset ID
Include band from FC -1 to 1, 
transparency 0.5
Footnote: ‘Comparison to placebo’ is 
the fold change on GSK2646264 
relative to placebo in log2 intensity at 
day 28.’
SAC
5.4.
Safety
PD_F5
Individual Plot of mRNA Expression of IFN Signatures in Skin 
Biopsies by Skin Type (Group B-Natural Lesions)
Symbol by CLE type, column panel by 
skin type.
X-axis – subject id
Symbol by CLE type
See Section 11.3.5 for list of genes and 
probe-sets to be summarised
SAC


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Pharmacodynamic (and or Biomarker) : Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.5.
Safety
PD_F6
Adjusted Mean Intensities (95% CI) for mRNA Expression IFN 
Signatures in Skin Biopsies (Group B-Natural Lesions)
Since only one timepoint, replace x-axis 
with skin type. 
Symbol by subject Id.
Include individual raw values 
SAC
5.6.
Safety
PD_F6
Adjusted Mean (95% CI) Fold Change in mRNA Expression of 
IFN Signatures in Skin Biopsies by Skin Type (Group B-Natural 
Lesions)
Page by Gene ID.
X-axis -  probeset ID
By Skin Type – symbol by skin type
Include band from FC -1 to 1, 
transparency 0.5
Footnote: ‘Comparison to uninvolved’ is 
the fold change on GSK2646264 
relative to placebo in log2 intensity.’
SAC
Exploratory PD endpoints
5.7.
Safety
PD_F1
Individual plot of cell markers from Immunohistochemistry
(Group B-Natural Lesions)
Symbol by subject id, column panel by 
treatment group (Placebo and 
GSK2646264)
Symbol by subject Id.
Line pattern by CLE type
Heading: [marker name and 
description]
SAC
5.8.
Safety
Similar to 
PD_F2
Plot of Mean and SE of cell markers from Immunohistochemistry
(Group B-Natural Lesions)
By treatment group (Placebo and 
GSK2646264)
Panel by CLE type (include All).
Heading: [marker name and 
description]
SAC


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Pharmacodynamic (and or Biomarker) : Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.9.
Safety
PD_F6
Plot of Mean and SE of cell markers from Immunohistochemistry
by Skin Type(Group B-Natural Lesions)
Since only one timepoint, replace x-axis 
with skin type.
Include individual raw values 
Symbol by subject Id.
Panel by CLE type (include All)
Heading: [marker name and 
description]
SAC
5.10.
Safety
PD_F1
Individual plot of Histopathology score and components in skin 
biopsies (Group B-Natural Lesions)
Symbol by subject id, column panel by 
treatment group (Placebo and 
GSK2646264)
Symbol by subject Id.
Line pattern by CLE type
SAC
5.11.
Safety
Similar to 
PD_F2
Plot of Mean and SE in Histopathology score and components in 
skin biopsies (Group B-Natural Lesions)
By treatment group (Placebo and 
GSK2646264)
Panel by CLE type (include All)
SAC
5.12.
Safety
PD_F6
Plot of Mean and SE in Histopathology score and components in 
skin biopsies by skin type (Group B-Natural Lesions)
Since only one timepoint, replace x-axis 
with skin type
Include individual raw values 
Symbol by subject Id.
Panel by CLE type (include All)
Heading: [type of score]
SAC


CONFIDENTIAL
204860
70
11.8.12.
ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
PV Failures
ES7
Listing of Reasons for Screen Failure (Group A- PV lesions)
SAC
2.
All Screened
ES7
Listing of Reasons for Screen Failure (Group B-Natural Lesions)
SAC
3.
Safety
ES2 
Listing of Reasons for Study Withdrawal (Group B-Natural 
Lesions)
SAC
4.
Safety
BL1 / BL2
Listing of Subjects for Whom the Treatment Blind was Broken 
(Group B-Natural Lesions)
SAC
5.
Safety
CP_RD1x
Listing of Planned and Actual Treatments (Group B-Natural 
Lesions)
SAC
Protocol Deviations
6.
Safety
DV2
Listing of Important Protocol Deviations (Group B-Natural 
Lesions)
SAC
7.
Safety
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
(Group B-Natural Lesions)
SAC
Populations Analysed
8.
All Screened
SA3a
Listing of Subjects Excluded from Any Population (Group B-
Natural Lesions)
SAC
Demographic and Baseline Characteristics
9.
Safety
DM2 
Listing of Demographic Characteristics (Group B-Natural 
Lesions)
Include BMI
SAC
10.
Safety
DM9 
Listing of Race (Group B-Natural Lesions)
SAC


