Clinical trial NCT02424799
Conditions: Urticaria
Keywords: Urticaria SYK Inhibitor
Sponsor: GlaxoSmithKline
Start date: 2014-11-17; Completion date: 2017-11-10
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This First Time in Human (FTIH) study, which will be performed in three parts, is designed to investigate the safety, local tolerability, pharmacokinetics and pharmacodynamics after single and repeat topical applications of up to 2 strengths of GSK2646264 and corresponding placebo within the same subject, in healthy adult subjects (Part A), subjects with cold urticaria (CU, Part B) and subjects with chronic spontaneous urticaria (CsU, Part C). The study will also measure short term effects of GSK2646264 on the number and size of weals in subjects with CsU, and in healthy subjects and subjects with CU following provocation tests.

Detailed description:

Arms: arm 1: Subjects will be treated topically with 0.5 % GSK2646264 cream and placebo cream on an area of approximately 12 x 3 centimetre (cm) on the volar aspect of the arm which approximates to 0.2% total body surface area (BSA), on each arm. On Day 2 and Day 3 subjects will receive active treatment and placebo on the same arms as on Day 1, with the percentage BSA being 1% on Day 2 and 5% on Day 3. arm 2: Subjects will be treated topically with 1 % GSK2646264 cream and placebo cream on the morning and evening of Day 1 starting at the final % BSA dosed at Day 3 in group 1 which is anticipated to be 5%. In dose group 2, the starting BSA will increase to 10% at Day 3 and then 20% by Day 5. Administration of the evening (PM) dose will be dependent on the data from Part A Dose group 1. arm 3: Cold urticaria subjects will receive treatment to 4 defined areas (right and left arms and legs). Subjects will be treated with maximum tolerated strength of GSK2646264 cream (0.5% or 1%) and placebo cream in morning or in morning and evening to 2 specified areas of \~5% BSA on the subject's legs for the CU assessment and to 2 specified areas of 0.2% BSA on the volar aspect of the arm. The maximum tolerated strength and evening dosing will be dependent on the data from the Part A arm 4: Chronic spontaneous urticaria subjects will be treated with the maximum tolerated strength of GSK2646264 cream from Part A (0.5% or 1%) and placebo cream onto defined areas (right and left arms and, legs and front torso) from Days 1 to 7. The total % BSA for an individual subject will be decided by the investigator prior to randomization. The maximum % BSA and the frequency of dosing will be decided after part A of the study.
Interventions: intervention 1: GSK2646264 0.5% topical cream intervention 2: GSK2646264 1% topical cream intervention 3: Placebo
Intervention descriptions: intervention 1: GSK2646264 0.5% topical cream is supplied as white-to-off-white aqueous cream stored in amber glass jars intervention 2: GSK2646264 1% topical cream is supplied as white-to-off-white aqueous cream stored in amber glass jars intervention 3: Placebo topical cream is supplied as white-to-off-white aqueous cream stored in amber glass jars

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
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.
Compound Number:
GSK2646264
Development Phase:
I
Effective Date:
13-OCT-2016
Protocol Amendment Number:  05
Author (s):
 (II TAU), 
 (II TAU), 
 (CPSSO), 
 (QSci) 
 (II TAU), 
 (CPMS), 
 
(CPSSO), 
 (GCSP), 
 (DMPK).
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2013N167482_00
2014-APR-16
Original
2013N167482_01
2014-SEP-05
Amendment No. 1
Reason for Amendment 01:
Changes have been made to safety related study specific dose adjustment criteria 
following MHRA review.
An update has been made to the exclusion criteria of the protocol Section 4.2.2. and a 
change has been made to Section 10.2 Regulatory and Ethical considerations following 
German (Berlin) Ethics Committee  review.
2013N167482_02
2014-DEC-10
Amendment No. 2
Reason for amendment 02:
Changes have been made to list all of the challenge agents to be used in the study 
following guidance from German Regulatory Agency (BfArM).
A table of the list of challenge agents has been added to the study treatment section. An 
update to the skin prick test procedure and the correct name of one of the challenge 
agents has been added to the inclusion criteria.
2013N167482_03
2015-JUN-07
Amendment No. 3
Part B and C have changed from a bilateral to a placebo-controlled randomised parallel 
design 3:1 active to placebo.
An informal review of data from the first 4 patients of Part B will be performed before 
starting part C
The number of subjects in Part C has increased (from n=12 up to n=16); and a 2-week 
PK, safety and biomarker endpoints sampling period for parts B & C has been 
implemented
2013N167482_04
2016-APR-11
Amendment No. 4
Updates have been made following the interim analysis of the first 4 subjects in Part B, 
related to the dosing in Parts B and C.
A change has been made to the inclusion and exclusion criteria, related to use of 
contraception for women of child bearing potential.


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Changes have been made to the PK sampling time points for Part C.
2013N167482_05
2016-OCT-13
Amendment No. 5
Administrative amendment to account for the change in primary medical monitor, as 
documented in the Medical Monitor and Sponsor Contact Information table.
In addition, the following corrections have been made that were previously captured in a 
note to file format. The following file note is hereby superseded:

File note dated 26th April, 2016 concerning two clarifications of typographic/edits 
errors: Timing of tolerability assessment, and timing of the complete physical 
exam. These have been updated in Section 6.1.4


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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell
/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
n/a
Experimental Medicine Unit,
Immuno-inflammation 
Therapy Unit
GlaxoSmithKline Medicines 
Stevenage, Hertfordshire
Secondary 
Medical 
Monitor
Experimental Medicine Unit,
Immuno-inflammation 
Therapy Unit
GlaxoSmithKline Medicines 
Stevenage, Hertfordshire 
SAE fax 
number 
XXX
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s):  EudraCT number: 2014-001015-39
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200196
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
LIST OF ABBREVIATIONS...........................................................................................12
1.
INTRODUCTION....................................................................................................14
1.1.
Study Rationale ..........................................................................................14
1.2.
Brief Background ........................................................................................14
2.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
2.1.
Primary objectives and endpoints for all study parts (A, B & C)...................15
2.2.
Secondary objectives and endpoints for all study parts (A, B & C)..............16
2.3.
Exploratory Objectives and Endpoints ........................................................16
2.3.1.
Part A: Healthy Subjects..............................................................16
2.3.2.
Part B: Cold urticaria Subjects .....................................................17
2.3.3.
Part C: Chronic Spontaneous Urticaria Subjects..........................18
3.
STUDY DESIGN ....................................................................................................18
3.1.
Study Design ..............................................................................................18
3.1.1.
Part A Healthy Subjects Schematic..............................................20
3.1.2.
Part A: Dose group 1: A double-blind (sponsor unblinded) 
placebo-controlled, randomised to bilateral  dose 
ascending treatments, single dose continuing to three 
days repeat dosing period, in healthy subjects.............................21
3.1.3.
Part A: Dose group 2: A double blind (sponsor unblinded) 
placebo-controlled, randomised to bilateral dose 
ascending treatments, single dose continuing to seven 
days repeat dosing period, in healthy subjects.............................22
3.1.3.1.
Changes after review of preliminary data of 
Part A Dosing Group 1 by the Safety 
Monitoring Committee ................................................23
3.1.4.
Part B:  A double blind (sponsor unblinded) placebo-
controlled, randomised to active or placebo treatment, 
three day repeat dose study, in cold urticaria subjects.................24
3.1.4.1.
Changes after review of preliminary data of 
n=4 from Part B by the Safety Monitoring 
Committee..................................................................25
3.1.5.
Part C : A double-blind (sponsor unblinded) placebo-
controlled, randomised to active or placebo treatment 
repeat dose study (3 doses over 7 days), in subjects with 
mild to moderate Chronic Spontaneous Urticaria (CsU)...............26
3.1.6.
Progression Criteria for dose escalation in the study ...................27
3.2.
Discussion of Study Design ........................................................................28
3.2.1.
Design Rationale .........................................................................28
3.2.1.1.
Part A: Healthy Subject Cohort...................................28
3.2.1.2.
Part B: Cold urticaria Subjects....................................28
3.2.1.3.
Part C: Chronic Spontaneous Urticaria 
Subjects .....................................................................29
3.2.2.
Dose Rationale ............................................................................29


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3.2.2.1.
Comparison of predicted human plasma 
exposures to animal safety study exposures ..............29
3.2.2.2.
Additional preliminary data from Part A.......................30
3.2.2.3.
Additional preliminary data from Part B.......................30
3.2.2.4.
GSK2646264 strength for Part B and C......................30
3.2.3.
Clinical Experience ......................................................................31
4.
STUDY POPULATION...........................................................................................34
4.1.
Number of Subjects ....................................................................................34
4.2.
Eligibility Criteria .........................................................................................34
4.2.1.
Inclusion Criteria..........................................................................34
4.2.1.1.
Inclusion criteria for all subjects in Parts A, B 
and C .........................................................................34
4.2.1.2.
Inclusion criteria specific for healthy subjects 
(Part A).......................................................................35
4.2.1.3.
Additional Inclusion criteria specific for subjects 
with cold urticaria (Part B)...........................................36
4.2.1.4.
Additional Inclusion criteria specific for subjects 
with chronic spontaneous urticaria (Part C) ................37
4.2.2.
All Cohorts Exclusion Criteria.......................................................38
4.2.2.1.
Country Specific Exclusion criteria wording for 
Germany that applies to Part A, Part B and 
Part C.........................................................................40
4.2.2.2.
Additional Exclusion for Part A – Healthy 
Subjects .....................................................................40
4.2.2.3.
Additional Exclusion for Part B – Cold urticaria 
Subjects .....................................................................40
4.2.2.4.
Additional Exclusion for Part C- Chronic 
Spontaneous Urticaria patients...................................40
4.3.
Lifestyle and/or Dietary Restrictions............................................................41
4.3.1.
Contraception Requirements .......................................................41
4.3.1.1.
Female Subjects.........................................................41
4.3.1.2.
Male Subjects.............................................................42
4.3.2.
Meals and Restrictions.................................................................42
4.3.2.1.
Caffeine, Alcohol, and Tobacco..................................42
4.3.2.2.
Fasting .......................................................................42
4.3.3.
Activity and other restrictions during the study.............................42
4.3.3.1.
Showering/bathing during the study............................43
4.3.3.2.
Clothing during the study............................................43
4.4.
Screen and Baseline Failures .....................................................................43
4.4.1.
Subjects exceeding screening visit window..................................43
4.5.
Withdrawal Criteria and Procedures............................................................43
4.6.
Subject Completion.....................................................................................44
5.
STUDY TREATMENT ............................................................................................44
5.1.
Investigational Product and Other Study Treatment....................................44
5.2.
Challenge Agents .......................................................................................46
5.2.1.
Skin prick test allergens...............................................................46
5.3.
Medical Devices..........................................................................................46
5.4.
Treatment Assignment................................................................................46
5.5.
Planned Dose Adjustments/Progression and Stopping criteria....................46
5.5.1.
Dose-Limiting Toxicity..................................................................47


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5.5.2.
Progression of dosing from sentinel subject to the rest of 
the dosing group (Part A).............................................................48
5.5.3.
Progression from dosing group 1 to dosing group 2 in Part 
A, and from Part A to Parts B and C ............................................49
5.5.3.1.
Progression from dosing group 1 to dosing 
group 2 in Part A ........................................................49
5.5.3.2.
Progression from Part A to Parts B and C ..................49
5.5.3.3.
Progression in Part B and from Part B to Part C.........50
5.5.3.4.
Progression within Part C ...........................................50
5.6.
Safety Related Study Specific Dose Adjustment Criteria.............................51
5.7.
Stopping Criteria for a subject.....................................................................51
5.7.1.
Liver Chemistry Stopping Criteria ................................................51
5.7.2.
QTcF Withdrawal Criteria.............................................................51
5.7.3.
Safety related Stopping criteria for an individual subject ..............52
5.8.
Dose Adjustment/Stopping Pharmacokinetic Criteria ..................................52
5.8.1.
Adjusting dose/ stopping dose escalation ....................................53
5.9.
Blinding.......................................................................................................53
5.10.
Packaging and Labelling.............................................................................53
5.11.
Preparation/Handling/Storage/Accountability..............................................54
5.11.1.
Part A and Part B.........................................................................54
5.11.2.
Part C ..........................................................................................54
5.12.
Assessment of Compliance ........................................................................55
5.13.
Treatment of Study Treatment Overdose....................................................55
5.14.
Treatment after the End of the Study ..........................................................55
5.15.
Concomitant Medications and Non-Drug Therapies....................................55
5.15.1.
Permitted Medications .................................................................55
5.15.1.1.
Parts A, B and C.........................................................55
5.15.1.2.
Part C only .................................................................55
5.15.2.
Prohibited Medications and Non-Drug Therapies.........................56
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................57
6.1.
Time and Events Table...............................................................................58
6.1.1.
Part A: Healthy Volunteer Time and Event Table Dose 
group 1 ........................................................................................58
6.1.2.
Part A: Healthy Volunteer Time and Event Table Dose 
group 2 ........................................................................................60
6.1.3.
Part B: Cold urticaria Subjects Time and Event table...................63
6.1.4.
Part C: Chronic Spontaneous Urticaria Cohort.............................65
6.2.
Demographic/Medical History Assessments ...............................................68
6.3.
Safety .........................................................................................................68
6.3.1.
Physical Exams ...........................................................................68
6.3.2.
Vital Signs....................................................................................68
6.3.3.
Electrocardiogram (ECG).............................................................68
6.3.4.
Clinical Laboratory Assessments .................................................68
6.3.4.1.
Tolerability..................................................................70
6.4.
Study Assessments ....................................................................................70
6.4.1.
Skin Prick Test (SPT)...................................................................70
6.4.2.
TempTest ....................................................................................71
6.4.3.
Blood and Urine Sample Collection..............................................71
6.4.3.1.
PK samples ................................................................71
6.4.3.2.
Systemic biomarker samples......................................71
6.4.3.3.
Urine Sample Collection .............................................71


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6.4.4.
Sample Analysis ..........................................................................72
6.5.
Pharmacodynamic Measures......................................................................72
6.5.1.
Part A & B....................................................................................72
6.5.2.
Part C ..........................................................................................72
6.5.2.1.
Urticaria Activity Score (UAS7)...................................72
6.5.2.2.
The Angioedema Activity Score (AAS) .......................72
6.6.
Health Outcomes........................................................................................73
6.6.1.
Dermatology Life Quality Index....................................................73
7.
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, PREGNANCY AND 
MEDICAL DEVICE INCIDENTS.............................................................................73
7.1.
Adverse Events (AE) and Serious Adverse Events (SAEs).........................73
7.1.1.
Time period for collecting AE and SAE information......................73
7.1.2.
Method of Detecting AEs and SAEs.............................................73
7.1.3.
Definition of Adverse Events........................................................74
7.1.4.
Definition of Serious Adverse Events...........................................75
7.1.5.
Cardiovascular Events.................................................................76
7.1.6.
Death Events...............................................................................76
7.1.7.
Prompt Reporting of SAEs to GSK...............................................76
7.1.8.
Regulatory Reporting Requirements for SAEs .............................77
7.2.
Pregnancy ..................................................................................................77
7.2.1.
Time period for collecting pregnancy information.........................77
7.2.2.
Action to be taken if pregnancy occurs ........................................77
7.2.3.
Action to be taken if pregnancy occurs in a female partner 
of a male study subject ................................................................78
8.
DATA MANAGEMENT ...........................................................................................78
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................78
9.1.
Hypotheses and Treatment Comparisons...................................................78
9.1.1.
Precision Estimation ....................................................................78
9.2.
Sample Size Considerations & Statistical Analyses ....................................79
9.2.1.
Sample Size Sensitivity................................................................79
9.2.2.
Sample Size Re-estimation..........................................................79
9.3.
Data Analysis Considerations .....................................................................80
9.3.1.
Interim Analysis ...........................................................................80
9.3.1.1.
Summary of safety reporting from Part A....................80
9.3.1.2.
Summary of exposure and safety reporting 
from Part B: first 4 subjects.........................................80
9.3.1.3.
Summary of exposure and safety reporting 
from Part C: first 4 subjects ........................................80
9.3.2.
Final Analyses .............................................................................80
9.3.2.1.
Safety Analyses..........................................................80
9.3.2.2.
Pharmacokinetic Analyses..........................................81
9.3.2.3.
Pharmacodynamic/Biomarker Analyses .....................81
9.3.2.3.1.
Part A & B: Healthy and Cold 
urticaria Subjects....................................81
9.3.2.3.2.
Part C: Chronic Spontaneous 
Urticaria Subjects ...................................81
9.3.2.4.
Health Outcomes Analyses ........................................82
9.3.2.4.1.
Dermatology Life Quality Index...............82


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10. STUDY GOVERNANCE CONSIDERATIONS........................................................83
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............83
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................83
10.2.1.
Urgent Safety Measures ..............................................................83
10.3.
Quality Control (Study Monitoring) ..............................................................83
10.4.
Quality Assurance.......................................................................................84
10.5.
Study and Site Closure ...............................................................................84
10.6.
Records Retention......................................................................................84
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................85
11. REFERENCES.......................................................................................................86
12. APPENDICES........................................................................................................88
12.1.
Appendix 1: Liver Safety Process ...............................................................88
12.2.
Appendix 2: Procedures for Detection, Evaluation, Follow-Up and 
Reporting of Adverse Events and Medical Device Incidents .......................91
12.3.
Appendix 3: Urticaria symptoms questionnaire and activity Score 
(UAS7)........................................................................................................94
12.4.
Appendix 4: Dermatology Life Quality Index (DLQI)....................................97
12.5.
Appendix 5: Calculation of predicted human exposure................................99
12.6.
Appendix 6: Comparison Of Predicted Human Plasma Exposures 
To Animal Safety Studies..........................................................................103
12.7.
Appendix 7: Angioedema Activity Score ...................................................105
12.8.
Appendix 8: Protocol Amendment Changes..............................................107


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LIST OF ABBREVIATIONS
AAS
Angioedema Activity Score
AE
Adverse Event
AUC
Area Under the Curve
BCR
B Cell Receptor
BHR
Basophil Histamine Release
BMI
Body Mass Index
BPM
Beats Per Minute
BSA
Body Surface Area
CLbq
Blood Clearance
Cmax
Peak plasma concentration of a drug after administration.
CPMS
Clinical Pharmacokinetics Modelling and Simulation
CsU
Chronic Spontaneous Urticaria
CTT
Critical Temperature Threshold
CU
Cold urticaria
CuQ2oL
Chronic Urticaria Quality of Life Questionnaire
DLQI
Dematology Life Quality Index
DMPK
Drug Metabolism and Pharmacokinetics
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FcεR1
Fc Epsilon receptor
FSH
Follicle Stimulating Hormone
GCSP
Global Clinical Safety and Pharmacovigilance
HBsAg
Hepatitis B surface Antigen
hCG
Human Chorionic Gonadotrophin 
HIV
Human Immunodeficiency Virus 
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
IgE
Immunoglobulin E
IUD
Intrauterine Device 
IUS
Intrauterine System
IV
Intra venous
MABEL
Minimum Anticipated Biological Effect Level
MSDS
Material Safety Data Sheet
NOAEL
NOEL
No Observed Adverse Effect Level
No Observed Effect Level
PD
Pharmacodynamic
PK
Pharmacokinetic
PUVA
Psoralen combined with Ultraviolet A
QOL
Quality of Life
QTcF
QTc interval Friderica’s
RAP
Reporting Analysis Plan
SAE
Serious Adverse Event
SAE
Serious Adverse event
SMC
Safety Monitoring Commitee
SPM
Study Procedures Manual
SPT
Skin Prick Test


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SYK
Spleen Tyrosine Kinase
Tmax
The time of Cmax occurring
TSH
Thyroid Stimulating Hormone
UAS7
Urticaria Activity Score 
VAS
Visual Analog Scale
Vss
Volume of distribution at Steady State
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Chiron RIBA
Dapsone
Inform
Phoenix (includes WinNonlin)
Zaditen


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1.
INTRODUCTION
1.1.
Study Rationale
This First Time in Human (FTIH) study, which will be performed in three parts is 
designed to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics 
after single and repeat topical applications of up to 2 strengths of GSK2646264 and 
corresponding placebo, in:

healthy adult subjects (Part A) 

subjects with cold urticaria (CU, Part B)

subjects with chronic spontaneous urticaria (CsU, Part C)
The study will also measure short term effects of GSK2646264 on the number and size of 
weals in subjects with CsU, the area and volume of weals following an allergen skin 
prick test in healthy volunteers and patients and a disease specific challenge (cold 
temperature test) for comparison of mechanism with the allergen skin prick test in the 
cold urticaria subjects.
1.2.
Brief Background
Spleen tyrosine kinase (SYK) is an intracellular protein tyrosine kinase involved in the 
downstream signalling events of several immunoreceptors in a variety of cell types, 
notably the B-cell receptor (BCR), the IgG receptors (FcgRI and III) and the Fc epsilon 
receptor (FcεR1). These immunoreceptors including the FcεR1, the high affinity receptor 
for IgE, are important in contributing to the pathology of IgE mediated diseases such as 
chronic urticaria, and thus pharmacological inhibition of these kinases could be beneficial 
in these predominantly mast cell driven diseases. 
Chronic urticaria is a common skin disease with up to 1% of the population affected 
(Maurer, 2011a). It is characterised by daily or almost daily itchy weals on the skin, with 
or without angioedema, that last for greater than 6 weeks. The classification of chronic 
urticaria includes six distinct patterns of which two will be investigated in this study.
Cold urticaria, a form of inducible urticaria, characterised by local skin reactions 
consisting of itchy weal and flare responses following cold exposures. These reactions 
can be induced on discrete areas of the skin using an electronic device called a TempTest 
thus allowing a critical temperature threshold (CTT) to be established. CTT and changes 
in CTT values can be correlated with disease severity and changes in disease activity 
respectively (Młynek, 2010). 
Chronic spontaneous urticaria characterised by itchy weals for greater than 6 weeks is 
thought in part to be mediated by auto-antibodies against the FcεR1 or IgE which bind to 
the FcεR1 on mast cells and basophils leading to the degranulation and release of pro-
inflammatory mediators from these cells (Greaves, 2000). 
Chronic urticaria can be difficult to treat, with patients demonstrating a variable response 
to first-line therapies including oral H1 antihistamines.  Second and third line treatments 


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include leukotrienes, cyclosporine and short term treatment with oral corticosteroids if no 
efficacy is obtained after increased dosage of antihistamines.
SYK inhibition, following IgE activation of the FcεR1, will reduce three main mast cell 
functions: the release of preformed mediators such as histamine, the secretion of 
cytokines including TNF alpha and the production of leukotrienes and prostaglandins. 
The majority of drugs currently used to treat IgE-mediated disorders target a single 
mediator e.g. antihistamines or leukotriene modifiers. The SYK inhibitor GSK2646264 
should stabilise the mast cells and prevent multiple mediators from being released. The 
dose-dependent inhibition of histamine release with GSK2646264, after anti-IgE 
stimulation in ex-vivo human skin, supports the potential for the use of this compound as 
a treatment for chronic urticarias. 
To further support this rationale, recent Phase 3 clinical trials of Omalizumab, a 
humanised monoclonal anti-IgE antibody which binds to free IgE preventing the 
interaction between IgE and mast cells or basophils, was shown to reduce clinical signs 
and symptoms in patients with chronic spontaneous urticaria who had not responded to 
H1 antihistamine therapy (Saini, 2011), (Maurer, 2011a). This data has supported an 
EMEA approval in adult and adolescent (12 years and above) patients with inadequate 
response to H1 antihistamine treatment.
Additionally, Omalizumab has shown benefit in a small population of cold urticaria 
patients and Phase 2 trials for this condition (Clinical Trials for Cold urticaria 
http://clinicaltrials.gov/ct2/show/ NCT01580592) are underway.  
As SYK is downstream of the FcεR1, a similar inhibition of this pathway is likely to 
occur in the presence of a SYK inhibitor suggesting that GSK2646264 may be beneficial 
in chronic spontaneous urticaria, cold urticaria and other skin disease where omalizumab 
shows improvement in disease activity.
2.
OBJECTIVE(S) AND ENDPOINT(S)
2.1.
Primary objectives and endpoints for all study parts (A, B & 
C)
Objectives
Endpoints
Safety and Tolerability
To investigate the safety and tolerability of 
topically applied GSK2646264 cream and its 
placebo in healthy subjects1, subjects with cold 
urticaria (CU1) and subjects with chronic 
spontaneous urticaria (CsU).
Safety and Tolerability

Number, severity and frequency of AEs and 
serious AEs (local and systemic)

heart rate

blood pressure

12- lead ECG

clinical laboratory safety tests

assessment of the local tolerability of the 
study medication 
1.
All Healthy subjects and the Cold urticaria subjects should be screened for  reactivity to one of the allergens used 
in skin prick test. (grass pollen, Dermatophagoides pteronyssinus, birch pollen and cat dander)


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2.2.
Secondary objectives and endpoints for all study parts (A, B 
& C)
Objectives 
Endpoints
Pharmacokinetics in plasma 
To evaluate the plasma concentrations of 
GSK2646264 in Healthy, CU and CsU subjects
Pharmacokinetics in plasma 

Plasma concentrations of GSK2646264 and 
pharmacokinetic parameters, including 
AUC, Cmax, Tmax, t1/2 if data allows
2.3.
Exploratory Objectives and Endpoints
2.3.1.
Part A: Healthy Subjects
Objectives 
Endpoints
Exploratory
Pharmacodynamic measure of Allergen 
Challenge
Assess measure of weal and flare size and 
erythema, in healthy subjects after allergen 
challenge (Skin Prick test, positive control 
(histamine) and negative control (saline)).

Duration of response in healthy subjects
Pharmacodynamic measure of Allergen 
Challenge

Percent inhibition on days 1,3, 4 and 6 will 
be derived for:
o
The longest weal diameter (measured 
by ruler).
o
Perpendicular weal length (measured 
by ruler).
o
Weal area calculated using weal 
diameter and length assuming 
ellipse  area.

Weal Volume as measured by:

Quantitative volumetric morphometry1
Flare erythema as measured by

Mexameter2
Percent of inhibition at 24 hours post final dose, 
will be derived for the endpoints above
1. Measured using digital camera using PRIMOS 5.075D instrument software produced by GMF
2. Measures erythema and melanin index values using narrow band spectrophotometry


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2.3.2.
Part B: Cold urticaria Subjects
Objectives
Endpoints
Exploratory
Pharmacodynamic measure of  Cold 
Provocation
Assess change in Cold Temperature Test 
values 
Pharmacodynamic measure of  Cold 
Provocation

Change from placebo of Cold Temperature 
Test3 values at day 3
Pharmacodynamic measure of  Allergen 
Challenge
Assess measure of weal and flare size, in 
subjects with Cold urticaria after allergen 
challenge (Skin Prick test, positive control 
(histamine) and negative control (saline)).
Pharmacodynamic measure of  Allergen 
Challenge

Percent of inhibition on day 3 will be derived 
for:
o
The longest weal diameter (measured 
by ruler).
o
Perpendicular weal length (measured 
by ruler).
o
Weal area calculated using weal 
diameter and length assuming 
ellipse area.

Weal Volume as measured by;

Quantitative volumetric morphometry1
Flare Erythema as measured by;

Mexameter2
Systemic measure of target pharmacology
Determine CD69 expression in an ex vivo blood 
sample following CD69 stimulation 
Systemic measure of target pharmacology

Percent inhibition of CD69 expressing cells 
in blood samples stimulated with anti-IgM .
1.
Measured using digital camera using PRIMOS 5.075D instrument software produced by GMF
2.
Measures erythema and melanin index values using narrow band spectrophotometry 
3.
TEMPTest 4.0


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2.3.3.
Part C: Chronic Spontaneous Urticaria Subjects
Objectives 
Endpoints
Exploratory
Pharmacodynamics as assessed by the 
Urticaria activity score 
Urticaria Activity Score: Assess measures of 
weal characterisation in CsU subjects within 
treated area only
Pharmacodynamics as assessed by the 
Urticaria activity score

Urticaria Activity Score, a composite score 
using key urticaria symptoms (number of 
weal, itch/pruritus), to derive change from 
baseline for the 7 days after dosing
To measure of Quality of Life 

Dermatology Life Quality Index (DLQI) 
questionnaire 
To measure disease activity

Angioedema Activity Score (AAS)
Investigate relationships between (basophil 
histamine release) BHR test and weal 
characteristics

Relationship of positive BHR test with 
reduction in number or size of weals
Systemic measure of target pharmacology
Determine CD69 expression in an ex vivo blood 
sample following CD69  stimulation 
Systemic measure of target pharmacology

Percent inhibition of CD69 expressing cells 
in blood samples stimulated with anti-IgM.
3.
STUDY DESIGN
3.1.
Study Design
This study will be conducted in three parts: Part A (healthy subject cohort, inpatient), Part 
B (cold urticaria subject cohort, inpatient) and Part C (chronic spontaneous urticaria 
subject cohort, outpatient) (Figure 1). Subjects will participate in the study if they fulfil 
the eligibility criteria at the time of screening and prior to randomisation for the relevant 
cohort for which they are assessed.


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Figure 1
Study Schematic Showing all 3 Cohorts
The study will enrol 1 sentinel subject for:

Part A dosing group1

Part A dosing group 2
Each sentinel subject will be dosed at least 1 day before any other subjects of their dosing 
group or cohort. Please refer to Section 5.5 to Section 5.7 for dose adjustments and 
stopping criteria.
The cream will be applied at 10 mg/cm2 for all doses but the dose escalation is based on 
both increase in cream strength (0.5 % strength for Group 1 Part A; and if data permits 
1.0% strength for Group 2 Part A), and increase in surface area of the body on which the 
cream will be applied. The escalation based on body surface area (BSA) starts at 0.2% 
BSA, then 1%, then 5% BSA, and up to 10% BSA. For the study, the total BSA has been 
chosen as 1.8 m2 and will not be measured individually, so the surface area on which the 
cream is applied is similar for all subjects as follows, regardless of their weight and 
height. All weights of cream are nominal and any one dose will not exceed 40 g : 
Nominal % BSA
Actual surface to spread 
the active or placebo 
cream on:
Weight of active or 
placebo cream to be 
applied
0.2% BSA
36 cm2
0.36g
1% BSA
180 cm2
1.8g
3.5% BSA
630 cm2
6.3g
5% BSA
900 cm2
9g
10% BSA
1800 cm2
18g
20%
3600 cm2
36g


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Specific assessments for each study Part A, B and C, are shown in the Time and Events 
Tables in Section 6.1. 
In Part A, randomisation will assign active and placebo to specified areas on left or right 
side of the body. The left or right side assignment of treatment always refers to the 
subject’s left or right. Each bottle of cream will be for single use only.
In Parts B and C, which will be a parallel design, randomisation will assign subjects to 
either active or placebo treatment. This will be a 3:1 ratio active to placebo respectively.
Each bottle of cream will be for single use only.
3.1.1.
Part A Healthy Subjects Schematic
Figure 2
Schematic showing Part A: ascending dose periods and increasing 
body surface area within periods in healthy volunteers
Key:
PD - Pharmacodynamics
SPT - Skin Prick Test
PK - Pharmacokinetics
BSA - Body Surface Area


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3.1.2.
Part A: Dose group 1: A double-blind (sponsor unblinded) 
placebo-controlled, randomised to bilateral  dose ascending 
treatments, single dose continuing to three days repeat dosing 
period, in healthy subjects
This healthy subject cohort will be run in 2 dose groups, where 1 and 2 will be 
administered an increasing dose strength of GSK2646264 and body surface area. Both 
groups will remain in-house at a phase 1 clinical pharmacology unit (hospital based) for 
the complete dose period and completion of all post dose assessments.
For day 1 in dose group 1, subjects will be treated with active and placebo on an area of 
approximately 12 x 3 cm on the volar aspect of the arm which approximates to 0.2% total 
BSA, on each arm. On days 2 and 3 subjects will receive active treatment and placebo on 
the same arms as on day 1, with the percentage BSA being 1% on day 2 and 5% on day 3. 
The area covered on day 1 will be included in the total area covered on days 2 and 3 and 
this will be the area where the skin prick test assessment will be performed.
Initially, a single dose of active GSK2646264 (0.5% strength) and placebo will be 
applied on one sentinel subject on the morning of day 1 and following a safety and 
tolerability assessment further subjects will be dosed. See Table 1, Figure 2 and Section 
5.5.
The timing of and the assessments to be completed at each visit are provided in the Time 
and Events table (Section 6.1.2).
Safety, tolerability and PK data will be reviewed at the end of the dosing period (See 
Section 5.5) and used to decide on progression to dose group 2.
Table 1
Treatment applied to specified areas per day on Part A; healthy 
subjects, n=9, dose group 1
Day 1
Day 2
Day 3
Area
Morning
Morning
Morning
Left Arm
(L)
0.36g of 0.5%  GSK2646264 
or placebo cream applied to 
36cm2 (~0.2% BSA)
1.8g of 0.5%  GSK2646264 
or placebo cream applied to 
180cm2 (~1% BSA)
9g of 0.5%  GSK2646264 or 
placebo cream  applied to 
900cm2 (~5% BSA)
Right Arm
(R)
0.36g  of 0.5%  
GSK2646264 or placebo 
cream applied to 36cm2
(~0.2% BSA)
1.8g of 0.5%  GSK2646264 
or placebo cream  applied to 
180cm2 (~1% BSA)
9g of 0.5%  GSK2646264 or 
placebo cream applied to 
900cm2 (~5% BSA)


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3.1.3.
Part A: Dose group 2: A double blind (sponsor unblinded) 
placebo-controlled, randomised to bilateral dose ascending 
treatments, single dose continuing to seven days repeat dosing 
period, in healthy subjects
Initially, a single dose of active and placebo will be applied to subjects on the morning of 
day 1 starting at the final % BSA dosed at day 3 in group 1 which is anticipated to be 5% 
BSA following a safety and tolerability assessment further subjects will be dosed. (See 
Table 2)
In dose group 2, the starting BSA will increase to 10% at day 3. If the 1% strength is not 
tolerated after single or repeat application, then a dose of 0.5% dose strength would be 
administered instead and the complete regime would be followed as in Table 2.  
Administration of the evening (PM) dose will be dependent on the data from Part A dose 
group 1.
The timing of and the assessments to be completed at each visit are provided in the Time 
and Events table (Section 6.1.2).


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Table 2
Treatment applied to specified areas per day on Part A; healthy 
subjects, n=9, dose group 2
Day 1-2
Day 3-4
Day 5-6
Day 7
(Morning Dose Only)
Area
AM
PMa
AM
PMa
AM
PMa
AM
Left 
Arm
0.36g of 1.0%b GSK2646264 or placebo cream applied to 36cm2
(~0.2% BSA)
0.36g of 1.0% b
GSK2646264 or 
placebo applied to 
36cm2 (~0.2% BSA) 
Right 
Arm
0.36g of 1.0%b GSK2646264 or placebo cream  applied to 36cm2
(~0.2% BSA) 
0.36g of 1.0% b
GSK2646264 or 
placebo applied to 
36cm2 (~0.2% BSA) 
Left 
Front 
Torso
9g of 1.0% b
GSK2646264 or 
placebo cream 
applied to 900cm2
(~5% BSA) 
18g of 1.0% b
GSK2646264 or 
placebo applied to 
1800cm2 (~10% 
BSA) 
18g of 1.0% b  
GSK2646264 or 
placebo applied to 
1800cm2 (~10% 
BSA) 
18g  of 1.0% b  
GSK2646264 or 
placebo applied to 
1800cm2 (~10% BSA) 
Right 
Front
Torso
9g of 1.0% b  
GSK2646264 or 
placebo applied to 
900cm2 (~5% BSA) 
18g of 1.0% b
GSK2646264 or 
placebo applied to 
1800cm2 (~10% 
BSA) 
18g of 1.0% b
GSK2646264 or 
placebo applied to 
1800cm2 (~10% 
BSA) 
18g of 1.0% b  
GSK2646264 or 
placebo applied to 
1800cm2 (~10% BSA) 
Right 
Leg
18g of 1.0% b  
GSK2646264 or 
placebo applied to 
1800cm2 (~10% 
BSA) 
18g of 1.0% b  
GSK2646264 or 
placebo applied to 
1800cm2 (~10% BSA) 
Left 
Leg
18g of 1.0% b
GSK2646264 or 
placebo applied to 
1800cm2 (~10% 
BSA) 
18g of 1.0% b  
GSK2646264 or 
placebo applied to 
1800cm2 (~10% BSA) 
a.
AM dosing only if  data for Part A, group 1 and/or group 2 supports
b.
0.5% strength may be used if  data  for Part A and/or group 2 supports
Criteria to enable progression and dose escalation (single to repeat and increasing BSA) 
are detailed in Section 5.5.
Safety and PK from this cohort will enable the dosing of Part B and Part C.  Criteria to 
enable this are detailed in Section 3.2.2 and Section 5.5.
3.1.3.1.
Changes after review of preliminary data of Part A Dosing Group 1 by 
the Safety Monitoring Committee
Following the review by the Safety Monitoring Committee (see Section 5.5), changes 
were made to Part A Group 2 dosing as shown in Table 3.


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Table 3
Treatment applied to specified areas per day on Part A; healthy 
subjects, n=9, dose group 2
Day 1-2
Day 3-4
Day 5 to 
7
Area
AMa
AMa
Left 
Arm
0.36g of 1.0%b GSK2646264 or placebo cream applied to 36cm2
(~0.2% BSA)
NO 
DOSING
Right 
Arm
0.36g of 1.0%b GSK2646264 or placebo cream  applied to 36cm2
(~0.2% BSA) 
NO 
DOSING
Left 
Torso
9g of 1.0% b GSK2646264 or 
placebo cream applied to 
900cm2 (~5% BSA) 
9g of 1.0% b GSK2646264 or 
placebo cream applied to 
900cm2 (~5% BSA) 
NO 
DOSING
Right 
Torso
9g of 1.0% b  GSK2646264 or 
placebo applied to 900cm2
(~5% BSA) 
9g of 1.0% b GSK2646264 or 
placebo cream applied to 
900cm2 (~5% BSA) 
NO 
DOSING
a.
AM dosing only
b.
0.5% strength may be used if  data  for Part A and/or group 2 supports
3.1.4.
Part B:  A double blind (sponsor unblinded) placebo-controlled, 
randomised to active or placebo treatment, three day repeat dose 
study, in cold urticaria subjects
Subjects will be randomised in a 3:1 ratio to receive either active treatment or placebo 
applied to defined areas once a day for 3 days. The first 4 subjects of Part B will be 
randomised so that one of the four subjects will receive placebo and the three other 
subjects will receive GSK2646264. An interim review of the preliminary data from the 
first 4 subjects, after they have completed the study, will be conducted before dosing the 
rest of the patients in Part B (n=12 total).  PK, safety and tolerability preliminary data up
to and including the follow-up visit, will be reviewed by the SMC (See Section 5.5). See 
Figure 3 for a visual representation.
If preliminary data indicates it is appropriate to review additional PD data, this may then 
be conducted, either in parallel to or before the remainder of Part B subjects are enrolled.
Criteria to choose dose strength and dose regime in Part B are detailed in Section 5.5.  
Further dose adjustments may be made as a result of reviewing preliminary data from the 
first n=4 subjects in Part B.
This cohort will remain in-house for the whole dosing period (until completion of the 
final dose on the morning of day 3) and completion of subsequent study assessments on 
day 4. 
The timing of the assessments to be completed at each visit are provided in the Time and 
Event table (Section 6.1.3). 


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Table 4
Part B: Cold urticaria treatment (first n=4 subjects)
Days 1-3
Area
Morning dosing
Both 
Arms
9g of 1% strength GSK2646264 or placebo 
applied to 900cm2 (5% BSA) on each arm and 
the volar aspect of each arm must be included.  
= Total BSA = 10% (18g)
3.1.4.1.
Changes after review of preliminary data of n=4 from Part B by the 
Safety Monitoring Committee
Following the review by the Safety Monitoring Committee (see Section 5.5), changes 
were made to Part B for the remaining n=8 subjects, as shown in Table 5.
Table 5
Part B: Cold urticaria treatment (remaining n=8 subjects)
Days 1-3
Area
Morning dosing
Both 
Arms
6.3g of 1% strength GSK2646264 or placebo to 
be applied to a total area of 630cm2 (3.5% 
BSA), spread over the 2 arms, and the volar 
aspect must be included. The investigator 
should use their discretion as to how much 
cream is applied to each arm, but it must be 
equivalent to 3.5% BSA in total. 
Following inclusion subjects will be randomised to either active or placebo. The 
investigator will use his judgement and discretion to decide on which area to apply the 
study treatment within requirements given in Table 4. 
Subjects will receive either 1% strength GSK2646264 cream or placebo cream. The skin 
prick test will be performed on the volar aspect of the arm only in subjects who have a 
positive allergen challenge test at screening, as per inclusion criteria. 


