Conditions: Asthma
Keywords: GSK2245035 TLR7 agonist allergic asthma FEV1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
This study will assess whether Toll like receptor 7 (TLR7)-mediated pharmacology, with intranasal (i.n.) GSK2245035 20 nanogram (ng) administered weekly for a period of 8 weeks, will lead to reduced allergic reactivity in the lower airways in subjects with mild allergic asthma.

This will be a randomised, double-blind (sponsor open), placebo-controlled, parallel group, 8-week treatment study.

The study will consist of a screening period of up to approximately 4 weeks (involving two screening visits), a blinded treatment period of 8 weeks, followed by a follow-up period of up to 3 months. The total duration of the study for each subject will therefore be a maximum of approximately 6 months.

Detailed description:

Arms:
arm 1: Participants will receive 20 ng of GSK2245035 Nasal spray solution (1 spray=10 ng GSK2245035 per actuation per nostril) every week for the duration of 8 weeks administered using a metered Valois VP7 pump arm 2: Participants will receive placebo Nasal spray solution (1 spray per nostril) every week for the duration of 8 weeks administered using a metered Valois VP7 pump

Interventions: intervention 1: GSK2245035 Nasal Spray Solution intervention 2: Placebo Nasal Spray Solution
Intervention descriptions: intervention 1: GSK2245035 Nasal Spray Solution 0.2 microgram (mcg)/mL delivering 10 ng GSK2245035 per actuation. A solution formulation in saline, preserved with Benzalkonium Chloride and Disodium Edetate. intervention 2: Nasal Spray Solution as for GSK2245035 without active ingredient.

Protocol document:
Prot_001.pdf: 
2015N264314_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
205540
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A randomised, double-blind (sponsor open) placebo-controlled, 
parallel group, 8-week treatment study to investigate the safety, 
pharmacodynamics and effect of the TLR7 agonist, 
GSK2245035, on the allergen-induced asthmatic response in 
subjects with mild allergic asthma.
Compound Number:
GSK2245035
Development Phase:
II
Effective Date:
10-JUL-2017
Protocol Amendment Number:  04
Author (s):
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2015N264314_04
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The GlaxoSmithKline group of companies
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2
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2015N264314_00
2016-APR-06
Original
2015N264314_01
2016-JUN-15
Amendment No. 1
Section 4.6.1 and Section 7.1.1 have been adjusted slightly to make it clearer that subjects 
will be provided with a thermometer to be able to record temperature as part of capturing 
adverse event (AE) information.
In Section 5.2, exclusion criterion 13 has been updated to reflect the revised 
recommended alcohol consumption guidelines.
2015N264314_02
2016-AUG-17
Amendment No. 2
The protocol title and text have been amended to clarify that while the investigator and 
subjects are blinded the sponsor-is unblinded. 
Details of the procedures required at early withdrawal visits have been added to the Time 
and Events Table, Section 7.1.
Details around the Safety Review Team have been added to include a consultant external 
to GSK to Section 6.3.
The inclusion and exclusion criteria have been updated in Section 5.1 and Section 5.2. 
and clarification around prohibited medications has been provided in Section 6.11.2. to 
align with updated exclusion criteria (Section 5.2).
Administrative changes have been made to the T&E table (Section 7.1) and text to ensure 
consistency throughout.
2015N264314_03
2017-MAY-26
Amendment No. 3
Changes in the Primary Medical Monitor and contact details.
Alignment of contraception requirements in Section 5.1 and Section 12.5.1 for partners of 
male subjects that are female of reproductive potential. 
Section 5.1, Inclusion Criteria, has been updated to align with Section 12.5.1 
contraception requirements for partners of male subjects that are female of reproductive 
potential. Changes made to these sections.
Section 5.1 Inclusion Criteria, bullets have been replaced with numbers.


2015N264314_04
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2015N264314_04
2017-JUL-10
Amendment No. 4
Section 4.4 Design Justification, has been updated to permit earlier interim analysis.
Section 5.3, Screening Failures/Re-Screening, has been updated to allow re-screening.
Section 7.1.1 Time and Events Table – Screening Visit(s), has been updated to clarify 
timing of screening visits.
Section 10.2 Regulatory and Ethical Considerations, Including the Informed Consent 
Process, to clarify that a new ICF should be completed for each re-screened subject.


PPD
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
 
 
MD
Gunnels 
Wood Road
Stevenage, 
SG1 2NY
UK
Secondary 
Medical 
Monitor 
 
 MD
Gunnels 
Wood Road
Stevenage, 
SG1 2NY
UK
SAE contact  
information 
Medical 
monitor 
as above 
and 
Study 
Manager, 
Gunnels 
Wood Road
Stevenage, 
SG1 2NY
UK
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):  2015-005645-31
PPD
PPD
PPD
PPD
PPD
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 205540
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205540......................................................10
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale/Brief background...............................................................13
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................14
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................16
4.3.
Type and Number of Subjects.....................................................................16
4.4.
Design Justification.....................................................................................17
4.5.
Dose Justification........................................................................................18
4.6.
Benefit: Risk Assessment ...........................................................................19
4.6.1.
Risk Assessment .........................................................................20
4.6.2.
Benefit Assessment.....................................................................26
4.6.3.
Overall Benefit: Risk Conclusion..................................................26
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............26
5.1.
Inclusion Criteria.........................................................................................26
5.2.
Exclusion Criteria........................................................................................29
5.3.
Screening Failures/Re-screening................................................................31
5.4.
Withdrawal/Stopping Criteria.......................................................................31
5.4.1.
Liver Chemistry Stopping Criteria ................................................32
5.4.1.1.
Study Treatment Restart or Rechallenge....................32
5.4.2.
QTc Stopping Criteria ..................................................................32
5.5.
Subject and Study Completion....................................................................33
6.
STUDY TREATMENT ............................................................................................33
6.1.
Investigational Product and Other Study Treatment....................................33
6.2.
Treatment Assignment................................................................................34
6.3.
Blinding.......................................................................................................35
6.4.
Packaging and Labeling..............................................................................36
6.5.
Preparation/Handling/Storage/Accountability..............................................36
6.6.
Compliance with Study Treatment Administration.......................................37
6.7.
Treatment of Study Treatment Overdose....................................................37
6.8.
Treatment after the End of the Study ..........................................................37
6.9.
Challenge Agents .......................................................................................37
6.9.1.
Bronchial, intranasal and intra-dermal allergen 
challenge/administration ..............................................................37
6.10.
Lifestyle and/or Dietary Restrictions............................................................38
6.10.1.
Meals and Dietary Restrictions ....................................................38
6.10.2.
Caffeine, Alcohol, and Tobacco ...................................................38
6.10.3.
Activity .........................................................................................38
6.11.
Concomitant Medications and Non-Drug Therapies....................................38
6.11.1.
Permitted Medications and Non-Drug Therapies..........................38
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................38
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................39
7.1.
Time and Events Tables .............................................................................41