CONFIDENTIAL
204860
71
ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Medical History
11.
Safety
MH2 
Listing of Medical History (Group B-Natural Lesions)
SAC
Prior and Concomitant Medications
12.
Safety
CP_CM3 
Listing of Concomitant Medications (Group B-Natural Lesions)
SAC
Exposure and Treatment Compliance
13.
Safety
EX3
Listing of Weight of Study Cream Applied (Group B-Natural 
Lesions)
If applicable adapt to study data
See Section 11.3.2 regarding total daily 
dose of cream i.e. each subject to have 
one row per day, with weight of cream
listed (the total weight calculated from 
the weight before and after application), 
column labelled as “Weight of Cream 
(g)” and each body location/side listed 
together on that single row.  
SAC
Adverse Events
14.
Safety
CP_AE8 
Listing of All Adverse Events (Group B-Natural Lesions)
No treatment heading.
SAC
15.
PV failures
CP_AE8 
Listing of All Adverse Events for subjects that were PV failures 
(Group A-PV Lesions)
No treatment heading.
SAC
16.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events (Group 
B-Natural Lesions)
Treatment column will not be displayed.
SAC
17.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text (Group B-Natural 
Lesions)
SAC


CONFIDENTIAL
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72
ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
18.
Safety
CP_AE8a 
Listing of Serious Adverse Events (Group B-Natural Lesions)
No treatment heading.
SAC
19.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event 
(Group B-Natural Lesions)
SAC
20.
Safety
CP_AE8 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment (Group B-
Natural Lesions)
No treatment heading.
SAC
Hepatobiliary (Liver)
21.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events (Group B-Natural Lesions)
Treatment column will not be displayed
SAC
22.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events (Group B-Natural Lesions)
Treatment column will not be displayed
SAC
All Laboratory
23.
Safety
LB5
Listing of Laboratory Data for Subjects with Abnormalities of 
Potential Clinical Concern (Group B-Natural Lesions)
No treatment heading.
SAC
24.
Safety
LB5
Listing of Laboratory Data for Subjects with Abnormalities of 
Potential Clinical Concern-Change from Baseline (Group B-
Natural Lesions)
No treatment heading.
SAC
25.
Safety
LB5 
Listing of Laboratory Data Abnormalities of Potential Clinical 
Importance (Group B-Natural Lesions)
No treatment heading.
SAC
26.
Safety
LB5 
Listing of Laboratory Data Abnormalities of Potential Clinical 
Importance- change from baseline (Group B-Natural Lesions)
No treatment heading.
SAC


CONFIDENTIAL
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73
ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
27.
Safety
CP_EG3 
Listing of All ECG Values for Subjects with a Value of Potential 
Clinical Importance (Group B-Natural Lesions) 
No treatment heading.
SAC
28.
Safety
CP_EG3 
Listing of ECG Values of Potential Clinical Importance (Group B-
Natural Lesions)
No treatment heading.
SAC
29.
Safety
CP_EG3 
Listing of All ECG Values for Subjects with a Value of Potential 
Clinical Importance- Change from Baseline (Group B-Natural 
Lesions) 
No treatment heading.
SAC
30.
Safety
CP_EG3 
Listing of ECG Values of Potential Clinical Importance-Change 
from Baseline (Group B-Natural Lesions)
No treatment heading.
SAC
31.
Safety
CP_EG5 
Listing of Abnormal ECG Findings (Group B-Natural Lesions)
No treatment heading.
SAC
Vital Signs
32.
Safety
CP_VS4
Listing of All Vital Signs for Subjects with Values of Potential 
Clinical Importance (Group B-Natural Lesions)
Treatment column will not be displayed
SAC
33.
Safety
CP_VS4
Listing of All Vital Signs for Subjects with Values of Potential 
Clinical Importance –Change from baseline (Group B-Natural 
Lesions)
Treatment column will not be displayed
SAC


CONFIDENTIAL
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74
11.8.13.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
34.
Safety
SAFE_L2
Listing of Type of CLE (Group B-Natural Lesions)
Obtained from medical conditions page 
in eCRF. Under Disease Diagnosis – 2. 
Disease characteristics.
Local tolerability
35.
Safety
SAFE_L1
Listing of local tolerability (Group B-Natural Lesions)
Include maximal dermal response
SAC
RCLASI
36.
Safety
PD_L1
Listing of RCLASI and components (Group B-Natural Lesions)
Include change from baseline.
Include a footnote to explain the 
derivation 
SAC