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Figure 3
Schematic showing Part B Dosing in Cold urticaria patients
Key:
PD - Pharmacodynamics
SPT - Skin Prick Test
PK - Pharmacokinetics
BSA - Body Surface Area
1⁰ - Primary Objective
2⁰ - Secondary Objective
3.1.5.
Part C : A double-blind (sponsor unblinded) placebo-controlled, 
randomised to active or placebo treatment repeat dose study (3 
doses over 7 days), in subjects with mild to moderate Chronic 
Spontaneous Urticaria (CsU)
Subjects will be randomised to a 3:1 ratio to receive active treatment or placebo applied 
to areas of the body chosen by the investigator once a day every 3 days, over a total 
period of 7 days.  Dosing will occur on days 1, 4 and 7. The chosen area where cream is 
applied will remain the same throughout the dosing period. Dosing in Part C will only 
commence once relevant data from the first four subjects in Part B have been reviewed, 
to allow greater confidence in predictions of the pharmacokinetics in Part C. The BSA 
over which study treatment will be administered in Part C will be 10%, but is subject to 
change, if appropriate, based on preliminary data from the first 4 subjects in Part C 
However, the maximum BSA will not exceed 20% (see Figure 4 for a visual 
representation of the dosing schedule).
The first 4 subjects of Part C will be randomised so that one of the 4 subjects will receive 
placebo and the three other subjects will receive GSK2646264. An informal review of the 
preliminary data from the first 4 subjects may be conducted after they have completed the 
study. PK, safety, and tolerability, up to and including the follow-up visit, will be 
reviewed by the Sponsor (See Section 5.5). If required, a discussion with the SMC 
regarding any changes or adjustments to the dosing regimen in Part C will be held. 
Recruitment of the full planned cohort (n=16) may continue during any data review.
The timing and the assessments to be completed at each visit are provided in the Time 
and Event tables (Section 6.1.4). Early termination of this patient group may occur due to 
feasibility of recruitment and stopping criteria see (Section 5.5 and Section 5.6). 
Following inclusion in the study, subjects will be randomised. 10 mg/cm2 of 1% 


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GSK2646264 cream or placebo cream will be applied to a given BSA once per day, every 
3 days, on  days 1, 4and 7, on areas of the body chosen by the investigator. The areas 
where cream is applied will remain the same for each day of dosing. The 10 % BSA can 
be distributed between the arms, legs and torso for an individual subject and will be 
decided by the investigator prior to randomisation. This pattern of cream application will 
remain the same for the duration of dosing. The maximum % BSA and the frequency of 
dosing will be decided after Part A and n=4 in Part B of the study but will not exceed 
20% BSA.  
The subjects will be dosed in the unit for the first dose on day 1 and then discharged from 
the clinic.  Subjects will return to the clinic prior to the dose and specified assessments on 
days 4 and 7..  Subjects will be asked to complete a daily diary over the 7 days. . Details 
of the diary will be provided in the Study Procedures Manual (SPM)
Figure 4
Schematic showing Part C dosing in Chronic Spontaneous Urticaria 
patients
Key:
PK - Pharmacokinetics
PD – Pharmacodynamics (UAS-7 
and AAS)
1⁰ - Primary Objective
BSA - Body Surface Area
AAS – Angioedema Activity Score
UAS7 – Urticaria activity score - 7
3.1.6.
Progression Criteria for dose escalation in the study
The steps for decisions on dose adjustments and progression criteria to the next stage are 
presented in Section 5.5.


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3.2.
Discussion of Study Design
3.2.1.
Design Rationale
This study is designed to evaluate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of single and repeat ascending dose of GSK2646264 in healthy 
subjects (First Time in Human study), cold urticaria and chronic spontaneous urticaria 
subjects. 
The proposed bilateral design for Part A is well established and most efficient study 
design in absence of any effect.  In this design, each subject in Part A will be his/her own 
control. The subject’s left and right side of the defined study body surface area will be 
randomised to either GSK2646264 or Placebo.
Parts B & C will be a placebo controlled randomised parallel design randomisation where 
subjects will receive either active or placebo study treatment, not both (unlike Part A of 
the study).
3.2.1.1.
Part A: Healthy Subject Cohort
Healthy male and female subjects (female subjects who are of non-child bearing potential 
will be included in Part A of the study) will be assessed for safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD) after once or twice daily dosing of 
GSK2646264. Safety assessments over the day 1 dosing period will enable a repeat dose 
period with increasing body surface and safety assessment from days 1 through to day 3 
in group 1. Also, based on the current understanding of SYK kinase inhibition, it is 
anticipated that target engagement will be determined by the pharmacodynamic endpoint 
of allergen challenge.
Safety and tolerability in these subjects will also enable covering an increase in strength 
and increasing body surface area from days 1 through to day 4 of the dosing period in 
group 2. In addition, PK will drive the decision of whether group 2 will be dosed once or 
twice daily. Safety, tolerability and systemic exposure data including any effect on IgM 
stimulated CD69 generated in Part A will be used to provide margins for the strength of 
GSK2646264 applied and also the body surface area (BSA) covered in cold urticaria 
subjects in Part B and in chronic spontaneous urticaria subjects in Part C. 
3.2.1.2.
Part B: Cold urticaria Subjects
This cohort will provide safety, tolerability and PK over 3 days of dosing (with an 
additional 2 weeks follow-up post last dose for PK, safety and biomarker endpoints) in 
this population and will enable further clinical studies. Also, based on the current 
understanding of SYK kinase inhibition, it is anticipated that target engagement will be 
determined by the pharmacodynamic endpoints of allergen challenge and critical 
temperature threshold testing.


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3.2.1.3.
Part C: Chronic Spontaneous Urticaria Subjects
This part of the study will provide safety, tolerability, PK and PD from dosing every 3 
days, over a total period of 7 days  (with an additional 2 weeks follow-up post last dose 
for PK, safety and biomarker endpoints) to enable further clinical studies in this 
population.
3.2.2.
Dose Rationale
GSK2646264 will be administered topically as a cream at two strengths of 0.5% and 1% 
(w/w). A corresponding placebo cream will also be applied. 
Previous to Part A of this protocol GSK2646264 had not been applied to humans 
therefore dose rationale is based on pre-clinical data.
Summary

The proposed starting dose applied to the smallest surface areas (0.5 % strength on 
0.2 % BSA e.g, 36 cm2) is unlikely to result in quantifiable plasma concentrations, 
however application to body surface areas from 5%  BSA up to 10% BSA are likely 
to show quantifiable plasma concentrations.

Based on the integrated data from the human in vitro dermal penetration and 
histamine release at 4 and 24h after topical administration both strengths of cream 
administered at 10mg/cm2 are predicted to lead to >90% inhibition of histamine
release from the skin mast cells. 

The maximum topically applied dose will be 10mg/cm2 of cream over 3600 cm2
(20% BSA 360mg of free base drug) with based on pre-clinical predictions,:-

6 fold systemic margin, compared to the Cmax at the NOEL (based on thyroid 
finding in rat IV)

3.5 fold systemic margin compared to the AUC(0-t) at the NOAEL and 3 to 6 fold 
local tolerability margin based on the applied dose to the skin. (based on lack of 
thyroid or skin findings in rat dermal study).

The recommended starting dose for this trial is predicted to deliver exposure lower 
than the systemic MABEL dose.  At a dose of 0.5% strength, no significant adverse 
events are expected as per the results from preclinical toxicology studies.

The protocol allows for some alteration from the currently outlined dosing schedule 
as described in Section 5.5, Section 5.6 and Section 5.7.  
3.2.2.1.
Comparison of predicted human plasma exposures to animal safety 
study exposures
The in vitro skin penetration study performed over 24 hours provided quantifiable levels 
of GSK2646264 in the receiving fluid thus allowing the determination of the maximum 
observed permeation rate (flux) for all of the cream strengths tested.  The flux determined 
for the 0.5 and 1% creams and the predicted human PK parameters (CLb: 13 mL/min/kg, 
Vss: 0.8 L/kg) were used to predict the maximum expected plasma concentrations and 


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AUC0-24h when applying the creams to the different BSA in the clinical study. The 
calculated values are displayed in Appendix 6.
As the maximum suggested dose to be applied topically in Part A group 1 is 45 mg of 
free base drug, the predicted maximum systemic exposure achieved is expected to be ~50 
fold lower than the Cmax NOEL achieved (~16ng/ml). 
In Part A and C the maximally applied dose of 360 mg of free drug will lead to systemic 
exposures that are expected to be 6 fold lower than Cmax NOEL and   ~ 1,882 and 447 
fold lower than the systemic concentration expected to inhibit SYK activity (MABEL) by 
80% (IC80 of 4835 ng/mL) and 20% (IC20 of 1150 ng/mL) respectively. 
Further details are available in the Investigator’s Brochure (IB) [GlaxosmithKline 
Document Number 2013N182566_00]. 
3.2.2.2.
Additional preliminary data from Part A
Preliminary human PK data from Part A (up to 1% strength, up to 10% BSA) 
demonstrated a geometric mean Cmax after 4 days dosing of 5.59 ng/ml, providing a 
margin of  2.8 in comparison to the Cmax NOEL achieved (~16ng/ml) . After 4 days of 
dosing the geometric mean AUC was 103.8 ng∙h/ml, allowing a 2.1 fold systemic margin 
compared to the AUC(0-t) at the NOAEL.
This allows 3 days dosing at 1% strength, 10% BSA for Part B.  For further progression 
of dosing in parts B and C refer to Section 5.5.3.3.
Further predictive modeling using the data from Part A, but with no inclusion of 
elimination rate, suggests that coverage of 10% BSA using the 1% cream over 7 days of 
dosing would lead to an estimated Cmax of 10.12ng/ml and an AUC of  219.8ng∙h/ml.
The information in the above paragraph is superseded by the information in Section 
3.2.2.3.
3.2.2.3.
Additional preliminary data from Part B
A population pharmacokinetic model integrating all plasma data from part A and the 
preliminary data from n=4 in part B lead to an estimation of the half life of 57 hours for 
GSK2646264. This model shows that in order to maintain a 1.8 fold margin with the 
AUC NOAEL to allow women of child bearing potential in the trial the doses of 180mg 
(10% BSA) should be administered every three days, over a total 7 day duration, rather 
than every day.
3.2.2.4.
GSK2646264 strength for Part B and C
Parts B and C of the study will recruit cold urticaria and chronic spontaneous urticaria 
patients, respectively. The drug strength (1%) selected for Parts B and C will be the 
highest strength tested in Part A that was not associated with clinically significant skin 
irritation and/or systemic adverse effects.


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Preliminary data from Part A (up to 1% strength cream, up to 4 days dosing, and up to 
10% BSA) showed that the 1% cream was well tolerated and did not identify clinically 
significant safety issues.  Therefore the 1% strength cream will be used in Parts B and C.
3.2.3.
Clinical Experience
This is the first clinical application for GSK2646264 in any formulation and therefore, 
the first exposure will be in an in-patient setting with healthy volunteers (Part A) 
followed by cold urticaria patients (Part B) and Chronic Spontaneous Urticaria patients 
(Part C) with monitoring of routine safety parameters including systematic review of 
signs and symptoms, physical examination, AEs, vital signs and clinical laboratory 
results. 
Preliminary data from Part A showed that dosing with up to 1% GSK2646264 cream, up 
to 4 days and up to 10% BSA in healthy volunteers was well tolerated and did not 
identify clinically significant safety issues. Clinically significant safety issues were also 
not observed in n=4 subjects in Part B (cold urticaria subjects).


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Table 6
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
Potential risk
Summary of data
Impact- eligibility criteria
Strategy-monitoring/stopping criteria
Hypersensitivity
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.  
There is no previous experience of 
GSK2646264 or of the matched 
placebo in humans
Subjects will be asked at screening if 
they are allergic to any of the ingredients 
– if known, 
Subjects will be excluded from the study 
if they are allergic to any ingredient of the 
study medications or if they have 
previously experienced an anaphylactic 
reaction. 
Subjects will undergo regular medical 
assessment and instructed what action to 
take in the event of experiencing an allergic 
reaction.  
Skin prick  
There have been rare reports of 
systemic allergic reactions following 
skin prick testing (Heinzerling, 
2013)
Subjects will be excluded from the study 
if have previously experienced an 
anaphylactic reaction. 
Subjects will be excluded from the study 
if the subject has a reaction which 
contraindicates to the study
Skin prick testing will be performed in a 
facility with appropriate emergency 
equipment available in case of the need for 
treatment for  systemic allergic reaction.  
Pregnancy and lactation
There is no data available on the 
effect of GSK 2646264 in 
pregnancy and lactation in humans.
Fetal malformations were seen 
after IV dosing to pregnant rabbits 
with a NOAEL that is expected to 
exceed the highest expected 
human exposure by >4 fold.  No 
similar changes were seen in the 
rat after substantially higher 
exposure 
Female subjects of non child bearing 
potential will be included in Part A of the 
study.
Female subjects that are of child-bearing 
potential will be required to follow the 
contraceptive requirements that are 
outlined in the protocol Section 4.2.1
inclusion criteria for Part B and C. 
A decision to allow females of child-
bearing potential in Parts B and C will be 
made based on the safety margin from 
the dosing in Part A of the study.
Female subjects that are of child-bearing 
potential will  undergo regular pregnancy 
testing and treatment stopped immediately if 
a subject is found to be pregnant during the 
study.
In part B, these subjects must be on oral 
contraceptives 28 days before screening 
begins. They will undergo serum pregnancy 
testing at day -28, day -7 to -4, a serum or 
urine pregnancy test the day of the start of 
the study prior to dosing, then testing on an 
approximately weekly basis and a serum 
pregnancy test at the follow up visit.
In Part C, a serum pregnancy test will be 


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Potential risk
Summary of data
Impact- eligibility criteria
Strategy-monitoring/stopping criteria
Nursing females will be excluded from 
participating in the study.  
performed on the day of screening. If this is 
between Days -13 and -7, a further 
pregnancy test will not be required until Day 
1.  However, if the day of screening is 
between Day -28 and -14, an additional 
serum pregnancy test will be required 
between Days -7 and -4.  A urine pregnancy 
test will be required prior to dosing on Day 1
Immune cell effects, including 
neutropenia
SYK is involved in immunoreceptor 
signalling in a number of cell types, 
including mast cells, basophils, B 
cells, neutrophils and macrophages 
(Riccaboni, 2010)
Studies with R788 in rheumatoid 
arthritis identified an increased risk 
of neutropenia in subjects treated 
with the oral SYK inhibitor 
compared to placebo (placebo 
0.7%, R788 150mg OD 6.6%, R788 
100mg BD 5.9%) (Weinblatt, 2010)   
Subjects with co-morbid conditions that 
would put them at risk or laboratory 
values outside the reference range at 
screening would be excluded from 
participating in the study.  
The product is being investigated in a topical 
formulation, which should limit potential 
systemic exposure.  Increasing exposure will 
be performed gradually.  
Subjects will undergo regular haematological 
assessments, including white blood cell 
counts during the study.  
Treatment would be stopped if laboratory 
test results are identified that would put the 
safety of the subject at risk. 
Thyroid 
Minimal thyroid follicular epithelial 
hypertrophy was observed in all 
doses following iv administration of 
GSK2646264 in rats for 4 weeks. 
Thyroid function test (TSH, free and 
total T3 and T4) at single timepoints 
12 hours post last dose were within 
normal range.
Requirement for normal TSH in all 
subjects in Part A, and normal TSH, free 
T4, T4 and T3 in Parts B and C.. 
Exclusion of subjects with history of 
Graves’ disease or any  thyroid cancer
The risk of thyroid effect in this study is 
considered not to be significant. Monitoring 
will be based on signs and symptoms and 
serum markers of thyroid function will be 
measured in patients in Parts B and C.


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4.
STUDY POPULATION
4.1.
Number of Subjects
The aim is to achieve approximately 18 randomised evaluable subjects in Part A (9 
subjects in dosing group 1 and 9 subjects in dosing group 2), approximately 12 
randomised evaluable subjects who complete the study in Part B and approximately 16 
subjects in Part C. In Parts A and B, it is anticipated that a proportion of subjects will not 
demonstrate weal and flare at the screening skin prick test (See Section 4.2.1.2 and 
Section 4.2.1.3).  However these proportions are not known, so enough subjects will be 
enrolled to achieve the target study population.
4.2.
Eligibility Criteria
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including all those 
specified in the Time and Events Table, are essential and required for study conduct.
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
For a subject to be included in the study they must fulfil all requirements for both the ‘All 
subjects’ Inclusion and Exclusion Criteria and then specific inclusion and exclusion for 
either healthy subjects, Cold urticaria subjects or Chronic Spontaneous subjects as shown 
in Section 4.2.
For those criteria where an investigator’s decision will be required to it will be 
documented on every occasion. 
4.2.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
4.2.1.1.
Inclusion criteria for all subjects in Parts A, B and C
1. Male or female subject aged at least 18 years at the time of signing the informed 
consent. The upper age limit of subjects is defined in the specific inclusion 
criteria for each cohort. 
2. 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, unless in the opinion of the investigator it will not compromise the 
subjects’ safety and quality of data. 


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3. 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.
4. 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.
5. Male subjects with female partners of child-bearing potential must agree to use 
one of the contraception methods listed in Section 4.3.1.  This criterion must be 
followed from the time of the first dose of study medication until the follow up 
visit or  12 days, whichever is the latter.
6. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. Willing, committed and 
able to return for all clinic visits and complete all study-related procedures. Able 
to read, understand and complete study- related questionnaires.
4.2.1.2.
Inclusion criteria specific for healthy subjects (Part A)
Subjects will be included in the healthy subject cohort if all the following criteria apply:
1. The subject is aged between 18 and 55 years of age inclusive, at the time of 
signing the informed consent.
2. Body weight 50 kg and BMI within the range 19 to 30 kg/m2 (inclusive). 
3. Healthy as determined by a responsible and experienced physician, based on a 
medical evaluation including medical history, physical examination, laboratory 
tests and cardiac monitoring.  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 GSK Medical monitor if 
required, agrees and documents that the finding is unlikely to introduce additional 
risk factors and will not interfere with the study procedures. 
4. Demonstration of a positive weal and flare reaction (≥ 3mm in diameter relative to 
negative control) to at least one allergen from a battery of allergens (Mixed grass 
pollen, Dermatophagoides pteronyssinus, birch pollen and cat dander) on skin 
prick testing at screening.
5. Subjects must be free from 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. Non –smokers or if the subject is a tobacco smoker: smokes less than 5 cigarettes 
per day and commits to not smoke tobacco for the duration of the in-house stay, 
and commits to stable and moderate use (as determined by the Investigator) of 
tobacco or nicotine-containing products, including nicotine patches/gum, during 
the course of the study, as long as the patches do not interfere with the study 
procedures. 
7. A female subject is eligible to participate if she is of:


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
Non-childbearing potential defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy for this definition, “documented” 
refers to the outcome of the investigator's/designee’s review of the subject's 
medical history for study eligibility, as obtained via a verbal interview with the 
subject or from the subject’s medical records; or postmenopausal defined as 12 
months of spontaneous amenorrhea in questionable cases a blood sample with 
simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 
40 pg/ml (<147 pmol/L) is confirmatory.  

Females on hormone replacement therapy (HRT) and whose menopausal status 
is in doubt will be required to use one of the contraception methods described 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.  For most forms of HRT, at least 2-4 weeks will elapse between the 
cessation of therapy and the blood draw; this interval depends on the type and 
dosage of HRT. Following confirmation of their post-menopausal status, they 
can resume use of HRT during the study without use of a contraceptive method.
4.2.1.3.
Additional Inclusion criteria specific for subjects with cold urticaria 
(Part B)
Subject will be included in the cold urticaria subject cohort if all the following criteria 
apply:
1. Diagnosed with cold urticaria for more than six weeks as confirmed by medical 
history and with a positive cold stimulation test assessed by TEMPTest 4.0 prior 
to first dose.
2. The subject is aged between 18 and 70 years of age inclusive, at the time of 
signing the informed consent.
3. Body weight 50 kg and BMI within the range 19 to 35 kg/m2 (inclusive). 
4. Other than a diagnosis of cold urticaria, the subject should have no other co-
morbidities which would introduce additional risk factors and will not interfere 
with the study procedures, as determined by a responsible and experienced 
physician, based on a medical evaluation including medical history, physical 
examination, laboratory tests and cardiac monitoring.  
5. 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 GSK Medical monitor if required, agrees and documents 
that the finding is unlikely to introduce additional risk factors and will not 
interfere with the study procedure.
6. In addition, the following criterion will apply to a minimum of 4 patients in Part 
B: 
Demonstration of a positive weal and flare reaction (≥3 mm relative to negative 
control) to at least one allergen from a battery of allergens (mixed grass pollen, 
Dermatophagoides pteronyssinus, birch pollen and cat dander)  on skin prick 
testing at screening, 


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7. Subjects must be free from any past or present benign or malignant skin 
conditions and disease, other than the specified condition required for eligibility 
of subjects as defined in the specific inclusion criteria for CU cohort unless in the 
opinion of the investigator it will not compromise the subjects safety and quality 
of data. 
8. Non–smokers or if the subject is a tobacco smoker: smokes less than 5 cigarettes 
per day and commits to not smoke tobacco for the duration of the in-house stay, 
and commits to stable and moderate use (as determined by the Investigator) of 
tobacco or nicotine-containing products, including nicotine patches/gum, during 
the course of the study, as long as the patches do not interfere with the study 
procedures.
9. Female subjects of child bearing potential must have been using one of the 
contraception methods listed in Section 4.3.1 at least 28 days before their 
screening visit and agree to continue with these methods until the follow up visit 
or 12 days after the last dose of study treatment, whichever is the longer.
If a patient who has been screened and is eligible for the study becomes unavailable to do 
the study at the initially planned dates due to exceptional circumstances, the subject may 
be re-screened for the study; in total a patient may be screened 2 times. This will only be 
at the discretion of the Investigator.
4.2.1.4.
Additional Inclusion criteria specific for subjects with chronic 
spontaneous urticaria (Part C)
Subjects will be included in the chronic spontaneous urticaria cohort if all the following 
criteria apply
1. The subject is aged between 18 and 70 years of age inclusive, at the time of 
signing the informed consent. 
2. Body weight 50 kg and BMI within the range 19 to 35 kg/m2 (inclusive)
3. Subjects who have a  score of >14 on the UAS7 questionnaire with  between 4-20  
weals observed in a defined area of the body will be included in this study. This 
area must include either arms, legs or torso for 7 consecutive days during the 
screening period, prior to the Day 1 visit. If  a subject has not completed 7 
consecutive days of UAS questionnaire prior to dosing on Day 1 due to 
exceptional circumstances, the screening period may be extended until the subject 
has completed 7 consecutive days of UAS questionnaire. This will only be at the 
discretion of the Investigator.
4. No other aetiology identified for chronic urticaria such as drug-related or 
inducible urticaria as determined by history, physical examination and laboratory 
studies.
5. Subjects must be free from any past or present benign or malignant skin 
conditions and disease, other than the specified condition required for eligibility 
of subjects as defined in the specific inclusion criteria for CsU cohort unless in the 
opinion of the investigator it will not compromise the subjects safety and quality 
of data. 


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6. Other than a diagnosis of chronic spontaneous urticaria the subject should have no 
other co-morbidities which would introduce additional risk factors and will not 
interfere with the study procedures, as determined by a responsible and 
experienced physician, based on a medical evaluation including medical history, 
physical examination, laboratory tests and cardiac monitoring. 
7. 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 GSK Medical monitor if required, agrees and documents 
that the finding is unlikely to introduce additional risk factors and will not 
interfere with the study procedures.
8. Female subjects of child bearing potential must have been using one of the 
contraception methods listed in Section 4.3.1 at least 28 days before their 
screening visit and agree to continue with these methods until the follow up visit 
or  12 days after the last dose of study treatment, whichever is the longer.
If a patient who has been screened and is eligible for the study becomes unavailable to do 
the study at initially planned dates due to exceptional circumstances, the subject may be 
re-screened for the study; in total a patient may be screened 2 times. This will only be at 
the discretion of the Investigator.
4.2.2.
All Cohorts Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
TSH levels outside the normal range. 
2.
Subjects with a history of Graves disease.
3.
Subjects with a history of any thyroid cancer.
4.
Unable or unwilling to avoid use of topical creams/lotions at sites where 
medication will be applied.  Washing with soap and water will be permitted.  
5.
Based on averaged QTcF values of triplicate ECGs obtained over a brief 
recording period:

QTc(F) > 450 msec; or QTc(F) > 480 msec in subjects with Bundle 
Branch Block.
6.
ALT, alkaline phosphatase and bilirubin ≥ 1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
7.
Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones or previous history of uncomplicated cholecystectomy).
8.
History of regular alcohol consumption within 6 months of the study defined as: 

An average weekly intake of >21 units for males or >14 units for females.  
One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 
glass (125 ml) of wine or 1 (25 ml) measure of spirits. 


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9.
History of sensitivity to any of the study medications, or components thereof, 
history of anaphylaxis or a history of drug or other allergy that, in the opinion of 
the investigator or GSK Medical monitor, contraindicates their participation. 
10. 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. 
11. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody 
result within 3 months of screening. 
12. A positive test for HIV antibody.
13. A positive drug screen at screening or Day -1 (parts A & B only). For Part B 
patients, a positive drug screen due to concomitant medication may be 
acceptable for inclusion in the study based on the Investigator’s opinion. The 
Investigator’s opinion must be based on interview of the subject, documented in 
the medical history and the Investigator is asked to document that the positive 
test can be explained by a relevant and permitted medication (see Section 
5.15.1.) and that the medication will not interfere with the study procedures or 
compromise subject safety. A drug screen will not be performed in Part C.
14. Lactating females.
15. Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within a 56 day period.
16. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the 
current study: 30 days, 5 half-lives or twice the duration of the biological effect 
of the investigational product (whichever is longer).
17. Exposure to more than four new chemical entities within 12 months prior to the 
first dosing day
18. Use of topical steroids or calcinurin inhibitors is prohibited during the study 
from screening to follow up (See Section 5.12).
19. Exclusion related to prior drug treatments:
a) Intake of oral corticosteroids within 7 days >10mg/day prior to first screening 
visit.
b) Use of depot corticosteroids within 7 days prior to first screening visit. 
c) Subjects who are taking anticoagulants (e.g. warfarin) must not be on warfarin 
within 21 days prior to screening. (See Section 5.15).
d) Subjects who are having psoralen combined with ultraviolet A (PUVA) 
treatment must not be using PUVA treatment within 21 days prior to screening.


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20. Subjects who work for the Sponsor, Contract Research Organisation (CRO), or 
one of the study centres. 
4.2.2.1.
Country Specific Exclusion criteria wording for Germany that applies to 
Part A, Part B and Part C
1.
Subjects who live in detention on court order or on regulatory action, see §40 
subsection 1 sentence 3 no. 4 AMG. (Arzneimittelgesetz) [MEDICINAL 
PRODUCTS ACT, 2015]. 
4.2.2.2.
Additional Exclusion for Part A – Healthy Subjects
2. Use of H1 antihistamines within 3 days prior to first screening visit 
4.2.2.3.
Additional Exclusion for Part B – Cold urticaria Subjects
1. fT4, T4, T3 outside the normal range.
2. Exclusion related to prior drug treatments:

Use of  zaditen (Ketotifen) within 14 days prior to first screening visit

Use of doxepin AZU and other tricyclic antidepressants with antihistaminergic 
properties within 14 days prior to first screening visit

Use of H2 antihistamines within 7 days prior to first screening visit 

Use of H1 antihistamines within 7 days prior to first screening visit 

Use of monteleukast or any other leukotriene antagonist within 7 days prior to 
first screening visit

Use of biologicals including omalizumab within 5 months prior to first 
screening visit
4.2.2.4.
Additional Exclusion for Part C- Chronic Spontaneous Urticaria 
patients
1. fT4, T4, T3 outside the normal range.
2. Exclusion related to prior drug treatments

Intake of cyclosporin within 10 days prior to first screening visit

Intake of other immunosuppressant drugs within 28 days of first screening visit

Use of monteleukast or any other leukotriene antagonist within 7 days prior to 
first screening visit

Use of dapsone within 7 days prior to first screening visit

Use of zaditen (Ketotifen) within 14 days prior to first screening visit

Use of doxepin AZU  and other tricyclic antidepressants with antihistaminergic 
properties within 14 days prior to first screening visit

Use of H2 antihistamines within 7 days prior first screening visit 


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
Use of biologicals including omalizumab within 5 months prior to first 
screening visit

Use of H1 antihistamines above the licensed dose within 3 days prior to first 
screening visit
4.3.
Lifestyle and/or Dietary Restrictions
4.3.1.
Contraception Requirements
4.3.1.1.
Female Subjects
In Part A: Female subjects of non-childbearing potential will be recruited onto the study. 
In Parts B and C: Female subjects of child bearing potential may be recruited onto the 
study, and must not become pregnant and so must be sexually inactive by abstinence or 
use contraceptive methods with a failure rate of < 1%.  Female subjects of childbearing 
potential with same sex partners are not required to be abstinent or to use contraception.  
Subjects in parts B and C will need to be on established contraceptive as listed in Section 
4.2.1 inclusion criteria at the time of screening (day -28) and will have regular 
serum/urine pregnancy testing throughout the duration of the study as listed in the Time
and Events Table Section 6.1.  Contraceptive use shall be continuous through the pre-
study, study and follow-up periods of the study.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Contraceptive Methods with a Failure Rate of < 1%

Combined oral contraceptive

Injectable progestogen 

Implants of etonogestrel or levonorgestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches

Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure 
rate as stated in the product label

Documented male partner sterilization prior to the female subject's entry into the 
study, and this male is the sole partner for that subject.  For this definition, 
“documented” refers to the outcome of the investigator's/designee’s review of the 
subject's medical history for study eligibility, as obtained via a verbal interview with 
the subject or from the subject’s medical records.

Male condom combined with a female diaphragm, either with or without a vaginal 
spermicidea (foam, gel, film, cream, or suppository) (Hatcher, 2007)


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NOTE: These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label.  The investigator is 
responsible for ensuring subjects understand how to properly use these methods of 
contraception.
4.3.1.2.
Male Subjects
Male subjects with female partners of child-bearing potential must use one of the 
following contraceptive methods after the first dose of study treatment and until the 
follow-up contact.  

Condom plus partner use of a highly effective contraceptive (see list in Section 
4.3.1.1). 

Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception
4.3.2.
Meals and Restrictions
4.3.2.1.
Caffeine, Alcohol, and Tobacco
Healthy volunteers (Part A) 

Will abstain from ingesting caffeine- or xanthine-containing products (e.g. coffee, 
tea, cola drinks, chocolate)  and alcohol for 24 hours prior to the start of dosing until 
collection of the final pharmacokinetic and/or pharmacodynamic sample
Subjects with Cold urticaria (Part B)

Will abstain from ingesting caffeine- or xanthine-containing products (e.g. coffee, 
tea, cola drinks, chocolate)  and alcohol for 24 hours prior to the start of dosing until 
discharge from the research unit.
Subjects with Chronic spontaneous urticaria (Part C) 

Will be allowed alcohol (an average weekly intake of <21 units for males or <14 
units for females).   

There are no caffeine, or tobacco restrictions for patients with chronic 
spontaneous urticaria.  
4.3.2.2.
Fasting

Subjects will be required to be fasted prior to the screening visit.
4.3.3.
Activity and other restrictions during the study
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 (e.g., watch television, read). 


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4.3.3.1.
Showering/bathing during the study
In all dose cohorts, subjects will be allowed to shower/bathe approximately 2 hours prior 
to dosing and approximately 18-22 hours following dosing. During showering/bathing 
the subject should only use mild, unscented, and non-medicated soap A mild shampoo 
can be used for washing hair. The site of blood sampling will be protected (taped off and 
covered) if required, allowing the subjects to shower freely, including washing the
application site(s). Subjects should refrain from rubbing the areas where the cream has 
been applied.
Timings of showering/bathing  must be recorded (as detailed in the SPM).
Subjects must refrain from taking part in water based activities such as swimming and 
use of sauna/steam room for the duration of dosing until the follow-up visit.
4.3.3.2.
Clothing during the study
Subjects will be allowed to use their normal clothing for the duration of the dosing period 
as long as it is not tight fitting. Subjects will not be allowed to put clothing over dosed 
areas until 60 minutes after application of the cream.
4.4.
Screen and Baseline Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any Serious Adverse Events.
4.4.1.
Subjects exceeding screening visit window
Subjects in Part B and Part C that are not randomized within the allotted screening 
window may be re-screened once, as per Section 4.2.1. If re-screening is performed, it is 
essential that subjects are assigned a different unique subject ID number for the 
additional screening attempt. See the SPM for specific details.
4.5.
Withdrawal Criteria and Procedures
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.
Refer to Section 5.5 for planned dose adjustment/stopping criteria and Section 5.7 for 
subject specific dose adaptation/stopping criteria including Liver Chemistry and QTcF. 
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event aetiology (in alignment with the FDA premarketing clinical 
liver safety guidance). See Section 5.7.1 for details.


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4.6.
Subject Completion
A completed subject is one who has completed all visits of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit which is a follow up visit.
5.
STUDY TREATMENT
5.1.
Investigational Product and Other Study Treatment
Table 7
Study treatment and Challenge agent table
Study Treatment
Product name:
0.5% 
GSK2646264
1%
GSK2646264
Placebo
Formulation description:
White to off white 
aqueous cream
White to off white 
aqueous cream
White to off white 
aqueous cream
Dosage form:
Topical
Topical
Topical
Unit dose strength(s)/Dosage 
level(s):
0.5% (w/w)
1% (w/w)
NA
Route/
Administration/
Duration:
Topical; ; SINGLE 
USE BOTTLES 
ONLY
Topical; ; SINGLE 
USE BOTTLES 
ONLY
Topical; ; SINGLE USE 
BOTTLES ONLY
Dosing instructions:
Should be applied 
topically as directed.
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
White-to-off-white 
aqueous cream stored 
in amber glass jars
Manufacturer/
source of procurement:
Medpharm Guildford
Medpharm Guildford
Medpharm Guildford
Each bottle of cream is for single use only.


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Challenge Agent  Treatments
Product name:
Dermatophagoides 
pteronyssinus 
Timothy Grass 
Pollen
Cat dander
Birch pollen  
Positive 
Control
Negative 
Control
Mixed Grass 
Pollen
Formulation 
description:
Solution for skin prick 
test
Solution for skin 
prick test
Solution for 
skin prick test
Solution for 
skin prick test
Solution for 
skin prick test
Solution for 
skin prick test
Solution for 
skin prick test
Dosage form:
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Unit dose 
strength(s)/Dosage 
level(s):
0.003 microlitres
0.003 microlitres
0.003 
microlitres
0.003 
microlitres
0.003 
microlitres
0.003 
microlitres
0.003 
microlitres
Route/
Administration/
Duration:
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Dosing 
instructions:
Superficial layer of skin 
is pierced with an ALK 
lancet perpendicular to 
the skin.
Superficial layer 
of skin is pierced 
with an ALK 
lancet 
perpendicular to 
the skin.
Superficial 
layer of skin is 
pierced with an 
ALK lancet 
perpendicular 
to the skin.
Superficial 
layer of skin is 
pierced with an 
ALK lancet 
perpendicular 
to the skin.
Superficial 
layer of skin is 
pierced with an 
ALK lancet 
perpendicular 
to the skin.
Superficial 
layer of skin is 
pierced with 
an ALK lancet 
perpendicular
to the skin.
Superficial 
layer of skin is 
pierced with an 
ALK lancet 
perpendicular 
to the skin.
Physical 
description:
Solution for skin prick 
testing
Solution for skin 
prick testing
Solution for 
skin prick 
testing
Solution for 
skin prick 
testing
Solution for 
skin prick 
testing
Solution for 
skin prick 
testing
Solution for 
skin prick 
testing
Manufacturer/
source of 
procurement:
ALK-Abello A/S
ALK-Abello A/S
ALK-Abello 
A/S
ALK-Abello 
A/S
ALK-Abello 
A/S
ALK-Abello 
A/S
ALK-Abello 
A/S


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5.2.
Challenge Agents
5.2.1.
Skin prick test allergens
A solution of each challenge agent will be applied using the skin prick method as 
described in The Global Allergy and Asthma European Network (GA2LEN) guidelines 
(Heinzerling, 2013). This is a widely accepted method used in allergy clinics to test for 
histamine and allergen sensitivity; causing pruritus, skin flare and a skin wheal. The skin 
prick method involves placing a drop of histamine or allergen solution onto the skin and 
using a lancet to gently pierce the superficial layer of the skin. The excess histamine or 
allergen solution is then wiped away.
The following challenge agents will be used as allergens as part of the skin prick 
test. Full details are listed in the table in Section 5.1

mixed grass pollen,

Dermatophagoides pteronyssinus, 

birch pollen, 

cat dander

positive control – histamine

negative control –  saline
5.3.
Medical Devices
Not applicable.
5.4.
Treatment Assignment
Subjects will be assigned to treatment in accordance with the randomization schedule 
generated by Parexel, prior to the start of the study. Randomisation will occur within each 
cohort of study. Subjects will be randomised to 1:1 to receive bilateral treatment of 
GSK2646264 or placebo in Part A.  For Parts B & C, subjects will be randomised 3:1 
active:placebo respectively, to receive either GSK2646264 or placebo.
5.5.
Planned Dose Adjustments/Progression and Stopping 
criteria
The study will enrol 1 sentinel subject for Part A dosing group 1 and, Part A dosing 
group 2. Each sentinel subject will be dosed 1 day at least before any other subjects of 
their dosing group or cohort. Please refer to Section 5.6 and Section 5.7 for dose 
adjustments and stopping criteria.  
This protocol allows some alteration from the currently outlined dosing schedule, but the 
the maximum topically applied dose at any one time will be 10mg/cm2 of cream (360mg 
of free base drug) over 3600 cm2 (20% BSA) with, based on preclinical modeling, a 6 
fold cover compared to the predicted Cmax at the NOEL (16 ng/mL) and 3.5 fold cover 


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compared to the predicted AUC at the NOAEL (220 ng.hr/mL), or the dose which will 
provide this Cmax and this AUC (See Section 3.2.2.). 
The GSK review team will be unblinded to the randomisation code and will usually 
include the GSK pharmacokineticist, GSK statistician, GSK data management, GSK 
medical monitor, GSK study team leader, GSK Global Clinical Safety and 
Pharmacovigilance and GSK Clinical Matrix Team leader.  Other GSK employees may 
be included in discussions around dose adjustments and progression if it is deemed 
necessary and relevant by the above mentioned team members.
The Investigator or designee, study co-ordinators and any other unit staff who have been 
involved in assessing subjects will remain blinded during the study; however, they will 
attend the start of each review meeting to update the GSK team on safety and tolerability 
summary from each cohort; these team members will not be part of the unblinded dose 
escalation discussions.  The investigator and/or designee should send the relevant data to 
the GSK review team prior to the meeting of the Safety Monitoring Committee (SMC). 
The study monitor will remain blinded.
The SMC will consist of the GSK review team and the Investigator and/or designee.  The 
SMC will:
- Approve escalation from dosing group 1 to dosing group 2 in Part A (See 
Section 5.5.3)
- Approve the selection of dosing regimen to be used in Parts B and C (See 
Section 5.5.3.2)
- Evaluate and confirm potential dose-limiting toxicities
- Pause enrolment and/or request safety-related changes to the trial protocol.
5.5.1.
Dose-Limiting Toxicity
Toxicity is defined as dose-limiting toxicity if it meets the following criteria:
- Occurs within 6 hours after any dose for Parts A & B, or within 24 hours after 
any dose for Part C.
- and is considered by the Investigator to be possibly or probably related to 
treatment
- 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 
6.3.4.1)


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5.5.2.
Progression of dosing from sentinel subject to the rest of the 
dosing group (Part A)
The study design allows for sentinel dosing prior to dose administration to the rest of the 
cohorts, in part A of the study. Guidance is given below for progression of dosing 
following dosing of the sentinel subjects, in Part A. 
Sentinel subjects in Part A should be under constant supervision after dosing. If dose 
limiting toxicity develop at any other time than described in the guidance below, the 
Investigator should contact the sponsor at the earliest convenience on the day when the 
observation is made. 
Table 8
Guidance for progression criteria for sentinel subjects to the rest of 
dosing group A
Day of Dosing:
Action:
Observation:
Result:
On Day 1 of the dosing of 
the sentinel subject, at 6 
hours post-dose 
(immediately prior to the 
skin prick)
The Investigator will review 
the available safety data 
from this subject. 
If NO dose limiting 
toxicity is observed, 
the skin prick test may 
be conducted at the 
Investigator’s 
discretion, according 
to protocol, and 
dosing may proceed 
for the rest of the 
dosing group. 
The Investigator is 
required to document 
this decision and to 
inform the sponsor in 
writing at the earliest 
convenience. This 
time should not 
exceed 24 hours post 
dose . 
If dose limiting toxicity 
is observed, the PI or 
designee should 
immediately contact 
the medical monitor or 
designee (on the day 
they observe issues). 
GSK will then decide 
whether it is 
necessary for the 
SMC to be convened 
immediately or not, 
and will advise on 
dose progression or 
not. 
On Day 2 of the dosing of 
the sentinel subject, and at 
6 hours post-dose of Day 
1* of the rest of the 
subjects.
The Investigator reviews 
the available data of 
sentinel subject’s Day 1 
and Day 2
AND available data of 3 
subjects at least from the 
rest of the subjects’ Day 1 
up to that point.
If NO dose limiting 
toxicity is observed, 
the skin prick test may 
be conducted at the 
Investigator’s 
discretion, according 
to protocol, in the rest 
of the subjects.
Dosing may proceed 
with Day 3 of the 
sentinel subject, and 
Day 2 of the rest of 
the dosing group.
If dose limiting toxicity 
is observed, the 
Investigator or 
designee should 
immediately contact 
the medical monitor or 
designee (on the day 
they observe issues).
GSK will then decide 
whether it is 
necessary for the 
SMC to be convened 
immediately or not, 
and will advise on 


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Day of Dosing:
Action:
Observation:
Result:
The Investigator is 
required to document 
this decision and to 
inform the sponsor in 
writing at the earliest 
convenience.
dose progression or 
not.
On Day 3 of the dosing of 
the sentinel subject, and at 
6 hours post-dose of Day 
2* of the rest of the 
subjects.
The Investigator reviews 
the available data of 
sentinel subject’s Day 2 
and Day 3
AND available data of 3 
subjects at least from the 
rest of the subjects’ Day 2 
up to that point.
If NO dose limiting 
toxicity is observed, 
the skin prick test may 
be conducted at the 
Investigator’s 
discretion, according 
to protocol, in the rest 
of the subjects.
Dosing may proceed 
with Day 3 of the rest 
of the dosing group.
The Investigator is 
required to document 
this decision and to 
inform the sponsor in 
writing at the earliest 
convenience.
If dose limiting toxicity 
is observed, the 
Investigator or 
designee should 
immediately contact 
the medical monitor or 
designee (on the day 
they observe issues). 
GSK will then decide 
whether it is 
necessary for the 
SMC to be convened 
immediately or not, 
and will advise on 
dose progression or 
not.
* Assuming the sentinel subject is dosed 1 day before the rest of the subjects.
5.5.3.
Progression from dosing group 1 to dosing group 2 in Part A, 
and from Part A to Parts B and C
5.5.3.1.
Progression from dosing group 1 to dosing group 2 in Part A
At the end of dosing group 1 in Part A, the decision to proceed to the next higher strength 
and dose for dosing group 2 will be made by the SMC based on a safety report from the 
PI or designee, on the clinical safety, tolerability, up to and including the follow up visit, 
and pharmacokinetic exposure up to 24 hours after the last dose, in at least 6 subjects at 
the highest dose level. 
These dose adjustments may involve either an increase or a decrease in the planned dose 
in terms of strength of cream used (0.5% or 1%) and/or extent of body surface area and 
the decision on whether to dose once or twice daily in Parts B and C.
5.5.3.2.
Progression from Part A to Parts B and C
At the end of Part A, the decision to proceed to the dosing of patients in Parts B and C 
will be made by the SMC based on a safety report from the PI or designee on the clinical 
safety, tolerability, pharmacokinetic exposure and effect on systemic biomarker (CD69 
expression), of all subjects in Part A. A decision will also be made whether the data 
support progressing with females of child-bearing potential in Parts B and C of the study. 