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7.1.1.
Time and Events Table – Screening Visit(s) ................................41
7.1.2.
Time and Events Table – Dosing visit (DV) 1 (Day 1) –
DV8 (Week 8) and Early Withdrawal Visit (EW) ...........................43
7.1.3.
Time and Events Table – Follow up visits (FUV1 to 3) 
(Weeks 9 to 20) ...........................................................................45
7.2.
Screening and Critical Baseline Assessments ............................................47
7.2.1.
Skin prick testing..........................................................................47
7.3.
Efficacy.......................................................................................................47
7.3.1.
Bronchial allergen challenges and spirometry..............................47
7.3.2.
Intranasal and intra-dermal allergen challenge ............................47
7.3.3.
Sputum induction.........................................................................47
7.3.4.
TNSS...........................................................................................48
7.3.5.
Nasal examination .......................................................................48
7.3.6.
Fractional Exhaled Nitric Oxide (FeNO) .......................................48
7.4.
Safety .........................................................................................................49
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........49
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................49
7.4.1.2.
Method of Detecting AEs and SAEs ...........................50
7.4.1.3.
Follow-up of AEs and SAEs........................................50
7.4.1.4.
Cardiovascular and Death Events ..............................50
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................51
7.4.1.6.
Regulatory Reporting Requirements for SAEs............51
7.4.1.7.
Cytokine Related Symptoms (CRS) -
Symptoms Grading.....................................................52
7.4.2.
Pregnancy ...................................................................................52
7.4.3.
Physical Exams ...........................................................................52
7.4.4.
Vital Signs....................................................................................52
7.4.5.
Electrocardiogram (ECG).............................................................52
7.4.6.
Clinical Safety Laboratory Assessments ......................................53
7.4.7.
PEF monitoring............................................................................55
7.5.
Pharmacokinetics .......................................................................................55
7.5.1.
Blood Sample Collection..............................................................55
7.5.2.
Sample Analysis ..........................................................................55
7.6.
Exploratory Biomarkers...............................................................................55
7.6.1.
Pharmacodynamic Markers .........................................................55
7.6.1.1.
PD blood samples ......................................................55
7.6.1.2.
Blood PAX collection ..................................................56
7.6.1.3.
PD nasal lavage samples ...........................................56
7.6.1.4.
Bronchial allergen challenge (BAC) associated 
biomarkers in induced sputum samples......................56
7.6.1.5.
Bronchial allergen challenge (BAC) associated 
biomarkers in blood samples......................................56
7.6.1.6.
Nasal allergen challenge associated 
biomarkers in nasal fluid samples...............................56
7.6.1.7.
Cellular profile of nasal mucosa..................................56
7.6.2.
Novel Biomarkers ........................................................................57
7.7.
Genetics .....................................................................................................57
8.
DATA MANAGEMENT ...........................................................................................57


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9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................58
9.1.
Hypotheses.................................................................................................58
9.2.
Sample Size Considerations.......................................................................58
9.2.1.
Sample Size Assumptions ...........................................................63
9.2.2.
Sample Size Sensitivity................................................................64
9.2.3.
Sample Size Re-estimation or Adjustment...................................64
9.3.
Data Analysis Considerations .....................................................................64
9.3.1.
Analysis Populations....................................................................64
9.3.2.
Interim Analysis ...........................................................................65
9.3.2.1.
Headline results for LAR endpoints at Follow 
Up 1 ...........................................................................67
9.4.
Key Elements of Analysis Plan ...................................................................68
9.4.1.
Primary Analyses.........................................................................68
9.4.2.
Secondary Analyses ....................................................................68
9.4.3.
Safety Analyses...........................................................................68
9.4.4.
Exploratory Analyses ...................................................................68
10. STUDY GOVERNANCE CONSIDERATIONS........................................................68
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............68
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................69
10.3.
Quality Control (Study Monitoring) ..............................................................69
10.4.
Quality Assurance.......................................................................................70
10.5.
Study and Site Closure ...............................................................................70
10.6.
Records Retention......................................................................................71
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................71
11. REFERENCES.......................................................................................................72
12. APPENDICES........................................................................................................73
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................73
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................76
12.3.
Appendix 3 - Genetic Research ..................................................................78
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................81
12.4.1.
Definition of Adverse Events........................................................81
12.4.2.
Definition and Grading of CRS-related Adverse Events ...............83
12.4.3.
Definition of Serious Adverse Events...........................................84
12.4.4.
Definition of Cardiovascular Events .............................................86
12.4.5.
Recording of AEs and SAEs ........................................................86
12.4.6.
Evaluating AEs and SAEs............................................................87
12.4.7.
Reporting of SAEs to GSK...........................................................88
12.5.
Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy and Collection of Pregnancy Information...................................89
12.5.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy ...................................................................................89
12.5.2.
Collection of Pregnancy Information ............................................89
12.5.3.
References ..................................................................................90
12.6.
Appendix 6 - Country Specific Requirements..............................................92
12.7.
Appendix 7: Protocol Amendment Changes................................................93