CONFIDENTIAL
204860
75
Non-ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
37.
PK
PKCl1P
Listing of Plasma GSK2646264 Pharmacokinetic Concentration-
Time Data (Group B-Natural Lesions)
SAC
38.
PK
PKPL1P
Listing of Derived Plasma GSK2646264 Pharmacokinetic 
Parameters (Group B-Natural Lesions)
SAC
Pharmacodynamic
39.
Safety
PD_L2
Listing of transcriptomic mRNA expression in skin biopsies for 
selected probesets (Group B-Natural Lesions)
See Section 11.3.5 for list of genes and 
probe-sets to be listed
SAC
40.
Safety
Raw SAS output from the statistical analysis of change from 
baseline IFN  proteins in skin biopsies (Group B-Natural 
Lesions)
SAC
41.
Safety
Raw SAS output from the statistical analysis of IFN proteins in 
skin biopsies by skin type (Group B-Natural Lesions)
SAC
42.
Safety
PD10
Listing of Cell Markers from Immunohistochemistry (Group B-
Natural Lesions)
Include change from baseline
SAC
43.
Safety
PD_L3
Listing of Histopathology score and components in skin biopsies 
(Group B-Natural Lesions)
Include change from baseline.
Column for Skin Area (e.g. F, G and H). 
Each subject has two forms. Thus 
listing will include both values.
SAC
44.
Safety
PD_L4
Listing of QC criteria from Histological scoring form (Group B-
Natural Lesions)
This will include listing of QC Criteria 
section of the form.
SAC


CONFIDENTIAL
204860
76
11.9.
Appendix 9: Example Mock Shells for Data Displays
Example 
: SAFE_T1
                                                     Page x of y
Protocol
: 204860
Population
: Safety
Table x.xx
Summary (Absolute and Change from Baseline) of Mean irritation score assessment
Summary: Mean Irritation score (Absolute)
Treatment
Time
N
n
Mean
S.D
Min
Median
Max
Placebo
X
x
X
xxx.x
xx.xx
xxx
xxx
xxx
X
x
X
xxx.x
xx.xx
xxx
xxx
xxx
X
x
X
xxx.x
xx.xx
xxx
xxx
xxx
.
.
.
.
.
.
.
GSK2646264
X
x
X
xxx.x
xx.xx
xxx
xxx
xxx
X
x
X
xxx.x
xx.xx
xxx
xxx
xxx
X
x
X
xxx.x
xx.xx
xxx
xxx
xxx
.
.
.
.
.
.
.


CONFIDENTIAL
204860
77
Example 
: SAFE_T2
                                                     Page x of y
Protocol
: 204860
Population
: Safety
Table x.xx
Summary of Tolerability: Maximum Dermal Response and Maximum Other Dermal Effects 
Assessment
Statistic
GSK2646264
(N = XX)
Placebo
(N = XX)
Maximum Dermal 
Response
0
1
n (%)
n (%)
XX (XX.XX)
XX (XX.XX)
XX (XX.XX)
XX (XX.XX)
2
n (%)
XX (XX.XX)
XX (XX.XX)
-
7
-
n (%)
-
XX (XX.XX)
-
XX (XX.XX)
Maximum Other 
Dermal Effects
Z
A
B
…
H
n (%)
n (%)
n (%)
…
n (%)
XX (XX.XX)
XX (XX.XX)
XX (XX.XX)
…
XX (XX.XX)
XX (XX.XX)
XX (XX.XX)
XX (XX.XX)
…
XX (XX.XX)
Note: NA = not applicable
Note: Treatment is GSK2646264 1% and matching Placebo, on the respective body surface area, one side each.
Note: Dermal Response: 0 = no evidence of irritation, 1 = minimal erythema, barely perceptible (pink), 2 = moderate erythema (definite 
redness), readily visible; minimal edema or minimal papular response, 3 = strong erythema (intense redness), or erythema and papules, 4 = 
definite edema, 5 = erythema, edema, and papules, 6 = vesicular eruption, 7 = strong reaction spreading beyond test site.
Note: Other Dermal Effects: Z = no other effect, A = slight glazed appearance, B = marked glazing, C = glazing with peeling and cracking, 
F = glazing with fissures, G = film of dried serous exudate covering all or part of the patch site, H = small petechial erosions and/or 
scabs.