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A decision may be made for the dose to take forward to Parts B and C only if data are 
available from dosing group 1 and dosing group 2 of Part A for at least 6 completed 
subjects in Group 2.  All the other data available for subjects who may not have 
completed the study should also be presented in the safety report from the PI or designee.
The actual doses to be administered may be adjusted based on safety, tolerability and 
preliminary pharmacokinetic data at previous dose levels; these dose adjustments may 
involve either an increase or a decrease in the planned dose.
The dosing schedule may also be adjusted to expand a dosing cohort to further evaluate 
safety, pharmacokinetic findings at a given dose level, or to add cohorts to evaluate up to 
1% strength and up to 20% BSA.  The study procedures for these additional subject(s) or 
cohort(s) will be the same as that described for other study subjects.
5.5.3.3.
Progression in Part B and from Part B to Part C
In Parts B, the first 4 subjects will be randomised so that one of the 4 subjects will 
receive placebo and the three other subjects will receive GSK2646264. An interim review 
of the preliminary data from the first 4 subjects, after they have completed the study, will 
be conducted before dosing the rest of the patients in Part B (n=12 total).  Preliminary 
PK, safety, and tolerability data up to and including the follow-up visit, will be reviewed 
by the SMC (See Section 5.5). In addition, further modeling of PK parameters after 3 
days of dosing in these first 4 cold urticaria patients focusing on the elimination of the 
compound, will be performed to aid the decision to move forward to  the rest of the 
subjects in Part B and to Part C, taking into account the pre-determined safety margins 
(See Appendix 6). 
5.5.3.4.
Progression within Part C
Dosing in Part C will only commence once relevant data from the first four subjects in 
Part B have been reviewed, (see Section 5.5.3.3) to allow greater confidence in 
predictions of the pharmacokinetics in Part C. The BSA over which study treatment will 
be administered in Part C is anticipated to be 10%, but is subject to change if appropriate 
based on preliminary data from Part B. However, the maximum BSA will not exceed 
20%.
The first four subjects of Part C will be randomised so that one of the four subjects will 
receive placebo and the three other subjects will receive GSK2646264. An informal 
review of the preliminary data from the first 4 subjects may be conducted after they have 
completed the study. PK, safety and tolerability data up to and including the follow-up 
visit, will be reviewed by the Sponsor. If required, a discussion with the SMC regarding 
any changes or adjustments to the dosing regimen in Part C will be held. Recruitment of 
the full planned cohort (n=16) may continue during any data review. The dosing regimen 
or study population may be adjusted as appropriate after this interim review for the rest of 
the subjects in Part C..


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5.6.
Safety Related Study Specific Dose Adjustment Criteria
If AEs which are of severe intensity and are similar across subjects in the group, or if 
unacceptable pharmacological effects, reasonably attributable in the opinion of the 
investigator to dosing with GSK2646264, or if dose limiting toxicity (see Section 5.5.1), 
are observed in 2 or more subjects in dosing group 1 or dosing group 2 of part A, the dose 
escalation will be stopped. Relevant reporting and discussion with the GSK medical 
monitor and the SMC will take place.  A substantial amendment will be submitted to the 
Ethics committees and Regulatory authorities for approval prior to any resumption of 
dosing. 
If AEs which are of severe intensity and are similar across subjects in either Part B or C, 
or if unacceptable pharmacological effects, reasonably attributable in the opinion of the 
investigator to dosing with GSK2646264, or if dose limiting toxicity (see Section 5.5.1), 
are observed in 2 or more subjects in either Part B or C, relevant reporting and discussion 
with the GSK medical monitor and the SMC will take place.
If a Serious Adverse Event (SAE) occurs in 1 subject and is deemed to be drug related, 
the dose escalation in Part A, or the study if in Part B or Part C,will be stopped. Relevant 
reporting and discussion with the GSK medical monitor and the SMC will take place.  A 
substantial amendment will be submitted to the Ethics committees and Regulatory 
authorities for approval prior to any resumption of dosing.
The above criteria will apply regardless of whether pharmacokinetics are less than the 
above mentioned PK stopping criteria and every effort will be made to take a blood 
sample at the time of the event for pharmacokinetics analysis in the presence of any of 
the above events.
5.7.
Stopping Criteria for a subject
5.7.1.
Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event aetiology (in alignment with the FDA premarketing clinical 
liver safety guidance). 
Study treatment will be stopped for a subject if the following liver chemistry stopping 
criteria is met: 

ALT 3xULN
NOTE: Refer to Appendix 1 for details of the required assessments if a subject meets the 
above criteria.
5.7.2.
QTcF Withdrawal 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.


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
QTcF > 500 msec,

Change from baseline: QTcF >60 msec
If a subject in Part B or Part C has underlying bundle branch block the following 
withdrawal criteria should be used instead:
Baseline QTcF value (with 
underlying bundle branch 
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
5.7.3.
Safety related Stopping criteria for an individual subject
A subject may be withdrawn from the study if they present dose limiting toxicity (as 
defined in Section 5.5.1; also refer to tolerability assessment definition in Section 
6.3.4.1.). If dose limiting toxicity is observed in an individual, the Investigator or 
designee may use their medical judgment and 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 SMC to be convened immediately or not, for review 
of the data and decision on dose adjustment or withdrawal of the individual subject.
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 listed in Section 
5.15.
Dosing to an individual may be stopped due to unacceptable local tolerability as 
evidenced by dose limiting toxicity (as defined in Section 5.5.1).
Tolerability assessments on treated skin areas will be made using the criteria in Section 
6.3.4.1.  
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.
5.8.
Dose Adjustment/Stopping Pharmacokinetic Criteria
Available pharmacokinetic, safety and tolerability data for at least 6 subjects in Part A, 
and 4 subjects in Part B following administration of each dose will be reviewed prior to 
progressing to the subsequent dose group or cohort in the study as described in Section 
5.5.2 and Section 5.5.3. The decision to proceed will be made by the Principal 
Investigator/ Physician designee together with the Medical monitor following discussion 


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at the SMC. If deemed necessary at any time, the dose escalation will be temporarily 
halted and no further subject will be dosed  and/or the planned number of doses of study 
medication received by a subject and/or amount of dose applied may be adjusted as 
appropriate to be lower or higher than currently proposed. 
After the first 4 subjects in Part C, available pharmacokinetic data may be reviewed by 
the sponsor (see Section 5.5.3.4). If required, a discussion with the SMC regarding any 
changes or adjustments to the dosing regimen in Part C will be held.
5.8.1.
Adjusting dose/ stopping dose escalation
If (cohort’s average) predicted or observed Cmaxor AUC(0-24 h after last dose)of GSK264624 is 
greater than 16 ng/mL or 220 ng.hr/mL, respectively, doses for subsequent cohorts may 
be adjusted based on tox cover and will need to be decided by the SMC but will not 
exceed agreed margins.
5.9.
Blinding
This will be a randomised double blind (sponsor unblinded), single, bilateral (Part A) and 
parallel (Parts B and C) repeat ascending dose First Time in Human study in healthy 
subjects, cold urticaria and chronic spontaneous urticaria subjects study. 
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 contact the GSK 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 
appropriate data collection tool.
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the eCRF.
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 clinical investigators in 
accordance with local regulations and/or GSK policy.
5.10.
Packaging and Labelling
The contents of the label and the packaging will be in accordance with all applicable 
regulatory requirements.


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5.11.
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 SPM. All bottles are for 
single use only.
5.11.1.
Part A and Part B
Study treatment must be dispensed or administered according to procedures described 
herein. Only subjects enrolled in the study may receive study treatment.  Only authorised 
site staff may supply or administer study treatment.  All study treatment must be stored in 
a secure area with access limited to the investigator and authorized site staff.  Study 
treatment is to be stored at 2-8C and protected from light.  Maintenance of a temperature 
log (manual or automated) is required.
5.11.2.
Part C
Study treatment must be dispensed or administered according to procedures described 
herein. Only subjects enrolled in the study may receive study treatment.  Only authorised 
site staff may supply or administer study treatment. .  All study treatment must be stored 
in a secure area with access limited to authorized staff.  Study treatment is to be stored at 
2-8C and protected from light. Maintenance of a temperature log (manual or automated) 
is required.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance.  
The investigator or the head of the medical institution (where applicable), or designated 
site staff (e.g., storage manager, where applicable) must maintain study treatment 
accountability records throughout the course of the study.  The responsible person(s) will 
document the amount of study treatment received from and returned to GSK and the 
amount supplied and/or administered to and/or returned by subjects.  The required 
accountability unit for this study will be a bottle.  Discrepancies are to be reconciled or 
resolved.  Procedures for final disposition of unused study treatment are listed in the 
SPM.
Investigational product is not expected to pose significant occupational safety risk to site 
staff under normal conditions of use and administration.  Gloves should be used during 
the application of this product to the body. Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists. In the case of unintentional 
occupational exposure notify the monitor, medical monitor and/or study manager.  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.
Precaution will be taken to avoid direct contact with the investigational product.  A 
Material Safety Data Sheet (MSDS) describing occupational hazards and recommended 
handling precautions will be provided to the investigator for the API (GSK2646264).


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The formulation used in this study has been developed specifically for assessment in the 
FTIH and is unlikely to be the final formulation. 
5.12.
Assessment of Compliance
When subjects are dosed at the study unit, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and start and end times 
of each dose administration in the clinic will be recorded in the source documents and 
transcribed into the InForm eCRF.  The dose of study treatment and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study treatment.  
5.13.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2646264 that is above that 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.
5.14.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because OR 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.
5.15.
Concomitant Medications and Non-Drug Therapies
Concomitant medication must be recorded (as detailed in the SPM).
5.15.1.
Permitted Medications
5.15.1.1.
Parts A, B and C
Paracetamol, at doses of up to 2 grams/day is permitted for use any time during the study. 
5.15.1.2.
Part C only
Any non-sedating, short-acting antihistamine at licensed dose is permitted for use as 
rescue medication any time during the study.
Other concomitant medication may be considered on a case by case basis by the 
investigator in consultation with the GSK Medical monitor if required.


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5.15.2.
Prohibited Medications and Non-Drug Therapies
Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a 
potential enzyme inducer), or 5 half-lives (whichever is longer or as specified in the 
inclusion / exclusion Section 4.1), or as indicated for specific medications, from 
screening until completion of the follow-up visit, unless in the opinion of the Investigator 
and sponsor if required, the medication will not interfere with the study, in which case the 
investigator is required to document the rationale for their opinion.  
Table 9
List of Prohibited Medications and Non-Drug Therapies
Medication
Examples
Use of anticoagulants 
e.g. warfarin
Use of systemic 
immunosupressants/immunomodulators 
e.g.ciclosporin A, dapsone, methotrexate, 
mycophenolate, chloroquine, and comparable 
drugs
Use of oral, depot, or topical corticosteroids 
e.g. prednisolone
Use of topical calcinurin inhibitors
e.g. tacrolimus, pimecrolimus
Use of tricyclic antidepressants with 
antihistaminergic properties
e.g. doxepin
Use of UV therapy 
including PUVA.
Use of Ketotifen, 
Use of H2 antihistamines 
e.g. ranitidine, cimetadine
Use of Leukotriene antagonists 
e.g. montelukast
Part A and Part B only:
e.g. cetirizine, loratadine
Use of H1 antihistamines 
Part C
Use of H1 antihistamines above the licensed dose
e.g. cetirizine, loratadine


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6.
STUDY ASSESSMENTS AND PROCEDURES
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 6.1. 
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, 
blood draws.  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 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 500 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 conditions or 
reactions which may occur during the study.


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6.1.
Time and Events Table
6.1.1.
Part A: Healthy Volunteer Time and Event Table Dose group 1
Day:
Screening
-1
1
2
3
4
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 5 to Day 7 
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without shoes
X
Brief physical
X
Medical/medication/drug/
alcohol history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and 
CV risk factors questionnaire
Vital signs
X
X
X
X
X
X
X
Urine drug/alcohol screen
X
X
HIV, Hep B and Hep C screen
X
Clinical Laboratory Tests
X
X
X
X
Allergen Challenge-
Skin Prick Test
X2,3
X2,4
X2,4
X5
2. SPT- Skin Prick Test analysis will 
be performed at ~15-20mins post 
challenge. 
3. SPT with all 4 specified allergens
4. SPT using one allergen will be 
performed 6 hours post dose (see 
Section 6.4.1)
5. SPT using one allergen will be 
performed 24 hrs after the last dose
TSH6
X
6. TSH test only at screening only
Randomisation
X


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Day:
Screening
-1
1
2
3
4
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 5 to Day 7 
Tolerability Assessment
  X7   --------------------------------------
7. Tolerability assessment at pre –
and ~6 hours post-dose
AE assessment 
X
-------------------------------------
X
Concomitant Medication
X
---------------------------------------
X
Pharmacokinetic 
Blood Sample8
X
X
X
X9
8.PK blood sample taken at pre 
dose, 1 ,2, 4, 8, 12 and 24hr post 
dose 
9.PK refers to sample 24 hours post 
dose
Study Treatment Dosing
X
X
X
Discharge from unit
X
Outpatient visit
X
X


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6.1.2.
Part A: Healthy Volunteer Time and Event Table Dose group 2
Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 9 – Day 
11 
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without shoes
X
Brief physical
X
Medical/medication/drug
/alcohol history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and 
CV risk factors 
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Urine drug/alcohol screen
X
X
Urine for metabolite analysis
X10
X22
10. Pre dose and pool samples 
taken 0-12 and 12-24 hours post 
dose 
22. Pool samples taken 0-12 and 
12-24 hours post
HIV, Hep B and Hep C screen
X
Clinical Laboratory Tests
X17
X17
X9
X9
X17
X17
X17
9. Pre-dose AST, ALT, Alkaline 
Phosphatase, Total Bilirubin Only- : 
results to be communicated to the 
GSK Medical monitor on the same 
day  
17.Clinical lab test as per Section 
6.3.4 of the protocol 


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Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 9 – Day 
11 
Allergen Challenge-
Skin Prick Test
X3,4
X3,5
X3,5
X3,5
X 3,7
3. SPT- Skin Prick Test 
measurements will be performed 
~15-20 mins post challenge. 
4. SPT with all 4 specified allergens
5. SPT will be performed 6 hours 
post dose
7. SPT will be performed 48 hours 
post dose of Day 4 (on the morning 
of Day 6)
TSH2
X
2. TSH test only at screening only
Randomisation
X
Tolerability Assessment
X11  ---------------------
        only on dosing days 1 to 4
11. Tolerability assessment at pre –
and ~6 hours post-dose on dosing 
days
AE assessment 
X
----------------------------------------------------
X
Concomitant Medication
X
----------------------------------------------------
X
Pharmacokinetic 
Blood Sample
X6
X6
X6
X6
X18
X19
X20
X21
6. PK blood sample taken at pre 
dose, 1, 2, 4, 8, 12 and 24hours 
post previous dose 
18. PK blood sample taken at 30, 
36, 48 hours, post dose of Day 4
19. PK blood sample taken at 54, 
60, 72 hours, post dose of Day 4
20. PK blood sample taken at 78, 
84 hours post dose of Day 4
21. PK blood sample taken at 96 
hours post dose of Day 4


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Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 9 – Day 
11 
Blood Sample for CD69 
expression
X12
X13
X14
X15
X16
12. Predose
13. 4 hours post dose of Day 4 
14. 24 hours post dose of Day 4 
(sample taken in the morning of day 
5) 
15. 72 hours post dose of Day 4
16. 96 hours post dose of Day 4
Study Treatment Dosing8
X
X
X
X
8.  This will be once daily dosing 
using fresh bottles at 1% strength in 
the morning
Discharge from unit
X
Outpatient visit
X
X


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6.1.3.
Part B: Cold urticaria Subjects Time and Event table
Day:
Screening
-1
1
2
3
4
Day 6 
to 15
Follow-up 
(Day 17-19)
Notes
Visit Window  (relative 
to Day 1)
-28 to -7   
days1
1. Screening can occur on any day between 28 days and 7 days prior to 
Day 1 dosing.
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without 
shoes
X
Brief physical
X
Medical/medication/
X
drug/alcohol history
12-lead ECG
X2
X
X
X
2. Triplicate ECG at screening and CV risk factors 
Vital signs3
X
X
X
X
X
X
X
3.  Should be performed at the same time points as PK samples are taken
Urine drug/alcohol 
screen
X
X
Pregnancy Test 
(women)4
X(S)
X(S/U)
X (S)
X(S)
4. Pregnancy test will be performed 3 times during screening, serum on 
day -28, day -7 to -4, and a serum or urine pregnancy test the day of the 
start of the study prior to dosing and a serum pregnancy test  between day 
10-12 (to coincide with a PK sample) and at the follow up visit. 
HIV, Hep B and Hep C 
screen
X
Clinical Laboratory 
Tests
X
X
X
X


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Day:
Screening
-1
1
2
3
4
Day 6 
to 15
Follow-up 
(Day 17-19)
Notes
Allergen Challenge-
SPT
X5,6
X5,8
X5,7
X5
5. SPT- Skin Prick Test measurements will be performed ~15-20mins post 
challenge
6. SPT using all 4 specified allergens
7. SPT will be performed at  6 hours post dose (see Section 6.4.1), and at 
24 hours post last dose on day 3
8. SPT will be performed pre-dose on Day 1
TSH, free T4, T4, T3
X
x
X9
x
9. One sample between  day 10-12 to coincide with PK sample
Cold Temp Test (Temp 
Test 4.0)
X
X10
X11
X12
10. Pre-dose
11. 6 hours post dose
12. 24 hours post last dose on Day 3
Randomisation
X
Tolerability 
Assessment
------X13-----
13. Tolerability assessment at pre – and ~6 hours post-dose
AE assessment 
------------------X--------------------
X
Concomitant 
Medication
X
---------------X--------------
X
Pharmacokinetic Blood 
Sample
X14
X14
X14
X15
X16
X
14.  PK blood sample taken at pre dose,1, 4, 8, 12hr post dose 
15. One PK sample to be taken 24 hours post last dose on Day 3
16. One PK blood sample per day will be taken as follows:. PK samples 
will be obtained on the following days (± 1 day): Day 6, 9, 12, & 15. 
Study Treatment 
Dosing
X
X
X
Discharge from unit
X
Outpatient visit
X
X
X
Blood Sample for CD69 
expression
X17
X18
X19
X19
17. Pre-dose
18. 4 hrs post-dose
19. Sample collection should coincide with PK sample collection.


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6.1.4.
Part C: Chronic Spontaneous Urticaria Cohort
Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
Visit Window 
(relative to Day 1)
-28 to -71
1. Screening can occur on any 
day between 28 days and 7 days 
prior to Day 1 dosing.
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) 
without shoes
X
Brief physical
X
Medical/medicatio
n/drug/alcohol 
history
X
12-lead ECG
X2
X
X
X
2. Triplicate ECG at screening and 
CV risk factors 
Vital signs
X
X
X
X
X3
X3
X3
3. To be performed on same day as 
PK samples 
Urine alcohol 
screen
X
X
Pregnancy Test 
(Women of child 
bearing potential)4
X(S)4
X (U)5
X(U)5
X (S)
X(S)
4. A serum (S) pregnancy test will be 
performed on the day of screening.  
If the day of screening is between 
Days -13 and -7, a further pregnancy 
test will not be required until Day 1. 
However, if the day of screening is 
between Days -28 and -14, an 
additional serum pregnancy test will 
be required between Days -7 and -4. 


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Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
5. A urine pregnancy test is required 
prior to dosing on Day 1 & Day 7
HIV, Hep B and 
Hep C screen
X
Clinical Laboratory 
Tests
X
X
X
X
TSH, free T4, T4, 
T3
X
X
X6
X6
X6
6. Sample to be taken on same day 
as PK sample 
Blood Sample for 
CD69 expression
X7
X8
X8
X9
X9
X9
7. Pre-dose
8.  4 hours post dose
9. Sample to be taken on same day 
as PK sample 
Randomisation
X
UAS-7 Diary
X10
X11
X11
X11
X11
X11
X11
X
10. Screening UAS7 diary will be 
completed for the 7 successive days 
before Randomisation (Day 1). If 
there is a lapse in any day prior to 
Day 1 the subject must complete the 
full 7 days worth of diary entries 
again during the screening period.
11.  The UAS-7 diary should be 
completed pre-dose on those days 
where dosing occurs 
QOL (DLQI)
X
X12
X
12.  The baseline DLQI assessment 
on Day 1, looking back over the 
previous 7 days prior to dosing, 
should be completed pre-dose


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Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
AAS
X13
X14
X14
X14
X14
X14
X14
X
13. Screening AAS will be completed 
for the 7 successive days before 
Randomisation (Day 1) (on the same 
days as the UAS7). If there is a 
lapse in any day prior to Day 1 the 
subject must complete the full 7 days 
worth of diary entries again during 
the screening period.
14.  The AAS assessment should be 
completed pre-dose on those days 
where dosing occurs
AE assessment
------------------------------------------------X--------------------------------------------
x
Tolerability 
Assessment at 
pre-dose
X15
X15
X15
15. Tolerability assessment at 1 to 2 
hours post-dose
BHR- Basophil 
Histamine Release 
Test  
X16
16. Two samples to be taken pre-
dose 
Pharmacokinetic 
Blood Sample
X17
X17
X17
X18
X18
X18
17. PK blood sample taken at pre-
dose and 4hr post dose
18.  Sample to be taken on same 
day as CD69 sample, TSH, free T4, 
T4, T3 samples and vital signs
Study Treatment 
Dosing
X
X
X
Con Meds 
------------------------------------------------X--------------------------------------------
X
Outpatient visit
X
X
X
X
x
X
X


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6.2.
Demographic/Medical History Assessments
The following demographic parameters will be captured: year of birth, gender, race and 
ethnicity.
Medical/medication/alcohol history will be assessed as related to the eligibility criteria 
listed in Section 4.2.  Cardiovascular medical history/risk factors including height, 
weight, blood pressure, smoking history, medical conditions will also be assessed at 
baseline.
6.3.
Safety
Planned timepoints for all safety assessments are listed in the Time and Events Table 
(Section 6.1).  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. This would not constitute a 
protocol amendment.
6.3.1.
Physical Exams

A complete physical examination will include assessments of the head, eyes, ears, 
nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and 
spleen), lymph nodes and extremities.  Height and weight will also be measured and 
recorded.

A brief physical examination will include assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
6.3.2.
Vital Signs

Vital sign measurements to be measured in semi-supine position after 10 minutes 
rest will include systolic and diastolic blood pressure and pulse rate. 
6.3.3.
Electrocardiogram (ECG)

Triplicate 12-lead ECGs will be obtained at screening and then during the study 
single ECGs will be taken. At each time point during the study ECG will be taken 
using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTcF intervals.  Refer to Section 5.7.2 for QTcF withdrawal criteria 
and additional QTcF readings that may be necessary.

A CV risk factors questionnaire will also be completed at screening
6.3.4.
Clinical Laboratory Assessments
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below.  Details for the preparation and shipment of samples will be provided by the 
local laboratory. Reference ranges for all safety parameters will be provided to the site 
by the laboratory.


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If additional non-protocol specified laboratory assessments are performed at the site’s 
local laboratory and result in a change in subject management or are considered clinical 
significant by the Investigator (for example SAE or AE or dose modification) the results 
must be captured and sent to GSK along with other study data as defined in  Section 7
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below:
Haematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Hemoglobin
MCHC
Monocytes
Hematocrit
Eosinophils
Basophils
Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Albumin
Glucose, (fasting 
at screening only)
Calcium
GGT
Total Protein
Sodium
Phosphate
Alkaline phosphatase
TSH , free T4, T4, 
T3
NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are 
given in Section 5.7.1.
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 -- if second generation Hepatitis C antibody positive, a hepatitis C 
antibody Chiron RIBA immunoblot assay (or other third generation immunoassay) should be 
reflexively performed on the same sample to confirm the result) 
FSH and estradiol (as needed in women of non-child bearing potential only)
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines).


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6.3.4.1.
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 patch site
H = small petechial erosions and/or scabs
6.4.
Study Assessments
6.4.1.
Skin Prick Test (SPT)
At screening a solution of each allergen (mixed grass pollen, Dermatophagoides 
pteronyssinus, birch pollen and cat dander along with the positive and negative 
controls) will be applied to the volar aspect of the subjects forearm using the skin prick 
method as described in The Global Allergy and Asthma European Network (GA2LEN) 
guidelines (Heinzerling, 2013). The skin prick method involves placing a drop of 
histamine or allergen solution onto the skin and using a lancet to gently pierce the 
superficial layer of the skin. The excess histamine or allergen solution is then wiped 
away. Study assessment will commence 15-20 mins after the skin has been pricked. 
During the dosing period only one allergen positive at screening and the positive control 
will be used as described in the SPM.


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6.4.2.
TempTest
The Temptest otherwise known as the cold stimulation test is an electronic testing device 
consisting of metallic cooling elements that can maintain a precise pre-set temperature 
from below 5◦C to above 40◦C. The device will be applied for a short period of time to the 
forearm or leg of the subject. This allows the determination of whether Cold urticaria  is 
present and the evaluation of the Cold Temperature Test values including critical 
temperature thresholds.
6.4.3.
Blood and Urine Sample Collection
6.4.3.1.
PK samples
Blood samples for pharmacokinetic analysis of GSK2646264 will be collected at the time 
points indicated in Section 6.1, Time and Events Table. The actual date and time of each 
blood sample collection will be recorded. The timing of PK samples may be altered 
and/or PK samples may be obtained at additional time points to ensure thorough PK 
monitoring.
Details of PK sample collection (including volume to be collected), processing, storage, 
and shipping procedures are provided in the SPM.
6.4.3.2.
Systemic biomarker samples
Blood samples to identify the effect of GSK2646264 on anti-IgM stimulated CD69 (and 
potentially other biomarkers of interest) will be collected at the time points indicated in 
Section 6.1, Time and Events Table. This assay was used to define the systemic 
concentration expected to inhibit SYK activity (MABEL) as detailed in Section 3.2. The 
timing of samples may be altered and/or samples may be obtained at additional time 
points depending on the PK data obtained.
Blood samples to test for donor basophil histamine release in-vitro will be taken in Part C 
at the time points indicated in Section 6.1, Time and Events Table.
Details of biomarker sample collection (including volume to be collected), processing, 
storage, and shipping procedures are provided in the SPM.
6.4.3.3.
Urine Sample Collection
Urine samples will be collected for analysis of any metabolite(s) from subjects in Part A, 
Group 2 at predose, and dosing Days 1 and 7   Results will be reported under a separate 
DMPK protocol.
Following review of PK in dose group 1 urine samples were collected for analysis of any 
metabolite(s) from subjects in Part A, Group 2 at predose, and dosing Days 1 and 4.
Details of urine sample collection (including volume to be collected), processing, storage, 
and shipping procedures are provided in the Study Procedures Manual (SPM).).


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6.4.4.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the Study Procedures Manual.
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 SPM).
Once the plasma has been analysed for GSK2646264 any remaining plasma and urine 
may be analysed for other compound-related metabolites and the results reported under a 
separate PTS-DMPK, GlaxoSmithKline protocol.
6.5.
Pharmacodynamic Measures
6.5.1.
Part A & B
The following PD measures will be assessed:

Longest weal diameter (measured by ruler).

Perpendicular weal length (measured by ruler).

Weal area (calculated using ellipse shape).

Weal volume (measured by quantitative volumetric morphometry) 

Flare erythema (measured by Mexameter).
For Part B only, the following PD measure will be assessed

Change in critical temperature thresholds..
6.5.2.
Part C
6.5.2.1.
Urticaria Activity Score (UAS7)
For the chronic spontaneous urticaria subjects in Part C, Urticaria activity score (UAS7), 
a composite endpoint, will be derived using key urticaria symptoms (number of weal, 
itch/pruritus):
UAS7 components will be captured using a daily diary for 7 days.  The daily UAS7 score 
will be the sum of each key component score. A detail of UAS7 daily diary is provided in 
Appendix 3.  The days on which to record in the UAS7 diary are captured in the T&E 
Table (Section 6.1.4).  On days where dosing occurs, the UAS7 diary will be completed 
pre-dose.
6.5.2.2.
The Angioedema Activity Score (AAS)
For the chronic spontaneous urticaria subjects in Part C, the Angioedema Activity Score 
(AAS) will be captured during Screening, and between Day 2 and Day 8.  Details of the 
questionnaire are provided in Appendix 7. The days on which to record the AAS are 


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captured in the T&E Table (Section 6.1.4).  On days where dosing occurs, the AAS will 
be completed pre-dose.
6.6.
Health Outcomes
6.6.1.
Dermatology Life Quality Index
For the chronic spontaneous urticaria subjects in Part C,  the health outcome measure of 
Quality of Life will be captured at Screening,  Baseline and Day 8, using a 10-item 
Dermatology Life Quality Index (DLQI) (Finlay, 1994) questionnaire.  An overall score 
will be calculated as well as the following domains: Symptoms and Feelings, Daily 
Activities, Leisure, Work and School, Personal Relationships, and Treatment. A detail of 
questionnaire is provided in Appendix 4.  The days on which to record the DLQI are 
captured in the T&E Table (Section 6.1.4).  On days where dosing occurs (Day 1 only), it 
will be completed pre-dose.
7.
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, 
PREGNANCY AND MEDICAL DEVICE INCIDENTS
7.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
7.1.1.
Time period for collecting AE and SAE information
AEs will be collected from the start of study treatment and until the follow-up contact (as 
detailed in the SPM).  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 CRF.
SAEs will be collected over the same time period as stated above for AEs.  However, 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.  All SAEs will be recorded and reported to GSK within 24 hours, as 
indicated in Appendix 2.
7.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” “Have you had any (other) medical problems since your last 
visit/contact?” “Have you taken any new medicines, other than those provided in this 
study, since your last visit/contact?” 


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7.1.3.
Definition of Adverse Events
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 the definition of an AE 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.).

When skin tolerability is assessed, a “dermal scoring” of 2 or above, and a score of 
C, F, G or H in “other effects scoring (ii)”, will be reported as adverse event.
Events that do not meet the definition of an AE include:

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.


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7.1.4.
Definition of Serious Adverse Events
If an event is not an AE per Section 7.1.3, 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).
An SAE is 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 fulfils any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
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, diarrhoea, 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.
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. 


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* 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 Appendix 1 for the required liver chemistry follow-up instructions.
7.1.5.
Cardiovascular Events
Investigators or designees will be required to fill out event specific data collection tools 
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 thrombosis

Deep Venous Thrombosis

Revascularization
This information should be recorded within one week of when the AE/SAE(s) are first 
reported.
7.1.6.
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and non-
cardiovascular death.
This information should be recorded within one week of when the death is first reported.
7.1.7.
Prompt Reporting of SAEs to GSK
Once the investigator determines that an event meets the protocol definition of an SAE, 
the SAE will be reported to GSK within 24 hours.  Any follow-up information on a 
previously reported SAE will also be reported to GSK within 24 hours.
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying GSK of the event and completing the 


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appropriate data collection tool.  The investigator will always provide an assessment of 
causality at the time of the initial report as described in Appendix 2.
7.1.8.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects 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 
regulatory authorities, IRBs/IECs 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 an SAE(s) or other specific safety information (e.g., summary or listing of 
SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
7.2.
Pregnancy
7.2.1.
Time period for collecting pregnancy information
All pregnancies in female subjects and/or female partners of male subjects will be 
collected after the start of dosing and until follow up.
7.2.2.
Action to be taken if pregnancy occurs
The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  The investigator will record pregnancy 
information on the appropriate form and submit it to GSK within 2 weeks of learning of a 
subject's pregnancy.  The subject will also be followed to determine the outcome of the 
pregnancy.  Information on the status of the mother and child will be forwarded to GSK.  
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.  Any premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK as 
described in Section 7.1.7. 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.


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Any female subject who becomes pregnant while participating will discontinue study 
medication and be withdrawn from the study.
7.2.3.
Action to be taken if pregnancy occurs in a female partner of a 
male study subject
The investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This applies 
only to subjects who are randomized to receive study medication. After obtaining the 
necessary written informed consent from the female partner directly, the investigator will 
record pregnancy information on the appropriate form and submit it to GSK within 2 
weeks of learning of the partner’s pregnancy.  The partner will also be followed to 
determine the outcome of the pregnancy.  Information on the status of the mother and 
child will be forwarded to GSK.  Generally, follow-up will be no longer than 6 to 8 
weeks following the estimated delivery date.  Any premature termination of the 
pregnancy will be reported.
8.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined electronic case report forms 
(eCRFs), transmitted electronically to GSK and combined with data provided from other 
sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA (Medical Dictionary for Regulatory Activities) and 
an internal validated medication dictionary, GSKDrug. eCRFs (including queries and 
audit trails) will be retained by GSK, and copies will be sent to the investigator to 
maintain as the investigator copy.  Subject initials will not be collected or transmitted to 
GSK according to GSK policy.
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
9.1.
Hypotheses and Treatment Comparisons
The primary focus of the statistical analysis is to describe safety and characterize the 
preliminary pharmacokinetics of GSK2646264 through estimates of parameters and their 
variability. Thus, an estimation approach will be taken to provide a plausible range of 
values, where appropriate, with no formal hypothesis testing.
9.1.1.
Precision Estimation
This study is designed to estimate the effect of GSK2646264 relative to Placebo on 
comparison of interest.  No formal hypothesis will be tested.  Point estimates and 
corresponding 95% confidence intervals will be constructed. 


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9.2.
Sample Size Considerations & Statistical Analyses
There are no formal hypotheses to be tested. An estimation approach will be taken and 
95% confidence intervals will be constructed to provide a range of plausible values for 
the comparisons of interest.
Approximately  42 subjects will be  randomised in total, consisting of 18 subjects in Part 
A (9 subjects on first dose group and 9 subjects in second dose group), 12 subjects in Part 
B and 16 subjects in Part C of the study.  The sample size is based on feasibility and not 
driven by any formal hypothesis testing.
9.2.1.
Sample Size Sensitivity
For Part A, based on a sample size of 9 randomised subjects, it is estimated that the 95% 
confidence interval for the percent of inhibition effect will be within 18.5% of the 
estimate for the weal size assuming standard deviation of 24, within 8.5% of the estimate 
for the flare size assuming standard deviation of 11 and within 17.7% of the estimate for 
the weal volume assuming standard deviation of 23 (Schoepke, 2011).
Table 10
Results of the sensitivity analyses for part A
Percent of Inhibition Weal 
Size
Percent of Inhibition Flare 
Size
Percent of Inhibition Weal Volume
N
Precision 
around 
estimate
SD
Precision 
around 
estimate
SD
Precision 
around 
estimate
SD
9
15.4
20
6.9
9
15.4
20
9
16.9
22
7.7
10
16.1
21
9
18.5
24
8.5
11
17.7
23
9
20.0
26
10
13
19.2
25
9
21.5
28
11.5
15
20.8
27
9.2.2.
Sample Size Re-estimation
No sample size re-estimation will be performed.
No sample size re-estimation is currently planned for this study. However, if during the 
course of the study, new information becomes available about clinically meaningful 
differences or variability estimates, a blinded sample size re-estimation may be 
conducted. Full details of the procedure used would be specified in the RAP, and any 
subsequent change to the target sample size would be documented in a protocol 
amendment.