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1.
PROTOCOL SYNOPSIS FOR STUDY 205540
Rationale
GSK2245035 is a highly selective Toll-like receptor 7 (TLR7) agonist that preferentially 
stimulates the induction of type I interferons.  Intranasal (i.n.) administration of 
GSK2245035 in humans has been shown to cause immune changes in the upper airways 
milieu that may alter bystander immune responsiveness to aeroallergens and contribute to 
reduction of allergic reactivity in subjects with respiratory allergies.
In a 8-week repeat dose safety study (TL7116958) with i.n. GSK2245035 20 ng and 
80 ng, target engagement was confirmed by dose-related increases in serum and nasal 
lavage interferon inducible protein-10 (IP-10) levels in subjects with symptomatic 
allergic rhinitis and mild asthma. Prolonged activation (up to 1 week in the serum and 
3 weeks in nasal lavage) of the interferon (IFN) α pathway was noted at the higher dose 
with no associated adverse effects during this follow-up period.  Eight weekly doses of 
both 20 ng and 80 ng reduced nasal symptoms and allergic biomarkers after nasal 
allergen challenge and those reductions were sustained up to 3 weeks post treatment.
This study will assess whether TLR7-mediated pharmacology, with i.n. GSK2245035 
20 ng administered weekly for a period of 8 weeks, will lead to reduced allergic reactivity 
in the lower airways in subjects with mild allergic asthma.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To evaluate the effect of treatment with 
i.n. GSK2245035 compared to placebo 
on the allergen-induced late asthmatic 
response (LAR) in subjects with allergic 
asthma.

LAR: minimum forced expiratory volume 
in 1 second (FEV1) between 4-10 hours 
following allergen challenge one week 
after treatment.

LAR: weighted mean FEV1 between 4-10 
hours following allergen challenge one 
week after treatment.
Secondary

To evaluate the effect of treatment with 
i.n. GSK2245035 compared to placebo 
on the allergen-induced early asthmatic 
response (EAR) in subjects with allergic 
asthma.

EAR: minimum FEV1 between 0-2 hours 
following allergen challenge one week 
after treatment.

EAR: weighted mean FEV1 between 0-2 
hours following allergen challenge one 
week after treatment.


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Objectives
Endpoints

Safety

To evaluate the safety and tolerability of 
treatment with eight weekly doses of 20 
ng i.n. GSK2245035

General safety endpoints including 
adverse events (AEs), peak expiratory 
flow (PEF), rescue salbutamol use, and 
clinical laboratory parameters

Exploratory

To evaluate the duration of effect of 
treatment with i.n. GSK2245035 
compared to placebo on the allergen-
induced asthmatic responses (LAR and 
EAR) in subjects with allergic asthma.

LAR: minimum and weighted mean 
FEV1 between 4-10 hours following 
allergen challenge approximately 4 and 
12 weeks after treatment.

EAR: minimum and weighted mean 
FEV1 between 0-2 hours following 
allergen challenge approximately 4 and 
12 weeks after treatment.

To evaluate the induction of TLR7-
associated pharmacodynamic (PD) 
biomarkers and exhaled nitric oxide 
(FeNO) following treatment with i.n. 
GSK2245035

TLR7-induced blood PD biomarkers.

TLR7 induced gene expression changes 
in blood

TLR7-induced nasal fluid PD biomarkers

Change in FeNO levels during the 
treatment phase

To evaluate the effect of treatment with 
i.n. GSK2245035 compared to placebo 
on Bronchial Allergen Challenge (BAC) 
associated allergic biomarkers

Allergic biomarkers in induced sputum

Allergic biomarkers in blood

Change in FeNO levels following BAC

To evaluate the effect of treatment with 
i.n. GSK2245035 compared to placebo 
on Nasal Allergen Challenge (NAC) 
associated allergic biomarkers

Allergic biomarkers in nasal fluids

Cellular profile of nasal mucosa

To evaluate the effect of treatment with 
i.n. GSK2245035 compared to placebo 
on Intradermal allergen challenge

Mean diameter early phase response

Mean diameter late phase response

To evaluate the effect of treatment with 
i.n. GSK2245035 compared to placebo 
on total nasal symptoms

Total nasal symptoms score (TNSS) 
assessed daily (AM and PM) throughout 
the study treatment phase

To evaluate systemic pharmacokinetics 
(PK) after administration of i.n. 
GSK2245035 

Plasma GSK2245035 concentrations


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Overall Design
This will be a randomised, double-blind (sponsor open), placebo-controlled, parallel 
group, 8-week treatment study. Study schematic below:
Week -4
1       2      3     4     5      6      7      8       9
12 
20
Screening
8 week treatment period
Follow-up
BAC -Bronchial allergen challenge; NAC – Nasal allergen challenge/administration
IC – Intradermalchallenge; DV – Dosing Visit; FU – Follow-up
DV1  DV2 DV3 DV4 DV5 DV6 DV7 DV8   FU1          FU2             FU3
Randomisation
BAC/
NAC/IC
BAC/
NAC/
IC
BAC/
NAC/
IC
BAC
Treatment Arms and Duration

The study will consist of a screening period of up to approximately 4 weeks 
(involving two screening visits), a blinded treatment period of 8 weeks, followed by a 
follow-up period of up to 3 months.  The total duration of the study for each subject 
will therefore be a maximum of approximately 6 months. All doses will be 
administered in the clinic.

Approximately 24 subjects per arm will be randomised in a 1:1 ratio to receive either 
i.n. 20 ng GSK2245035 or placebo every week for the duration of 8 weeks.
Type and Number of Subjects

Subjects with allergic asthma who are sensitized to perennial or seasonal allergen(s) 
will be enrolled in the study.  Based on the restriction of concomitant medications as 
shown in the exclusion criteria, the target population includes subjects with mild 
asthma not requiring maintenance treatment with inhaled corticosteroid who are able 
to be treated with short acting beta2-agonist (SABA) alone for the duration of the 
study (up until the final follow-up visit).