CONFIDENTIAL
204860
78
Example 
: SAFE_T3
                                                     
Protocol
: 204860
Population
: Safety
Table x.xx
Summary of Type of CLE (Group B-Natural Lesions)
CLE type
    N=XX
Chronic
Acute
Sub-acute 
LTE
n (%)
n (%)
n (%)
n (%)


CONFIDENTIAL
204860
79
Example 
: PD_T1 
Page 1 of n
Protocol
: 204860
Population
: Safety
Table Summary of [RCLASI/PD endpoints]
[Insert Title]
Type of CLE
Treatment
N
Visit
n
Mean
95% CI of Mean
SD
Median
Min.
Max.
Sub-Acute 
GSK2646264
X
Day 1 
Predose
24
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
Day 14
24
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
Day 28
23
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
Placebo
X
Day 1 
predose
24
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
21
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
Day 14
21
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
Day 28
21
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
Chronic
GSK2646264
X
Day 1 
Predose
24
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
Day 14
24
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
Day 28
23
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
Placebo
X
Day 1 
predose
24
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
21
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
Day 14
21
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx
All
Day 28
21
xxxx.xx
(xxxx.xx, xxxx.xx)
xx.xx
xxxx.x
xxxx
xxxx


CONFIDENTIAL
204860
80
Example: PD_T2
Protocol: 204860                                                                     Page 1 of x
Population: Safety
Table XX.XX : 
                             n                     n                            Comparison to Placebo 
Treatment              Adjusted Mean         Adjusted Mean        Fold Change         Fold Change     
Group        Visit         95% CI                95% CI              95% CI             95% CI        
_________________________________________________________________________________________________________
___
                                                                                                            
Placebo     Baseline         4                     4                                                  
                         10033.48              13337.45                                                          
(N=XX)               (5015.87, 20070.45)   (4806.65, 37008.63)    
                                                                                                            
            Day 28
4
4
                           8118.18               6830.11             -1.19                                         
                     (3264.70, 20187.10)   (2150.27, 21695.19)   (-1.96, 1.39)                        
GSKXXXXX    Baseline         4                     4                                                  
                         10033.48              13337.45                                                          
(N=XX)               (5015.87, 20070.45)   (4806.65, 37008.63)    
                                                                                                            
            Day 28
4
4
                           8118.18               6830.11             -1.19               -1.19                      
                     (3264.70, 20187.10)   (2150.27, 21695.19)   (-1.96, 1.39)       (-1.96, 1.39)
               


CONFIDENTIAL
204860
81
Example: PD_T3
Protocol: 204860
Page 1 of x
Population: Safety
Table XX.XX :
Summary of Analysis for Microarray mRNA Data from xxxx
n
n
Comparison to Uninvolved
Skin
Adjusted Mean
Adjusted Mean
Fold Change
Type
95% CI
95% CI
95% CI
_________________________________________________________________________________________________________
___
Uninvolved
4
4
10033.48
13337.45
(N=XX)
(5015.87, 20070.45)
(4806.65, 37008.63)
Placebo
5
5
8118.18
6830.11
-1.19
(N=XX)
(3264.70, 20187.10)
(2150.27, 21695.19)
(-1.96, 1.39)
GSKXXXXXX
8
8
8118.18
6830.11
-1.19
(N=XX)
(3264.70, 20187.10)
(2150.27, 21695.19)
(-1.96, 1.39)


CONFIDENTIAL
204860
82
Example 
: PD_F1 
Page 1 of n
Protocol
: 204860
Population
: Safety
Figure: Individual profile plot of {RCLASI/PD endpoints]
[Insert Title]
USER ID:directory/program.sas  01JAN2002 12:01
          Placebo
      GSK2646264   
Trea
PPD


CONFIDENTIAL
204860
83
Example 
: PD_F2 
Page 1 of n
Protocol
: 204860
Population
: Safety
Figure: Mean (±95% CI)  [RCLASI/PD endpoints]
[Insert Title]
         CLE type: Chronic
CLE type: Sub-Acute
CLE type: All     
USER ID:directory/program.sas  01JAN2002 12:01
Example: PD_F3


CONFIDENTIAL
204860
84
Protocol: 204860
Page 1 of x
Population: Safety
Figure XX.XX: 
Adjusted mean probe set intensity values (95% CI) by time from xxxx
Gene ID: XXXX Probeset ID: xxxx
Example: PD_F4