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9.3.
Data Analysis Considerations
9.3.1.
Interim Analysis
No formal interim analyses are planned. 
9.3.1.1.
Summary of safety reporting from Part A
A summary of the safety data from Part A will be performed once all subjects are 
recruited and completed all visits. This summary will include PK and PD data from Part 
A of study cohort. All safety data including adverse events, laboratory tests, ECGs and 
vital signs will be reviewed.  The decision to proceed to higher dose strengths will be 
made by the investigator and the GSK SMC review team based on assessment of safety 
and pharmacokinetic data of the studied doses.
9.3.1.2.
Summary of exposure and safety reporting from Part B: first 4 subjects
The safety, tolerability, and preliminary exposure data from Part B (first 4 subjects) will 
be reviewed by the SMC once those subjects have completed the study up to and 
including the follow-up visit. The decision for the dosing regimen and study population 
for the remainder of Part B, and Part C will be made by the SMC review based on 
assessment of safety, and pharmacokinetic data of the studied doses.
This study is double blind (sponsor open), where the subject, investigator and site staff 
will remain blinded to the treatment allocation.
9.3.1.3.
Summary of exposure and safety reporting from Part C: first 4 subjects
Preliminary safety and tolerability, and potentially biomarkers of interest), and 
preliminary exposure data from Part C (first 4 subjects) may be reviewed by the sponsor 
once those subjects have completed the study up to and including the follow-up visit. The 
decision for the potential adjustment of the dosing regimen and/or study population for 
the rest of Part C will be made by the sponsor review based on assessment of safety and 
pharmacokinetic data of the studied doses. If required, a discussion with the SMC 
regarding any changes or adjustments to the dosing regimen in Part C will be held.
Other experts from CPMS and DMPK, at GSK, may be consulted to review blinded 
placebo/active data (safety, PK and any available PD) during the study for further 
relevant input.  In-stream review of the data may also take place at any time at SRT 
(Safety Review Team) meetings. 
9.3.2.
Final Analyses
9.3.2.1.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s standards.
No formal statistical analysis of the safety data will be conducted.  The following safety 
assessments will be listed and summarized where appropriate: extent of systemic 


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exposure, local skin reactions, adverse events, clinical laboratory evaluations, concurrent 
medications, vital signs, ECG interval data, and other relevant safety assessments.  
Adverse events, local skin reaction assessments, and liver chemistry will be summarized 
by doses strength (where possible) and BSA.
9.3.2.2.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modelling and Simulation Department, CPMS, GlaxoSmithKline and Parexel.  Plasma 
concentration-time data will be recorded in tabular and/or graphical form.  From 
GSK2646264 concentration-time data, the following pharmacokinetic parameters will be 
determined using the currently approved and validated software, as data permit:  
maximum plasma concentration (Cmax); time of maximum plasma concentration (Tmax); 
area under the plasma concentration-time curve (AUC) and apparent terminal elimination 
half-life (t1/2), if data permit.
Pharmacokinetic data will be presented in graphical and/or tabular form and descriptively 
summarized.  Pharmacokinetic data will be stored in the Archive, GlaxoSmithKline.
9.3.2.3.
Pharmacodynamic/Biomarker Analyses
9.3.2.3.1.
Part A & B: Healthy and Cold urticaria Subjects
Raw data and percent of inhibition for each PD parameter (i.e. longest weal diameter, 
perpendicular weal length, weal area, weal volume, and flare erythema assessments) will 
be provided by strength, BSA, and day.  Descriptive summary statistics (i.e. n, minimum, 
arithmetic mean, standard error, median, maximum) for both raw and percent of 
inhibition for Part B will be calculated by dose strength, BSA, and day. Additionally, 
figures will be produced for PD parameters. No formal statistical testing of the PD data 
will be conducted.
Descriptive summary statistics for percent of inhibition of systemic CD69 biomarker will 
be provided by strength, BSA and day.
9.3.2.3.2.
Part C: Chronic Spontaneous Urticaria Subjects
UAS7
PD assessment in CsU subjects will be measured using a composite score UAS7. 
The UAS7 score will be calculated using the 7 consecutive days sum. A score will be 
derived for the screening visits and for the post dose visits In the presence of one or more 
missing daily UAS7 scores, the following algorithm will be applied:

If a patient has at least 4 non-missing daily UAS7 scores within the 7 days, the 
UAS7 score will be calculated as the sum of the available eDiary UAS7 scores 
in that week, divided by the number of days that have a non-missing diary 
UAS7 score, multiplied by 7.


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
If there are less than 4 non-missing daily UAS7 scores, then the UAS7 score 
will be missing.
Change from baseline in UAS7 will be derived as post dose UAS7 total score minus the 
Baseline UAS7 total score (screening).  The mean and standard deviation of the change 
from baseline in UAS7 for each treatment group will be presented.  The change from 
baseline in UAS7 will be analysed using the ANCOVA model including treatment, 
baseline UAS7 and location of treatment. Estimates of the means  and treatment 
difference and associated 95% confidence intervals will be presented. Analysis of each 
component will be performed similar to UAS7 analysis.
Summary statistics for each component of UAS7 questionaire will be provided by visit.
For CsU Subjects (Part C), descriptive summary statistics for percent of inhibition of 
CD69 biomarker will be provided by strength, BSA and day if samples are taken in Part 
C. 
More details will be provided in the RAP.
The Angioedema Activity Score
Each AAS item will be scored between 0 to 3 and daily total score AAS score will range 
between 0 and 15. The daily AAS score will summed to compute a 7-day total scores for 
screening (baseline) and post dose. Change from baseline, the 7 day total and individual 
item scores will be calculated. The mean and standard deviation of the change from 
baseline in total and individual item score for each treatment group will be presented.. 
The change from baseline will be analysed using the ANCOVA model including 
treatment, baseline and location of treatment as covariates. Point estimates and 95% 
confidence intervals will be presented. Missing values will not be imputed.  More details 
will be provided in RAP.
9.3.2.4.
Health Outcomes Analyses
For CsU subjects, quality of life will be measured using the Dermatology Life 
Quality Index (DLQI) questionnaire.
9.3.2.4.1.
Dermatology Life Quality Index
A total score and its six individual domains (symptoms and feelings, daily activities, 
leisure, work and school, personal relationships, and treatment) will be calculated. 
Change in DLQI score from baseline in total and individual domain scores will be 
calculated. The mean and standard deviation of the change from baseline in total and 
individual domain score will be presented. The change from baseline will be analysed 
using the ANCOVA model including treatment, baseline and location of treatment as 
covariates.Point Estimates and 95% confidence intervals will be presented. More details 
on scoring method will be provided in 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 enrolment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study 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.
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 1996 
Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favourable opinion/approval to conduct the study and of any 
subsequent relevant amended documents

Written informed consent (and any amendments) to be obtained for each subject 
before participation in the study

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)
Written informed consent must be obtained from each subject prior to participation in the 
study.
10.2.1.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the 
study treatment, and this new event is likely to affect the safety of subjects, the sponsor 
and the investigator will take appropriate urgent safety measures to protect subjects 
against any immediate hazard.
The sponsor will work with the investigator to ensure the IEC/IRB is notified.
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 CRF will 
serve as the source document.


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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 monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations including GCP, and GSK procedures.
In addition, 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 this with the 
investigator or the head of the medical institution (where applicable), including the 
reasons for taking such action.  When feasible, GSK will provide advance notification to 
the investigator or the head of the medical institution, where applicable, of the impending 
action prior to it taking effect.
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform investigators or the head of the medical institution (where applicable) 
and the 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 by someone else, in a safe and secure location.  The records 


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must be maintained to allow easy and timely retrieval, when needed (e.g., audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and 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 assure that all reproductions are legible and are a true and accurate copy 
of the originals, 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, or GSK standards/procedures; otherwise, the 
retention period will default to 15 years.
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 leaves the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.  


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11.
REFERENCES
Center for Drug Evaluation and Research (CDER). December 1999. Skin Irritation *and 
Sensitization. Testing of Generic Transdermal Drug Products. 
(http://www.fda.gov/ohrms/dockets/98fr/990236Gd.pdf, accessed 02 Dec 2013)
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical 
measure for routine clinical use. Clin Exp Dermatol. 1994 May;19(3):210-6.
Greaves MW Chronic Urticaria J allergy Clin Immunol 2000 105: 664-72  
GSK2646264 Investigator's Brochure GlaxoSmithKline Document Number 
2013N182566_00 15 Apr 2014
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, 
editors.Contraceptive Technology. 19th edition. New York: Ardent Media, 2007: 28.
Heinzerling.  The skin prick test – European standards.  Clinical and Translational 
Allergy 2013; 3:3 
Maurer M, M.D., Karin Rosén, M.D., Ph.D., Hsin-Ju Hsieh, Ph.D., Sarbjit Saini, M.D., 
Clive Grattan, M.D., Ana Gimenéz-Arnau, M.D., Ph.D., Sunil Agarwal, M.D., Ramona 
Doyle, M.D., Janice Canvin, M.D., Allen Kaplan, M.D., and Thomas Casale, 
M.D.Omalizumab for the Treatment of Chronic Idiopathic or Spontaneous Urticaria N 
Engl J Med 2013; 368:924-935 
Maurer M, MD, Sabine Altrichter, MD, Thomas Bieber, MD, Tilo Biedermann, MD, 
Matthias Brautigam, PhD,Stefan Seyfried, PhD, Randolf Brehler, MD, J€urgen Grabbe, 
MD,Nicolas Hunzelmann, MD, Thilo Jakob, MD, Andreas Jung, MD, J€org Kleine-
Tebbe, MD, Martin Mempel, MD, Michael Meurer, MD, Kristian Reich, MD, Franziska 
Ru€eff, MD, Knut Sch€akel, MD, Kaushik Sengupta, BDS, MScD, Christian Sieder, 
MSc, Jan C. Simon, MD  Bettina Wedi, MD,Torsten Zuberbier, MD, Vera Mahler, MD, 
and Petra Staubach, MD Efficacy and safety of omalizumab in patients with 
chronicurticaria who exhibit IgE against thyroperoxidase J Allergy Clin Immune 2011a 
128(1) 202 -209
Maurer M, Weller, C. Bindslev-Jensen, A. Giménez-Arnau, P. J. Bousquet, J. Bousquet, 
G. W. Canonica, M. K. Church, K. V. Godse,C. E. H. Grattan, M. W. Greaves, M. Hide, 
D. Kalogeromitros, A. P. Kaplan, S. S. Saini, X. J. Zhu andT. Zuberbier Unmet clinical 
needs in chronic spontaneous urticaria. A GA2LEN task force report1 Allergy 2011b 
66:317-330  
MEDICINAL PRODUCTS ACT (THE DRUG LAW)  (ARZNEIMITTELGESETZ –
AMG) of the FEDERAL REPUBLIC OF GERMANY.  http://www.gesetze-im-
internet.de/englisch_amg/. 2015.
Młynek A.,Magerl M.,Siebenhaar F.,Weller K.,Vieira R. Vieira dos Santos, Zuberbier T., 
Zalewska-Janowska A. and Maurer M. Results and relevance of critical temperature 


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threshold testing in patients with acquired cold urticaria British Journal of Dermatology 
2010, 162: 198-200
Obach RS1, Baxter JG, Liston TE, Silber BM, Jones BC, MacIntyre F, Rance DJ, Wastall 
P.The prediction of human pharmacokinetic parameters from preclinical and in vitro 
metabolism data. J Pharmacol Exp Ther. 1997 Oct;283(1):46-58.
Riccaboni M.  Spleen tyrosine kinase: biology, therapeutic targets and drugs. Drug 
Discovery Today. 2010; 15: 517-530 
Saini S, Rosen KE, Hsieh HJ, et al. A randomized, placebo-controlled, dose-ranging 
study of single-dose omalizumab in patients with H1-antihistamine-refractory chronic 
idiopathic urticaria. J Allergy Clin Immunol 2011; 128: 567-73.
Schoepke N, Church, MK and Maurer, M; Acta Derm Venereol 2013; 93: 286–
293Lukas Kofler,1 Hanno Ulmer,2 and Heinz Kofler Histamine 50-Skin-Prick Test: A 
Tool to Diagnose Histamine Intolerance ISRN Allergy Volume 2011 (2011), Article 
ID 353045
Siraganian RP.  Mast cell signalling: The role of protein tyrosine kinase SYK, its 
activation and screening methods for new pathway participants.Current Opinion in 
Immunology 2003, 15:639–646
U.S. Department of Health and Human Services, Food and Drug Administration
Weinblatt M, Kavanaugh, Arthur M.D., Genovese, Mark C. M.D., Musser, Theresa K. 
B.A.,. Grossbard, Elliott B M.D., and Magilavy, Daniel B. M.D. An oral spleen tyrosine 
kinase (SYK) inhibitor for rheumatoid arthritis.  NEJM 2010; 363: 1303-12 


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12.
APPENDICES
12.1.
Appendix 1: Liver Safety Process
The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined in Section 5.7.1:

Immediately withdraw the subject from study treatment 

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
confirm the subject’s study treatment cessation and follow-up.

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event case report forms.  If the event also meets the criteria of an 
SAE (see Section 7.1.4), the SAE data collection tool will be completed separately 
with the relevant details.

Upon completion of the safety follow-up withdraw the subject from the study unless 
further safety follow up is required  

Do not restart investigational product 

Refer to the Flow chart for a visual presentation of the procedures listed below.
Safety Follow-Up Procedures for subjects with ALT 3xULN:

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.
Safety Follow-Up Procedures for subjects with ALT 3xULN and total bilirubin 
2xULN (>35% direct bilirubin); or ALT 3xULN and INR1 > 1.5:

This event is considered an SAE (see Section 7.1.4).  Serum bilirubin fractionation 
should be performed if testing is available. If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury).

Make every reasonable attempt to have subjects return to the clinic within 24 hours 
for repeat liver chemistries, additional testing, and close monitoring (with specialist 
or hepatology consultation recommended).

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
In addition, for all subjects with ALT 3xULN, every attempt must be made to also 
obtain the following:

Viral hepatitis serology including:
                                                
1 INR testing not required per protocol and the threshold value does not apply to subjects receiving 
anticoagulants.


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
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.

Blood sample for pharmacokinetic (PK) analysis, obtained within 24 hours of last 
dose. 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 included in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) 
on the AE CRF.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications 
CRF.

Record alcohol use on the Liver Events CRF.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN 
(>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in the 
preceding 

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.

The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these tests 
are performed.


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Refer to the diagram below for a visual presentation of the procedures listed above.
ALT≥3xULN ?
Bilirubin ≥ 2xULN
(or INR > 1.5 if 
measured)* ?
No
No
Yes
Yes
Continue investigational product (IP)
Instruct subject to stop IP
Notify GSK within 24 hrs 
Obtain weekly liver chemistries until resolved, stabilized or returned 
to baseline values
Perform liver event follow up assessments (serology, PK sample, etc 
as in protocol) 
Complete liver event CRF
Withdraw subject from study after liver chemistry monitoring 
complete + do not re-challenge with IP
Instruct subject to stop IP
Notify GSK and arrange clinical followup within 24 hrs
Perform liver event follow up assessments (serology, PK sample etc 
as in protocol) 
Report as SAE (excl. hepatic impairment or cirrhosis studies); 
complete SAE & liver event CRF + liver imaging  
and biopsy CRFs (if these tests are performed)
Obtain twice weekly liver chemistries until resolved, stabilized or 
returned to baseline values 
Consultation with hepatologist/specialist recommended
Withdraw subject from study after liver chemistry monitoring 
complete + do not re-challenge with IP
*INR threshold does not apply to 
subjects receiving anticoagulants.


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12.2.
Appendix 2: Procedures for Detection, Evaluation, Follow-
Up and Reporting of Adverse Events and Medical Device 
Incidents
Recording of AEs and SAEs
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 appropriate data collection tool. 
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 data collection tool.  
However, 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 health outcomes questionnaires and the collection of AE data are 
independent components of the study.  Responses to each question in the health outcomes 
questionnaire will be treated in accordance with standard scoring and statistical 
procedures detailed by the scale’s developer.  The use of a single question from a 
multidimensional health survey to designate a cause-effect relationship to an AE is 
inappropriate.
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.


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Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out.  The investigator will use clinical judgment to determine the 
relationship.  Alternative causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study treatment will be considered and investigated.  The investigator will also consult 
the Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to GSK.  The investigator may change his/her 
opinion of causality in light of follow-up information, amending the SAE data collection 
tool accordingly.  The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All AEs and SAEs will be followed until 
resolution, until the condition stabilizes, until the event is otherwise explained, or until 
the subject is lost to follow-up.
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 data collection 
tool.  The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
Reporting of SAEs to GSK
The 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 GSK Medical monitor.  Then the site 


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will enter the serious adverse event data into the electronic system as soon as it becomes 
available.
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 participant 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 their 
GSK protocol contact by telephone.
GSK contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical monitor Contact Information page.


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12.3.
Appendix 3: Urticaria symptoms questionnaire and activity 
Score (UAS7)


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12.4.
Appendix 4: Dermatology Life Quality Index (DLQI)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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12.5.
Appendix 5: Calculation of predicted human exposure
Dermal concentrations achieved:
The GSK2646264 dermal recovery data generated by Medpharm (Report No. 007-1311-
01R) was taken and converted into a dermal concentration assuming the following skin 
section dimensions; 0.6 cm2 surface area, 0.03 cm depth equating to a volume of 0.018 
cm3 (1 mL equivalent to 1 cm3). Dermal concentration was then converted to µM and the 
mean concentration calculated from the replicate experiments from 3 donors.
Arlacel Cream Formulation 
Strength (%)
24 h Dermal 
Concentration (µM)
1
63
0.5
49
Estimation of the maximum penetration rates:
The cumulative receiving fluid concentration data generated by Medpharm (Report No. 
007-1311-01R) was taken and plotted as individual values on a graph of cumulative 
concentration (ng/mL) against time (h). The maximum observed concentration at each 


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time point was then taken as the maximum observed penetration and the rate of 
penetration equates to the slope of this line (See examples and table below). 
Arlacel Cream 
Formulation Strength (%)
Max observed penetration 
rate (ng/cm2/h)
1
27.17
0.5
13.76
Calculation of Predicted human exposure
The rate of penetration values are in effect the dose of GSK2646264 which reaches the 
systemic circulation per cm2 per hour. We assumed that the rate of penetration remains 
constant over a 24 hour period and thereby acts like a constant infusion into the blood. 
The dose in 24 h is therefore reliant on the surface area covered by the cream 
formulation. We have assumed 10% body surface area coverage on a 70 kg human (1.8 
m2) which is therefore 1800 cm2.
Dose in 24 h = Penetration Rate * 24 * 1800
The flux determined for the creams and the predicted human PK parameters (CLb: 13 
mL/min/kg, Vss: 0.8 L/kg) were used to predict the Cmax and AUC0-24h when applying 
the creams to the different BSA in the clinical study. Predictions were performed in 
WinNonlin (Phoenix v6.3.0.395) using an IV infusion model. 
The derived Cmax and AUC were converted to plasma using the human blood:plasma 
ratio of 0.7 and also displayed corrected for fraction unbound using a human Fup of 
1.05%. The calculated values are displayed below and in Section 3.2.2.1 of the protocol.


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12.6.
Appendix 6: Comparison Of Predicted Human Plasma 
Exposures To Animal Safety Studies
MABEL
Human WB CD69 IC20: 1150 
ng/mL
Exposure with 1% cream 
(20% BSA) expected 
447- fold lower than the 
IC20.
Human predicted PK 
parameters
Clearance (in vivo CLb)
13 mL/min/kg 
(60% LBF)
IVIVE
Volume (Vss in human)
0.8 L/kg
Single species scaling. 
Rat Vss corrected for 
species Fub diff. (Obach. 
1997)
Half-life
0.7h
Estimated from CLb and 
Vss
Cmax 
(ng/mL)
AUC 
(ng.h/mL)
Dose 
(mg/cm2)
[mg of 
free 
drug]
%BSA 
[cm2]
Predicted 
margin to 
NOEL  
Cmax 
(thyroid 
finding)
Predicted  
margin to  
NOAEL  
AUC (0-t)
3% 
dermal
Predicted  
margin  
MABEL 
IC20
Predicted 
margin to  
Cmax 
NOAEL 
(EFD 
findings)
Predicted  
margin to  
AUC 
NOAEL 
(EFD 
findings)
Rat (0.5% 
strength)
1.4 - 6.6
15.3 - 57
20-44
[4.1-9.0]
10%
NA
NA
NA
NA
NA
Pig (0.5% 
strength)
1.9 - 47
20 - 118
43
[8.7]
10%
NA
NA
NA
NA
NA
Human 
Starting 
dose 0.5% 
strength 
(predicted)
0.01
0.31
10
[1.8]
0.2%
[36]
1600
700
115,000
16,700
719
Human 
Highest 
dose 
group 1 
and CU 
0.5% 
strength 
(predicted)
0.32
7.8
10
[45]
5%
[900]
50
30
3600
521
28.5


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Cmax 
(ng/mL)
AUC 
(ng.h/mL)
Dose 
(mg/cm2)
[mg of 
free 
drug]
%BSA 
[cm2]
Predicted 
margin to 
NOEL  
Cmax 
(thyroid 
finding)
Predicted  
margin to  
NOAEL  
AUC (0-t)
3% 
dermal
Predicted  
margin  
MABEL 
IC20
Predicted 
margin to  
Cmax 
NOAEL 
(EFD 
findings)
Predicted  
margin to  
AUC 
NOAEL 
(EFD 
findings)
Human 
Highest 
Dose 
Group 2 
and CsU 
1% 
strength 
(predicted)
2.57
61.4
10
[360]
20%
[3600]
6
3.5
447
65
3.6
Human 
Highest 
Dose 
Group 2 
and CsU 
1% 
strength 
dib 
(predicted)
2.57
61.4
10
[720]
20%
[3600]
3
1.75
224
32.5
1.8
Systemic levels in human predicted using the maximum observed penetration rates for each cream strength (0.5 and 
1%) and predicted human PK parameters. (IVIVE: in vitro-in vivo extrapolation).
Application of the 1% and 0.5% creams (10 mg/cm2) are expected to produce dermal concentrations above the 
IC90 as determined by the in vitro skin penetration and ex vivo histamine release assays.


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12.7.
Appendix 7: Angioedema Activity Score
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected 
by third party copyright laws and therefore have been excluded.


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12.8.
Appendix 8: Protocol Amendment Changes
AMENDMENT 1
Summary of Amendment Changes with Rationale
Changes have been made to safety related study specific dose adjustment criteria 
following MHRA review.
List of Specific Changes
Section 5.6 Safety Related Study Specific Dose Adjustment Criteria
PREVIOUS TEXT
If AEs which are of severe intensity and are similar across subjects in the group, or if 
unacceptable pharmacological effects, reasonably attributable in the opinion of the 
investigator to dosing with GSK2646264, or if dose limiting toxicity (see Section 5.5.1), 
are observed in 2 or more subjects in dosing group 1 or dosing group 2, the dose 
escalation will be temporarily halted and no further subject will be dosed until a full 
safety review of the study has taken place. Relevant reporting and discussion with the 
GSK medical monitor and the SMC, and with the Ethics Committee and regulatory 
authorities according to local regulations and processes, will then take place prior to any 
resumption of dosing.
If a similar Serious Adverse Event (SAE) occurs in 2 or more subjects and is deemed to 
be drug related, the dose escalation will be temporarily halted and no further subject will 
be dosed until a full safety review of the data has taken place. Relevant reporting and 
discussion with the GSK medical monitor and SMC, relevant GSK personnel, and with 
the Ethics Committee and regulatory authorities according to local regulations and 
processes, will then take place prior to any resumption of dosing.
The above criteria will apply regardless of whether pharmacokinetics are less than the 
above mentioned PK stopping criteria and every effort will be made to take a blood 
sample at the time of the event for pharmacokinetics analysis in the presence of any of 
the above events.
REVISED TEXT
If AEs which are of severe intensity and are similar across subjects in the group, or if 
unacceptable pharmacological effects, reasonably attributable in the opinion of the 
investigator to dosing with GSK2646264, or if dose limiting toxicity (see Section 5.5.1), 
are observed in 2 or more subjects in dosing group 1 or dosing group 2, the dose 
escalation will be stopped. Relevant reporting and discussion with the GSK medical 
monitor and the SMC will take place.  A substantial amendment will be submitted 
to the Ethics committees and Regulatory authorities for approval prior to any 
resumption of dosing.


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If a Serious Adverse Event (SAE) occurs in 1 subject and is deemed to be drug 
related, the dose escalation will be stopped. Relevant reporting and discussion with 
the GSK medical monitor and the SMC will take place.  A substantial amendment 
will be submitted to the Ethics committees and Regulatory authorities for approval 
prior to any resumption of dosing.
The above criteria will apply regardless of whether pharmacokinetics are less than the 
above mentioned PK stopping criteria and every effort will be made to take a blood 
sample at the time of the event for pharmacokinetics analysis in the presence of any of 
the above events.
Summary of Amendment Changes with Rationale
An update has been made to the exclusion criteria of the protocol Section 4.2.2. and a 
change has been made to Section 10.2 Regulatory and Ethical considerations following 
German (Berlin) Ethics Committee  review.
List of Specific Changes
Section 4.2.2.  
PREVIOUS TEXT
4.2.2 All Cohorts Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. TSH levels outside normal range. 
2. Subjects with a history of Graves disease.
3. Subjects with a history of any thyroid cancer.
4. Unable or unwilling to avoid use of topical creams/lotions at sites where 
medication will be applied.  Washing with soap and water will be permitted.  
5. Based on averaged QTcF values of triplicate ECGs obtained over a brief 
recording period:

QTc(F) > 450 msec; or QTc(F) > 480 msec in subjects with Bundle 
Branch Block.
6. ALT, alkaline phosphatase and bilirubin ≥ 1.5xULN (isolated bilirubin >1.5xULN 
is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
7. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones) or previous history of uncomplicated cholecystectomy.
8. History of regular alcohol consumption within 6 months of the study defined as: 


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
An average weekly intake of >21 units for males or >14 units for females. 
One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 
glass (125 ml) of wine or 1 (25 ml) measure of spirits. 
9. History of sensitivity to any of the study medications, or components thereof, 
history of anaphylaxis or a history of drug or other allergy that, in the opinion of 
the investigator or GSK Medical monitor, contraindicates their participation. 
10. 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. 
11. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody 
result within 3 months of screening. 
12. A positive test for HIV antibody.
13. Lactating females.
14. Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within a 56 day period.
15. 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).
16. Exposure to more than four new chemical entities within 12 months prior to the 
first dosing day
17. Use of topical steroids or calcinurin inhibitors are prohibited during the study 
from screening to follow up (See Section 5.12).
18. Exclusion related to prior drug treatments:
a) Intake of oral corticosteroids within 7 days >10mg/day prior to first screening 
visit.
b) Use of depot corticosteroids within 7 days prior to first screening visit. 
c) Subjects who are taking anticoagulants (e.g. warfarin) must not be on warfarin 
within 21 days prior to screening. (See Section 5.12).
d) Subjects who are having psoralen combined with ultraviolet A (PUVA) 
treatment must not be using PUVA treatment within 21 days prior to screening.
4.2.2.1
Additional Exclusion for Part A – Healthy Subjects
1. Use of H1 antihistamines within 3 days prior to first screening visit 
4.2.2.2
Additional Exclusion for Part B – Cold urticaria Subjects
1. Exclusion related to prior drug treatments:


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
Use of  Zaditen (Ketotifen) within 14 days prior to first screening visit

Use of Doxepin AZU and other tricyclic antidepressants with antihistaminergic 
properties within 14 days prior to first screening visit

Use of H2 antihistamines within 7 days prior to first screening visit 

Use of H1 antihistamines within 7 days prior to first screening visit 

Use of monteleukast or any other leukotriene antagonist within 7 days prior to 
first screening visit

Use of biologicals including omalizumab within 5 months prior to first 
screening visit
4.2.2.3
Additional Exclusion for Part C- Chronic Spontaneous Urticaria 
patients
3.
Exclusion related to prior drug treatments

Intake of cyclosporin within 10 days prior to first screening visit

Intake of other immunosuppressant drugs within 28 days of first screening visit

Use of monteleukast or any other leukotriene antagonist within 7 days prior to 
first screening visit

Use of Dapsone within 7 days prior to first screening visit

Use of Zaditen (Ketotifen) within 14 days prior to first screening visit

Use of Doxepin AZU  and other tricyclic antidepressants with antihistaminergic 
properties within 14 days prior to first screening visit

Use of H2 antihistamines within 7 days prior first screening visit 

Use of biologicals including omalizumab within 5 months prior to first 
screening visit

Use of H1 antihistamines above the licensed dose within 3 days prior to first 
screening visit
REVISED TEXT
4.2.2 All Cohorts Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. TSH levels outside normal range. 
2. Subjects with a history of Graves disease.
3. Subjects with a history of any thyroid cancer.
4. Unable or unwilling to avoid use of topical creams/lotions at sites where 
medication will be applied.  Washing with soap and water will be permitted.  


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5. Based on averaged QTcF values of triplicate ECGs obtained over a brief 
recording period:

QTc(F) > 450 msec; or QTc(F) > 480 msec in subjects with Bundle Branch 
Block.
6. ALT, alkaline phosphatase and bilirubin ≥ 1.5xULN (isolated bilirubin >1.5xULN 
is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
7. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones) or previous history of uncomplicated cholecystectomy.
8. History of regular alcohol consumption within 6 months of the study defined as: 

An average weekly intake of >21 units for males or >14 units for females.  
One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass 
(125 ml) of wine or 1 (25 ml) measure of spirits. 
9. History of sensitivity to any of the study medications, or components thereof, 
history of anaphylaxis or a history of drug or other allergy that, in the opinion of 
the investigator or GSK Medical monitor, contraindicates their participation. 
10. 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. 
11. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody 
result within 3 months of screening. 
12. A positive test for HIV antibody.
13. Lactating females.
14. Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within a 56 day period.
15. 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).
16. Exposure to more than four new chemical entities within 12 months prior to the 
first dosing day
17. Use of topical steroids or calcinurin inhibitors are prohibited during the study 
from screening to follow up (See Section 5.12).
18. Exclusion related to prior drug treatments:
a) Intake of oral corticosteroids within 7 days >10mg/day prior to first screening 
visit.


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b) Use of depot corticosteroids within 7 days prior to first screening visit. 
c) Subjects who are taking anticoagulants (e.g. warfarin) must not be on warfarin 
within 21 days prior to screening. (See Section 5.12).
d) Subjects who are having psoralen combined with ultraviolet A (PUVA) 
treatment must not be using PUVA treatment within 21 days prior to screening.
19. Subjects who work for the Sponsor, CRO, or one of the study centres.  
4.2.2.1.1. Country Specific Exclusion criteria wording for Germany that applies to 
Part A, Part B and Part C
2.
Subjects who live in detention on court order or on regulatory action, 
see §40 subsection 1 sentence 3 no. 4 AMG. (Arzneimittelgesetz). 
List of Specific Changes
Section 10.2 Regulatory and Ethical Considerations, Including the Informed Consent 
Process 
PREVIOUS TEXT
Prior to initiation of a study 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.
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 2008 
Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval to conduct the study and of any 
subsequent relevant amended documents

Written informed consent (and any amendments) to be obtained for each subject 
before participation in the study

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)
Written informed consent must be obtained from each subject prior to participation in the 
study.
REVISED TEXT
Prior to initiation of a study 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.


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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 1996
Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval to conduct the study and of any 
subsequent relevant amended documents

Written informed consent (and any amendments) to be obtained for each subject 
before participation in the study

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)
Written informed consent must be obtained from each subject prior to participation in the 
study.


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AMENDMENT 2
Summary of Amendment Changes with Rationale
Changes have been made to list all of the challenge agents to be used in the study 
following guidance from German Regulatory Agency (BfArM).
A table of the list of challenge agents has been added to the study treatment section. An 
update to the skin prick test procedure and the correct name of one of the challenge 
agents has been added to the inclusion criteria.
List of Specific Changes
Section 4.2.1.2 Inclusion criteria specific to healthy subjects (Part A) – Criteria number 4.
PREVIOUS TEXT
4. Demonstration of a positive weal and flare reaction (≥ 3mm in diameter relative 
to negative control) to at least one allergen from a battery of allergens (grass 
pollen, Dermatophagoides pteronyssinus, birch pollen and cat dander) on skin 
prick testing at screening.
REVISED TEXT
4. Demonstration of a positive weal and flare reaction (≥ 3mm in diameter relative 
to negative control) to at least one allergen from a battery of allergens (Mixed
grass pollen, Dermatophagoides pteronyssinus, birch pollen and cat dander) on
skin prick testing at screening.
List of Specific Changes
Section 4.2.1.3 Additional Inclusion criteria specific for subjects with cold urticaria (Part 
B) – Criteria number 6.
PREVIOUS TEXT
6. In addition, the following criterion will apply to a minimum of 4 patients in Part B: 
a) Demonstration of a positive weal and flare reaction (≥3 mm relative to 
negative control) to at least one allergen from a battery of allergens (grass 
pollen, Dermatophagoides pteronyssinus, birch pollen and cat dander)  on 
skin prick testing at screening, 
REVISED TEXT
6. In addition, the following criterion will apply to a minimum of 4 patients in Part B: 
a) Demonstration of a positive weal and flare reaction (≥3 mm relative to 
negative control) to at least one allergen from a battery of allergens 
(Mixed grass pollen, Dermatophagoides pteronyssinus, birch pollen and 
cat dander)  on skin prick testing at screening, 


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List of Specific Changes
Section 5.1 Investigational Product and Other Study Treatment
PREVIOUS TEXT
5.1
Investigational Product and Other Study Treatment
Table 6
Study treatment table
Study Treatment
Product name:
0.5% 
GSK2646264
1%
GSK2646264
Placebo
Formulation description:
White to off white 
aqueous cream
White to off white 
aqueous cream
White to off white 
aqueous cream
Dosage form:
Topical
Topical
Topical
Unit dose strength(s)/Dosage 
level(s):
0.5% (w/w)
1% (w/w)
NA
Route/
Administration/
Duration:
Topical
Topical
Topical
Dosing instructions:
Should be applied 
topically as directed
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
White-to-off-white 
aqueous cream stored 
in amber glass jars
Manufacturer/
source of procurement:
Medpharm Guildford
Medpharm Guildford
Medpharm Guildford
REVISED TEXT
Table 6
Study treatment table
Study Treatment
Product name:
0.5% 
GSK2646264
1%
GSK2646264
Placebo
Formulation description:
White to off white 
aqueous cream
White to off white 
aqueous cream
White to off white 
aqueous cream
Dosage form:
Topical
Topical
Topical
Unit dose strength(s)/Dosage 
level(s):
0.5% (w/w)
1% (w/w)
NA
Route/
Administration/
Duration:
Topical
Topical
Topical
Dosing instructions:
Should be applied 
topically as directed
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
White-to-off-white 
aqueous cream stored 
in amber glass jars
Manufacturer/
source of procurement:
Medpharm Guildford
Medpharm Guildford
Medpharm Guildford


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Challenge Agent  Treatments
Product name:
Dermatophagoides 
pteronyssinus 
Timothy Grass 
Pollen
Cat dander
Birch pollen  
Positive 
Control
Negative 
Control
Mixed Grass 
Pollen
Formulation 
description:
Solution for skin prick 
test
Solution for skin 
prick test
Solution for 
skin prick test
Solution for 
skin prick test
Solution for 
skin prick test
Solution for 
skin prick 
test
Solution for 
skin prick test
Dosage form:
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Unit dose 
strength(s)/Dosage 
level(s):
0.003 microlitres
0.003 microlitres
0.003 
microlitres
0.003 
microlitres
0.003 
microlitres
0.003 
microlitres
0.003 
microlitres
Route/
Administration/
Duration:
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Cutaneous
Dosing 
instructions:
Superficial layer of skin 
is pierced with an ALK 
lancet perpendicular to 
the skin.
Superficial layer 
of skin is pierced 
with an ALK 
lancet 
perpendicular to 
the skin.
Superficial 
layer of skin is 
pierced with an 
ALK lancet 
perpendicular 
to the skin.
Superficial 
layer of skin is 
pierced with an 
ALK lancet 
perpendicular 
to the skin.
Superficial 
layer of skin is 
pierced with an 
ALK lancet 
perpendicular 
to the skin.
Superficial 
layer of skin 
is pierced 
with an ALK 
lancet 
perpendicular 
to the skin.
Superficial 
layer of skin is 
pierced with an 
ALK lancet 
perpendicular 
to the skin.
Physical 
description:
Solution for skin prick 
testing
Solution for skin 
prick testing
Solution for 
skin prick 
testing
Solution for 
skin prick 
testing
Solution for 
skin prick 
testing
Solution for 
skin prick 
testing
Solution for 
skin prick 
testing
Manufacturer/
source of 
procurement:
ALK-Abello A/S
ALK-Abello A/S
ALK-Abello 
A/S
ALK-Abello 
A/S
ALK-Abello 
A/S
ALK-Abello 
A/S
ALK-Abello 
A/S


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List of Specific Changes
Section 5.2.1 Skin prick test allergens
PREVIOUS TEXT
5.2.1 Skin prick test allergens
A solution of each challenge agent will be applied using the skin prick method as 
described in The Global Allergy and Asthma European Network (GA2LEN) guidelines 
(Heinzerling, 2013). This is a widely accepted method used in allergy clinics to test for 
histamine and allergen sensitivity; causing pruritus, skin flare and a skin wheal. The skin 
prick method involves placing a drop of histamine or allergen solution onto the skin and 
using a lancet to gently pierce the superficial layer of the skin. The excess histamine or 
allergen solution is then wiped away.

histamine

grass pollen, 

Dermatophagoides pteronyssinus, 

birch pollen, 

cat dander
REVISED TEXT
5.2.1 Skin prick test allergens
A solution of each challenge agent will be applied using the skin prick method as 
described in The Global Allergy and Asthma European Network (GA2LEN) guidelines 
(Heinzerling, 2013). This is a widely accepted method used in allergy clinics to test for 
histamine and allergen sensitivity; causing pruritus, skin flare and a skin wheal. The skin 
prick method involves placing a drop of histamine or allergen solution onto the skin and 
using a lancet to gently pierce the superficial layer of the skin. The excess histamine or 
allergen solution is then wiped away.
The following challenge agents will be used as allergens as part of the skin prick 
test. Full details are listed in the table in Section 5.1 

mixed grass pollen,

dDermatophagoides pteronyssinus, 

birch pollen, 

cat dander

positive control – histamine

negative control - saline


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List of Specific Changes
Section 6.4.1 Skin Prick Test (SPT) 
PREVIOUS TEXT
6.4.1 Skin Prick Test (SPT)
At screening a solution of each allergen (mixed grass pollen, dDermatophagoides 
pteronyssinus, birch pollen and cat dander) will be applied to the volar aspect of the 
subjects forearm using the skin prick method as described in The Global Allergy and 
Asthma European Network (GA2LEN) guidelines (Heinzerling, 2013). The skin prick 
method involves placing a drop of histamine or allergen solution onto the skin and using 
a lancet to gently pierce the superficial layer of the skin. The excess histamine or allergen 
solution is then wiped away. Study assessment will commence 15-20 mins after the skin 
has been pricked. 
REVISED TEXT
6.4.1 Skin Prick Test (SPT)
At screening a solution of each allergen (mixed grass pollen, dDermatophagoides 
pteronyssinus, birch pollen and cat dander along with the positive and negative 
controls) will be applied to the volar aspect of the subjects forearm using the skin prick 
method as described in The Global Allergy and Asthma European Network (GA2LEN) 
guidelines (Heinzerling, 2013). The skin prick method involves placing a drop of 
histamine or allergen solution onto the skin and using a lancet to gently pierce the 
superficial layer of the skin. The excess histamine or allergen solution is then wiped 
away. Study assessment will commence 15-20 mins after the skin has been pricked. 
During the dosing period only one allergen positive at screening and the positive control 
will be used as described in the SPM.


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AMENDMENT 3
Summary of Amendment Changes with Rationale
As a result of an informal preliminary data review from Part A of this study, several 
changes have been made to the design of Parts B and C of this study. The changes 
represent a more conservative strategy (staggering part C start relative to Part B), and 
reflect the necessity to fully understand the terminal elimination phase of GSK2646264 
via the dermal route. 
Becuase the terminal elimination phase was longer than anticipated it is proposed that 
thyroid function will be monitored via blood sample testing for the duration of exposure 
until the follow-up visit in parts B and C. The risk benefit with regards to thyroid 
function has not changed.
Changes are as follows:

Part B and C have changed from a bilateral to a placebo-controlled randomised 
parallel design 3:1 active to placebo.

An informal review of data from the first 4 patients of Part B will be performed 
before starting part C.

The number of subjects in Part C has increased (from n=12 up to n=16); and a 2-
week PK/PD sampling period for parts B & C has been implemented.

Free T4, T4 and T3 monitoring has been included for parts B and C at intervals 
until the follow-up visit.


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List of Specific Changes
Section 3.1
PREVIOUS TEXT
Figure 2 Study Schematic Showing all 3 Cohorts
PREVIOUS TEXT
Randomisation will assign active and placebo to specified areas on left or right side of the 
body.
REVISED TEXT
In Part A, randomisation will assign active and placebo to specified areas on left or right 
side of the body.
NEW TEXT
In Parts B and C, which will be a parallel design, randomisation will assign subjects 
to either active or placebo treatment. This will be a 3:1 ratio active to placebo 
respectively.