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
A sufficient number of subjects will be enrolled to ensure that 20 per treatment arm 
complete the 8 week study treatment period and the BAC at the one week follow-up 
visit (one week after the 8th dose of study treatment).
Analysis
Statistical models will be fitted separately to each primary endpoint.  These endpoints 
will be analysed using analysis of covariance (ANCOVA) with treatment and baseline in 
the model; other covariates such as centre, allergen exposure (‘presumed’/’unknown’) 
and allergen exposure by treatment interaction may be included in the model.
Treatment comparisons of GSK2245035 vs Placebo will be presented with results also 
expressed as percentage attenuations to aid clinical interpretation. The posterior 
distribution for GSK2245035 vs Placebo will be obtained and expressed as percentage 
attenuation. The posterior probability of any percentage attenuation will be obtained, 
along with appropriate summary statistics from the posterior distribution (e.g. 70% equi-
tail Credible Intervals).
The principle inferences are expected to come from models with non-informative priors. 
Sensitivity analyses using informative priors based on AstraZeneca (AZ) data may be 
fitted [Leaker , 2012].
An interim analysis will be conducted to assess how many subjects on placebo did not 
experience an LAR as such subjects will reduce the chances of establishing the primary 
objective of this study.  This interim analysis will determine whether i) further 
recruitment into the trial should continue (i.e. a futility analysis), or ii) additional subjects 
should be enrolled to counteract the impact.
2.
INTRODUCTION
2.1.
Study Rationale/Brief background
The immunological milieu of the airways plays a critical role in shaping the nature of 
host responsiveness to inhaled allergens with predominant induction of aberrant Th2 
responses driving the development of respiratory allergies and asthma. The scientific 
hypothesis is that intranasal delivery of a TLR7 agonist will activate local dendritic cells, 
inducing a type 1 IFN response, and result in the modification of the nature of both B and 
T cell responses to allergen. Driving the development of Th1/Treg responses may reduce 
the magnitude of mucosal Th2 reactivity and reduce local IgE responses.
GSK2245035 is a highly selective Toll-like receptor 7 (TLR7) agonist that stimulates 
preferentially the induction of type I interferons.  In a 8-week repeat dose safety study 
(TL7116958) [GlaxoSmithKline Document Number 2013N174200_00] with i.n. 
GSK2245035 20ng and 80 ng, target engagement was confirmed by dose-related 
increases in serum and nasal lavage IP-10, (interferon inducible protein 10) levels in 
subjects with symptomatic allergic rhinitis and mild asthma.  Prolonged activation (up to 
1 week in the serum and 3 weeks in nasal lavage) of the IFNα pathway was noted at the 
higher dose with no associated adverse effects during this follow-up period.  Eight 
weekly doses of both 20 ng and 80 ng reduced nasal symptoms and allergic biomarkers 


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after nasal allergen challenge and those reductions were sustained up to 3 weeks post 
treatment.
Having demonstrated the effects i.n. GSK2245035 in patients with allergic rhinitis, this 
study will assess whether TLR7-mediated pharmacology, with i.n. GSK2245035 20 ng 
administered weekly for a period of 8 weeks, will lead to reduced allergic reactivity in the 
lower airways in subjects with mild allergic asthma using a bronchial allergen challenge 
model (BAC) at various time-points following treatment.  For asthma patients who have 
allergic triggers for their disease, an i.n. treatment may be considered ideal to maximize 
co-localization with both its target, local dendritic cells, and aeroallergen.  Clinical 
evidence to support the hypothesis that an intranasal TLR7 agonist can reduce the 
response to allergen in the lower airways using a BAC model has been reported (Leaker , 
2012). 
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To evaluate the effect of treatment with i.n. 
GSK2245035 compared to placebo on the 
allergen-induced late asthmatic response 
(LAR) in subjects with allergic asthma.

LAR: minimum FEV1 between 4-10 hours 
following allergen challenge one week after 
treatment.

LAR: weighted mean FEV1 between 4-10 
hours following allergen challenge one 
week after treatment.
Secondary

To evaluate the effect of treatment with i.n.
GSK2245035 compared to placebo on the 
allergen-induced early asthmatic response 
(EAR) in subjects with allergic asthma.

EAR: minimum FEV1 between 0-2 hours 
following allergen challenge one week after 
treatment.

EAR: weighted mean FEV1 between 0-2 
hours following allergen challenge one 
week after treatment.

Safety

To evaluate the safety and tolerability of 
treatment with eight weekly doses of 20 ng 
i.n. GSK2245035

General safety endpoints including AE, 
peak expiratory flow (PEF), rescue 
salbutamol use, and clinical laboratory 
parameters


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Objectives
Endpoints

Exploratory

To evaluate the duration of effect of 
treatment with i.n. GSK2245035 compared 
to placebo on the allergen-induced 
asthmatic responses (LAR and EAR) in 
subjects with allergic asthma.

LAR: minimum and weighted mean FEV1
between 4-10 hours following allergen 
challenge approximately 4 and 12 weeks 
after treatment.

EAR: minimum and weighted mean FEV1
between 0-2 hours following allergen 
challenge approximately 4 and 12 weeks 
after treatment.

To evaluate the induction of TLR7-
associated PD biomarkers and FeNO 
following treatment with i.n. GSK2245035

TLR7-induced blood PD biomarkers.