CONFIDENTIAL
204860
85
Protocol: 204860
Page 1 of x
Population: Safety
Figure XX.XX: 
Adjusted Fold Change in mRNA Expression
Gene ID: XXXX
Example: PD_F5
Protocol: 204860
Page 1 of x
Population: Safety


CONFIDENTIAL
204860
86
Figure XX.XX: 
PPD
PPD


CONFIDENTIAL
204860
87
Example: PD_F6
Protocol: 204860                                                                    Page 1 of x
Population: Safety
Figure XX.XX: 
PPD


CONFIDENTIAL
204860
88
Example 
: SAFE_L1 
Page 1 of n
Protocol
: 204860
Population
: Safety
Listing: Listing of local tolerability
Subject
  
Treatment
Visit
Location
Side
Dermal 
Response
Other 
Dermal 
Effects
Skin 
Irritation 
Score 
Skin 
Irritation 
Score Cfb
XXX
GSK2646264 
    XX
XX
XX
XX
XX
    XX
    XX
XX
XX
XX
XX
XX 
XX
XX
--
--
--
--
--
--
--
--
XXX
XX
XX
XX
XX
XX
XX
XX
Note: Dermal Response 0-7, Other Dermal Effects Z, A-H. 
              Note: cfb: Change from baseline


CONFIDENTIAL
204860
89
Example 
: SAFE_L2
Page 1 of n
Protocol
: 204860
Population
: Safety
Listing of Type of CLE (Group B-Natural Lesions)
Subject
     CLE Type       Disease Diagnosis    
XXX
XXX
XXX
  Chronic          DD/MMM/YYYY
  Acute            DD/MMM/YYYY
  Acute            DD/MMM/YYYY


CONFIDENTIAL
204860
90
Example 
: PD_L1
Page 1 of n
Protocol
: 204860
Population
: Safety
Listing of RCLASI and components
Subject
Sequence
  
Skin site
Treatment
Visit
Planned 
time
Eyrthema
Scaling
.....
RCLASI 
score
RCLASI 
activity 
score
XXX
xxxx
xxxx
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
--
--
--
--
--
--
--
--
XXX
XX
XX
XX
XX
XX
XX
XX
Programming notes: include all RCLASI components.


CONFIDENTIAL
204860
91
Example 
: PD_L2
Page 1 of n
Protocol
: 204860
Population
: Safety
Listing XX: 
Listing of transcriptomic mRNA expression for selected probesets by visit from xxxx  
                                                                                                              
                              Visit./                                      
                           Visit date./                                      Normalised       
               
Skin Site       Subj.   Study day     
Probeset      GeneID            
Expression          
Placebo
       XXX     XXX/          XXXXXX 
XXXXXXXXXXXXXXX
XX.X         
                           XX/XX/XX/     
                           Baseline      
      
    XXX/      
    XXXXXX 
  XXXXXXXXXXXXXXX
      XX.X        
   
     XX/XX/XX/     
   
     Week XX      
     XXX/      
    XXXXXX        XXXXXXXXXXXXXXX
      XX.X       
   
     XX/XX/XX/     
   
     Week XX      
  
     XXX/      
    XXXXXX       
XXXXXXXXXXXXXXX         
XX.X       
     XX/XX/XX/     
  
     Week XX      


CONFIDENTIAL
204860
92
Example 
: PD_L3
Page 1 of n
Protocol
: 204860
Population
: Safety
Table x.xx
Listing of Histopathology score and components in skin biopsies (Group B-Natural Lesions)
Subj
Skin Area
Scoring: Histological Features 
     Score                  Score         Average 
  1           2           1          2     Score   
XXXX
F
Parakeratosis
Ballooning / Hydropic Degeneration
Epidermal Cell Death
Junctional Inflammation
Dermal Inflammation
Histological Score
None        None        0           0       0
Weak        None        1           0       0.5
Fair 
None       2            0       1
Fair 
None       2            0       1
Fair 
None       2            0       1
NA
NA        7            0       3.5


CONFIDENTIAL
204860
93
Example 
: PD_L4
Page 1 of n
Protocol
: 204860
Population
: Safety
Table x.xx
Listing of QC criteria from Histological scoring form (Group B-Natural Lesions)
Subj
Skin Area
QC Criteria
    Score
1           2
XXXX
F
Quality of the skin specimen is sufficient 
This is a lesional skin biopsy form an inflamed skin 
area
The correct diagnosis for this skins specimen most 
probably is CLE
Correct CLE subtype for this skin sample
Yes        Yes
Yes        No
Yes        Yes