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REVISED TEXT
Figure 1 Study Schematic Showing all 3 Cohorts
Section 3.1.4
PREVIOUS TEXT
Initially, a single dose of 1 active treatment and placebo will be applied to defined areas 
on subjects on the morning of day 1 and following a safety and tolerability assessment 
further subjects will be dosed; this will enable a second dose in the evening of day 1 and 
will enable the twice daily repeat dose period on days 2 unless Part A indicates once daily 
dosing is acceptable in which case once daily dosing will apply (see Table 4 and 
Figure 3).
Criteria to choose dose strength and dose regime in Part B are detailed in Section 5.5.  
This cohort will remain in-house for the whole dosing period and until completion of the 
final dose on the morning of day 3 and completion of subsequent study assessments on 
day 4.
REVISED TEXT
Subjects will be randomised in a 3:1 ratio to receive either active treatment or 
placebo applied to defined areas once a day for 3 days. The first four subjects of 
Part B will be randomised so that one of the four subjects will receive placebo and 
the three other subjects will receive GSK2646264. An interim review of the 
preliminary data from the first 4 subjects, after they have completed the study, will 
be conducted before dosing the rest of the patients in Part B (n=12 total).  PK, safety 
and tolerability preliminary data up to and including the follow-up visit, will be 
reviewed by the SMC (See Section 5.5). See Figure 3 for a visual representation.


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If preliminary data indicates it is appropriate to review additional PD data, this may 
then be conducted, either in parallel to or before the remainder of Part B subjects 
are enrolled.
Criteria to choose dose strength and dose regime in Part B are detailed in Section 5.5.  
Further dose adjustments may be made as a result of reviewing preliminary data 
from the first n=4 subjects in Part B.
This cohort will remain in-house for the whole dosing period (until completion of the 
final dose on the morning of day 3) and completion of subsequent study assessments on 
day 4. 
PREVIOUS TEXT
Table 3
Part B: Cold Urticaria treatment
Days 1+2
Day 3
Area
AM
PMa
AM
Left 
Arm
0.36g maximum tolerated dose of GSK2646264 or 
placebo applied to 36 cm2 (~0.2% BSA) 
0.36gmaximum tolerated dose of GSK2646264 or 
placebo applied to 36 cm2 (~0.2% BSA) 
Right 
Arm
0.36gmaximum tolerated dose of GSK2646264 or 
placebo applied to 36 cm2 (~0.2% BSA) 
0.36gmaximum tolerated dose of GSK2646264 or 
placebo applied to 36 cm2 (~0.2% BSA) 
Left 
Leg
9g maximum tolerated dose of GSK2646264 or 
placebo applied to 900 cm2 (~5% BSA) 
9g maximum tolerated dose of GSK2646264 or 
placebo applied to 900 cm2 (~5% BSA) 
Right 
Leg
9g maximum tolerated dose of GSK2646264 or 
placebo applied to 900 cm2 (~5% BSA) 
9gmaximum tolerated dose of GSK2646264 or 
placebo applied to 900 cm2 (~5% BSA) 
a.
AM dosing only if  data for Part A, group 1 and/or group 2 supports


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REVISED TEXT
Table 4
Part B: Cold Urticaria treatment
Days 1-3
Area
Morning dosing
Both 
Arms
9g of 1% strength GSK2646264 or placebo applied 
to 900cm2 (5% BSA) on each arm and the volar 
aspect of each arm must be included.  = Total 
BSA = 10% (18g)
Following inclusion subjects will be randomised to either active or placebo. The 
investigator will use his judgement and discretion to decide on which area to apply the 
study treatment within requirements given in Table 4. 
Subjects will receive either 1% strength GSK2646264 cream or placebo cream. The skin 
prick test will be performed on the volar aspect of the arm only in subjects who have a 
positive allergen challenge test at screening, as per inclusion criteria.
PREVIOUS TEXT
Figure 3 Schematic showing Part B Dosing in Cold Urticaria patients


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REVISED TEXT
Figure 3 Schematic showing Part B Dosing in Cold Urticaria patients
Section 3.1.5
PREVIOUS TEXT
Initially, a single dose of the maximum tolerated strength from Part A and placebo will be 
applied to defined areas on subjects on the morning of day 1 and following a safety and 
tolerability assessment further subjects will be dosed. This will enable a second dose in 
the evening of day 1. In turn this will enable the twice daily repeat dose period from days 
2 through to day 7. Once daily dosing may occur if supported by data from Part A of the 
study.
The timing and the assessments to be completed at each visit are provided in the Time 
and Event tables (Section 6.1.4). Early termination of this patient group may occur due to 
feasibility of recruitment and stopping criteria see (Section 5.5 and Section 5.6).
Following inclusion in the study subjects will be randomised. 10 mg/cm2 of either the 
0.5% or 1% and placebo will be applied to a given BSA (up to a maximum of 20% BSA) 
morning and evening on days 1 to 7. The total % BSA for an individual subject will be 
decided by the investigator prior to randomisation.  The maximum % BSA and the 
frequency of dosing will be decided after part A of the study.  
The subjects will be dosed in the unit for the first dose on day 1. Following completion of 
all day 1 assessments, the subjects will be discharged from the clinic at the clinical 
investigator’s discretion.  Subjects will return to the unit prior to the morning dose and 
specified assessments on days 4 and 7. Dosing will occur at home on days 2, 3, 5 and 6.  
Subjects will be asked to complete a daily diary over the 7 days. Details of the diary will 
be provided in the Study procedures manual (SPM). 


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Table 4
Part C: Chronic Spontaneous Urticaria treatment
Days 1-7
Area
AM
PMa
Left Arm
9g of maximum tolerated dose of 
GSK2646264 or placebo cream applied to 
900cm2 (~5% BSA) 
9g of maximum tolerated dose of GSK2646264 
or placebo cream applied to 900cm2 (~5% BSA) 
Right Arm
9g of maximum tolerated dose of 
GSK2646264 or placebo cream applied to 
900cm2 (~5% BSA) 
9g of maximum tolerated dose of GSK2646264 
or placebo cream applied to 900cm2 (~5% BSA) 
Left Leg
9g of maximum tolerated dose of  
GSK2646264 or placebo cream applied to 
900cm2 (~5% BSA) 
9g  of maximum tolerated dose of GSK2646264 
or placebo cream applied to 900cm2 (~5% BSA
Right Leg
9g  of maximum tolerated dose of  
GSK2646264 or placebo cream applied to 
900cm2 (~5% BSA) 
9g of maximum tolerated dose of GSK2646264 
or placebo cream applied to 900cm2 (~5% BSA) 
Left Front 
Torso
18g of maximum tolerated dose of 
GSK2646264 or placebo cream applied to 
1800cm2 (~10% BSA) 
18g of maximum tolerated dose of 
GSK2646264 or placebo cream applied to 
1800cm2 (~10% BSA) 
Right 
Front 
Torso
18g of maximum tolerated dose of 
GSK2646264 or placebo cream applied to 
1800cm2 (~10% BSA)
18g  of maximum tolerated dose of 
GSK2646264 or placebo cream applied to 
1800cm2 (~10% BSA) 
a.
AM dosing only if supported by data from Part A
REVISED TEXT
Subjects will be randomised to 3:1 ratio to receive active treatment or placebo 
applied to areas of the body chosen by the investigator once a day for 7 days. The 
chosen area where cream is applied will remain the same throughout the dosing 
period. Dosing in Part C will only commence once relevant data from the first four 
subjects in Part B have been reviewed, to allow greater confidence in predictions of 
the pharmacokinetics in Part C. The BSA over which study treatment will be 
administered in Part C is anticipated to be 10%, but is subject to change, if 
appropriate, based on preliminary data from Part B (see Figure 4 for a visual 
representation). However, the maximum BSA will not exceed 20%.
The first four subjects of Part C will be randomised so that one of the four subjects 
will receive placebo and the three other subjects will receive GSK2646264. An 
informal review of the preliminary data from the first 4 subjects will be conducted 
after they have completed the study. PK, safety, and tolerability, up to and including 
the follow-up visit, will be reviewed by the Sponsor (See Section 5.5). If required, a 
discussion with the SMC regarding any changes or adjustments to the dosing 
regimen in Part C will be held. Recruitment of the full planned cohort (n=16) may 
continue during any data review.
Following inclusion in the study, subjects will be randomised. 10 mg/cm2 of 1% active 
cream or placebo cream will be applied to a given BSA once per day on days 1 to 7, 
inclusive, on areas of the body chosen by the investigator once a day for 7 days. The 


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areas where cream is applied will remain the same for each day of dosing. The 10 % 
BSA can be distributed between the arms, legs and torso for an individual subjectwill be 
decided by the investigator prior to randomisation. This pattern of cream application 
will remain the same for the duration of dosing. The maximum % BSA and the 
frequency of dosing will be decided after part A of the study but will not exceed 20% 
BSA.
Section 4.2.1.3
NEW TEXT
If a patient who has been screened and is eligible for the study becomes unavailable 
to do the study at the initially planned dates due to exceptional circumstances, the 
subject may be re-screened for the study; in total a patient may be screened 2 times. 
This will only be at the discretion of the Investigator.
Section 4.2.1.4
NEW TEXT
If a patient who has been screened and is eligible for the study becomes unavailable 
to do the study at the initially planned dates due to exceptional circumstances, the 
subject may be re-screened for the study; in total a patient may be screened 2 times. 
This will only be at the discretion of the Investigator.
Section 4.2.2.3
NEW TEXT
Additional Exclusion for Part B – Cold urticaria Subjects
1. fT4, T4, T3 levels outside normal range.
Section 4.2.2.4
NEW TEXT
Additional Exclusion for Part C – Chronic Spontaneous Urticaria patients
1. fT4, T4, T3 levels outside normal range.
Section 4.3.2.1
NEW TEXT
Subjects with Cold Urticaria (Part B)
will abstain from ingesting caffeine- or xanthine-containing products (e.g. coffee, 
tea, cola drinks, chocolate)  and alcohol for 24 hours prior to the start of dosing until 
discharge from the research unit.


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Section 4.4.1
NEW TEXT
Subjects exceeding screening visit window
Subjects in Part B and Part C that are not randomized within the allotted screening 
window may be re-screened once, as per Section 4.2.1. If re-screening is performed, 
it is essential that subjects are assigned a different unique subject ID number for the 
additional screening attempt. See the SPM for specific details.
Section 5.4 Treatment Assignment
PREVIOUS TEXT
Subjects will be assigned to treatment in accordance with the randomization schedule 
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software, RandAll NG. Randomisation will occur within each cohort of study. Subject 
will be randomised to 1:1 to receive bilateral treatment of GSK2646264 or placebo.
REVISED TEXT
Subjects will be assigned to treatment in accordance with the randomization schedule 
generated by Parexel, prior to the start of the study. Randomisation will occur within 
each cohort of study. Subjects will be randomised to 1:1 to receive bilateral treatment of 
GSK2646264 or placebo in Part A.  For Parts B & C, subjects will be randomised 3:1 
active:placebo respectively, to receive either GSK2646264 or placebo.
Section 5.5.1
PREVIOUS TEXT
Toxicity is defined as dose-limiting toxicity if it meets the following criteria:
- Occurs within 6 hours after any dose.
REVISED TEXT
Toxicity is defined as dose-limiting toxicity if it meets the following criteria:
- Occurs within 6 hours after any dose for Parts A & B, or within 24 hours after any 
dose for Part C.
Section 5.5.3.3
NEW TEXT
In Parts B,the first four 4subjects will be randomised so that one of the four 4 
subjects will receive placebo and the three other subjects will receive GSK2646264. 
An interim review of the preliminary data from the first 4 subjects, after they have 
completed the study, will be conducted before dosing the rest of the patients in Part 


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B (n=12 total).  PK, safety, and tolerabilitytolerabilityand systemic CD69 
preliminary data up to and including the follow-up visit, will be reviewed by the 
SMC (See Section 5.5). In addition, further modeling of PK parameters after 4 days 
of dosing in these first 4 cold urticaria patients focusing on the elimination of the 
compound, will be performed to aid the decision to move forward to  the rest of the 
subjects in Part B and to Part C, taking into account the pre-determined safety 
margins (See Appendix 6).
Section 5.5.3.4
NEW TEXT
Dosing in part C will only commence once relevant data from the first four subjects 
in Part B have been reviewed (see Section  5.5.3.3.) to allow greater confidence in 
predictions of the pharmacokinetics in Part C. The BSA over which study treatment 
will be administered in Part C is anticipated to be 10%, but is subject to change if 
appropriate based on preliminary data from Part B. However, the maximum BSA 
will not exceed 20%.
The first four subjects of Part C will be randomised so that one of the four subjects 
will receive placebo and the three other subjects will receive GSK2646264. An 
informal review of the preliminary data from the first 4 subjects may be conducted 
after they have completed the study. PK, safety and tolerability data up to and 
including the follow-up visit, will be reviewed by the Sponsor. If required, a 
discussion with the SMC regarding any changes or adjustments to the dosing 
regimen in Part C will be held. Recruitment of the full planned cohort (n=16) may 
continue during any data review. The dosing regimen or study population may be 
adjusted as appropriate after this interim review for the rest of the subjects in Part 
C.
Section 5.6
NEW TEXT
If AEs which are of severe intensity and are similar across subjects in either Part B 
or C, or if unacceptable pharmacological effects, reasonably attributable in the 
opinion of the investigator to dosing with GSK2646264, or if dose limiting toxicity 
(see Section 5.5.1), are observed in 2 or more subjects in either Part B or C, relevant 
reporting and discussion with the GSK medical monitor and the SMC will take 
place.
Section 5.8
NEW TEXT
After the first 4 subjects in Part C, available pharmacokinetic data will be reviewed 
by the sponsor (see Section 5.5.3.4). If required, a discussion with the SMC 
regarding any changes or adjustments to the dosing regimen in Part C will be held.


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If required, a discussion with the SMC regarding any changes or adjustments to the 
dosing regimen in Part C will be held.
Section 5.8.1
PREVIOUS TEXT
If (cohort’s average) predicted or observed Cmax or AUC(0-∞t) of GSK264624 is greater 
than 16 ng/mL or 220 ng.hr/mL, doses for subsequent cohorts will need to be decided by 
the SMC.
REVISED TEXT
If (cohort’s 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, doses for subsequent cohorts 
may be adjusted based on tox cover and will need to be decided by the SMC but will 
not exceed agreed margins.
Section 5.9
PREVIOUS TEXT
This will be a randomised double blind (sponsor unblinded), single, bilateral and repeat 
ascending dose First Time in Human study in healthy subjects, cold urticaria and chronic 
spontaneous urticaria subjects study.
REVISED TEXT
This will be a randomised double blind (sponsor unblinded), single, bilateral (Part A) 
and paralled (Parts B and C)repeat ascending dose First Time in Human study in 
healthy subjects, cold urticaria and chronic spontaneous urticaria subjects study.


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Section 6.1.2
PREVIOUS TEXT
Part A: Healthy Volunteer Time and Event Table Dose group 2
Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
9-11 days 
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without shoes
X
Brief physical
X
Medical/medication/drug
/alcohol history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and 
CV risk factors questionnaire 
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Urine drug/alcohol screen
X
X
Urine for metabolite analysis
X15
X15
15. Pre dose,and pool samples 
taken 0-12 and 12-24 hours post 
dose 
HIV, Hep B and Hep C screen
X
Clinical Laboratory Tests
X
X
X
X


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Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
9-11 days 
Allergen Challenge-
Skin Prick Test
X3,4
X3,5
X3,5
X3,5
X 7
3. SPT- Skin Prick Test 
measurements will be performed 
~15-20mins post challenge. 
4. SPT with all 4 specificed 
allergens
5. SPT will be performed 6 hours 
post dose (see Section 6.4.1)
7. SPT will be performed 24 hours 
post dose 
TSH2
X
2. TSH test only at screening only
Randomisation
X
Tolerability Assessment
X11  ----------------------------------------------
11. Tolerability assessment at pre –
and ~6 hours post-dose
AE assessment 
X
----------------------------------------------------
X
Concomitant Medication
X
----------------------------------------------------
X
Pharmacokinetic 
Blood Sample6
X
X
X
X
X
X
X
X10
6. PK blood sample taken at pre 
dose, 1, 2, 4, 8, 12 and 24hr post 
dose
10. PK refers to sample 24 hours 
post dose
Blood Sample for CD69 
expression
X12
X13
X14
X13
X14
12. Predose
13.  4 hours after previous dose
14  24 hours after previous dose 
Study Treatment Dosing8
X
X
X
X
X
X
X9
8.  This could be once or twice daily 
dosing
9. Single AM dose on Day 7
Discharge from unit
X
Outpatient visit
X
X


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Part B: Cold Urticaria Subjects Time and Event table
Day:
Screening
-1
1
2
3
4
Follow-
up
Notes
Visit Window  
(relative to Day 1)
-28 to -7 
days
Day 5 
to Day 
7 after 
last 
dose
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without 
shoes
X
Brief physical
X
Medical/medication/
drug/alcohol 
history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and 
CV risk factors questionnaire 
Vital signs
X
X
X
X
X
X
Urine drug/alcohol 
screen
X
X
Pregnancy Test 
(women)2
X(S)
X(S/U)
X(S)
2. Pregnancy test will be 
performed 3 times during 
screening, serum on day -28, day 
-7 to -4, and a serum or urine 
pregnancy test the day of the start 
of the study prior to dosing and a 
serum pregnancy test at the follow 
up visit
HIV, Hep B and Hep 
C screen
X
Clinical Laboratory 
Tests
X
X
X
X
Allergen Challenge-
SPT
X4,5
X4,6
X4,6
4. SPT- Skin Prick Test 
measurements will be performed 
~15-20mins post challenge
5. SPT using all 4 specified 
allergens
6. SPT will be performed at  6 
hours post dose (see Section 
6.4.1)
TSH3
X
3. TSH test only at screening only
Cold Temp Test 
(Temp Test 4.0)
X
X
X
X7
7. 24 hours after last dose
Review of eligibility 
criteria and 
medication prior to 
randomisation
X


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Day:
Screening
-1
1
2
3
4
Follow-
up
Notes
Visit Window  
(relative to Day 1)
-28 to -7 
days
Day 5 
to Day 
7 after 
last 
dose
Randomisation
X
Tolerability 
Assessment
X10          ---------------
10. Tolerability assessment at pre 
– and ~6 hours post-dose
AE assessment 
X
---------------------------
X
Concomitant 
Medication
X
----------------------------
X
Pharmacokinetic 
Blood Sample8
X
X
X9
8.  PK blood sample taken at pre 
dose,1,2,4, 8, 12hr post dose
9. If only once daily dosing then a 
PK sample will be taken at 24h 
post dose
Study Treatment 
Dosing
X
X
X
Discharge from unit
X
Outpatient visit
X
X


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Part C: Chronic Spontaneous Urticaria Cohort
Day:
Screening
1
2
3
4
5
6
7
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 days
9-14 days after last dose
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without shoes
X
Brief physical
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening 
and CV risk factors questionnaire 
Vital signs
X
X
X
X
X
Urine drug/alcohol screen
X
X
Pregnancy Test (women)2
X(S)
X 
(S/
U)
X(S)
2. Pregnancy test will be 
performed 3 times during 
screening, serum (S) on day -28, 
day -7 to -4, and a serum or urine 
(U) pregnancy test the day of the 
start of the study prior to dosing 
and a serum pregnancy test at 
the follow up visit
HIV, Hep B and Hep C screen
X
Clinical Laboratory Tests
X
X
X
X
TSH3
X
3. TSH test only at screening only
Blood Sample for CD69 
expression11
X9
X10
9. Predose
10.  4 hours post dose
11 A decision will be made after 
Part A on whether samples are 
taken in Part C 


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Day:
Screening
1
2
3
4
5
6
7
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 days
9-14 days after last dose
Randomisation
X
UAS-7 Diary4
X
X
X
X
X
X
X
X
4. Screening UAS7 diary will be 
completed  using 7 successive 
days before randomisation (day 
1). If there is a lapse in any day 
prior to day 1 the subject must 
complete the full 7 days worth of 
diary entries again during the 
screening period.
QOL (DLQI)
X
X
X
AAS
X
X
X
X
X
X
X
X
AE assessment
X8 -------------------------------------------
X
8. Tolerability assessment at pre 
– and post-dose
BHR- Basophil Histamine Release 
Test
X5
5. Sample taken predose 
Pharmacokinetic Blood Sample6
X
X
X
6. PK blood sample taken at pre-
dose sample and  2 and 4hr post 
dose
Study Treatment Dosing
X
X7
X7
X
X7
X7
X
7. The nurse will visit the subject 
at home to apply the dose
Outpatient visit
X
X
X
X
X


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REVISED TEXT
Part A: Healthy Volunteer Time and Event Table Dose group 2
Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 9 – Day 
11 
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without shoes
X
Brief physical
X
Medical/medication/drug
/alcohol history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and 
CV risk factors questionnaire 
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Urine drug/alcohol screen
X
X
Urine for metabolite analysis
X10
X22
10. Pre dose and pool samples 
taken 0-12 and 12-24 hours post 
dose 
22. Pool samples taken 0-12 and 
12-24 hours post
HIV, Hep B and Hep C screen
X
Clinical Laboratory Tests
X17
X17
X9
X9
X17
X17
X17
9. Pre-dose AST, ALT, Alkaline 
Phosphatase, Total Bilirubin Only- : 
results to be communicated to the 
GSK Medical monitor on the same 
day  
17.Clinical lab test as per Section 
6.3.4 of the protocol 


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Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 9 – Day 
11 
Allergen Challenge-
Skin Prick Test
X3,4
X3,5
X3,5
X3,
5
X 3,7
3. SPT- Skin Prick Test 
measurements will be performed 
~15-20 mins post challenge. 
4. SPT with all 4 specified allergens
5. SPT will be performed 6 hours 
post dose
7. SPT will be performed 48 hours 
post dose of Day 4 (on the morning 
of Day 6)
TSH2
X
2. TSH test only at screening only
Randomisation
X
Tolerability Assessment
X11  ---------------------
        only on dosing days 1 to 4
11. Tolerability assessment at pre –
and ~6 hours post-dose on dosing 
days
AE assessment 
X
----------------------------------------------------
X
Concomitant Medication
X
----------------------------------------------------
X
Pharmacokinetic 
Blood Sample
X6
X6
X6
X6
X18
X19
X20
X21
6. PK blood sample taken at pre 
dose, 1, 2, 4, 8, 12 and 24hours 
post previous dose 
18. PK blood sample taken at 30, 
36, 48 hours, post dose of Day 4
19. PK blood sample taken at 54, 
60, 72 hours, post dose of Day 4
20. PK blood sample taken at 78, 
84 hours post dose of Day 4
21. PK blood sample taken at 96 
hours post dose of Day 4


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Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 9 – Day 
11 
Blood Sample for CD69 
expression
X12
X13
X14
X15
X16
12. Predose
13. 4 hours post dose of Day 4 
14. 24 hours post dose of Day 4 
(sample taken in the morning of day 
5) 
15. 72 hours post dose of Day 4
16. 96 hours post dose of Day 4
Study Treatment Dosing8
X
X
X
X
8.  This will be once daily dosing 
using fresh bottles at 1% strength in 
the morning
Discharge from unit
X
Outpatient visit
X
X


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Part B: Cold urticaria Subjects Time and Event table
Day:
Screening
-1
1
2
3
4
Day 6 to 15
Follow-
up (Day 
17-19)
Notes
Visit Window  
(relative to Day 1)
-28 to -7   
days
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without 
shoes
X
Brief physical
X
Medical/medication/
X
drug/alcohol history
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and CV risk factors questionnaire 
Vital signs
X
X
X
X
X
X
X
Urine drug/alcohol 
screen
X
X
Pregnancy Test 
(women)2
X(S)
X(S/U)
X (S)
X(S)
2. Pregnancy test will be performed 3 times during screening, serum on day 
-28, day -7 to -4, and a serum or urine pregnancy test the day of the start of 
the study prior to dosing and a serum pregnancy test  between day 10-12 (to 
coincide with a PK sample) and at the follow up visit. 
HIV, Hep B and Hep 
C screen
X
Clinical Laboratory 
Tests
X
X
X
X
Allergen Challenge-
SPT
X3,4
X3,6
X3,5
X9
3. SPT- Skin Prick Test measurements will be performed ~15-20mins post 
challenge
4. SPT using all 4 specified allergens
5. SPT will be performed at  6 hours post dose (see Section 6.4.1)
6. SPT will be performed pre-dose
TSH, free T4, T4, T3
X
x
X7
x
7. One sample between  day 10-12


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Day:
Screening
-1
1
2
3
4
Day 6 to 15
Follow-
up (Day 
17-19)
Notes
Cold Temp Test 
(Temp Test 4.0)
X
X8
X10
X9
8. Pre-dose
9. 24 hours post dose
10. 6 hours post dose
Randomisation
X
Tolerability 
Assessment
----- X11 -----
11. Tolerability assessment at pre – and ~6 hours post-dose
AE assessment 
X
---------X--------
X
Concomitant 
Medication
X
-------X-----------
X
Pharmacokinetic 
Blood Sample
X12
X12
X12
X12
X13
X
12.  PK blood sample taken at pre dose,1, 4, 8, 12hr post dose 
13. One PK blood sample per day will be taken as follows:. PK samples will 
be obtained on the following days (1 day): Day 6, 9, 12, & 15. 
Study Treatment 
Dosing
X
X
X
Discharge from unit
X
Outpatient visit
X
X
X
Blood Sample for 
CD69 expression12
X10
X11
X
X
10. Pre-dose
11. 4 hrs post-dose
12. Sample collection should coincide with PK sample collection.


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Part C: Chronic Spontaneous Urticaria Cohort
Day:
Screening
1
2
3
4
5
6
7
Day 
10 to 
19
Follow-up
Notes
Visit Window 
(relative to Day 1)
-28 to -7
21-23
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without 
shoes
X
Brief physical
X
X
Medical/medication/
drug/alcohol 
history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and CV risk factors questionnaire 
Vital signs
X
X
X
X
X13
X
13. Only conducted if subjects is attending the clinical site.
Urine drug/alcohol 
screen
X
X
Pregnancy Test 
(women)2
X(S)
X 
(S/U)
X(S)14
X(S)
2. Pregnancy test will be performed 3 times during screening, 
serum (S) on day -28, day -7 to -4, and a serum or urine (U) 
pregnancy test the day of the start of the study prior to dosing and 
a serum pregnancy test between day 14-16 and at the follow up 
visit
14. Samples should be obtained at approximately 1 week 
intervals
HIV, Hep B and Hep 
C screen
X


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Day:
Screening
1
2
3
4
5
6
7
Day 
10 to 
19
Follow-up
Notes
Clinical Laboratory 
Tests
X
X
X
X
TSH, free T4, T4, T3
X
X
X3
X
3. Between Days 14-16 
Blood Sample for 
CD69 expression
X4
X5
X5
X6
X
4. Predose
5.  4 hours post dose
6. Sample to be taken every time a PK sample is taken
Randomisation
X
UAS-7 Diary7
X
X
X
X
X
X
X
X
7. Screening UAS7 diary will be completed  using 7 successive 
days before randomisation (day 1). If there is a lapse in any day 
prior to day 1 the subject must complete the full 7 days worth of 
diary entries again during the screening period.
QOL (DLQI)
X
X
X
AAS
X15
X
X
X
X
X
X
X
15. Screening AAS  will be completed  using 7 successive days 
before randomisation (day 1) on the same days as the UAS7. If 
there is a lapse in any day prior to day 1 the subject must 
complete the full 7 days worth of diary entries again during the 
screening period.
AE assessment
X ---------------------------------
X
Tolerability 
Assessment at pre-
dose
X8 --------------------------------
8. Tolerability assessment at pre dose on each day.
BHR- Basophil 
Histamine Release 
Test  
X9
9. Two samples to be taken predose 
Pharmacokinetic 
X10
X10
X10
X11
X
10. PK blood sample taken at pre-dose and 4hr post dose


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Day:
Screening
1
2
3
4
5
6
7
Day 
10 to 
19
Follow-up
Notes
Blood Sample
11. One PK blood sample will be taken during this period at each 
of the following timepoints:. PK samples will be obtained on the 
following days (1 day): Day 10, 13, 16, 19 and 22, with each 
sample being no more than 3 days, apart.
Study Treatment 
Dosing
X
X12
X12
X
X12
X12
X
12. The subject may have study treatment applied at home by a 
nurse or they can travel to the clinic
Con Meds 
X ----------------------------------
Outpatient visit
X
X
X
X
x
X


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Section 6.3.4
PREVIOUS TEXT
Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Albumin
Glucose, fasting
Calcium
GGT
Total Protein
Sodium
Phosphate
Alkaline phosphatase
REVISED TEXT
Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Albumin
Glucose, fasting
Calcium
GGT
Total Protein
Sodium
Phosphate
Alkaline phosphatase
TSH , free T4, T4, 
T3
Section 6.4.3.3 
NEW TEXT
Following review of PK in dose group 1 urine samples were collected for analysis of 
any metabolite(s) from subjects in Part A, Group 2 at predose, and dosing Days 1 
and 4.
Section 9.2.1
PREVIOUS TEXT
Table 9 Results of the sensitivity analyses
Percent of Inhibition Weal 
Size
Percent of Inhibition Flare 
Size
Percent of Inhibition Weal Volume
N
Precision 
around 
estimate
SD
Precision 
around 
estimate
SD
Precision 
around 
estimate
SD
9
15.4
20
6.9
9
15.4
20
9
16.9
22
7.7
10
16.1
21
9
18.5
24
8.5
11
17.7
23
9
20.0
26
10
13
19.2
25
9
21.5
28
11.5
15
20.8
27


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REVISED TEXT
For Part A, based on a sample size of 9 randomised subjects, it is estimated that the 
95% confidence interval for the percent of inhibition effect will be within 18.5% of 
the estimate for the weal size assuming standard deviation of 24, within 8.5% of the 
estimate for the flare size assuming standard deviation of 11 and within 17.7% of 
the estimate for the weal volume assuming standard deviation of 23 (Schoepke, 
2013).
Table 9 
Results of the sensitivity analyses for part A
Percent of Inhibition Weal 
Size
Percent of Inhibition Flare 
Size
Percent of Inhibition Weal Volume
N
Precision
around 
estimate
SD
Precision 
around 
estimate
SD
Precision 
around 
estimate
SD
9
15.4
20
6.9
9
15.4
20
9
16.9
22
7.7
10
16.1
21
9
18.5
24
8.5
11
17.7
23
9
20.0
26
10
13
19.2
25
9
21.5
28
11.5
15
20.8
27
Section 9.3.1
NEW TEXT
Summary of exposure and safety reporting from Part B: first 4 subjects
The safety, tolerability, and preliminary exposure data from Part B (first 4 subjects) will 
be reviewed by the SMC once those subjects have completed the study up to and 
including the follow-up visit. The decision for the dosing regimen and study population 
for the remainder of Part B, and Part C will be made by the SMC review based on 
assessment of safety, and pharmacokinetic data of the studied doses.
This study is double blind (sponsor open), where the subject, investigator and site staff 
will remain blinded to the treatment allocation.
Summary of exposure and safety reporting from Part C: first 4 subjects
Preliminary safety and tolerability, and potentially biomarkers of interest), and 
preliminary exposure data from Part C (first 4 subjects) may be reviewed by the sponsor 
once those subjects have completed the study up to and including the follow-up visit. The 
decision for the potential adjustment of the dosing regimen and/or study population for 


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the rest of Part C will be made by the sponsor review based on assessment of safety and 
pharmacokinetic data of the studied doses. If required, a discussion with the SMC 
regarding any changes or adjustments to the dosing regimen in Part C will be held.
Other experts from CPMS and DMPK, at GSK, may be consulted to review blinded 
placebo/active data (safety, PK and any available PD) during the study for further 
relevant input.
Section 9.3.2.3 
Part A & B: Healthy and Cold Urticaria Subjects
PREVIOUS TEXT
Raw data and percent of inhibition for each PD parameter (i.e. weal area, weal volume, 
weal height and flare area and erythema assessments) will be provided by strength, BSA, 
and day.  Descriptive summary statistics (i.e. n, minimum, arithmetic mean, standard 
error, median, maximum) for both raw and percent of inhibition and change from 
baseline values will be calculated by dose strength, BSA, and day. Additionally, figures 
will be produced for PD parameters. No formal statistical testing of the PD data will be 
conducted.
For Health Subjects (Part A), descriptive summary statistics for percent of inhibition of 
CD69 biomarker will be provided by strength, BSA and day.
PD assessment in CsU subjects will be measured using a composite score UAS7. Change 
from baseline in UAS7 at day 7 is the Day UAS7 minus the Baseline UAS7 score.  The 
mean and standard deviation of the change from baseline in UAS7 for each treatment 
group will be presented.  The change from baseline in UAS7 at day 7 will be analysed 
using the ANCOVA model including treatment, baseline UAS7and location of treatment.
Estimates of the mean  and treatment difference and associated 95% confidence intervals 
will be presented. Analysis of each component will be performed similar to UAS7 
analysis. 
The UAS7 score will be calculated using the 7 consecutive days sum. In presence of one 
or more missing daily UAS7 scores, the following algorithm will be applied:

If a patient has at least 4 non-missing daily UAS7 scores within the 7 days, the 
UAS7 score will be calculated as the sum of the available eDiary UAS7 scores 
in that week, divided by the number of days that have a non-missing diary 
UAS7 score, multiplied by 7.

If there are less than 4 non-missing daily UAS7 scores, then the UAS7 score 
will be missing.
Summary statistics for each component of UAS7 questionaire will be provided by visit.
For CsU Subjects (Part C), descriptive summary statistics for percent of inhibition of 
CD69 biomarker will be provided by strength, BSA and day if samples are taken in Part 
C. 


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More details will be provided in the RAP.
REVISED TEXT
Part A & B: Healthy and Cold Urticaria Subjects
Raw data and percent of inhibition for each PD parameter (i.e. longest weal diameter, 
perpendicular weal length, weal area, weal volume, and flare erythema assessments) will 
be provided by strength, BSA, and day.  Descriptive summary statistics (i.e. n, minimum, 
arithmetic mean, standard error, median, maximum) for both raw and percent of 
inhibition for Part B will be calculated by dose strength, BSA, and day. Additionally, 
figures will be produced for PD parameters. No formal statistical testing of the PD data 
will be conducted.
Descriptive summary statistics for percent of inhibition of systemic CD69 biomarker will 
be provided by strength, BSA and day. 
Part C: Chronic Spontaneous Urticaria Subjects
PD assessment in CsU subjects will be measured using a composite score UAS7. 
The UAS7 score will be calculated using the 7 consecutive days sum. A score will be 
derived for the screening visits and for the post dose visits In presence of one or more 
missing daily UAS7 scores, the following algorithm will be applied:

If a patient has at least 4 non-missing daily UAS7 scores within the 7 days, the 
UAS7 score will be calculated as the sum of the available eDiary UAS7 scores 
in that week, divided by the number of days that have a non-missing diary 
UAS7 score, multiplied by 7.

If there are less than 4 non-missing daily UAS7 scores, then the UAS7 score 
will be missing.
Change from baseline in UAS7 will be derived as post dose UAS7 total score  minus the 
Baseline UAS7 total score (screening).  The mean and standard deviation of the change 
from baseline in UAS7 for each treatment group will be presented.  The change from 
baseline in UAS7  will be analysed using the ANCOVA model including treatment, 
baseline UAS7 and location of treatment. Estimates of the means  and treatment 
difference and associated 95% confidence intervals will be presented. Analysis of each 
component will be performed similar to UAS7 analysis.
Summary statistics for each component of UAS7 questionaire will be provided by visit.
For CsU Subjects (Part C), descriptive summary statistics for percent of inhibition of 
CD69 biomarker will be provided by strength, BSA and day if samples are taken in Part 
C. 
More details will be provided in the RAP.


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AMENDMENT 4
Summary of Amendment Changes with Rationale
After a data review from the first 4 subjects in Part B of this study, several changes have 
been made to the design of Parts B and C of this study. The major changes are to the dose 
level for Part B, the dosing regimen for Part C, and update of the contraception criteria 
for women of child bearing potential. Additional typographical errors have been 
corrected also.
List of specific changes:
PREVIOUS TEXT
2.3.2 Part B: Cold urticaria Subjects
Objectives
Endpoints
Exploratory
Pharmacodynamic measure of  Cold 
Provocation
Assess change in Cold Temperature Test 
values 
Pharmacodynamic measure of  Cold 
Provocation

Change from placebo of Cold Temperature 
Test3 values at day 3
Pharmacodynamic measure of  Allergen 
Challenge
Assess measure of weal and flare size, in 
subjects with Cold urticaria after allergen 
challenge (Skin Prick test, positive control 
(histamine) and negative control (saline)).
Pharmacodynamic measure of Allergen 
Challenge

Percent of inhibition on day 3 will be derived 
for:
o
The longest weal diameter (measured 
by ruler).
o
Perpendicular weal length (measured 
by ruler).
o
Weal area calculated using weal 
diameter and length assuming 
ellipse area.

Weal Volume as measured by;

Quantitative volumetric morphometry1
Flare Erythema as measured by;

Mexameter2


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REVISED TEXT
2.3.2 Part B: Cold urticaria Subjects
Objectives
Endpoints
Exploratory
Pharmacodynamic measure of  Cold 
Provocation
Assess change in Cold Temperature Test 
values 
Pharmacodynamic measure of  Cold 
Provocation

Change from placebo of Cold Temperature 
Test3 values at day 3
Pharmacodynamic measure of  Allergen 
Challenge
Assess measure of weal and flare size, in 
subjects with Cold urticaria after allergen 
challenge (Skin Prick test, positive control 
(histamine) and negative control (saline)).
Pharmacodynamic measure of  Allergen 
Challenge

Percent of inhibition on day 3 will be derived 
for:
o
The longest weal diameter (measured 
by ruler).
o
Perpendicular weal length (measured 
by ruler).
o
Weal area calculated using weal 
diameter and length assuming 
ellipse area.

Weal Volume as measured by;

Quantitative volumetric morphometry1
Flare Erythema as measured by;

Mexameter2
Systemic measure of target pharmacology
Determine CD69 expression in an ex vivo blood 
sample following CD69 stimulation 
Systemic measure of target pharmacology

Percent inhibition of CD69 expressing cells 
in blood samples stimulated with anti-IgM .


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PREVIOUS TEXT
2.3.3 Part C: Chronic Spontaneous Urticaria Subjects
Objectives 
Endpoints
Exploratory
Pharmacodynamics as assessed by the 
Urticaria activity score 
Urticaria Activity Score: Assess measures of 
weal characterisation in CsU subjects within 
treated area only
Pharmacodynamics as assessed by the 
Urticaria activity score

Urticaria Activity Score, a composite score 
using key urticaria symptoms (number of 
weal, itch/pruritus), to derive change from 
baseline for the 7 days after dosing
To measure of Quality of Life 

Dermatology Life Quality Index (DLQI) 
questionnaire 
To measure disease activity

Angioedema Activity Score (AAS)
Investigate relationships between (basophil 
histamine release) BHR test and weal 
characteristics

Relationship of positive BHR test with 
reduction in number or size of weals
Systemic measure of target pharmacology
Determine CD69 expression in an ex vivo blood 
sample following CD69  stimulation 
Systemic measure of target pharmacology

Percent inhibition of CD69 expressing cells 
in blood samples stimulated with anti-IgM.
PREVIOUS TEXT
Nominal % BSA
Actual surface to spread 
the active or placebo 
cream on:
Weight of active or 
placebo cream to be 
applied
0.2% BSA
36 cm2
0.36g
1% BSA
180 cm2
1.8g
5% BSA
900 cm2
9g
10% BSA
1800 cm2
18g
20%
3600 cm2
36g
REVISED TEXT
Nominal % BSA
Actual surface to spread 
the active or placebo 
cream on:
Weight of active or 
placebo cream to be 
applied
0.2% BSA
36 cm2
0.36g
1% BSA
180 cm2
1.8g
3.5% BSA
630 cm2
6.3g
5% BSA
900 cm2
9g
10% BSA
1800 cm2
18g
20%
3600 cm2
36g


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PREVIOUS TEXT
Table 6
Part B: Cold urticaria treatment
Days 1-3
Area
Morning dosing
Both 
Arms
9g of 1% strength GSK2646264 or placebo applied 
to 900cm2 (5% BSA) on each arm and the volar 
aspect of each arm must be included.  = Total 
BSA = 10% (18g)
REVISED TEXT
Table 7
Part B: Cold urticaria treatment (first n=4 subjects)
Days 1-3
Area
Morning dosing
Both 
Arms
9g of 1% strength GSK2646264 or placebo applied 
to 900cm2 (5% BSA) on each arm and the volar 
aspect of each arm must be included.  = Total 
BSA = 10% (18g)
12.8.1.1
Changes after review of preliminary data of n=4 from Part B by the 
Safety Monitoring Committee
Following the review by the Safety Monitoring Committee (see Section 5.5), changes 
were made to Part B for the remaining n=8 subjects, as shown in Table 5.
Table 8
Part B: Cold urticaria treatment (remaining n=8 subjects)
Days 1-3
Area
Morning dosing
Both 
Arms
6.3g of 1% strength GSK2646264 or 
placebo to be applied to a total area of 
630cm2 (3.5% BSA), spread over the 2 
arms, and the volar aspect must be 
included. The investigator should use 
their discretion as to how much cream 
is applied to each arm, but it must be 
equivalent to 3.5% BSA in total. 