TLR7 induced gene expression changes in 
blood

TLR7-induced nasal fluid PD biomarkers

Change in FeNO levels during the 
treatment period

To evaluate the effect of treatment with i.n. 
GSK2245035 compared to placebo on 
Bronchial Allergen Challenge (BAC) 
associated allergic biomarkers

Allergic biomarkers in induced sputum

Allergic biomarkers in blood

Change in FeNO levels following BAC

To evaluate the effect of treatment with i.n. 
GSK2245035 compared to placebo on 
Nasal Allergen Challenge (NAC) 
associated allergic biomarkers

Allergic biomarkers in nasal fluids

Cellular profile of nasal mucosa

To evaluate the effect of treatment with i.n. 
GSK2245035 compared to placebo on 
Intradermal allergen challenge

Mean diameter early phase response

Mean diameter late phase response

To evaluate the effect of treatment with i.n. 
GSK2245035 compared to placebo on total 
nasal symptoms

Total nasal symptoms score (TNSS) 
assessed daily (AM and PM) throughout 
the study treatment phase

To evaluate systemic pharmacokinetics 
(PK) after administration of i.n. 
GSK2245035 

Plasma GSK2245035 concentrations


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4.
STUDY DESIGN
4.1.
Overall Design

This will be a randomised, double-blind (sponsor open), placebo-controlled, parallel 
group, 8-week treatment study. Study schematic below:
Week -4
1       2      3     4     5      6      7      8       9
12 
20
Screening
8 week treatment period
Follow-up
BAC -Bronchial allergen challenge; NAC – Nasal allergen challenge/administration
IC – Intradermalchallenge; DV – Dosing Visit; FU – Follow-up
DV1  DV2 DV3 DV4 DV5 DV6 DV7 DV8   FU1          FU2             FU3
Randomisation
BAC/
NAC/IC
BAC/
NAC/
IC
BAC/
NAC/
IC
BAC
4.2.
Treatment Arms and Duration

The study will consist of a screening period of up to approximately 4 weeks 
(involving two screening visits), a blinded treatment period of 8 weeks, followed by a 
follow-up period of up to 3 months.  The total duration of the study for each subject 
will therefore be a maximum of approximately 6 months. All doses will be 
administered in the clinic.

Approximately 24 subjects per treatment arm will be randomised in a 1:1 ratio to 
receive either i.n. 20ng GSK2245035 or placebo every week for the duration of 8 
weeks.
4.3.
Type and Number of Subjects

Subjects with allergic asthma who are sensitized to perennial or seasonal allergen(s) 
will be enrolled in the study.  Based on the restriction of concomitant medications as 
shown in the exclusion criteria, the target population includes subjects with mild 
asthma not requiring maintenance treatment with inhaled corticosteroid who are able 


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to be treated with short acting beta2-agonist (SABA) alone for the duration of the 
study (up until the final follow-up visit).

A sufficient number of subjects will be enrolled to ensure that 20 per treatment arm 
complete the 8 week study treatment period and the BAC at the one week follow-up 
visit (one week after the 8th dose of study treatment).
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and assigned the next available randomisation number, at the discretion of the 
Sponsor, in consultation with the investigator.
Following the interim analysis, additional subjects may also be enrolled to counteract the 
impact of individuals not exhibiting an LAR response on placebo.
Accounting for replacements and interim analysis recommendations, the total number of 
subjects to be randomised in this study is not expected to exceed 60.
4.4.
Design Justification

GSK2245035 is currently being developed for patients with allergic asthma.  It has 
been studied in healthy volunteers (HVT) and subjects with allergic rhinitis with and 
without mild asthma.  

This study will assess the safety, target engagement, and efficacy of GSK2245035 in 
subjects with allergic asthma using a placebo-controlled, parallel group design and a 
BAC model.  The BAC model is an established methodology and will be used in this 
study to determine whether 8 weekly doses of 20 ng i.n. GSK2245035 attenuates 
allergen-induced asthmatic responses compared to placebo.  In addition to the 
assessment after BAC at the end of the 8-week treatment (1 week after the 8th dose), 
additional BACs will be performed at approximately 4 weeks and 12 weeks after the 
8th dose to assess the durability of the effect.

In an 8-week repeat dose safety study TL7116958 [GlaxoSmithKline Document 
Number 2013N174200_00], there was a reduction of TNSS at15 minutes post-NAC. 
This could indicate an effect of GSK2245035 treatment on mast cell activation and 
mediator release. In the current study, nasal lining fluid will be collected before and 
up to 5 minutes after nasal allergen challenges to evaluate the impact of GSK2245035 
on mast cell mediator release. NACs will be performed approximately 24 hours after 
the BACs that are conducted at screening and at approximately 1 week and 4 weeks 
after the final dose.

Interim analysis: Previous experience within GSK suggests some individuals 
(approximately 20%) fail to demonstrate a LAR response after the screening visit (i.e. 
they pass the screening criteria but do not demonstrate another LAR response when 
receiving placebo during the on-treatment phase). Those GSK studies were mainly 
crossover designs with a placebo in every sequence, so subjects who did not 
demonstrate a post screening LAR could be retrospectively identified and excluded 
from the statistical analyses. However this study has parallel groups and the profiles 
of a “perfect” drug effect and an inconsistent LAR subject are indistinguishable so 
retrospective exclusions cannot be made for the GSK2245035 arm. If the rate of 
“non-reproducible LAR” subjects is large it will reduce the probability of success. 


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The purpose of the interim analysis is to evaluate whether the non-reproducible LAR 
rate is reducing the expected probability of success by more than 10% and, if it is, to 
perform an unblinded review of the observed data to assess the impact and cease 
further recruitment into the study, or enrol additional subjects to counteract the 
effects. Simulations were used to quantify the expected reduction in probability of 
success, using an estimate of the non-responder rate from the placebo arm only. The 
timing of the interim is linked to the enrolment rates and will be triggered by 
whichever occurs first i) Approximately 1 year after the first subject successfully 
completes the Follow Up 1 assessments or, ii) When 28 subjects have successfully 
completed the Follow Up 1 assessments or iii) At the discretion of the GSK Study 
Team up to the time that 28 subjects have successfully completed the Follow Up 1 
assessment.

It is hypothesized that TLR7-mediated immunomodulation requires allergen to be 
present and exposure to aeroallergens may fluctuate or remain relatively constant 
depending on the allergen, time of year, and a subject's household characteristics or 
activities.  Further, exposure to certain aeroallergens may be presumed and, in other 
instances, is unknown unless outdoor air and household samples are analyzed.  For 
example, allergen exposure may be presumed if a subject who is sensitized to and 
challenged with grass pollen enrolls during grass pollen season or whose treatment is 
expected to coincide with grass pollen season.  A subject sensitized to animal 
epithelia who has that animal in his/her house or has occupational exposure may be 
presumed to have exposure.  These subjects will potentially exhibit a different 
response to study drug to someone without similar exposure to the allergen.  
Exposure to certain allergens, particularly perennial allergens (i.e. house dust mite) 
cannot be presumed and will be considered unknown for the purposes of this 
protocol.  Therefore, the allergen a subject is administered for the BAC will need to 
be considered according to whether the subject has exposure to that allergen outside 
of the challenge.  Consequently, the randomization will be stratified by ‘presumed’ 
and ‘unknown’ exposure to allergen in addition to stratification by centre.
4.5.
Dose Justification
The 20ng weekly i.n. dose of GSK2245035 was selected based on previous single and 
repeat dose studies in healthy volunteers (HVTs) and allergic rhinitis subjects with and 
without mild asthma.

In the first time in human study TL7114450 (dose range 2 ng – 100 ng) 
[GlaxoSmithKline Document Number 2011N120740_00], single i.n. administration 
of doses up to 40 ng GSK2245035 was well tolerated in HVT and subjects with 
symptomatic seasonal allergic rhinitis.

In the 4-week repeat dose study TL7116392 [GlaxoSmithKline Document Number 
2011N126275_00], the repeat dose of i.n. GSK2245035 40 and 80 ng had an 
acceptable safety profile.  Adverse events (AEs) likely related to TLR7-induced 
cytokines, such as headache, fever, chills/rigors and nausea were observed in one 
subject receiving placebo, 4 of 6 subjects receiving 40 ng GSK2245035 and one of 7 
subjects receiving 80 ng GSK2245035.


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
In a 8-week repeat dose safety study TL7116958 [GlaxoSmithKline Document 
Number 2013N174200_00] with i.n. GSK2245035 in subjects with symptomatic 
allergic rhinitis and mild asthma, 20 ng and 80 ng weekly doses produced sustained 
reductions in nasal allergic reactivity based on the total nasal symptom score after 
nasal allergen challenge up to 3 weeks post treatment.  The tolerability of 20 ng 
GSK2245035 was similar to placebo with no reports of cytokine-related fever.  
Cytokine release syndrome (CRS)-related symptoms were self-resolving and occurred 
infrequently over the 8-week study period in subjects receiving 20 ng GSK2245035.  
GSK2245035 80 ng was poorly tolerated.  All but one subject receiving 80 ng 
experienced flu-like symptoms.  Although CRS-related symptoms were also self-
resolving at the 80 ng dose, subjects experienced them fairly consistently over the 
study period.  TLR7-induced biomarkers indicated target engagement at both doses, 
with evidence for sustained activation of TLR7-mediated pathway intranasally up to 3 
weeks post treatment only at the 80ng dose.  Reviewing the totality of data obtained 
in these previous studies supports further study of a repeated weekly dose of 20 ng 
i.n. GSK2245035.
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2245035 can be found in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2010N110564_04]. The following section outlines the risk assessment and 
mitigation strategy for this protocol:  