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PREVIOUS TEXT
3.1.5 Part C :A double-blind (sponsor unblinded) placebo-controlled, 
randomised to active or placebo treatment 7 days repeat dose study, 
in subjects with mild to moderate Chronic Spontaneous Urticaria 
(CsU)
Subjects will be randomised to 3:1 ratio to receive active treatment or placebo applied to 
areas of the body chosen by the investigator once a day for 7 days. The chosen area 
where cream is applied will remain the same throughout the dosing period. Dosing in Part 
C will only commence once relevant data from the first four subjects in Part B have been 
reviewed, to allow greater confidence in predictions of the pharmacokinetics in Part C. 
The BSA over which study treatment will be administered in Part C is anticipated to be 
10%, but is subject to change, if appropriate, based on preliminary data from Part B (see 
Figure 4 for a visual representation). However, the maximum BSA will not exceed 20%.
The first four subjects of Part C will be randomised so that one of the four subjects will 
receive placebo and the three other subjects will receive GSK2646264. An informal 
review of the preliminary data from the first 4 subjects may be conducted after they have 
completed the study. PK, safety, and tolerability, up to and including the follow-up visit, 
will be reviewed by the Sponsor (See Section 5.5). If required, a discussion with the SMC 
regarding any changes or adjustments to the dosing regimen in Part C will be held. 
Recruitment of the full planned cohort (n=16) may continue during any data review.
The timing and the assessments to be completed at each visit are provided in the Time 
and Event tables (Section 6.1.4). Early termination of this patient group may occur due to 
feasibility of recruitment and stopping criteria see (Section 5.5 and Section 5.6). 
Following inclusion in the study, subjects will be randomised. 10 mg/cm2 of 1% 
GSK2646264cream or placebo cream will be applied to a given BSA once per day on 
days 1 to 7, inclusive, on areas of the body chosen by the investigator once a day for 7 
days. The areas where cream is applied will remain the same for each day of dosing.The 
10 % BSA can be distributed between the arms, legs and torso for an individual subject 
and will be decided by the investigator prior to randomisation. This pattern of cream 
application will remain the same for the duration of dosing. The maximum % BSA and 
the frequency of dosing will be decided after part A of the study but will not exceed 20% 
BSA.  
The subjects will be dosed in the unit for the first dose on day 1 and then discharged from 
the clinic. Doses and assessments on days 2 and 3 can occur either in the clinic or at 
home with the study nurse.  Subjects will return to the clinic prior to the dose and 
specified assessments on days 4 and 7. Dosing can occur at home or at the clinic on days  
5 and 6.  Subjects will be asked to complete a daily diary over the 7 days. Details of the 
diary will be provided in the Study Procedures Manual (SPM)
18g of 1% GSK2646264 cream or placebo cream will be applied to 1800cm2 (~10% 
BSA) on Day 1.  The same 1800 cm2 will be used for the 7 days duration of dosing. The 
cream can be applied to any of the arms, legs or torso and the location and size of each 
application documented but must be the same area every day.


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REVISED TEXT
3.1.5 Part C : A double-blind (sponsor unblinded) placebo-controlled, 
randomised to active or placebo treatment repeat dose study (3 
doses over 7 days), in subjects with mild to moderate Chronic 
Spontaneous Urticaria (CsU)
Subjects will be randomised to a 3:1 ratio to receive active treatment or placebo applied 
to areas of the body chosen by the investigator once a day every 3 days, over a total 
period of 7 days.  Dosing will occur on days 1, 4 and 7. The chosen area where cream is 
applied will remain the same throughout the dosing period. Dosing in Part C will only 
commence once relevant data from the first four subjects in Part B have been reviewed, 
to allow greater confidence in predictions of the pharmacokinetics in Part C. The BSA 
over which study treatment will be administered in Part C will be 10%, but is subject to 
change, if appropriate, based on preliminary data from the first 4 subjects in Part C 
However, the maximum BSA will not exceed 20% (see Figure 4 for a visual 
representation of the dosing schedule).
The first 4 subjects of Part C will be randomised so that one of the 4 subjects will receive 
placebo and the three other subjects will receive GSK2646264. An informal review of the 
preliminary data from the first 4 subjects may be conducted after they have completed the 
study. PK, safety, and tolerability, up to and including the follow-up visit, will be 
reviewed by the Sponsor (See Section 5.5). If required, a discussion with the SMC 
regarding any changes or adjustments to the dosing regimen in Part C will be held. 
Recruitment of the full planned cohort (n=16) may continue during any data review.
The timing and the assessments to be completed at each visit are provided in the Time 
and Event tables (Section 6.1.4). Early termination of this patient group may occur due to 
feasibility of recruitment and stopping criteria see (Section 5.5 and Section 5.6). 
Following inclusion in the study, subjects will be randomised. 10 mg/cm2 of 1% 
GSK2646264 cream or placebo cream will be applied to a given BSA once per day, every 
3 days, on  days 1, 4and 7, on areas of the body chosen by the investigator. The areas 
where cream is applied will remain the same for each day of dosing. The 10 % BSA can 
be distributed between the arms, legs and torso for an individual subject and will be 
decided by the investigator prior to randomisation. This pattern of cream application will 
remain the same for the duration of dosing. The maximum % BSA and the frequency of 
dosing will be decided after Part A and n=4 in Part B of the study but will not exceed 
20% BSA.  
The subjects will be dosed in the unit for the first dose on day 1 and then discharged from 
the clinic.  Subjects will return to the clinic prior to the dose and specified assessments on 
days 4 and 7. Subjects will be asked to complete a daily diary over the 7 days. Details of 
the diary will be provided in the Study Procedures Manual (SPM).


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PREVIOUS TEXT
3.2.1.3
Part C: Chronic Spontaneous Urticaria Subjects
This part of the study will provide safety, tolerability, PK and PD over 7 days of dosing
(with an additional 2 weeks follow-up post last dose for PK, safety and biomarker 
endpoints) to enable further clinical studies in this population.
REVISED TEXT
3.2.1.3
Part C: Chronic Spontaneous Urticaria Subjects
This part of the study will provide safety, tolerability, PK and PD from dosing every 3 
days, over a total period of 7 days  (with an additional 2 weeks follow-up post last dose 
for PK, safety and biomarker endpoints) to enable further clinical studies in this 
population.
ADDITIONAL TEXT
3.2.2.2 Additional preliminary data from Part A
Preliminary human PK data from Part A (up to 1% strength, up to 10% BSA) 
demonstrated a geometric mean Cmax after 4 days dosing of 5.59 ng/ml, providing a 
margin of  2.8 in comparison to the Cmax NOEL achieved (~16ng/ml) . After 4 days of 
dosing the geometric mean AUC was 103.8 ng∙h/ml, allowing a 2.1 fold systemic margin 
compared to the AUC(0-t) at the NOAEL.
This allows 3 days dosing at 1% strength, 10% BSA for Part B.  For further progression 
of dosing in parts B and C refer to Section 5.5.3.3
Further predictive modeling using the data from Part A, but with no inclusion of 
elimination rate, suggests that coverage of 10% BSA using the 1% cream over 7 days of 
dosing would lead to an estimated Cmax of 10.12ng/ml and an AUC of  219.8ng∙h/ml.
The information in the above paragraph is superseded by the information in section 
3.2.2.3.
3.2.2.3 Additional preliminary data from Part B
A population pharmacokinetic model integrating all plasma data from part A and 
the preliminary data from n=4 in part B lead to an estimation of the half life of 57 
hours for GSK2646264. This model shows that in order to maintain a 1.8 fold 
margin with the AUC NOAEL to allow women of child bearing potential in the trial 
the doses should be administered every three days, over a total 7 day duration, 
rather than every day.


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PREVIOUS TEXT
Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-
monitoring/stopping 
criteria
Hypersensitivity
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.  
There is no previous 
experience of 
GSK2646264 or of the 
matched placebo in 
humans
Subjects will be asked 
at screening if they are 
allergic to any of the 
ingredients – if known, 
Subjects will be 
excluded from the study 
if they are allergic to 
any ingredient of the 
study medications or if 
they have previously 
experienced an 
anaphylactic reaction. 
Subjects will undergo regular 
medical assessment and 
instructed what action to take 
in the event of experiencing 
an allergic reaction.  
Skin prick  
There have been rare 
reports of systemic 
allergic reactions 
following skin prick 
testing (Heinzerling, 
2013)
Subjects will be 
excluded from the study 
if have previously 
experienced an 
anaphylactic reaction. 
Subjects will be 
excluded from the study 
if the subject has a 
reaction which 
contraindicates to the 
study
Skin prick testing will be 
performed in a facility with 
appropriate emergency 
equipment available in case 
of the need for treatment for  
systemic allergic reaction.  
Pregnancy and 
lactation
There is no data 
available on the effect 
of GSK 2646264 in 
pregnancy and 
lactation in humans.
Fetal malformations 
were seen after IV 
dosing to pregnant 
rabbits with a NOAEL 
that is expected to 
exceed the highest 
expected human 
exposure by >4 fold.  
No similar changes 
were seen in the rat 
after substantially 
higher exposure 
Female subjects of non 
child bearing potential 
will be included in Part 
A of the study.
Female subjects that 
are of child-bearing 
potential will be required 
to follow the 
contraceptive 
requirements that are 
outlined in the protocol 
Section 4.2.1 inclusion 
criteria for Part B and C. 
A decision to allow 
females of child-bearing 
potential in Parts B and 
C will be made based 
on the safety margin 
from the dosing in Part 
Female subjects that are of 
child-bearing potential will  
undergo regular pregnancy 
testing and treatment stopped 
immediately if a subject is 
found to be pregnant during 
the study.
These subjects must be on 
oral contraceptives 28 days 
before screening begins. 
They will undergo serum 
pregnancy testing at day -28, 
day -7 to -4, a serum or urine 
pregnancy test the day of the 
start of the study prior to 
dosing, then testing on an 
approximately weekly basis 
and a serum pregnancy test 
at the follow up visit.


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Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-
monitoring/stopping 
criteria
A of the study.
Nursing females will be 
excluded from 
participating in the 
study.  
Immune cell effects, 
including neutropenia
SYK is involved in 
immunoreceptor 
signalling in a number 
of cell types, including 
mast cells, basophils, 
B cells, neutrophils 
and macrophages 
(Riccaboni, 2010)
Studies with R788 in 
rheumatoid arthritis 
identified an increased 
risk of neutropenia in 
subjects treated with 
the oral SYK inhibitor 
compared to placebo 
(placebo 0.7%, R788 
150mg OD 6.6%, 
R788 100mg BD 
5.9%) (Weinblatt,
2010)   
Subjects with co-morbid 
conditions that would 
put them at risk or 
laboratory values 
outside the reference 
range at screening 
would be excluded from 
participating in the 
study.  
The product is being 
investigated in a topical 
formulation, which should 
limit potential systemic 
exposure.  Increasing 
exposure will be performed 
gradually.  
Subjects will undergo regular 
haematological assessments, 
including white blood cell 
counts during the study.  
Treatment would be stopped 
if laboratory test results are 
identified that would put the 
safety of the subject at risk. 
Thyroid 
Minimal thyroid 
follicular epithelial 
hypertrophy was 
observed in all doses 
following iv 
administration of 
GSK2646264 in rats 
for 4 weeks. 
Thyroid function test 
(TSH, free and total T3 
and T4) at single 
timepoints 12 hours 
post last dose were 
within normal range.
Requirement for normal 
TSH in all subjects in 
Part A, and normal 
TSH, free T4, T4 and 
T3 in Parts B and C.. 
Exclusion of subjects 
with history of Graves’ 
disease or any  thyroid 
cancer
The risk of thyroid effect in 
this study is considered not to 
be significant. Monitoring will 
be based on signs and 
symptoms and serum 
markers of thyroid function 
will be measured in patients 
in Parts B and C.


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REVISED TEXT
Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-
monitoring/stopping 
criteria
Hypersensitivity
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.  
There is no previous 
experience of 
GSK2646264 or of the 
matched placebo in 
humans
Subjects will be asked 
at screening if they are 
allergic to any of the 
ingredients – if known, 
Subjects will be 
excluded from the study 
if they are allergic to 
any ingredient of the 
study medications or if 
they have previously 
experienced an 
anaphylactic reaction. 
Subjects will undergo regular 
medical assessment and 
instructed what action to take 
in the event of experiencing 
an allergic reaction.  
Skin prick 
There have been rare 
reports of systemic 
allergic reactions 
following skin prick 
testing (Heinzerling, 
2013)
Subjects will be 
excluded from the study 
if have previously 
experienced an 
anaphylactic reaction. 
Subjects will be 
excluded from the study 
if the subject has a 
reaction which 
contraindicates to the 
study
Skin prick testing will be 
performed in a facility with 
appropriate emergency 
equipment available in case 
of the need for treatment for  
systemic allergic reaction.  
Pregnancy and 
lactation
There is no data 
available on the effect 
of GSK 2646264 in 
pregnancy and 
lactation in humans.
Fetal malformations 
were seen after IV 
dosing to pregnant 
rabbits with a NOAEL 
that is expected to 
exceed the highest 
expected human 
exposure by >4 fold.  
No similar changes 
were seen in the rat 
after substantially 
higher exposure 
Female subjects of non 
child bearing potential 
will be included in Part 
A of the study.
Female subjects that 
are of child-bearing 
potential will be required 
to follow the 
contraceptive
requirements that are 
outlined in the protocol 
Section 4.2.1 inclusion 
criteria for Part B and C. 
A decision to allow 
females of child-bearing 
potential in Parts B and 
C will be made based 
on the safety margin 
from the dosing in Part 
Female subjects that are of 
child-bearing potential will  
undergo regular pregnancy 
testing and treatment stopped 
immediately if a subject is 
found to be pregnant during 
the study.
In part B, these subjects 
must be on oral 
contraceptives 28 days 
before screening begins. 
They will undergo serum 
pregnancy testing at day -28, 
day -7 to -4, a serum or urine 
pregnancy test the day of the 
start of the study prior to 
dosing, then testing on an 
approximately weekly basis 
and a serum pregnancy test 
at the follow up visit.


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Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-
monitoring/stopping 
criteria
A of the study.
Nursing females will be 
excluded from 
participating in the 
study.  
In Part C, a serum 
pregnancy test will be 
performed on the day of 
screening. If this is 
between Days -13 and -7, a 
further pregnancy test will 
not be required until Day 1.  
However, if the day of 
screening is between Day -
28 and -14, an additional 
serum pregnancy test will 
be required between Days -
7 and -4.  A urine 
pregnancy test will be 
required prior to dosing on 
Day 1
Immune cell effects, 
including neutropenia
SYK is involved in
immunoreceptor 
signalling in a number 
of cell types, including 
mast cells, basophils, 
B cells, neutrophils 
and macrophages 
(Riccaboni, 2010)
Studies with R788 in 
rheumatoid arthritis 
identified an increased 
risk of neutropenia in 
subjects treated with 
the oral SYK inhibitor 
compared to placebo 
(placebo 0.7%, R788 
150mg OD 6.6%, 
R788 100mg BD 
5.9%) (Weinblatt, 
2010)   
Subjects with co-morbid 
conditions that would 
put them at risk or 
laboratory values 
outside the reference 
range at screening 
would be excluded from 
participating in the 
study.  
The product is being 
investigated in a topical 
formulation, which should 
limit potential systemic 
exposure.  Increasing 
exposure will be performed 
gradually.  
Subjects will undergo regular 
haematological assessments, 
including white blood cell 
counts during the study.  
Treatment would be stopped 
if laboratory test results are 
identified that would put the 
safety of the subject at risk. 
Thyroid 
Minimal thyroid 
follicular epithelial 
hypertrophy was 
observed in all doses 
following iv 
administration of 
GSK2646264 in rats 
for 4 weeks. 
Thyroid function test 
(TSH, free and total T3 
and T4) at single 
Requirement for normal 
TSH in all subjects in 
Part A, and normal 
TSH, free T4, T4 and 
T3 in Parts B and C.. 
Exclusion of subjects 
with history of Graves’ 
disease or any  thyroid 
cancer
The risk of thyroid effect in 
this study is considered not to 
be significant. Monitoring will 
be based on signs and 
symptoms and serum 
markers of thyroid function 
will be measured in patients 
in Parts B and C.


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Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-
monitoring/stopping 
criteria
timepoints 12 hours 
post last dose were 
within normal range.
PREVIOUS TEXT
Section 4.2.1.3 and Section 4.2.1.4
9. Female subjects must agree to use one of the contraception methods listed in Section 
4.3.1 28 days before their screening visit and until the followup visit or  a time period 
that is 5 terminal half-live post-last dose which will be determined following Part A 
of the studylonger.
REVISED TEXT
Section 4.2.1.3 and Section 4.2.1.4
9. Female subjects of child bearing potential must have been using one of the 
contraception methods listed in Section 4.3.1 at least 28 days before their screening 
visit and agree to continue with these methods until the follow up visit or 12 days 
after the last dose of study treatment, whichever is the longer.
Section 4.2.2
ADDITIONAL TEXT
13. A positive drug screen at screening or Day -1. For Part B and Part C patients, a 
positive drug screen due to concomitant medication may be acceptable for inclusion in 
the study based on the Investigator’s opinion. The Investigator’s opinion must be based 
on interview of the subject, documented in the medical history and the Investigator is 
asked to document that the positive test can be explained by a relevant and permitted 
medication (see Section 5.1.5.1.) and that the medication will not interfere with the study 
procedures or compromise subject safety.
Section 4.3.2.2
ADDITIONAL TEXT
Fasting

Subjects will be required to be fasted prior to the screening visit.
Section 4.3.3.1


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PREVIOUS TEXT
In all dose cohorts, subjects will be allowed to shower/bathe approximately 2 hours prior 
to dosing and approximately 18-22 hours following dosing. During showering/bathing 
the subject should use their normal soap or shower gel (mild, unscented and non-
medicated). A mild shampoo can be used for washing hair. The site of blood sampling 
will be protected (taped off and covered) allowing the subjects to shower freely, 
including washing the application site(s).
Timings of showering/bathing will be recorded.
Subjects must refrain from taking part in water based activities such as swimming and 
use of sauna/steam room for the duration of dosing until the follow-up visit.
REVISED TEXT
In all dose cohorts, subjects will be allowed to shower/bathe approximately 2 hours prior 
to dosing and approximately 18-22 hours following dosing. During showering/bathing 
the subject should only use mild, unscented, and non-medicated soap A mild shampoo 
can be used for washing hair. The site of blood sampling will be protected (taped off and 
covered) if required, allowing the subjects to shower freely, including washing the 
application site(s). Subjects should refrain from rubbing the areas where the cream has 
been applied.
Timings of showering/bathing must be recorded (as detailed in the SPM).
Subjects must refrain from taking part in water based activities such as swimming and 
use of sauna/steam room for the duration of dosing until the follow-up visit.
Section 5.12 Assessment of Compliance
PREVIOUS TEXT
In Part A & B - When subjects are dosed at the study unit, they will receive study 
treatment directly from the investigator or designee, under medical supervision.  The date 
and start and end times of each dose administration in the clinic will be recorded in the 
source documents and transcribed into the InForm eCRF.  The dose of study treatment 
and study participant identification will be confirmed at the time of dosing by a member 
of the study site staff other than the person administering the study treatment.  
In Part C- Subjects will visit the unit on the days as listed in the Time and Events table. 
On days where they do not visit the unit a study nurse will transport the treatment in the 
bottles (of known weight) as required for the nominal dose to be applied, from the site 
pharmacy to the subject’s home. The study nurse shall administer the study treatment to 
the subject in their home environment. The date, start and end times of each dose 
administration will be recorded on cource documents and transcribed into the InForm 
eCRF. After the study visit is completed, the study nurse will return the bottles to the site 
pharmacy and weigh the bottles.


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REVISED TEXT
When subjects are dosed at the study unit, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and start and end times 
of each dose administration in the clinic will be recorded in the source documents and 
transcribed into the InForm eCRF.  The dose of study treatment and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study treatment.


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Section 6.1.3
PREVIOUS TEXT
Day:
Screening
-1
1
2
3
4
Day 6 to 15
Follow-
up (Day 
17-19)
Notes
Visit Window  
(relative to Day 1)
-28 to -7   
days
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without 
shoes
X
Brief physical
X
Medical/medication/
X
drug/alcohol history
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and CV risk factors questionnaire 
Vital signs
X
X
X
X
X
X
X
Urine drug/alcohol 
screen
X
X
Pregnancy Test 
(women)2
X(S)
X(S/U)
X (S)
X(S)
2. Pregnancy test will be performed 3 times during screening, serum on day 
-28, day -7 to -4, and a serum or urine pregnancy test the day of the start of 
the study prior to dosing and a serum pregnancy test  between day 10-12 (to 
coincide with a PK sample) and at the follow up visit. 
HIV, Hep B and Hep 
C screen
X
Clinical Laboratory 
Tests
X
X
X
X
Allergen Challenge-
SPT
X3,4
X3,6
X3,5
X9
3. SPT- Skin Prick Test measurements will be performed ~15-20mins post 
challenge
13.
4. SPT using all 4 specified allergens


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Day:
Screening
-1
1
2
3
4
Day 6 to 15
Follow-
up (Day 
17-19)
Notes
14.
5. SPT will be performed at  6 hours post dose (see Section 
6.4.1)
6. SPT will be performed pre-dose
TSH, free T4, T4, T3
X
x
X7
x
7. One sample between  day 10-12
Cold Temp Test 
(Temp Test 4.0)
X
X8
X10
X9
8. Pre-dose
9. 24 hours post dose
10. 6 hours post dose
Randomisation
X
Tolerability 
Assessment
----- X11 -----
11. Tolerability assessment at pre – and ~6 hours post-dose
AE assessment 
X
---------X--------
X
Concomitant 
Medication
X
-------X-----------
X
Pharmacokinetic 
Blood Sample
X12
X12
X12
X12
X13
X
12.  PK blood sample taken at pre dose,1, 4, 8, 12hr post dose 
13. One PK blood sample per day will be taken as follows:. PK samples will 
be obtained on the following days (1 day): Day 6, 9, 12, & 15. 
Study Treatment 
Dosing
X
X
X
Discharge from unit
X
Outpatient visit
X
X
X
Blood Sample for 
CD69 expression12
X10
X11
X
X
10. Pre-dose
11. 4 hrs post-dose
12. Sample collection should coincide with PK sample collection.


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REVISED TEXT
Day:
Screening
-1
1
2
3
4
Day 6 
to 15
Follow-up 
(Day 17-19)
Notes
Visit Window  (relative 
to Day 1)
-28 to -7   
days1
1. Screening can occur on any day between 28 days and 7 days prior to 
Day 1 dosing.
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without 
shoes
X
Brief physical
X
Medical/medication/
X
drug/alcohol history
12-lead ECG
X2
X
X
X
2. Triplicate ECG at screening and CV risk factors 
Vital signs3
X
X
X
X
X
X
X
3.  Should be performed at the same time points as PK samples are taken
Urine drug/alcohol 
screen
X
X
Pregnancy Test 
(women)4
X(S)
X(S/U)
X (S)
X(S)
4. Pregnancy test will be performed 3 times during screening, serum on 
day -28, day -7 to -4, and a serum or urine pregnancy test the day of the 
start of the study prior to dosing and a serum pregnancy test  between day 
10-12 (to coincide with a PK sample) and at the follow up visit. 
HIV, Hep B and Hep C 
screen
X
Clinical Laboratory 
Tests
X
X
X
X
Allergen Challenge-
SPT
X5,6
X5,8
X5,7
X5
5. SPT- Skin Prick Test measurements will be performed ~15-20mins post 
challenge
6. SPT using all 4 specified allergens
7. SPT will be performed at  6 hours post dose (see Section 6.4.1), and at 
24 hours post last dose on day 3


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Day:
Screening
-1
1
2
3
4
Day 6 
to 15
Follow-up 
(Day 17-19)
Notes
8. SPT will be performed pre-dose on Day 1
TSH, free T4, T4, T3
X
x
X9
x
9. One sample between  day 10-12 to coincide with PK sample
Cold Temp Test (Temp 
Test 4.0)
X
X10
X11
X12
10. Pre-dose
11. 6 hours post dose
12. 24 hours post last dose on Day 3
Randomisation
X
Tolerability 
Assessment
------X13-----
13. Tolerability assessment at pre – and ~6 hours post-dose
AE assessment 
------------------X--------------------
X
Concomitant 
Medication
X
---------------X--------------
X
Pharmacokinetic Blood 
Sample
X14
X14
X14
X15
X16
X
14.  PK blood sample taken at pre dose,1, 4, 8, 12hr post dose 
15. One PK sample to be taken 24 hours post last dose on Day 3
16. One PK blood sample per day will be taken as follows:. PK samples 
will be obtained on the following days (± 1 day): Day 6, 9, 12, & 15. 
Study Treatment 
Dosing
X
X
X
Discharge from unit
X
Outpatient visit
X
X
X
Blood Sample for CD69 
expression
X17
X18
X19
X19
17. Pre-dose
18. 4 hrs post-dose
19. Sample collection should coincide with PK sample collection.


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Section 6.1.4
PREVIOUS TEXT
Day:
Screening
1
2
3
4
5
6
7
Day 
10 
Follow-
up
Notes
Visit Window (relative 
to Day 1)
-28 to -7
21-23
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without 
shoes
X
Brief physical
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and CV 
risk factors questionnaire
Vital signs
X
X
X
X
X13
X
13. nly conducted if subjects is 
attending the clinical site.
Urine drug/alcohol 
screen
X
X
Pregnancy Test 
(women)2
X(S)
X 
(S/U)
X(S)14
X(S)
2. Pregnancy test will be performed 3 
times during screening, serum (S) on 
day -28, day -7 to -4, and a serum or 
urine (U) pregnancy test the day of the 
start of the study prior to dosing and a 
serum pregnancy test between day 14-
16 and at the follow up visit
14. Samples should be obtained at 
approximately 1 week intervals


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Day:
Screening
1
2
3
4
5
6
7
Day 
10 
Follow-
up
Notes
HIV, Hep B and Hep C 
screen
X
Clinical Laboratory 
Tests
X
X
X
X
TSH, free T4, T4, T3
X
X
X
3. Between Days 14-16
Blood Sample for 
CD69 expression
X4
X5
X5
X6
X
4. Predose
5. 4 hours post dose
6. Sample to be taken every time a PK
sample is taken
Randomisation
X
UAS-7 Diary7
X
X
X
X
X
X
X
X
7. Screening UAS7 diary will be
completed  using 7 successive days
before randomisation (day 1). If there is
a lapse in any day prior to day 1 the
subject must complete the full 7 days
worth of diary entries again during the
screening period.
QOL (DLQI)
X
X
X
AAS
X15
X
X
X
X
X
X
X
15. Screening AAS  will be completed
using 7 successive days before
randomisation (day 1) on the same
days as the UAS7. If there is a lapse in
any day prior to day 1 the subject must
complete the full 7 days worth of diary
entries again during the screening
period.
AE assessment
X --------------------------------
X


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Day:
Screening
1
2
3
4
5
6
7
Day 
10 
Follow-
up
Notes
Tolerability 
Assessment at pre-
dose
X8 -------------------------------
8. Tolerability assessment at pre dose
on each day.
BHR- Basophil 
Histamine Release 
Test  
X9
9. Two samples to be taken predose
Pharmacokinetic 
Blood Sample
X10
X10
X10
Study Treatment 
Dosing
X
X12
14.1.
X12
X
14.2.
X12
X12
X
12. The subject may have study
treatment applied at home by a nurse
or they can travel to the clinic
Con Meds 
X ---------------------------------
Outpatient visit
X
X
X
X
x
X
REVISED TEXT
Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
Visit Window 
(relative to Day 1)
-28 to -71
1. Screening can occur on any
day between 28 days and 7 days
prior to Day 1 dosing.
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) 
without shoes
X
Brief physical
X
X


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Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
Medical/medicatio
n/drug/alcohol 
history
X
12-lead ECG
X2
X
X
X
2. Triplicate ECG at screening and 
CV risk factors 
Vital signs
X
X
X
X
X3
X3
X3
3. To be performed on same day as 
PK samples 
Urine alcohol 
screen
X
X
Pregnancy Test 
(Women of child 
bearing potential)4
X(S)4
X (U)5
X(U)5
X (S)
X(S)
4. A serum (S) pregnancy test will be 
performed on the day of screening.  
If the day of screening is between 
Days -13 and -7, a further pregnancy 
test will not be required until Day 1. 
However, if the day of screening is 
between Days -28 and -14, an 
additional serum pregnancy test will 
be required between Days -7 and -4. 
5. A urine pregnancy test is required 
prior to dosing on Day 1 & Day 7
HIV, Hep B and 
Hep C screen
X
Clinical Laboratory 
Tests
X
X
X
X
TSH, free T4, T4, 
T3
X
X
X6
X6
X6
6. Sample to be taken on same day 
as PK sample 
Blood Sample for 
CD69 expression
X7
X8
X8
X9
X9
X9
7. Pre-dose
8.  4 hours post dose
9. Sample to be taken on same day 
as PK sample 
Randomisation
X


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Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
UAS-7 Diary
X10
X11
X11
X11
X11
X11
X11
X
10. Screening UAS7 diary will be 
completed for the 7 successive days 
before Randomisation (Day 1). If 
there is a lapse in any day prior to 
Day 1 the subject must complete the 
full 7 days worth of diary entries 
again during the screening period.
11.  The UAS-7 diary should be 
completed pre-dose on those days 
where dosing occurs 
QOL (DLQI)
X
X12
X
12.  The baseline DLQI assessment 
on Day 1, looking back over the 
previous 7 days prior to dosing, 
should be completed pre-dose
AAS
X13
X14
X14
X14
X14
X14
X14
X
13. Screening AAS will be completed 
for the 7 successive days before 
Randomisation (Day 1) (on the same 
days as the UAS7). If there is a 
lapse in any day prior to Day 1 the 
subject must complete the full 7 days 
worth of diary entries again during 
the screening period.
14.  The AAS assessment should be 
completed pre-dose on those days 
where dosing occurs
AE assessment
------------------------------------------------X--------------------------------------------
x
Tolerability 
Assessment at 
pre-dose
X15
X15
X15
15. Tolerability assessment at pre-
dose on each day.
BHR- Basophil 
Histamine Release 
Test  
X16
16. Two samples to be taken pre-
dose 


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Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
Pharmacokinetic 
Blood Sample
X17
X17
X17
X18
X18
X18
17. PK blood sample taken at pre-
dose and 4hr post dose
18. Sample to be taken on same 
day as CD69 sample, TSH, free T4, 
T4, T3 samples and vital signs
Study Treatment 
Dosing
X
X
X
Con Meds 
------------------------------------------------X--------------------------------------------
X
Outpatient visit
X
X
X
X
x
X
X


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Section 6.3.3 Electrocardiogram (ECG)
ADDITIONAL TEXT

A CV risk factors questionnaire will also be completed at screening
Section 6.3.4 Clinical Laboratory Assessments
PREVIOUS TEXT
Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Albumin
Glucose (fasting)
Calcium
GGT
Total Protein
Sodium
Phosphate
Alkaline phosphatase
TSH , free T4, T4, 
T3
REVISED TEXT
Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Albumin
Glucose, (fasting 
at screening 
only)
Calcium
GGT
Total Protein
Sodium
Phosphate
Alkaline phosphatase
TSH , free T4, T4, 
T3
Section 6.5.2
PREVIOUS TEXT
Part C
For the chronic spontaneous urticaria subjects, Urticaria activity score (UAS7), a 
composite endpoint, will be derived using key urticaria symptoms (number of weal, 
itch/pruritus):
UAS7 components will be captured using a daily diary for 7 days.  The daily UAS7 score 
will be the sum of each key component score. A detail of UAS7 daily diary is provided in 
Appendix 3.
The Angioedema Activity Score (AAS)
For the chronic spontaneous urticaria subjects, will be captured between baseline and 
Day 7 using the Angioedema Activity Score (AAS).  Details of the questionnaire are 


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provided in Appendix 7.
Health Outcomes
Dermatology Life Quality Index
For the chronic spontaneous urticaria subjects, health outcome measure will be captured 
at baseline and Day 7, using a 10-item Dermatology Life Quality Index (DLQI) (Finlay, 
1994) questionnaire.  An overall score will be calculated as well as the following 
domains: Symptoms and Feelings, Daily Activities, Leisure, Work and School, Personal 
Relationships, and Treatment. A detail of questionnaire is provided in Appendix 4.
REVISED TEXT
Part C
Urticaria Activity Score (UAS7)
For the chronic spontaneous urticaria subjects in Part C, Urticaria activity score (UAS7), 
a composite endpoint, will be derived using key urticaria symptoms (number of weal, 
itch/pruritus):
UAS7 components will be captured using a daily diary for 7 days.  The daily UAS7 score 
will be the sum of each key component score. A detail of UAS7 daily diary is provided in 
Appendix 3. The days on which to record in the UAS7 diary are captured in the 
T&E Table (Section 6.1.4).  On days where dosing occurs, the UAS7 diary will be 
completed pre-dose.
The Angioedema Activity Score (AAS)
For the chronic spontaneous urticaria subjects in Part C, the Angioedema Activity Score 
(AAS) will be captured during Screening, and between Day 2 and Day 8.  Details of the 
questionnaire are provided in Appendix 7. The days on which to record the AAS are 
captured in the T&E Table (Section 6.1.4).  On days where dosing occurs, the AAS 
will be completed pre-dose.
6.6 Health Outcomes
6.6.1 Dermatology Life Quality Index
For the chronic spontaneous urticaria subjects in Part C,  the health outcome measure of 
Quality of Life will be captured at Screening,  Baseline and Day 8, using a 10-item 
Dermatology Life Quality Index (DLQI) (Finlay, 1994) questionnaire.  An overall score 
will be calculated as well as the following domains: Symptoms and Feelings, Daily 
Activities, Leisure, Work and School, Personal Relationships, and Treatment. A detail of 
questionnaire is provided in Appendix 4.  The days on which to record the DLQI are 
captured in the T&E Table (Section 6.1.4).  On days where dosing occurs (Day 1 
only), it will be completed pre-dose.


2013N167482_05
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174
AMEDMENT 5
Summary of Amendment Changes with Rationale
The reason for this amendment is to document an administrative change in GSK primary 
medical monitor. Minor corrections also included below for the Part C T&E table.
List of specific changes:
SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
PREVIOUS TEXT:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell
/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
GSK Clinical Unit 
Cambridge, Addenbrooke’s 
Hospital, Box 128, ACCI 
Building, Hills Road, 
Cambridge CB2 0GG, UK
Secondary 
Medical 
Monitor
Experimental Medicine Unit,
Immuno-inflammation 
Therapy Unit
GlaxoSmithKline Medicines 
Stevenage, Hertfordshire 
SAE fax 
number 
XXX
PPD


2013N167482_05
CONFIDENTIAL
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175
REVISED TEXT:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell
/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
n/a
Experimental Medicine Unit,
Immuno-inflammation 
Therapy Unit
GlaxoSmithKline Medicines 
Stevenage, Hertfordshire
Secondary 
Medical 
Monitor
Experimental Medicine Unit,
Immuno-inflammation 
Therapy Unit
GlaxoSmithKline Medicines 
Stevenage, Hertfordshire 
SAE fax 
number 
XXX
PPD
PPD


2013N167482_05
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176
Section 6.1.4, Part C T&E Table
PREVIOUS TEXT:
Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
Visit Window 
(relative to Day 1)
-28 to -71
1. Screening can occur on any 
day between 28 days and 7 days 
prior to Day 1 dosing.
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) 
without shoes
X
Brief physical
X
X
Medical/medicatio
n/drug/alcohol 
history
X
12-lead ECG
X2
X
X
X
2. Triplicate ECG at screening and 
CV risk factors 
Vital signs
X
X
X
X
X3
X3
X3
3. To be performed on same day as 
PK samples 
Urine alcohol 
screen
X
X


2013N167482_05
CONFIDENTIAL
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177
Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
Pregnancy Test 
(Women of child 
bearing potential)4
X(S)4
X (U)5
X(U)5
X (S)
X(S)
4. A serum (S) pregnancy test will be 
performed on the day of screening.  
If the day of screening is between 
Days -13 and -7, a further pregnancy 
test will not be required until Day 1. 
However, if the day of screening is 
between Days -28 and -14, an 
additional serum pregnancy test will 
be required between Days -7 and -4. 
5. A urine pregnancy test is required 
prior to dosing on Day 1 & Day 7
HIV, Hep B and 
Hep C screen
X
Clinical Laboratory 
Tests
X
X
X
X
TSH, free T4, T4, 
T3
X
X
X6
X6
X6
6. Sample to be taken on same day 
as PK sample 
Blood Sample for 
CD69 expression
X7
X8
X8
X9
X9
X9
7. Pre-dose
8.  4 hours post dose
9. Sample to be taken on same day 
as PK sample 
Randomisation
X
UAS-7 Diary
X10
X11
X11
X11
X11
X11
X11
X
10. Screening UAS7 diary will be 
completed for the 7 successive days 
before Randomisation (Day 1). If 
there is a lapse in any day prior to 
Day 1 the subject must complete the 
full 7 days worth of diary entries 
again during the screening period.
11.  The UAS-7 diary should be 
completed pre-dose on those days 
where dosing occurs 


2013N167482_05
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Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
QOL (DLQI)
X
X12
X
12.  The baseline DLQI assessment 
on Day 1, looking back over the 
previous 7 days prior to dosing, 
should be completed pre-dose
AAS
X13
X14
X14
X14
X14
X14
X14
X
13. Screening AAS will be completed 
for the 7 successive days before 
Randomisation (Day 1) (on the same 
days as the UAS7). If there is a 
lapse in any day prior to Day 1 the 
subject must complete the full 7 days 
worth of diary entries again during 
the screening period.
14.  The AAS assessment should be 
completed pre-dose on those days 
where dosing occurs
AE assessment
------------------------------------------------X--------------------------------------------
x
Tolerability 
Assessment at 
pre-dose
X15
X15
X15
15. Tolerability assessment at pre-
dose on each day
BHR- Basophil 
Histamine Release 
Test  
X16
16. Two samples to be taken pre-
dose 
Pharmacokinetic 
Blood Sample
X17
X17
X17
X18
X18
X18
17. PK blood sample taken at pre-
dose and 4hr post dose
18.  Sample to be taken on same 
day as CD69 sample, TSH, free T4, 
T4, T3 samples and vital signs
Study Treatment 
Dosing
X
X
X
Con Meds 
------------------------------------------------X--------------------------------------------
X
Outpatient visit
X
X
X
X
x
X
X


2013N167482_05
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179
REVISED TEXT:
Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
Visit Window 
(relative to Day 1)
-28 to -71
1. Screening can occur on any 
day between 28 days and 7 days 
prior to Day 1 dosing.
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) 
without shoes
X
Brief physical
X
Medical/medicatio
n/drug/alcohol 
history
X
12-lead ECG
X2
X
X
X
2. Triplicate ECG at screening and 
CV risk factors 
Vital signs
X
X
X
X
X3
X3
X3
3. To be performed on same day as 
PK samples 
Urine alcohol 
screen
X
X
Pregnancy Test 
(Women of child 
bearing potential)4
X(S)4
X (U)5
X(U)5
X (S)
X(S)
4. A serum (S) pregnancy test will be 
performed on the day of screening.  
If the day of screening is between 
Days -13 and -7, a further pregnancy 
test will not be required until Day 1. 
However, if the day of screening is 
between Days -28 and -14, an 
additional serum pregnancy test will 
be required between Days -7 and -4. 