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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK2245035]
Events potentially related to cytokine 
induction.
The principal systemic effect seen with 
GSK2245035 in intranasal studies in 
animals (mice, rats, rabbits, and monkeys) 
up to 8 weeks in duration with weekly 
dosing was increases in the levels of 
specific cytokines; all other findings were 
considered to be secondary to this primary 
response (i.e., nasal irritancy, increased 
body temperature, increased heart rate, 
alterations in splenic and lymph node 
cellularity and minor changes in some 
clinical chemistry parameters).  With the 
exception of the splenic and lymph node 
effects, all the observed changes would be 
readily monitorable in humans.  The effects 
that were seen in the spleen and lymph node 
were of low severity and were shown to be 
fully reversible on withdrawal from 
treatment in the monkey.  The observed 
cytokine response is consistent with the 
known TLR7 pharmacology of 
GSK2245035.  Although a no effect level 
for cytokine response was not determined in 
the monkey, a No Observed Adverse Event 
Level (NOAEL) of 35.9 ng/kg/day was 
determined for the only secondary finding 
The study will be undertaken at experienced 
research units. The sites have all necessary 
facilities to handle medical emergencies. All 
subjects will receive each dose in the unit 
and will be monitored closely after each 
dose (for approximately 1-2 hours). Each 
subject will receive a phone call 
approximately 12 hours following 
administration of at least the first two doses 
to assess tolerability. They will be provided 
with a thermometer to measure body 
temperature. Thorough monitoring of any 
AEs will be performed throughout the 
treatment period to allow early assessment 
and mitigation of risk.
Only subjects in good general health with a 
diagnosis of mild asthma will participate in 
this study (see Inclusion/Exclusion Criteria, 
Section 5.1 and Section 5.2). Subjects with 
history of severe asthma are excluded from 
the study.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
considered to be adverse, nasal irritancy 
[GlaxoSmithKline Document Number 
2010N110564_04].
GSK2245035 has been previously tested in 
subjects with allergic rhinitis with or 
without mild asthma at the same dose (20 
ng) and the same i.n. regimen (8 weekly 
administrations) proposed for this study.
I.n. GSK2245035 induced transient dose 
related increases in body temperature 
(GSK2245035 80 ng maximum 1.37ºC; 
GSK2245035 20 ng group maximum 
0.34ºC). 
I.n. GSK2245035 induced dose related 
increases in the frequency and severity of 
AEs possibly related to cytokine induction. 
Headache was the most frequently reported 
cytokine related AE for all treatments (79% 
subjects in GSK2245035 80 ng, 29% 
subjects in GSK2245035 20 ng and 21% 
subjects in placebo group), including mild, 
moderate and severe reports. 
Fever was a frequently reported cytokine 
related AE at GSK2245035 80 ng (58%) 
while no reports of cytokine related fever 
were noted at GSK2245035 20ng or 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
placebo. Cytokine related fever mainly 
emerged after the second dosing visit; most 
cytokine related fever occurred within 12 
hours of dosing. 
One subject receiving GSK2245035 80ng 
was withdrawn due to severe myalgia 
occurring after the second dose. One 
GSK2245035 20ng subject reported myalgia 
and arthralgia of moderate severity. 
At both doses cytokine related AEs were 
self resolving with a median duration of 
approximately ≤ 1 day.
No severe cytokine related events were 
reported at GSK2245035 20ng.
There were no reports of vomiting, diarrhea 
or hypotension in any treatment group.
Nasal irritancy
Nasal irritancy was noted in rats and 
monkeys after repeat intranasal dosing; the 
effects in the rat were seen only at very high 
dose levels/concentrations (Section 4.5 of 
the Investigator Brochure (IB)) 
[GlaxoSmithKline Document Number 
2010N110564_04].
The finding from the rat and monkey studies 
Thorough monitoring of nasal AEs will be 
performed throughout the treatment period 
to allow early mitigation of risk. Nasal 
examinations will be performed pre-dose 
and 24 hours post-dose on dosing visits 1 
and 8.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
is considered to be clinically relevant, but it 
is unlikely to occur in humans at the 
proposed clinical doses; should unexpected 
irritancy be seen, it would be readily 
detectable and has been shown to be readily 
reversible on withdrawal from treatment in 
the monkey.  The no observed adverse 
effect level (NOAEL) in the monkey for 
nasal irritancy (35.9 ng/kg/day) provides 
adequate cover for the proposed 20 ng 
weekly dose in this study.  Therefore, 
GSK2245035 displays an acceptable safety 
profile for an intranasal medicine.
Nasal irritancy has been assessed in clinical 
studies up to 8 weeks’ duration. I.n. 
GSK2245035 is well-tolerated locally as 
determined by nasal examinations, adverse 
events and nasal symptom scores. 
Study Procedures
Anaphylaxis, including bronchospasm 
occurring after bronchial, intranasal, or 
intradermal administration of allergen.
Subjects will inhale (orally and intranasally) 
various concentrations of allergen to which 
they are sensitized. Bronchial allergen 
challenges will be performed at screening, 
and at the follow-up visits (1, 4 and 12 
weeks post final dose).
Intranasal allergen and intradermal testing 
Only sites that have a significant experience 
with administering bronchial, intranasal, and 
intradermal allergen challenges and in the 
management of anaphylaxis and acute 
bronchospasm will be used in this study. 
Careful monitoring of all symptoms will 
take place to assure safety. The responsible 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
will be conducted approximately 24 hours 
after the bronchial allergen challenges 
performed at screening and at the 1 and 4 
week follow-up visits.
Allergen testing procedures may induce 
anaphylaxis, including acute bronchospasm.
physician will be appropriately trained to 
treat anaphylaxis and acute bronchospasm, 
including appropriate use of resuscitation 
equipment, which must be close enough to 
respond quickly to an emergency.
Subjects will be continually monitored at 
the study centre for at least 10 hours after 
each bronchial allergen challenge and 6 
hours after intranasal and intradermal 
challenges.  The procedure should be 
stopped immediately if signs/symptoms of 
anaphylaxis and/or acute bronchospam 
develop and rescue medication treatments 
will be readily available.
Subjects will be allowed to leave the unit 
only after the investigator has reviewed and 
assessed the available safety data.
Subjects will receive a Peak Expiratory 
Flow (PEF) meter to measure PEF at home 
from the start of dosing through to 
completion of the 4 week follow-up visit 
assessments. The subject will be instructed 
to contact the investigator if PEF 
measurements are outside the normal range 
for the subject. Subjects will also have their 
PEF levels checked in the unit after 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
administration of the final bronchial 
allergen challenge at the 12 week follow-up 
visit.
Sputum induction 
Bronchoconstriction may occur following 
inhalation of saline.
In the event of bronchoconstriction, the 
procedure will be stopped immediately and 
the subject treated with a short-acting 
inhaled bronchodilator.


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4.6.2.
Benefit Assessment
Benefit considerations may include:

Potential benefit of receiving study drug for the study duration that may reduce 
allergic reactivity.

Contributing to the process of developing possible disease-modifying therapies for 
asthma.

Medical evaluations/assessments associated with study procedures [e.g. a physical 
examination, Electrocardiogram (ECG), vital signs, clinical laboratory assessments, 
to screen any potential health issues].
4.6.3.
Overall Benefit: Risk Conclusion
Measures taken to minimise and manage potential risk to subjects participating in this 
study, coupled with the potential benefits justify the conduct of a Phase IIa study with i.n. 
GSK2245035 in mild asthmatics.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number 2010N110564_04].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Between 18 and 65 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Diagnosis of asthma, as defined by the history of respiratory symptoms such as 
wheeze, shortness of breath, chest tightness and cough that vary over time and in 
intensity, together with variable expiratory airflow limitation [GINA guideline, 2015] 
for at least 6 months prior to screening.
3.
Current asthma therapy. Intermittent short-acting beta-agonist (SABA) alone (on 