2013N167482_05
CONFIDENTIAL
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180
Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
5. A urine pregnancy test is required 
prior to dosing on Day 1 & Day 7
HIV, Hep B and 
Hep C screen
X
Clinical Laboratory 
Tests
X
X
X
X
TSH, free T4, T4, 
T3
X
X
X6
X6
X6
6. Sample to be taken on same day 
as PK sample 
Blood Sample for 
CD69 expression
X7
X8
X8
X9
X9
X9
7. Pre-dose
8.  4 hours post dose
9. Sample to be taken on same day 
as PK sample 
Randomisation
X
UAS-7 Diary
X10
X11
X11
X11
X11
X11
X11
X
10. Screening UAS7 diary will be 
completed for the 7 successive days 
before Randomisation (Day 1). If 
there is a lapse in any day prior to 
Day 1 the subject must complete the 
full 7 days worth of diary entries 
again during the screening period.
11.  The UAS-7 diary should be 
completed pre-dose on those days 
where dosing occurs 
QOL (DLQI)
X
X12
X
12.  The baseline DLQI assessment 
on Day 1, looking back over the 
previous 7 days prior to dosing, 
should be completed pre-dose


2013N167482_05
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181
Day:
Screening
1
2
3
4
5
6
7
8
Day 10 (± 
1 day)
Day 15 (± 1 
day)
Follow-up 
Day 22 (± 1 
day)
Notes
AAS
X13
X14
X14
X14
X14
X14
X14
X
13. Screening AAS will be completed 
for the 7 successive days before 
Randomisation (Day 1) (on the same 
days as the UAS7). If there is a 
lapse in any day prior to Day 1 the 
subject must complete the full 7 days 
worth of diary entries again during 
the screening period.
14.  The AAS assessment should be 
completed pre-dose on those days 
where dosing occurs
AE assessment
------------------------------------------------X--------------------------------------------
x
Tolerability 
Assessment at 
pre-dose
X15
X15
X15
15. Tolerability assessment at 1 to 2 
hours post-dose
BHR- Basophil 
Histamine Release 
Test  
X16
16. Two samples to be taken pre-
dose 
Pharmacokinetic 
Blood Sample
X17
X17
X17
X18
X18
X18
17. PK blood sample taken at pre-
dose and 4hr post dose
18.  Sample to be taken on same 
day as CD69 sample, TSH, free T4, 
T4, T3 samples and vital signs
Study Treatment 
Dosing
X
X
X
Con Meds 
------------------------------------------------X--------------------------------------------
X
Outpatient visit
X
X
X
X
x
X
X

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
200196
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for study 200196 A randomised 
double blind (sponsor unblinded), single and repeat ascending 
dose First Time in Human study in healthy subjects, cold 
urticaria and chronic spontaneous urticarial subjects to 
investigate safety, tolerability, pharmacodynamics and 
pharmacokinetics of GSK2646264
Compound Number 
:
GSK2646264
Effective Date 
:
30-MAR-2015
Description :

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 200196 [2013N167482_01].

This RAP is intended to describe the safety, pharmacokinetics and 
pharmacodynamics analyses required for the study for Parts A, B and C. 

An informal interim review of the data following Part A, so as to provide project 
team and GSK stakeholders with key data to inform internal decision making, in 
order to start the Part B and C (cold urticaria and spontaneous urticaria subjects) of 
this study will be performed.

This RAP will be provided to the study team members to convey the content of the 
[Reference as Required: Statistical Analysis Complete (SAC)] deliverable.
Author’s Name and Functional Area: 
30-MAR-2015
Principal Biostatistician (PAREXEL Early Phase)
Approved by: 
30-MAR-2015
Manager, Clinical Statistics
Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
200196
2
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.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analysis (Informal Data review).......................................................10
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................13
6.1.
Overview of Planned Analyses ...................................................................13
7.
PRIMARY STATISTICAL ANALYSES....................................................................14
7.1.
Safety Analyses..........................................................................................14
7.1.1.
Overview of Planned Analyses ....................................................14
7.1.1.1.
Dose Escalations........................................................15
8.
SECONDARY STATISTICAL ANALYSES .............................................................15
8.1.
Pharmacokinetic Analyses..........................................................................15
8.1.1.
Drug Concentration Measures .....................................................16
8.1.2.
Pharmacokinetic Parameters.......................................................16
8.1.2.1.
Deriving Pharmacokinetic Parameters........................16
8.1.2.2.
Statistical Analysis of Pharmacokinetic 
Parameters.................................................................17
9.
EXPLORATORY STATISTICAL ANALYSIS...........................................................17
9.1.
Pharmacodynamic and Biomarker Analyses...............................................17
9.1.1.
Overview of Planned Pharmacodynamic Analyses ......................17
9.1.2.
Planned Pharmacodynamic Statistical Analyses..........................19
9.1.2.1.
Part C: Chronic Spontaneous Urticaria 
Subjects .....................................................................19
9.1.2.2.
The Angioedema Activity Score (AAS) .......................19
9.1.2.3.
Relationships between Basophil Histamine 
Release (BHR) Test and Weal Characteristics ...........20
9.1.3.
Planned Health Outcome Statistical Analyses .............................21
9.1.3.1.
Health Outcomes Analyses/ Dermatology Life 
Quality Index ..............................................................21
9.1.4.
Overview of Planned Biomarker Analyses ...................................22
9.2.
Pharmacokinetics and Biomarker Analyses ................................................22


CONFIDENTIAL
200196
3
10. REFERENCES.......................................................................................................23
11. APPENDICES........................................................................................................24
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................25
11.1.1.
Protocol Deviation Definitions for Exclusion from 
predefined Populations ................................................................25
11.1.2.
Exclusions from Per Protocol Population .....................................25
11.2.
Appendix 2: Time & Events.........................................................................26
11.2.1.
Protocol Defined Time & Events ..................................................26
11.2.1.1.
Part A, Dose Group 1 (Healthy Volunteers)................26
11.2.1.2.
Part A: Healthy Volunteer Time and Event 
Table Dose group 2....................................................28
11.2.1.3.
Part B (Cold Urticaria Subjects)..................................30
11.2.1.4.
Part C (Chronic Spontaneous Urticaria Cohort)..........32
11.3.
Appendix 3: Data Display Standards & Handling Conventions....................35
11.3.1.
Study Treatment & Sub-group Display Descriptors......................35
11.3.2.
Baseline Definition & Derivations .................................................36
11.3.2.1.
Baseline Definitions....................................................36
11.3.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................37
11.3.3.
Reporting Process & Standards...................................................37
11.4.
Appendix 4: Derived and Transformed Data ...............................................40
11.4.1.
General........................................................................................40
11.4.2.
Study Population..........................................................................40
11.4.3.
Safety ..........................................................................................41
11.5.
Appendix 5: Premature Withdrawals & Handling of Missing Data ...............43
11.5.1.
Premature Withdrawals................................................................43
11.5.2.
Handling of Missing Data.............................................................43
11.5.2.1.
Handling of Missing Dates..........................................44
11.5.2.2.
Handling of Partial Dates............................................44
11.6.
Appendix 6: Values of Potential Clinical Importance ...................................45
11.6.1.
Laboratory Values........................................................................45
11.6.2.
ECG.............................................................................................46
11.6.3.
Vital Signs....................................................................................46
11.7.
Appendix 7: Examination of Covariates, Subgroups & Other Strata............48
11.7.1.
Handling of Covariates, Subgroups & Other Strata......................48
11.8.
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................49
11.8.1.
Statistical Analysis Assumptions..................................................49
11.9.
Appendix 9: Abbreviations & Trade Marks ..................................................50
11.9.1.
Abbreviations...............................................................................50
11.9.2.
Trademarks .................................................................................51
11.10. Appendix 10: List of Data Displays..............................................................52
11.10.1. Data Display Numbering..............................................................52
11.10.2. Mock Example Shell Referencing ................................................52
11.10.3. Deliverable [Priority].....................................................................52
11.10.4. Study Population Tables..............................................................53
11.10.5. Efficacy Tables ............................................................................54
11.10.6. Safety Tables...............................................................................55
11.10.7. Safety Figures .............................................................................58
11.10.8. Pharmacokinetic Tables...............................................................59


CONFIDENTIAL
200196
4
11.10.9. Pharmacokinetic Figures .............................................................60
11.10.10.Pharmacodynamic and Biomarker Tables....................................61
11.10.11.Pharmacodynamic Figures ..........................................................65
11.10.12.ICH Listings .................................................................................71
11.10.13.Non-ICH Listings..........................................................................74
11.11. Appendix 11: Example Mock Shells for Data Displays ................................76


CONFIDENTIAL
200196
5
1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose
The purpose of this RAP is to describe:

An informal interim analysis, so as to provide project team and GSK 
stakeholders with key data to inform internal decision making, in order to start 
the Part B and C (cold urticaria and spontaneous urticaria subjects) of this 
study.

This RAP will be provided to the study team members to convey the content of 
the [Reference as Required: Statistical Analysis Complete (SAC)] deliverable.
Protocol

This RAP is based on the protocol amendment 2 [(Dated: 10/DEC/2014) of 
study GSK2646264 (GSK Document Number: 2013N167482_01] and eCRF 
Version (Version 1, 09OCT2014).
Primary 
Objective

The primary objective is  to investigate the safety and tolerability of topically 
applied GSK2646264 cream and its placebo in healthy subjects, subjects with 
cold urticaria (CU) and subjects with chronic spontaneous urticaria (CsU)
Primary 
Endpoint

Safety and Tolerability (Number, severity and frequency of AEs and serious 
AEs (local and systemic), heart rate, blood pressure, 12- lead ECG, clinical 
laboratory safety tests, assessment of the local tolerability of the study 
medication
Study 
Design

Randomised, double blind (sponsor unblinded), bilateral, single and repeat 
ascending dose First Time in Human study in healthy subjects, cold urticaria 
and chronic spontaneous urticaria subjects.

Approximately 18 randomised evaluable subjects in Part A, and approximately 
12 randomised evaluable subjects in part B and C of study.
Planned 
Analyses

Safety and Tolerability, PK, PD (Allergen challenge, UAS7, AAS), Health 
Outcome (DLQI)
Analysis 
Populations

Primary: Safety population, 

Other: PK, PD, Per-Protocol populations
Hypothesis

There are no formal hypotheses being tested in the study; instead an estimation 
and inference approach will be adopted to evaluate the objectives.
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

Individual GSK2646264 plasma concentration-time profiles and median/mean 
(±SD) profiles will be plotted and listed. Plasma concentration time data for 
GSK2646264 will be analyzed by non-compartmental methods using WinNonlin 
and derived PK parameters (AUC, Cmax, Tmax, t1/2) summarized, listed and 
plotted. No formal statistical analyses will be conducted.
Exploratory
Analyses

All PD endpoints will be summarized, listed and graphically presented. Where 


CONFIDENTIAL
200196
6
Overview
Key Elements of the RAP
applicable, Paired t-Tests and/or ANCOVA model will be performed. Point 
estimates, and 95% confidence interval will be provided. 


CONFIDENTIAL
200196
7
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
The following changes or deviations to the originally planned statistical analysis 
specified in the protocol [(Dated: 10/DEC/2014)].

Study endpoints were modified for Part A of the study as some of the data points 
mentioned in original planned protocol analyses were not feasible to obtain via 
method and equipment used in the study. 

After Dose escalation meeting (at the end of dose group 1), dosing of dose group 2 in 
Part A study was modified. In a new design, subjects will be dosed up to 4 days only 
and up to a maximum BSA level of 10% in order to further understand the 
elimination phase of the systemic drug concentration. Therefore, all analyses will be 
carried out using new dosing plan. 
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
Part A, B and C
Part A, B and C

To investigate the safety and 
tolerability of topically applied 
GSK2646264 cream and its placebo 
in healthy1 subjects, subjects with 
cold urticaria (CU1) and subjects with 
chronic spontaneous urticaria (CsU).

Number, severity and frequency of AEs and serious AEs 
(local and systemic)

Heart rate

Blood pressure

12- lead ECG

Clinical laboratory safety tests

Assessment of the local tolerability of the study 
medication
Secondary Objectives
Secondary Endpoints
Part A, B and C
Part A, B and C

To evaluate the plasma 
concentrations of GSK2646264 in 
Healthy, CU and CsU subjects

Plasma concentrations of GSK2646264 and 
pharmacokinetic parameters, including AUC, Cmax, Tmax, 
t1/2, if data allows
Exploratory Objectives
Exploratory Endpoints
Part A: Healthy Subjects
Part A: Healthy Subjects

Assess the pharmacodynamic effect 
of GSK2646264 on weal and flare 
sizes and erythema, in healthy 
subjects after allergen challenge (Skin 
Prick test, positive control (histamine) 
and negative control (Saline)). 

Duration of response in healthy 
subjects

Percent inhibition on days 1, 3, 4 and 66 for the longest 
weal diameter (measured by ruler).

Percent inhibition on days 1, 3, 4 and 66 for perpendicular 
weal length (measured by ruler).

Percent inhibition on days 1, 3, 4 and 66 for weal area 
(calculated5).

Percent inhibition on days 1, 3, 4 and 66 for Weal volume 
(measured by quantitative volumetric morphometry2) 

Percent inhibition on days 1, 3, 4 and 66 for Flare 
erythema (measured by Mexameter3).
Percent of inhibition at 48 hours post final dose, will be 
derived for the endpoints above


CONFIDENTIAL
200196
8
Objectives
Endpoints
Part B: Cold Urticaria Subjects
Part B: Cold Urticaria Subjects

To assess the pharmacodynamic 
effect of GSK2646264 on weal and 
flare sizes and erythema, in cold 
urticaria subjects after allergen 
challenge (Skin Prick test, positive 
control (histamine) and negative 
control (Saline)).

Percent inhibition on days 1, and 3 for the longest weal 
diameter (measured by ruler).

Percent inhibition on days 1, and 3 for perpendicular weal 
length (measured by ruler).

Percent inhibition on days 1, and 3 for weal area 
(calculated).

Percent inhibition on days 1, and 3 for Weal volume 
(measured by quantitative volumetric morphometry1) 

Percent inhibition on days 1, and 3 for Flare erythema 
(measured by Mexameter2).

To assess the effect of GSK2646264 
on Cold Temperature Test values

Change in Cold Temperature Test4 values at day 1 and 
day 3
Part C: Chronic Spontaneous Urticaria 
Subjects
Part C: Chronic Spontaneous Urticaria Subjects

To assess the effect of GSK2646264  
on weal characterisation in CsU 
subjects within treated area only

Urticaria Activity Score, a composite score using key 
urticaria symptoms (number of weals, Itch/Pruritus), to 
derive change from baseline on Day 1 through to Day 7

To assess the Quality of Life in CsU 
subjects.

Change from baseline in total Dermatology Life Quality 
Index (DLQI) score

To assess the disease activity in CsU 
subjects.

Change from baseline in Angioedema Activity Score 
(AAS)

To investigate the relationships 
between (basophil histamine release) 
BHR test and weal characteristics

Relationship of positive BHR test with reduction in 
number or size of weals
1 All Healthy subjects and the Cold Urticaria subjects should be screened for reactivity to one of the allergens used in 
skin prick test. (grass pollen, Dermatophagoides pteronyssinus, birch pollen and cat dander)
2 Measured using digital camera using PRIMOS 5.075D instrument software produced by GMF
3 Measures erythema and melanin index values using narrow band spectrophotometry
4 TEMPTest 4.0
5 Calculated as ellipse or oval area


CONFIDENTIAL
200196
9
2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features

This is a randomized double blind (sponsor unblinded), single, bilateral and 
repeat ascending dose First Time in Human study designed to evaluate the 
safety, tolerability, pharmacokinetics and pharmacodynamics of 
GSK2646264 or matching placebo conducted in three parts: Part A (healthy 
subject cohort, inpatient), Part B (cold urticaria subject cohort, inpatient) and 
Part C (chronic spontaneous urticarial subject cohort, outpatient).
Dosing

There will be a 7-28 day period from screening to admission to the clinic on 
Day -1.

Subjects randomised on Day -1 in Part A and B and on Day 1 in Part C of 
study.

Dosing will start on Day 1. The cream will be applied at 10 mg/cm2 for all 
doses but the dose escalation is based on both increase in cream strength 
(0.5 % strength for Group 1 Part A; and if data permits 1.0% strength for 
Group 2 Part A), and increase in surface area of the body on which the 
cream will be applied. The escalation based on body surface area (BSA) 
starts at 0.2% BSA, then 1%, then 5% BSA, then 10% BSA,. For the study, 
the total BSA has been chosen as 1.8 m2 and will not be measured 
individually, so the surface area on which the cream is applied is similar for 
all subjects as follows, regardless of their weight and height. All weights of 
cream are nominal and any one dose will not exceed 40 g.
Treatment 
Assignment

Subjects will participate in the study if they fulfil the eligibility criteria at the 
time of screening and prior to randomisation for the relevant cohort for which 
they are assessed. This is the first clinical application for GSK2646264 in 
any formulation and therefore first exposure in each part of the study will 
enroll 1 sentinel subject for:
o
Part A dosing group1


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Overview of Study Design and Key Features
o
Part A dosing group 2
o
Part B
o
Part C
Each sentinel subject will be dosed at least 1 day before any other subjects 
of their dosing group or cohort.

Subjects will be assigned to treatment in accordance with the randomization 
schedule using IVRS system. Randomisation will occur within each cohort 
of study. Each subject will be randomised to receive bilateral treatment of 
GSK2646264 or placebo. Randomisation will assign active and placebo to 
specified areas on left or right side of the body. The left or right side 
assignment of treatment always refers to the subject’s left or right.
Interim 
Analysis
Informal data 
review

No formal interim analyses are planned. 

An informal summary of the safety, tolerability, PK and PD data from Part-A 
will be performed once all subjects are recruited and completed all visits.
2.4.
Statistical Hypotheses
The primary focus of the statistical analysis is to describe safety and characterize the 
preliminary pharmacokinetics of GSK2646264 through estimates of parameters and their 
variability. Thus, an estimation approach will be taken and 95% confidence intervals will 
be constructed to provide a plausible range of values, where appropriate, with no formal 
hypothesis testing. Sample size estimations and results of succeeding sensitivity analyses 
are given in 9.2 of the protocol.
3.
PLANNED ANALYSES
3.1.
Interim Analysis (Informal Data review)
No formal interim analyses are planned. 
Analysis
Definition / Criteria
Analyses Evaluated
During the study
There will be ongoing data reviews conducted by the study team of the 
unblinded safety and pharmacodynamic data, and any available 
pharmacokinetic data throughout the trial progression.
Dose Escalation 
Dose escalation meetings will be performed as stated in the protocol. At the 
end of dosing group 1 in Part A, the decision to proceed to the next higher 
strength and dose for dosing group 2 will be made by the SMC based on a 
safety report from the PI or designee, on the clinical safety, tolerability, up to 
and including the follow up visit, and pharmacokinetic exposure up to 24 hours 
after the last dose, in at least 6 subjects at the highest dose level. The GSK 
review team will be unblinded to the randomisation code and will usually 
include the GSK pharmacokineticist, GSK statistician, GSK data management, 
GSK medical monitor, GSK study team leader, GSK Global Clinical Safety and 


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Analysis
Definition / Criteria
Analyses Evaluated
Pharmacovigilance and GSK Clinical Matrix Team leader.
Part A 
Completion
A summary of the safety, tolerability, PK and PD data from Part-A will be 
performed once all subjects are recruited and completed all visits. This 
summary will include PK and PD data from Part-A of study cohort. All safety 
data including adverse events, tolerability, laboratory tests, ECGs and vital 
signs will be reviewed. The decision to proceed to Part B and C will be made 
by the investigator and the GSK SMC review team based on assessment of 
safety and pharmacokinetic data of the studied doses.
The Investigator or designee, study coordinators and any other unit staff who have been 
involved in assessing subjects will remain blinded during the study; however, they will 
attend the start of each review meeting to update the GSK team on safety and tolerability 
summary from each cohort; these team members will not be part of the unblinded dose 
escalation discussions. The investigator and/or designee should send the relevant data to 
the GSK review team prior to the meeting of the Safety Monitoring Committee (SMC). 
The study monitor will remain blinded.
The Safety Monitoring Committee (SMC) will consist of the GSK review team and the 
Investigator and/or designee. (See Section 5.5. of the protocol for further information)
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed (including for those subjects who withdrew or were 
withdrawn) the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
released.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to procedure.
5.
Database freeze has been declared by Data Management


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Safety Population
Comprise of subjects who receive at least one 
dose of study medication.
Study Population
Safety
Pharmacokinetic 
(PK) Population
Comprise of all randomised subjects of the Safety 
Population for whom a pharmacokinetic sample 
was obtained and analysed.
PK-Analyses
Pharmacodynamic 
(PD) Population
Comprise of all randomised subjects of the Safety 
Population for whom a pharmacodynamic 
measurement sample was obtained and analysed.
Analysis will be based on the actual treatment the 
subject received for the assigned area
PD -Analyses
Per-Protocol
Population

Comprise of all PD population subjects who 
receive at least one dose of study treatment 
and who comply with the protocol.

Protocol deviations that would exclude
subjects from the PP population are defined 
in Appendix 1 (Protocol Deviation 
Management Plan) for Definition Per-Protocol 
Population).
As required for PD-
Analyses
NOTES : 

Please refer to Appendix 10: List of Data Displays which details the population to be used for each displays 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.

Important deviations which result in exclusion from the analysis population will also 
be summarised and listed. (Please refer to Appendix 1: Protocol Deviation 
Management and Definitions for Per Protocol Population)].

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviations Management Plan.
o
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised in the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.


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
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.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS

There are no planned examination of covariates and subgroups.

There are no planned adjustments made for multiple centres in this study.

There are no planned adjustments for multiple comparisons or multiplicity.
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: Protocol Deviation Management and Definitions for Per Protocol 
Population
11.2
Appendix 2: Time & Events
11.3
Appendix 3: Data Display Standards & Handling Conventions
11.4
Appendix 4: Derived and Transformed Data
11.5
Appendix 5: Premature Withdrawals & Handling of Missing Data
11.6
Appendix 6: Values of Potential Clinical Importance
11.7
Appendix 7: Examination of Covariates, Subgroups & Other Strata
11.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
11.9
Appendix 9: Abbreviations & Trade Marks
11.10
Appendix 10: List of Data Displays
11.11
Appendix 11: Example Mock Shells for Data Displays
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 10: List of Data Displays.


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Table 2
Overview of Planned Study Population Analyses for Part A, B and C 
of study
[Endpoint / Parameter / Display Type]
Data Displays Generated
Table
Figure
Listing
Randomisation 
Randomisation
Y
Disposition
Subject Disposition
Y
Investigational Product Status
Y
Reasons for screen failure
Y
Reasons for withdrawals
Y
Important Protocol Deviations
Y
Y
Deviation leading to exclusion from PP population
Y
Inclusion and exclusion criteria deviation
Y
Study Population
Y
Demographics
Demographic Characteristics
Y
Y
Race and Racial Combinations
Y
Y
Medical History
Medical History
Y
Y
Concomitant Medication
Concomitant Medication
Y
Y
NOTES :

Y = Yes display generated.
7.
PRIMARY STATISTICAL ANALYSES
7.1.
Safety Analyses
7.1.1.
Overview of Planned Analyses
The safety analyses will be based on the ‘Safety’ population, unless otherwise specified.
Table 3 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays.
Table 3
Overview of Planned Safety Analyses for Part A, B and C of study
Endpoint / Parameter/ 
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Drug Exposure
Exposure to Study 
Drug
Y
Y
Adverse Events
Summary of All 
Adverse Events  
Y
Y
Drug-Related Adverse 
Events
Y


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Endpoint / Parameter/ 
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Summary of All 
Localised Adverse 
Events
Y
Serious Adverse 
Events
Y
Y
AEs Leading to 
Discontinuation
Y
Y
AE by Maximum 
Intensity
Y
Clinical Laboratory Assessments
Clinical Chemistry 
Y
Y
Y
Y
Haematology
Y
Y
Y
Y
Urinalysis
Y
Y1
Y
Electrocardiogram (ECG)
ECG Findings
Y
Y
Y
Y
ECG Values
Y
Y
Y
Y
Vital Signs
Vital Signs
Y
Y
Y
Y
Tolerability assessment
Tolerability scores
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 (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     

Tolerability analyses will be produced for Part A and B only.
1  Urinalysis will only list abnormal assessments
7.1.1.1.
Dose Escalations
The principal investigator and study monitor will provide a report of findings during the 
last treatment for progressing to the next cohort, as defined in the protocol, but remain 
blinded. As required, ongoing data reviews will be conducted by the unblinded GSK 
study team throughout the trial progression.
8.
SECONDARY STATISTICAL ANALYSES
8.1.
Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
Table 4 provides an overview of the planned analyses, with full details being presented in 
Appendix 10: List of Data Displays


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Table 4
Overview of Planned Pharmacokinetic Analyses for Part A, B and C 
of study
Endpoint / Parameter/ 
Display Type
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Pharmacokinetics
PK concentrations
Y
Y
Y
Y
Y
PK parameters
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.    
8.1.1.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.3.3
Reporting Process & Standards).
8.1.2.
Pharmacokinetic Parameters
8.1.2.1.
Deriving Pharmacokinetic Parameters

Refer to Appendix : Data Display Standards & Handling Conventions (Section 11.3.3
Reporting Process & Standards).

The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix WNL v6.3.

All calculations of non-compartmental parameters will be based on actual sampling 
times.

Pharmacokinetic parameters described in Error! Reference source not found. Table 
5 will be determined from the plasma concentration-time data, as data permits.


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Table 5
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(0-24)
Area under the concentration-time curve from time zero to 24 hours after dosing
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.
8.1.2.2.
Statistical Analysis of Pharmacokinetic Parameters
All the derived parameters described above will be listed. The first point, last point and 
number of points used in the determination of z will be included on the listing of the 
derived parameters. For each of the PK parameters, except tmax and %AUCextrap, the 
following summary statistics will be calculated for each active treatment group: median, 
maximum, minimum, arithmetic mean, standard deviation, coefficient of variation, 
geometric mean, 95% confidence interval for the geometric mean and standard deviation 
of logarithmically transformed data.  For tmax and %AUCextrap, median, maximum, 
minimum, arithmetic mean and standard deviation will be calculated. All statistical 
analysis results of these PK parameters will be presented in relation to the actual dose 
given (i.e. the BSA covered)
9.
EXPLORATORY STATISTICAL ANALYSIS
9.1.
Pharmacodynamic and Biomarker Analyses
9.1.1.
Overview of Planned Pharmacodynamic Analyses
The pharmacodynamic analyses will be based on the ‘Pharmacodynamic’ and Per-
protocol populations, unless otherwise specified. All summaries will be presented by 
treatment group and/or include total column. Figures comparing the different treatments 
will be displayed overlayed where possible.

If endpoints are listed, then all data will be listed.
Table 6 provides an overview of the planned pharmacodynamic analyses, with full details 
of data displays being presented in Appendix 10: List of Data Displays.


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Table 6
Overview of Planned Pharmacodynamic Analyses for Part A
[Endpoint / 
Parameter/ Display 
Type]
Untransformed
Absolute
Percent of Inhibition
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Allergen Challenge - Part A : Healthy  Subjects
Weal area (mm2)
Y
Y
Y
Y
Y
Y
Y
Weal volume (mm3)
Y
Y
Y
Y
Y
Y
Y
Longest Weal diameter
(mm)
Y
Y
Y
Y
Y
Y
Y
Weal perpendicular 
length (Height) (mm)
Y
Y
Y
Y
Y
Y
Y
Flare erythema ((mm2)
Y
Y
Y
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. Summary 
will be presented by dose strength, BSA and day (if applicable)

Individual = Represents FL related to any displays of individual subject observed raw data.

Weal area derived from weal longest diameter and perpendicular length; assuming elliptic shape.
Table 7
Overview of Planned Pharmacodynamic Analyses for Part B
[Endpoint / 
Parameter/ Display 
Type]
Untransformed
Absolute
Percent of Inhibition/Change 1
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Allergen Challenge - Part B: Cold Urticaria Subjects
Weal area (mm2)
Y
Y
Y
Y
Y
Y
Y
Weal volume (mm3)
Y
Y
Y
Y
Y
Y
Y
Weal longest diameter 
(mm)
Y
Y
Y
Y
Y
Y
Y
Weal perpendicular 
length (Height) (mm)
Y
Y
Y
Y
Y
Y
Y
Flare erythema ((mm2)
Y
Y
Y
Y
Y
Y
Y
Cold Temperature Test
Y
Y
Y
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.

Summary will be presented by dose strength, BSA and day (if applicable)
1.
Change will be produced for Cold Tem Test endpoint


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Table 8
Overview of Planned Pharmacodynamic Analyses for Part C
[Endpoint / 
Parameter/ Display 
Type]
Untransformed
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Pharmacodynamic  - Part C: Chronic Spontaneous Urticaria Subjects
UAS7 score
Y
Y
Y
Y
Y
Y
Angioedema Activity 
Score (AAS
Y
Y
Y
Y
Y
Y
UAS7 components
(Number of weals,  
Extent of Itch)
Y
Y
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.

Summary will be presented by dose strength, BSA and day (if applicable)
9.1.2.
Planned Pharmacodynamic Statistical Analyses
9.1.2.1.
Part C: Chronic Spontaneous Urticaria Subjects
Planned Statistical Analyses
Endpoint(s)

Change from baseline in composite total UAS7 score and components
Model Specification

Endpoint will be analysed using paired t test and ANCOVA to compare the treatment groups.

ANCOVA model will be fitted as: Post-Pre dose as response and pre dose as covariate.
Model Checking

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Estimated treatment difference and 95% confidence intervals will be presented.
Analysis of UAS7 Components

Analysis of UAS7 components will be performed similar to total UAS7 composite score

Summary Statistics for each component of UAS7 questionnaire will be provided by visit.
Note: 

Composite score UAS7 will be derived using key urticaria symptoms (number of weal, 
Itch/Pruritus). The UAS7 score will be calculated using the summation of the 7 consecutive 
days sum.

Other questions collected as part of UAS7 questionnaire will be listed.
9.1.2.2.
The Angioedema Activity Score (AAS)
Planned Statistical Analyses


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Planned Statistical Analyses
Endpoint(s)

Change from baseline in total and individual item score
Model Specification

Endpoint will be analyzed using paired t test and ANCOVA to compare the treatment groups.

ANCOVA model will be fitted as: Post-Pre dose as response and pre dose as covariate.
Model Checking

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Estimated treatment difference and 95% confidence intervals will be presented.
Analysis of AAS Components

Summary Statistics for each component AAS questionnaire will be provided by visit.
Note:

Details of the Angioedema Activity Score (AAS) questionnaire are provided in Appendix 7
of the protocol. Each AAS item will be scored between 0 to 3 and daily total score AAS 
score will range between 0 and 15. The daily AAS score will be summed up to compute 7-
day total scores
9.1.2.3.
Relationships between Basophil Histamine Release (BHR) Test and 
Weal Characteristics
Planned Statistical Analyses
Endpoint(s)

Positive BHR Test
Model Specification

Endpoint will be analyzed using logistic regression with weal characteristics (i.e. weal length) 
as covariate to establish the relationship between BHR test and weal characteristics.
Model Checking

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Odds Ratio and 95% Confidence intervals


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9.1.3.
Planned Health Outcome Statistical Analyses
Table 9
Overview of Planned Health Outcome Analyses for Part C
[Endpoint / 
Parameter/ Display 
Type]
Untransformed
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Health Outcome  - Part C: Chronic Spontaneous Urticaria Subjects
Dermatology Life 
Quality Index (DLQI)
Y
Y
Y
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.

Summary will be presented by dose strength, BSA and day (if applicable)
9.1.3.1.
Health Outcomes Analyses/ Dermatology Life Quality Index
Planned Statistical Analyses
Endpoint(s)

Change from baseline in total and individual domain scores
Model Specification

Endpoint will be analyzed using paired t test to compare the improvement in quality of life
Model Checking

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Estimated treatment difference and 95% confidence intervals will be presented.
Note:  The scoring of each question is as follows: 
Very much
scored 3
A lot
scored 2
A little
scored 1
Not at all
scored 0
Not relevant
scored 0
Question unanswered
scored 0
Question 7: "prevented work or studying"
scored 3

The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a 
minimum of 0. The higher the score, the more quality of life is impaired.

The six subscores will be derived as follows:


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Planned Statistical Analyses
Symptoms and feelings 
Questions 1 and 2
Score maximum 6
Daily activities 
Questions 3 and 4
Score maximum 6
Leisure 
Questions 5 and 6
Score maximum 6
Work and School 
Question 7
Score maximum 3
Personal relationships 
Questions 8 and 9
Score maximum 6
Treatment 
Question 10
Score maximum 3
9.1.4.
Overview of Planned Biomarker Analyses
The biomarker analyses will be based on the ‘Pharmacodynamic’ population, unless 
otherwise specified.
Table 10 provides an overview of the planned pharmacodynamic analyses, with full 
details of data displays being presented in Appendix 10: List of Data Displays.
Table 10
Overview of Planned Biomarker Analyses
Endpoint / Parameter/ 
Display Type
Untransformed
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Biomarker - Part A: Healthy Subjects
Percent inhibition of 
CD69 biomarker
Y
Y
Y
Biomarker - Part C: Chronic Spontaneous Urticaria Subjects
Percent Inhibition of 
CD69 biomarker
Y
Y
Y
9.2.
Pharmacokinetics and Biomarker Analyses
A potential relationship between plasma exposures of GSK2646264 (Cmin) and changes 
in biomarker levels and primary endpoints will be explored graphically by plotting their 
respective time course profiles and systemic exposure versus response profiles. The 
responsibility for conducting PK-PD analyses will be CPMS. These analyses will not be 
part of this SAP and will be reported separately.


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10.
REFERENCES
GlaxoSmithKline Document Number  2013N167482_01 (Protocol Amendment – 02-10-
DEC-2014): 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 GSK2646264 .
ICH E9, ICH HARMONISED TRIPARTITE GUIDELINE 1998 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/St
ep4/E9_Guideline.pdf


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11.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 11.2
Appendix 2: Time and Events
Section 11.3
Appendix 3: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 11.4
Appendix 4: Derived and Transformed Data

General, Study Population & Safety

Efficacy

Pharmacokinetic

Pharmacodynamic and or Biomarkers
Section 11.5
Appendix 5: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 11.6
Appendix 6: Values of Potential Clinical Importance
Section 11.7
Appendix 7: Examination of Covariates and Subgroups
Section 11.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 11.9
Appendix 9: Abbreviations & Trade Marks
Section 11.10
Appendix 10: List of Data Displays
Section 11.11
Appendix 11: Example Mock Shells for Data Displays


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11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
11.1.1.
Protocol Deviation Definitions for Exclusion from predefined 
Populations

Exclusions from the Study Populations should be defined prior to unblinding and 
should be summarized and listed [ICH E9, 1998, Section 5.2.2.]  This will be 
included in Section 6.1 – Study Populations.
o
Exclusions from study populations may be defined as a subset of the Important 
Deviations as appropriate.  These details should be documented in the Plan for 
Managing Protocol Deviations and in the RAP.
o
Any planned exclusions from study populations which are not considered to be 
deviations, should be defined in the RAP with rationale and any programming 
details as appropriate.
11.1.2.
Exclusions from Per Protocol Population
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01

Failure of any inclusion/exclusion criteria
02

Subjects who developed the withdrawal criteria but were not withdrawn
03

Any deviation that impact the safety of subjects
04

Failed to provide scheduled assessment
05

Major deviation from the conduct of trial
Protocol deviation definition criteria and resulting exclusion from analysis populations 
will be agreed and summarized in a separate protocol deviation definition document that 
has to be updated and reviewed on a regular basis.


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11.2.
Appendix 2: Time & Events
11.2.1.
Protocol Defined Time & Events
11.2.1.1.
Part A, Dose Group 1 (Healthy Volunteers)
Day:
Screening
-1
1
2
3
4
Follow-up
Notes
Visit Window (relative to 
Day 1)
-28 to -7 
Day 5 to Day 
7 
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without 
shoes
X
Brief physical
X
Medical/medication/drug/
alcohol history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and 
CV risk factors questionnaire
Vital signs
X
X
X
X
X
X
X
Urine drug/alcohol 
screen
X
X
HIV, Hep B and Hep C 
screen
X
Clinical Laboratory Tests
X
X
X
X


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Day:
Screening
-1
1
2
3
4
Follow-up
Notes
Visit Window (relative to 
Day 1)
-28 to -7 
Day 5 to Day 
7 
Allergen Challenge-
Skin Prick Test
X3,4
X3, 5
X3,5
X7
3. SPT- Skin Prick Test analysis 
will be performed at ~15-20mins 
post challenge. 
4. SPT with all 4 specified allergens
5. SPT using one allergen will be 
performed 6 hours post dose (see 
Clinical Trial Protocol Section 6.4.1)
7. SPT using one allergen will be 
performed 24 hrs after the last dose
TSH2
X
2. TSH test only at screening only
Randomisation
X
Tolerability Assessment
  X9   --------------------
9. Tolerability assessment at pre –
and ~6 hours post-dose
Note: No tolerability assessment on 
day 4.
AE assessment 
X
----------------------------
X
Concomitant Medication
X
----------------------------
X
Pharmacokinetic 
Blood Sample6
X
X
X
X8
6.PK blood sample taken at pre 
dose, 1 ,2, 4, 8, 12 and 24hr post 
dose 
8.PK refers to sample 24 hours 
post dose
Study Treatment Dosing
X
X
X
Discharge from unit
X
Outpatient visit
X
X


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11.2.1.2.
Part A: Healthy Volunteer Time and Event Table Dose group 2
Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 9 – Day 
11 
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without shoes
X
Brief physical
X
Medical/medication/drug
/alcohol history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and 
CV risk factors questionnaire 
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Urine drug/alcohol screen
X
X
Urine for metabolite analysis
X10
X22
10. Pre dose and pool samples 
taken 0-12 and 12-24 hours post 
dose 
22. Pool samples taken 0-12 and 
12-24 hours post
HIV, Hep B and Hep C screen
X
Clinical Laboratory Tests
X17
X17
X9
X9
X17
X17
X17
9. Pre-dose AST, ALT, Alkaline 
Phosphatase, Total Bilirubin Only- : 
results to be communicated to the 
GSK Medical monitor on the same 
day  
17.Clinical lab test as per Section 
6.3.4 of the protocol 


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Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 9 – Day 
11 
Allergen Challenge-
Skin Prick Test
X3,4
X3,5
X3,5
X3,
5
X 3,7
3. SPT- Skin Prick Test 
measurements will be performed 
~15-20 mins post challenge. 
4. SPT with all 4 specified allergens
5. SPT will be performed 6 hours 
post dose
7. SPT will be performed 48 hours 
post dose of Day 4 (on the morning 
of Day 6)
TSH2
X
2. TSH test only at screening only
Randomisation
X
Tolerability Assessment
X11  ---------------------
        only on dosing days 1 to 4
11. Tolerability assessment at pre –
and ~6 hours post-dose on dosing 
days
AE assessment 
X
----------------------------------------------------
X
Concomitant Medication
X
----------------------------------------------------
X
Pharmacokinetic 
Blood Sample
X6
X6
X6
X6
X18
X19
X20
X21
6. PK blood sample taken at pre 
dose, 1, 2, 4, 8, 12 and 24hours 
post previous dose 
18. PK blood sample taken at 30, 
36, 48 hours, post dose of Day 4
19. PK blood sample taken at 54, 
60, 72 hours, post dose of Day 4
20. PK blood sample taken at 78, 
84 hours post dose of Day 4
21. PK blood sample taken at 96 
hours post dose of Day 4


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Day:
Screening
-1
1
2
3
4
5
6
7
8
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 
Day 9 – Day 
11 
Blood Sample for CD69 
expression
X12
X13
X14
X15
X16
12. Predose
13. 4 hours post dose of Day 4 
14. 24 hours post dose of Day 4 
(sample taken in the morning of day 
5) 
15. 72 hours post dose of Day 4
16. 96 hours post dose of Day 4
Study Treatment Dosing8
X
X
X
X
8.  This will be once daily dosing 
using fresh bottles at 1% strength in 
the morning
Discharge from unit
X
Outpatient visit
X
X
11.2.1.3.
Part B (Cold Urticaria Subjects)
Day:
Screening
-1
1
2
3
4
Follow-up
Notes
Visit Window  (relative to 
Day 1)
-28 to -7 
days
Day 5 to 
Day 7 after 
last dose
Admission to Unit
X
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without 
shoes
X
Brief physical
X
Medical/medication/
drug/alcohol history
X


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Day:
Screening
-1
1
2
3
4
Follow-up
Notes
Visit Window  (relative to 
Day 1)
-28 to -7 
days
Day 5 to 
Day 7 after 
last dose
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening and CV risk factors 
questionnaire 
Vital signs
X
X
X
X
X
X
Urine drug/alcohol 
screen
X
X
Pregnancy Test (women)2
X(S)
X(S/U)
X(S)
2. Pregnancy test will be performed 3 times during 
screening, serum on day -28, day -7 to -4, and a serum or 
urine pregnancy test the day of the start of the study prior 
to dosing and a serum pregnancy test at the follow up visit
HIV, Hep B and Hep C 
screen
X
Clinical Laboratory Tests
X
X
X
X
Allergen Challenge- SPT
X4,5
X4,6
X4,6
4. SPT- Skin Prick Test measurements will be performed 
~15-20mins post challenge
5. SPT using all 4 specified allergens
6. SPT will be performed at  6 hours post dose (see 
Clinical Trial Protocol Section 6.4.1)
TSH3
X
3. TSH test only at screening only
Cold Temp Test (Temp 
Test 4.0)
X
X
X
X7
7. 24 hours after last dose
Review of eligibility 
criteria and medication 
prior to randomisation
X
Randomisation
X
Tolerability Assessment
X10          ---------------
10. Tolerability assessment at pre – and ~6 hours post-
dose
AE assessment 
X
---------------------------
X
Concomitant Medication
X
----------------------------
X


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Day:
Screening
-1
1
2
3
4
Follow-up
Notes
Visit Window  (relative to 
Day 1)
-28 to -7 
days
Day 5 to 
Day 7 after 
last dose
Pharmacokinetic Blood 
Sample8
X
X
X9
8.  PK blood sample taken at pre dose,1,2,4, 8, 12hr post 
dose
9. If only once daily dosing then a PK sample will be taken 
at 24h post dose
Study Treatment Dosing
X
X
X
Discharge from unit
X
Outpatient visit
X
X
11.2.1.4.
Part C (Chronic Spontaneous Urticaria Cohort)
Day:
Screening
1
2
3
4
5
6
7
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 days
9-14 days after last dose
Informed Consent
X
Demographics
X
Complete physical
X
X
Body weight (kg)
X
Height (cm) without shoes
X
Brief physical
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECG1
X
X
X
X
1. Triplicate ECG at screening 
and CV risk factors questionnaire 
Vital signs
X
X
X
X
X
Urine drug/alcohol screen
X
X


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Day:
Screening
1
2
3
4
5
6
7
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 days
9-14 days after last dose
Pregnancy Test (women)2
X(S)
X 
(S/U)
X(S)
2. Pregnancy test will be 
performed 3 times during 
screening, serum (S) on day -28, 
day -7 to -4, and a serum or urine 
(U) pregnancy test the day of the 
start of the study prior to dosing 
and a serum pregnancy test at 
the follow up visit
HIV, Hep B and Hep C screen
X
Clinical Laboratory Tests
X
X
X
X
TSH3
X
3. TSH test only at screening only
Blood Sample for CD69 
expression11
X9
X10
9. Predose
10.  4 hours post dose
11 A decision will be made after 
Part A on whether samples are 
taken in Part C 
Randomisation
X
UAS-7 Diary4
X
X
X
X
X
X
X
X
4. Screening UAS7 diary will be 
completed  using 7 successive 
days before randomisation (day 
1). If there is a lapse in any day 
prior to day 1 the subject must 
complete the full 7 days worth of 
diary entries again during the 
screening period.
QOL (DLQI)
X
X
X
AAS
X
X
X
X
X
X
X
X
AE assessment
X8 -------------------------------------------
X
8. Tolerability assessment at pre 
– and post-dose


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Day:
Screening
1
2
3
4
5
6
7
Follow-up
Notes
Visit Window (relative to Day 1)
-28 to -7 days
9-14 days after last dose
BHR- Basophil Histamine Release 
Test
X5
5. Sample taken predose 
Pharmacokinetic Blood Sample6
X
X
X
6. PK blood sample taken at pre-
dose sample and  2 and 4hr post 
dose
Study Treatment Dosing
X
X7
X7
X
X7
X7
X
7. The nurse will visit the subject 
at home to apply the dose
Outpatient visit
X
X
X
X
X


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11.3.
Appendix 3: Data Display Standards & Handling 
Conventions
11.3.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
GSK2646264 X.X mg
GSKX.X mg
2
P
Placebo
Placebo
1
NOTES:
1.
Order represents treatments being presented in TFL. Placebo is to be presented at start in Tables, Figures and 
Listings. Dosing of GSK treatment will be displayed in ascending order, where appropriate.
In accordance with the body surface area (BSA) to be used Arm, Leg and Front Torso of 
the subjects had to be treated on the different body sides with either GSK2646264 or 
matching placebo treatment as displayed below:
Table 11
Overview of Treatments Doses and Analyses.
Part
Dose
BSA
treated per 
body side
(left/right)
Day
of Treatment
(Tests 
performed)
Comment
A
0.5%
(Group 1)
0.2%
1%
5%
D1 (PK/PD)
D2 (PK)
D3 (PK/PD)
qd
A
1.0%
(Group 2)
5%
5%
10%
10%
D1 (PK/PD)
D2 (PK)
D3 (PK/PD)
D4 (PK)
qd
B
.0.5 or 1%
0.2%+5%
0.2%+5%
0.2%+5%
D1(PK/PD)
D2
D3(PK/PD)
qd or bid
(D3 morning 
dose only)
C
.0.5 or 1%
X.X2%
D1 (PK/PD)
D2 (PD)
D3 (PD)
D4 (PK/PD)
D5 (PD)
D6 (PD)
D7 (PK/PD)
Qd or bid
1 maximum tolerated dose (taken from Part A)
2 maximum BSA treated (taken from Part A)


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The following changes to treatment dosing were made to dose group 2 (Part A) in light of 
dose escalation review meeting at the end of dose group 1:
Table 12
Treatment applied to specified areas per day on Part A; healthy 
subjects, n=9, dose group 2
Day 1-2
Day 3-4
Day 5 to 7
Area
AMa
AMa
Left 
Arm
0.36g of 1.0%b GSK2646264 or placebo cream applied to 36cm2 (~0.2% BSA)
NO 
DOSING
Right 
Arm
0.36g of 1.0%b GSK2646264 or placebo cream  applied to 36cm2 (~0.2% BSA) 
NO 
DOSING
Left 
Front 
Torso
9g of 1.0% b GSK2646264 or placebo 
cream applied to 900cm2 (~5% BSA) 
18g of 1.0% b GSK2646264 or placebo 
applied to 1800cm2 (~10% BSA) 
NO 
DOSING
Right 
Front
Torso
9g of 1.0% b  GSK2646264 or placebo 
applied to 900cm2 (~5% BSA) 
18g of 1.0% b  GSK2646264 or placebo 
applied to 1800cm2 (~10% BSA) 
NO 
DOSING
a.
AM dosing only
b.
0.5% strength may be used if  data  for Part A and/or group 2 supports
11.3.2.
Baseline Definition & Derivations
11.3.2.1.
Baseline Definitions
For all endpoints (expect as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment. 
Parameter
Study Assessments Considered As Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety Assessment
Laboratory
X
X2
Day -1, 
(Part A & B)
Screening (Part C)
Vital Signs 
X
X
Day 1 (pre) 
ECG
X
X
Screening1
Pharmacodynamics
Allergen Challenge 
SPT (Part A & B)
No baseline
Cold Temp test 
(Part B)
No baseline
UAS7 (Part C)
X
Screening
AAS (Part C)
X
Screening


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Parameter
Study Assessments Considered As Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Health Outcome
DLQI (Part C)
X
Screening
NOTES :
1.
Use the mean of replicate assessments at any given time point as the value for that time point in all summaries, 
figures and statistical analyses.
2.
Not in Part C
11.3.2.2.
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]
% inhibition
=[(control – treatment)/control]x100
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 11.3.2.1 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.

As only one baseline will be defined for all parameters (i.e. at the start of the study), there will only be one 
baseline on all summaries (i.e. not a separate baseline for each subsequent repeat dose).

The baseline definition will be footnoted on all change from baseline outputs, where applicable.

If baseline value for (day -1) is missing, screening value will be used as baseline. If both assessments are 
missing then no derivation will be performed and will be set to missing..
11.3.3.
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 (tables, figures, and listings).
Reporting Area
HARP Server
PHU058
HARP Area
: \ARWORK\GSK2646264\final  or \ARWORK\GSK2646264\final
QC Spreadsheet
: Not applicable ]
Analysis Datasets 

Analysis datasets will be created according to CDISC / ADaM Standards Library standards. For 
creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of Files

PDF files will be generated.


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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 
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
N, n, mean, 95% CI of the mean, standard deviation (SD), median, 
minimum (min) and maximum (max).
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
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD)
of logged data and [between and or within] geometric coefficient of variation


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Reporting Standards
(Log Transformed)
(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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11.4.
Appendix 4: Derived and Transformed Data
11.4.1.
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.

If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken.

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 

Randomisation 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    
11.4.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Subjects who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.


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11.4.3.
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 : 
Adverse Events
AE Type
Derivations
AE Onset Time
Since First Dose
(Days)
If Treatment Start Date ˃ AE Onset Date : 
     = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date : 
      = AE Onset Date – Treatment Start Date + 1
Missing otherwise 
AE Duration (Days)
AE Resolution Date – AE Onset Date + 1
AE = On Treatment
If AE onset date is on or after the treatment start date and on or 
before the treatment stop date.
AE = Post Treatment
If AE onset date is after the treatment stop date.
AE = Drug-related
If relationship is marked ‘YES’ on eCRF OR value is missing.
Current update 
MedRA version 
17.1 will be used 


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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    
Tolerability Assessments
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 
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. A maximum score of 3 is allowed.
Mean irritation score for each subject will be computed through the study period. Mean 
score will be analyzed.


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11.5.
Appendix 5: Premature Withdrawals & Handling of Missing 
Data
11.5.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as 
subjects who completed all visits of the study including the follow-up visit. 

Withdrawn subjects were not 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.
11.5.2.
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.
UAS7 score
In presence of one or more missing daily UAS7 scores, the following algorithm will 
be applied:

If a patient has at least 4 non-missing daily UAS7 scores within the 7 days, 
the UAS7 score will be calculated as the sum of the available eDiary UAS7 
scores in that week, divided by the number of days that have a non-missing 
diary UAS7 score, multiplied by 7.

If there are less than 4 non-missing daily UAS7 scores, then the UAS7 score 
will be missing.
AAS
Missing values will not be imputed
DLQI
1. If one question is left unanswered this is scored 0 and the scores are summed 
and expressed as usual out of a maximum of 30.
2. If two or more questions are left unanswered the questionnaire is not scored.
3. If question 7 is answered 'yes' this is scored 3. If question 7 is answered 'no' or 
'not relevant' but then either 'a lot' or 'a little' is ticked this is then scored 2 or 1. If it is 
answered 'no', but the second half is left incomplete, the score will remain 0.
4. If two or more response options are ticked, the response option with the highest 
score should be recorded.
5. If there is a response between two tick boxes, the lower of the two score options 


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Element
Reporting Detail
should be recorded.
6. When using sub-scales, if the answer to one question in a sub-scale is missing, 
that sub-scale should not be scored. 
11.5.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment.
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.
11.5.2.2.
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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11.6.
Appendix 6: Values of Potential Clinical Importance
11.6.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Red Blood Cell Count (RBC)
x106
cells/μL
4.2
5.9
Mean Corpuscular Volume (MCV)
fL
80
100
Mean Corpuscular Hemoglobin 
(MCH)
pg
28
32
Mean Corpuscular Hemoglobin 
Concentration (MCHC)
g/L
32
36
Monocytes
x109/ L
0.208
Eosinophils
x109/ L
0.44
Basophils
x109/ L
0.01
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
mmol/L
1.3*ULN
µmol/L
159
µmol/L
∆from BL
44
Glucose
mmol/L
3
11.1
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Liver Function
Test Analyte
Units
Category
Clinical Concern Range


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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
1.5x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT
Urea Nitrogen (BUN)
mmol/L
Low
<2.9
Urea Nitrogen (BUN)
mmol/L
High
>7.1
Chloride
mmol/L
Low
<98
mmol/L
High
>106
Gamma-glutamyl Transpeptidase 
(GGT)
U/L
Low
<8
U/L
High
>78
Direct Bilirubin
μmol/L
High
>5.1
Total Protein
g/L
Low
<60
g/L
High
>78
11.6.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 [2]
≤ 479 [2]
≥ 480 [2]
≤ 499 [2]
≥ 500 [2]
Absolute PR Interval
msec
< 110
> 220 
Absolute QRS Interval
msec
< 75 [
> 110
Change from Baseline
Increase from Baseline QTc
msec
> 60 
msec
> 30  
≤ 59 
msec
≥ 60  [
11.6.3.
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


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Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥20
≥40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥10
≥20
≥ 10
≥ 20
Heart Rate
bpm
≥15
≥30
≥ 15
≥ 30


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11.7.
Appendix 7: Examination of Covariates, Subgroups & Other 
Strata
11.7.1.
Handling of Covariates, Subgroups & Other Strata

Not applicable.


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11.8.
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses
11.8.1.
Statistical Analysis Assumptions
Endpoint(s)

PD Parameters
Analysis

ANOVA to estimate the effect of GSK2646264 relative to Placebo as 
comparison of interest. Point estimates and corresponding 95% confidence 
intervals will be constructed.
Analysis

ANCOVA.

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.
Analysis

Logistic Regression

Model fit will be assesses by
o
plotting observed probability vs predictive probability
o
Chi-square test for goodness fit test


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11.9.
Appendix 9: Abbreviations & Trade Marks
11.9.1.
Abbreviations
Abbreviation
Description
AAS
Angioedema Activity Score
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration 
AUC(0-)
Area under the concentration-time curve over the dosing interval
BHR
Basophil Histamine Release
BMI
Body mass index
BP
Blood pressure
BPM
Beat Per Minute
BQL
Below the quantification limit
BUN
Blood urea nitrogen
CI
Confidence Interval
Cmax
Maximum observed concentration 
CPDS
Clinical Pharmacology Data Sciences
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modelling & Simulation
CPSR
Clinical Pharmacology Study Report
CsU
Chronic spontaneous Urticaria
CU
Cold Urticaria
CV
Coefficient of variance
DBP
Diastolic blood pressure
ECG
Electrocardiogram
FTIH
First time in humans
GGT
Gamma glutamyltransferase
GSK
GlaxoSmithKline
hCG
Human chorionic gonadotropin
HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
HR
Heart rate
IP
Investigational Product
IU
International Unit
Kg
Kilogram
z
Terminal phase rate constant
L
Liter
ln
Naperian (natural) logarithm


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Abbreviation
Description
LOQ
Limit of quantification
LLQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
msec
Milliseconds
NQ
Non-quantifiable concentration measured as below LLQ
PD
Pharmacodynamic
PK
Pharmacokinetic
QD
Once daily
RAP
Reporting and Analysis Plan
RBC
Red blood cells
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software
SD
Standard deviation
SUSAR
Suspected, Unexpected, Serious Adverse drug Reaction
t½
Terminal phase half-life
τ
Dosing interval
tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
WBC
White blood cells
GSK
GlaxoSmithKline
11.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
SAS/STAT


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11.10.
Appendix 10: List of Data Displays
11.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.8
Not applicable
Safety
3.1 to 3.18
Not applicable
Pharmacokinetic
4.1 to 4.3
4.1 to 4.3
Pharmacodynamic and / or Biomarker
5.1 to 5.15
5.1 to 5.14
Section
Listings
ICH Listings
1 to 28
Other Listings
29 to 35
11.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Other Listings
OTHER_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
11.10.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
IA [X]
Interim Analysis Statistical Analysis Complete
SAC [X]
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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11.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Disposition
1.1.
Safety
CP_ES1
Summary of Subject Disposition 
Programmer to update primary 
reason for withdrawal to be study 
specific.
Please only include Total column 
(not treatment columns)
IA[1], SAC [1]
1.2.
Safety
SA1
Summary of Study Populations
IA[1],SAC [1]
1.3.
Safety
DVA1
Summary of Important Protocol Deviations
Generated, if data permits.
As required, refer to PDMP.
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
1.4.
Safety
SD1
Summary of Investigational Product Status
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
Demographics
1.5.
Safety
DM1
Summary of Demographic Characteristics 
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
1.6.
Safety
DM5
Summary of Race and Racial Combinations 
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
Medical History
1.7.
Safety
MH4
Summary of Medical History
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
Concomitant Medication


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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.8.
Safety
CP_CM1
Summary of Concomitant Medications by Generic Term
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
11.10.5.
Efficacy Tables
Not applicable.


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11.10.6.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Drug Exposure
3.1.
Safety
EX1
Summary of Exposure to Study Drug
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
Adverse Events
3.2.
Safety
CP_AE1p
Summary of All Adverse Events  
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
3.3.
Safety
CP_AE1p
Summary of Drug-Related Adverse Events 
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
3.4.
Safety
CP_AE1p
Summary of All Localised Adverse Events  
IA[1],SAC [1]
3.5.
Safety
CP_AE1p
Summary of Serious Adverse Events 
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
3.6.
Safety
CP_AE1p
Summary of AEs Leading to Permanent Discontinuation of 
Study Drug or Withdrawal from Study
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
3.7.
Safety
AE5
Summary of Adverse Events by Maximum Intensity/Grade
Please only include Total column 
(not treatment columns)
IA[1],SAC [1]
3.8.
Safety
AE2
Relationship between System Organ Class and Verbatim Text
IA[1],SAC [1]
Clinical Laboratory Assessments
3.9.
Safety
LB1
Summary (Absolute and Change from Baseline) of Clinical 
Chemistry Laboratory Values 
Please only include Total column 
(not treatment columns).
Order parameters alphabetically
IA[1],SAC [1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.10.
Safety
LB2
Summary of Clinical Chemistry Data Outside the Reference 
Range
Order parameters alphabetically
IA[1],SAC [1]
3.11.
Safety
LB1
Summary (Absolute and Change from Baseline) of Haematology 
Laboratory Values 
Please only include Total column 
(not treatment columns).Order 
parameters alphabetically
IA[1],SAC [1]
3.12.
Safety
LB2
Summary of Haematology Data Outside the Reference Range
Order parameters alphabetically
IA[1],SAC [1]
3.13.
Safety
UR3
Summary of Urinalysis Dipstick Results 
Please only include Total column 
(not treatment columns).Order 
parameters alphabetically
IA[1],SAC [1]
Electrocardiogram (ECG)
3.14.
Safety
EG1
Summary (Absolute and Change from Baseline) of ECG 
Findings
Please only include Total column 
(not treatment columns).Order 
parameters alphabetically
IA[1],SAC [1]
3.15.
Safety
EG2
Summary (Absolute and Change from Baseline) of ECG Values
Please only include Total column 
(not treatment columns).Order 
parameters alphabetically
IA[1],SAC [1]
Vital Signs
3.16.
Safety
VS1
Summary (Absolute and Change from Baseline) of Vital Signs 
Please only include Total column 
(not treatment columns).Order 
parameters alphabetically
IA[1],SAC [1]
Tolerability assessment
3.17.
Safety
Non- Standard
SAFE_T1
Summary (Absolute and Change from Baseline) of Mean 
irritation score assessment 
IA[1],SAC [1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.18.
Safety
Non- Standard
SAFE_T2
Assessment of Maximum Dermal Reactions and Response
IA[1],SAC [1]


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11.10.7.
Safety Figures
Not applicable.


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11.10.8.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetics
4.1.
PK
PKCT1
Summary of Serum GSK2646264 Pharmacokinetic 
Concentrations versus time by actual dose
IA[1],SAC [1]
4.2.
PK
PKPT1
Summary of Derived Serum GSK2646264 Pharmacokinetic 
Parameters by actual dose
IA[1],SAC [1]
4.3.
PK
PKPT3
Summary of Log-Transformed Derived Serum GSK2646264 
Pharmacokinetic Parameters by actual dose
IA[1],SAC [1]


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11.10.9.
Pharmacokinetic Figures
Pharmacokinetic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetics
4.1.
PK
PKCF1
Individual Serum GSK2646264 Concentration-Time Plot (Linear 
and Semi-log)
1. x-axis should display Actual 
relative time 
2. Include line for LLQ along with 
footnote defining LLQ value.
3. Include values below LLQ
IA[1],SAC [1]
4.2.
PK
PKCF3
Median Serum GSK2646264 Concentration-Time Plot (Linear 
and Semi-log)
1. X-axis should display Planned 
relative time 
2. Include line for LLQ along with 
footnote defining LLQ value.
3. Include values below LLQ
Use different symbols for treatments
IA[1],SAC [1]
4.3.
PK
PKCF4
Mean and SD of Serum GSK2646264 Concentration-Time Plot 
(Liner and Semi-log)
1. X-axis should display Planned 
relative time 
2. Include line for LLQ along with 
footnote defining LLQ value.
3. Include values below LLQ
Use different symbols for treatments
IA[1],SAC [1]


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11.10.10. Pharmacodynamic and Biomarker Tables
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacodynamics
5.1.
PD
Non-
Standard_PDT
1
Allergen Challenge, Weal Area - Summary Statistics (Absolute 
and Percent of Inhibition)
Absolute and Percent of Inhibition
Part A + B
IA[1],SAC [1]
5.2.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
Allergen Challenge, Weal Volume – Summary Statistics
(Absolute and Percent of Inhibition)
Absolute and Percent of Inhibition
Part A + B
IA[1],SAC [1]
5.3.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
Allergen Challenge, Longest Weal Diameter- Summary Statistics
(Absolute and Percent of Inhibition)
Absolute and Percent of Inhibition
Part A + B
IA[1],SAC [1]
5.4.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
Allergen Challenge, Weal perpendicular length - Summary 
Statistics (Absolute and Percent of Inhibition)
Absolute and Percent of Inhibition
Part A + B
IA[1],SAC [1]
5.5.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
Allergen Challenge, Flare Erythema - Summary Statistics
(Absolute and Percent of Inhibition)
Absolute and Percent of Inhibition
Part A + B
IA[1],SAC [1]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.6.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
Cold Temp Test, Change in critical temperature thresholds
Absolute 
Part B only
SAC [1]
5.7.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
UAS7 Scores – Summary Statistics (Absolute and Change from 
Baseline)
Absolute and Change from Baseline
Part C only
SAC [1]
5.8.
PD
Example Non-
Standard_PDT
2 
Change from baseline in composite total UAS7 Scores –
Treatment Comparison
Paired t-Test (95%CI) and 
ANCOVA to compare treatments 
groups.
Pre-Dose Value as Covariate
Part C only
SAC [1]
5.9.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
UAS7 Components – Summary Statistics (Absolute and Change 
from Baseline)
Absolute and Change from Baseline
Part C only
SAC [1]
5.10.
PD
Example Non-
Standard_PDT
2 modified 
based on 
endpoint.
Change from baseline in composite total UAS7 Components –
Treatment Comparison
Paired t-Test (95%CI) and 
ANCOVA to compare treatments 
groups.
Pre-Dose Value as Covariate
Part C only
SAC [1]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.11.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
Angioedema Activity Score (AAS) – Summary Statistics
(Absolute and Change from Baseline)
Absolute and Change from Baseline
Part C only
SAC [1]
5.12.
PD
Example Non-
Standard_PDT
2 modified 
based on 
endpoint.
Change from baseline in total Angioedema Activity Score (AAS) 
– Treatment Comparison
Paired t-Test (95%CI) and 
ANCOVA to compare treatments 
groups.
Pre-Dose Value as Covariate
Part C only
SAC [1]
5.13.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
Dermatology Life Quality Index (DLQI) – Summary Statistics
(Absolute and Change from Baseline)
Absolute and Change from Baseline
Part C only
Sum-Score and Analysis of 
Subscores
SAC [1]
5.14.
PD
Example Non-
Standard_PDT
2 modified 
based on 
endpoint.
Change from baseline in total Dermatology Life Quality Index 
(DLQI) – Comparison Improvement from baseline
Paired t-Test (95%CI)
Part C only
No treatment comparison involved. 
Improvement from baseline in 
Quality Index 
SAC [1]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarker
5.15.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
Inhibition of CD69 biomarker by strength, BSA and day –
Summary Statistics
Part A + C
IA[1],SAC [2]
5.16.
PD
Example Non-
Standard_PDT
1 modified 
based on 
endpoint.
Relationship between Basophil Histamine (BHR) test and Weal 
Characteristics
Part C only
No treatment comparison involved.
SAC[2]


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11.10.11. Pharmacodynamic Figures
Pharmacodynamic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacodynamics
5.1.
PD
Non-Standard 
_PD_F1
Allergen Challenge, Weal Area (Percent of Inhibition) - Individual 
Subject Plot
Part A + B
Page by : Treatment
X-Axis
: Continuous scale for visit 
  (days)
Y-Axis
: Scaled accordingly to 
  Parameter and include parameter 
name
Legend : Subject
SAC [1]
5.2.
PD
Non-Standard 
_PD_F2
Allergen Challenge, Weal Area (Percent of Inhibition, absolute 
value) - Box Plot
Part A + B
X-Axis
: Days
Y-Axis
: Result
Legend : Treatment
SAC [1]


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Pharmacodynamic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.3.
PD
Example Non-
Standard 
_PD_F1
Allergen Challenge, Weal Volume (Percent of Inhibition) -
Individual Subject Plot
Part A + B
Page by : Treatment
X-Axis
: Continuous scale for visit 
  (days)
Y-Axis
: Scaled accordingly to 
  Parameter and include parameter 
name
Legend : Subject
SAC [1]


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Pharmacodynamic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.4.
PD
Example Non-
Standard 
_PD_F2
Allergen Challenge, Weal Volume (Percent of Inhibition, 
absolute value) - Box Plot
Part A + B
X-Axis
: Days
Y-Axis
: Result
Legend : Treatment
SAC [1]
5.5.
PD
Example Non-
Standard 
_PD_F1
Allergen Challenge, longest weal Diameter (Percent of 
Inhibition) - Individual Subject Plot
Part A + B
Page by : Treatment
X-Axis
: Continuous scale for visit 
  (days)
Y-Axis
: Scaled accordingly to 
  Parameter and include parameter 
name
Legend : Subject
IA[1],SAC [1]
5.6.
PD
Example Non-
Standard 
_PD_F2
Allergen Challenge, longest Weal Diameter  (Percent of 
Inhibition, absolute value) - Box Plot 
Part A + B
X-Axis
: Days
Y-Axis
: Result
Legend : Treatment
IA[1],SAC [1]


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Pharmacodynamic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.7.
PD
Example Non-
Standard 
_PD_F1
Allergen Challenge, Weal perpendicular length (Percent of 
Inhibition) - Individual Subject Plot 
Part A + B
Page by : Treatment
X-Axis
: Continuous scale for visit 
  (days)
Y-Axis
: Scaled accordingly to 
  Parameter and include parameter 
name
Legend : Subject
IA[1],SAC [1]
5.8.
PD
Example Non-
Standard 
_PD_F2
Allergen Challenge, Weal perpendicular length (Percent of 
Inhibition, absolute value) - Box Plot
Part A + B
X-Axis
: Days
Y-Axis
: Result
Legend : Treatment
IA[1],SAC [1]
5.9.
PD
Example Non-
Standard 
_PD_F1
Allergen Challenge, Flare Erythema (Percent of Inhibition) -
Individual Subject Plot 
Part A + B
Page by : Treatment
X-Axis
: Continuous scale for visit 
  (days)
Y-Axis
: Scaled accordingly to 
  Parameter and include parameter 
name
Legend : Subject
IA[1],SAC [1]


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Pharmacodynamic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.10.
PD
Example Non-
Standard 
_PD_F2
Allergen Challenge, Flare Erythema (Percent of Inhibition, 
absolute value) - Box Plot
Part A + B
X-Axis
: Days
Y-Axis
: Result
Legend : Treatment
IA[1],SAC [1]
5.11.
PD
Example Non-
Standard 
_PD_F1
Cold Temp Test (Change) - Individual Subject Plot 
Part B only
Page by : Treatment
X-Axis
: Continuous scale for visit 
  (days)
Y-Axis
: Scaled accordingly to 
  Parameter and include parameter 
name
Legend : Subject
SAC [1]
5.12.
PD
Example Non-
Standard 
_PD_F2
Cold Temp Test (Change) - Mean (95% CI) Plot 
Part B only
X-Axis
: Days
Y-Axis
: Mean (± 95% CI) Result
Legend : Treatment
SAC [1]
5.13.
PD
Example Non-
Standard 
_PD_F2
UAS7 Score (Change from Baseline) - Mean (95% CI) Plot
Part C only
X-Axis
: Days
Y-Axis
: Mean (± 95% CI) Result
Legend : Treatment
,SAC [1]


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Pharmacodynamic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.14.
PD
Example Non-
Standard 
_PD_F2
Angiodema Activity ScoreScore (AAS) (Change from Baseline) -
Mean (95% CI) Plot 
Part C only
X-Axis
: Days
Y-Axis
: Mean (± 95% CI) Result
Legend : Treatment
SAC [1]
5.15.
PD
Example Non-
Standard 
_PD_F2
Dermatology Life Quality Index (DLQI) - Box Plot 
Part C only
X-Axis
: Days
Y-Axis
: Result
Legend : Treatment
SAC [1]


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11.10.12. ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Randomisation
1.
Safety
CP_TA1
Listing of Randomised and Actual Treatments
IA [1], SAC [1]
Subject Disposition
2.
Safety
ES7
Listing of Reasons for Screen Failure
IA [1], SAC [1]
3.
Safety
ES2
Listing of Reasons for Withdrawal
IA [1], SAC [1]
4.
Safety
DV2
Listing of Important Protocol Deviations
IA (SAC)
5.
Safety
ES2
Listing of Exclusions from Per Protocol Population
IA (SAC)
Inclusion and Exclusion Criteria
6.
Safety
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
IA [1], SAC [1]
Demograhics
7.
Safety
DM2
Listing of Demographic Characteristics
IA [1], SAC [1]
8.
Safety
DM9
Listing of Race
IA [1], SAC [1]
Medical History
9.
Safety
MH2
Listing of Medical History
IA [1], SAC [1]
Concomitant Medication
10.
Safety
CP_CM3
Listing of Concomitant Medication by Generic Term
IA [1], SAC [1]
Study Drug Exposure
11.
Safety
EX3
Listing of Exposure Data
If applicable adapt to study data
IA [1], SAC [1]


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
12.
Safety
AE7
Listing of All Adverse Events
IA [1], SAC [1]
13.
Safety
CP_AE8
Listing of Subject Numbers for Individual Adverse Events
IA [1], SAC [1]
14.
Safety
CP_AE8a
Listing of Serious Adverse Events
IA [1], SAC [1]
15.
Safety
CP_AE8
Listing of Adverse Events Leading to Withdrawal from Study
IA [1], SAC [1]
Clinical Laboratory Assessments
16.
Safety
CP_LB5
Listing of Haematology Abnormalities of Potential Clinical 
Importance
IA [1], SAC [1]
17.
Safety
CP_LB5
Listing of All Haematology Laboratory Data for Subjects with 
Abnormalities of Potential Clinical Importance
Including change from Baseline
IA [1], SAC [1]
18.
Safety
CP_LB5
Listing of Clinical Chemistry Abnormalities of Potential Clinical 
Importance
IA [1], SAC [1]
19.
Safety
CP_LB5
Listing of Clinical Chemistry Laboratory Data for Subjects with 
Abnormalities of Potential Clinical Importance
Including change from Baseline
IA [1], SAC [1]
20.
Safety
CP_LB5
Listing of All Hematology Laboratory Data for Subjects with 
Adverse Events of Interest
IA [1], SAC [1]
21.
Safety
UR2b
Listing of Urinalysis Data for Subjects with Abnormalities of 
Potential Clinical Concern
IA [1], SAC [1]
Electrocardiogram (ECG)
22.
Safety
CP_EG3
Listing of ECG Values of Potential Clinical Importance
IA [1], SAC [1]


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
23.
Safety
CP_EG3
Listing of All ECG Values for Subjects with a Value of Potential 
Clinical Importance
Including change from Baseline
IA [1], SAC [1]
24.
Safety
CP_EG5
Listing of Abnormal ECG Findings
IA [1], SAC [1]
Vital Signs
25.
Safety
CP_VS4
Listing of Vital Signs of Potential Clinical Importance
IA [1], SAC [1]
26.
Safety
CP_EG3
Listing of All Vital Sign for Subjects with a Value of Potential 
Clinical Importance
Including change from Baseline
IA [1], SAC [1]
27.
Safety
CP_VS4
Listing of All Vital Signs for Subjects with Values of Potential 
Clinical Importance
IA [1], SAC [1]


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11.10.13. Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Tolerability assessment
28.
Safety
Non-
Standard_Other
_L1
Listing of irritation score assessment
IA [1], SAC [1]
Pharmacokinetics
29.
PD
pkcl1p
Listing of GSK2646264 plasma PK Concentration-Time Data
IA[1],SAC [1]
30.
PD
pkpl1p
Listing of derived GSK2646264 plasma PK parameters
IA[1],SAC [1]
Pharmacodynamics
31.
PD
Non-Standard 
_Other_L2
Listing of Allergen Challenge Parameters
Absolute and percent of inhibition to 
be presented.
Part A + B
IA[1],SAC [1]
32.
PD
Example Non-
Standard 
_Other_L2
modified based 
on endpoint.
Listing of Critical Temperature Thresholds
Absolute and change from baseline 
result to be presented.
Part B only
SAC [1]
33.
PD
Example Non-
Standard 
_Other_L2
modified based 
on endpoint.
Listing of UAS7 Scores and Subscores
Absolute and change from baseline 
result to be presented.
Part C only
SAC [1]


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
34.
PD
Example Non-
Standard 
_Other_L2
modified based 
on endpoint.
Listing of Angioedema Activity Score(AAS)
Absolute and change from baseline 
result to be presented.
Part C only
SAC [1]
35.
PD
Example Non-
Standard 
_Other_L2
modified based 
on endpoint.
Listing of Dermatology Life Quality Index (DLQI)
Absolute and change from baseline 
result to be presented.
Total score and Subscores
Part C only
SAC [1]


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11.11.
Appendix 11: Example Mock Shells for Data Displays
Example  
: Non- Standard_SAFE_T1
                                                     Page x of y
Protocol
: 2013N167482_01
Population
: Safety
Table 3.17
Summary (Absolute and Change from Baseline) of Mean irritation score assessment
Treatment
Visit
Mean Irritation 
Score
Mean of change 
from baseline 
Irritation Score
GSK2646264 0.5%
XX
XX
XX
XXXX
XX
XX
XX
--
--
--
--
Placebo
XX
XX
XX
Programming Notes : 
[1] As required to be modified based on data and any applicable IDSL standard principals for listings


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Example  
: Non- Standard_SAFE_T2
                                                     Page x of y
Protocol
: 2013N167482_01
Population
: Safety
Table 3.18
Assessment of Maximum Dermal Reactions and Response
Assessment
Reaction 
Grade
Statistic
GSK2646264 
(0.5%)
(N = XX)
GSK2646264 
(1.0%)
(N = XX)
Placebo
(N = XX)
Dermal Response
1
n (%)
XX (XX.XX)
XX (XX.XX)
XX (XX.XX)
2
n (%)
XX (XX.XX)
XX (XX.XX)
XX (XX.XX)
-
-
-
-
-
-
7
n (%)
XX (XX.XX)
XX (XX.XX)
XX (XX.XX)
Any Dermal 
Reaction
n (%)
XX (XX.XX)
XX (XX.XX)
XX (XX.XX)
Grade 3 reaction
(the mean time to 
get Grade 3)
n (%)(mean 
time (days))
XX (XX.XX)
(XX.XX)
XX (XX.XX)
(XX.XX)
XX (XX.XX)
(XX.XX)
score ≥3 on the 
dermal response 
grading scale or 
a letter score of 
F, G, or H for 
other effects
n (%)(mean 
time (days))
XX (XX.XX)
(XX.XX)
XX (XX.XX)
(XX.XX)
XX (XX.XX)
(XX.XX)
N: Number of subjects dosed with each treatment; n: Number of subjects with adverse event with particular reaction grade;
%: Calculated using the number of subjects treated with each treatment as the denominator (n/N*100);
Programming Notes : 
[1] As required to be modified based on data and any applicable IDSL standard principals for listings


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Example 
: Non-Standard_PD_T1
                                                            
Page 1 of X
Protocol
: 2013N167482_01
Population
: PD
Table 5.1
Allergen challenge, Weal Area- Summary Statistics (Absolute and Percent of Inhibition)
Summary: Absolute
Treatment
Time
CI 95%
CI 95%
N
Mean
Lower
Upper
S.D
Min
Median
Max
Placebo
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
.
.
.
.
.
.
.
.
.
GSK2646264 
(0.5%)
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
.
.
.
.
.
.
.
.
.
GSK2646264 
(1.0%)
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
.
.
.
.
.
.
.
.
.
ETC
Programming Notes :
[1] For applicable endpoints, include parameter as either a BY parameter or as first column in the table
[²] If absolute and percent inhibition fit in one table results can be unified in one table.


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Example 
: Non-Standard_PD_T1 (Continued)
                                                            Page 1 of X
Protocol
: 2013N167482_01
Population
: PD
Table 5.1
Allergen challenge, Weal Area- Summary Statistics (Absolute and Percent of Inhibition)
Summary: Percent of Inhibition
Treatment
Time
CI 95%
CI 95%
N
Mean
Lower
Upper
S.D
Min
Median
Max
Placebo
X
x
xxx.x
X
x
xxx.x
X
x
xxx.x
.
.
.
.
.
.
.
.
.
GSK2646264 
(0.5%)
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
.
.
.
.
.
.
.
.
.
GSK2646264 
(1.0%)
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
X
x
xxx.x
xxx.x
xxx.x
xx.xx
xxx
xxx
xxx
.
.
.
.
.
.
.
.
.
ETC
Programming Notes : 
[1] For applicable endpoints, include parameter as either a BY parameter or as first column in the table
[²] If absolute and percent inhibition fit in one table results can be unified in one table.


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Example 
: Non-Standard _PD_T2
                                                            Page 1 of X
Protocol
: 2013N167482_01
Population
: PD
Table 3.17
Change from baseline in composite total UAS7 Scores – Comparison
Treatment
N
Mean
Mean Difference vs. 
Placebo and CI 95% of 
mean difference
Placebo
x
xxx.x
GSK2646264 (0.5%)
x
xxx.x
xx.x (xx.x, xx.x)
GSK2646264 (1.0%)
x
xxx.x
xx.x (xx.x, xx.x)
.
.
.
Programming Notes : 
[1] As required to be modified based on data and any applicable IDSL standard principals for listings


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Example 
: Non-Standard _Other_L1
                                                            Page 1 of X
Protocol
: 2013N167482_01
Population
: Safety
Listing 28
Listing of irritation score assessment
Subject
  
Treatment
Visit
Irritation 
Score 
assessment
XXX
GSK2646264 
(0.5%)
    XX
    XX
XX
XX
--
--
--
XXX
XX
XX
Programming Notes : 
[1] As required to be modified based on data and any applicable IDSL standard principals for listings


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Example 
: Non-Standard _Other_L2
                                                            Page 1 of X
Protocol
: 2013N167482_01
Population
: PD
Listing 31
Listing of Allergen Challenge Parameters
Treatment
Inv./
Subj.
Visit
Parameter 
(Unit)
Result
Percent of 
Inhibition
XXXXX
XXXXX/
XXX
XXXX
XXXXX
XXX.XX
XXX.XX
XXXXX
XXX.XX
XXX.XX
XXXXX
XXX.XX
XXX.XX
XXXXX
XXX.XX
XXX.XX
XXXXX
XXX.XX
XXX.XX
XXXX
XXXXX
XXX.XX
XXX.XX
XXXXX
XXX.XX
XXX.XX
XXXXX
XXX.XX
XXX.XX
Programming Notes : 
[1] As required to be modified based on data and any applicable IDSL standard principals for listings


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Example 
: Non-Standard _PD_F1
                                                            Page 1 of X
Protocol
: 2013N167482_01
Population
: PD
Figure 5.1
Allergen Challenge, Weal Area (Percent of Inhibition) - Individual Subject Plot
Programming Notes : 
[1] Plot adapted accordingly based on study data (overlayed by treatment)
[2] Subject will have two values one for treatment and another for placebo. Therefore use one colour for the subject id and two symbols for 
treatment (e.g. ο=placebo, +=Treatment). Adapt the graph correspondingly.
PPD


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Example 
: Non-Standard _PD_F1
                                                            Page 1 of X
Protocol
: 2013N167482_01
Population
: PD
Figure 5.2
Allergen Challenge, Weal Area  (Percent of Inhibition) - Mean (95% CI) Plot
Treatment: A= Verum, B=Placebo
Programming Notes : 
[1] Plot adapted accordingly based on study data.
[2] Replicate this box plot to other similar plots, eg. for absolute values..