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average for no more than 2 days per week)
4. Positive skin prick test (3mm or more greater than negative control) to common 
perennial or seasonal aeroallergen(s) (i.e., house dust mite, cat dander, grass pollen) 
at screening.
5. Pre-bronchodilator FEV1 >70 % predicted normal at Screening Visit 1
NOTE: Predicted values will be based upon Quanjer, 2012.
6. EAR with 20 % FEV1 decrease between 5 and 30 minutes after the final allergen 
concentration is obtained at the screening BAC (decreases relative to the saline).
7. LAR with three FEV1 decreases of 15 % between 4 and 10 hours after the final 
allergen concentration is obtained at the screening bronchial allergen challenge, with 
two FEV1 decreases being at consecutive time points (decreases relative to the 
saline).
8. Subjects who are current non-smokers (defined as no use of any tobacco products in 
the 6-month period preceding the screening visit) and have a pack history of < 10 
pack years
Number of pack years = (number of cigarettes per day/20) x number of years smoked
WEIGHT
9. Bodyweight ≥ 45kg
SEX
10. Male OR female of non-reproductive potential
Males:
Male subjects with female partners of child bearing potential must comply with the  
contraception requirements in Appendix 5 (Modified List of Highly Effective Methods 
for Avoiding Pregnancy) from the time of first dose of study medication until the final 
follow-up visit.
This is an all-inclusive list of those methods that meet the following GSK definition of 
highly effective: having a failure rate of less than 1% per year when used consistently and 
correctly and, when applicable, in accordance with the product label. For non-product 
methods (e.g., male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the International 
Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) [ICH M3 (R2), 2009].”
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.


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Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative [serum or urine] human chorionic gonadotrophin (hCG) test), not lactating, and 
where the following condition applies:
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
INFORMED CONSENT
11. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.


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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Alanine transaminase (ALT) >2xUpper Limit of Normal (ULN) and bilirubin 
>1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and 
direct bilirubin <35%).
2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
3. Heart rate corrected QT interval (QTc) > 450 msec or QTc > 480 msec in subjects 
with Bundle Branch Block
NOTES:

The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), or another method, machine-read 
or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
4. Asthma exacerbation requiring treatment with oral corticosteroids or hospitalization 
within 3 months prior to screening
5. History of life-threatening asthma, defined as an asthma episode that required 
intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic 
seizures within the last 10 years.
6. Evidence of concurrent respiratory diseases such as pneumonia, pneumothroax, 
atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, 
cystic fibrosis, bronchopulmonary dysplasia, or other respiratory abnormalities other 
than asthma.
7. Other concurrent diseases/abnormalities: A subject must not have any clinically 
significant, uncontrolled condition or disease state that, in the opinion of the 
investigator, would put the safety of the subject at risk through study participation or 
would confound the interpretation of the efficacy results if the condition/disease 
exacerbated during the study.
8. Respiratory tract infection that is not resolved within 2 weeks prior to screening.


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CONCOMITANT MEDICATIONS
9. Treatment with intranasal steroid, inhaled corticosteroid (ICS) with or without long-
acting beta2-agonist (LABA), and treatment with non-ICS controller asthma 
medications (i.e., leukotriene modifier, methylxanthines) within 4 weeks prior to 
screening.
10. Use of long-acting antihistamines within 7 days’ or short-acting antihistamines within 
72 hours prior to the screening skin prick test.
11. Treatment with systemic corticosteroids within 6 weeks prior to screening.
12. Use of inhaled SABAs as rescue treatment on average for more than 2 days per week.
RELEVANT HABITS
13. History of regular alcohol consumption within 6 months of the study defined as: 
An average weekly intake of >14 units for males and 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.
CONTRAINDICATIONS 
14. Patient known to be intolerant to salbutamol or albuterol
15. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or GSK 
Medical Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
16. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.  For 
potent immunosuppressive agents, subjects with presence of hepatitis B core antibody 
(HBcAb) should also be excluded.
17. A positive pre-study drug/alcohol screen
18. A positive test for Human Immunodeficiency Virus (HIV) antibody
19. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within a 56 day period.
20. 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)
21. Exposure to more than 4 investigational medicinal products within 12 months prior to 
the first dosing day


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5.3.
Screening Failures/Re-screening
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.4.1.6).
Re-screening will be permitted in this study, in discussion with the Medical Monitor. 
Sites are encouraged to screen subjects who have previously undergone BAC and have 
demonstrated a LAR. 
Re-screened subjects should be assigned a separate number from their initial screening 
number and complete a new informed consent form. 
5.4.
Withdrawal/Stopping Criteria
Reasons for withdrawal from the study may include:

Use of a prohibited medication that cannot be safely discontinued while maintaining 
the subject’s health.

Treatment code is unblinded.

Pregnancy: Any female subject who becomes pregnant.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records.


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Subjects withdrawn from the study while already exposed to IP will be asked to complete 
all safety assessments as outlined in the Time and Events Table (Section 7.1.2). Relevant 
pages of the case report form (CRF) should be completed by the investigator.
The replacement of withdrawn subjects will be at the discretion of the sponsor. If a 
subject misses one treatment dose, the investigator will consult with the GSK medical 
monitor as to whether the subject can receive further treatment. If more than one 
treatment dose is missed, then the subject may be withdrawn from the study, at the 
discretion of the Sponsor, in consultation with the investigator.
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and assigned the next available randomisation number, at the discretion of the 
Sponsor, in consultation with the investigator.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the Food and 
Drug Administration (FDA) premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria
The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTc > 500 msec OR Uncorrected QT > 600 msec


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
Change from baseline of QTc > 60 msec
For subjects with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including all of the 
follow-up visits.
The date of the end of the study is defined as the date of the last subject’s last follow-up 
visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.


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Study Treatment
Product name:
GSK2245035 Nasal Spray 
Solution 0.2 mcg/mL
Placebo
Formulation 
description:
A solution formulation in saline 
preserved with Benzalkonium 
Chloride and Disodium Edetate
As for GSK2245035 nasal spray 
solution except for omission of 
the active ingredient
Dosage form:
Nasal spray solution
Nasal spray solution
Unit dose 
strength(s)/Dosage 
level(s):
10 ng per actuation
Not applicable
Route of 
Administration:
Intranasal
Once weekly
Intranasal
Once weekly
Dosing 
instructions:
1 spray per nostril
1 spray per nostril
Physical 
description:
An amber glass bottle fitted 
with a screw fit atomizing pump
Visually matched to the active
Device:
Type 1 amber glass bottle fitted 
with a metered Valois VP7 
pump
Type 1 amber glass bottle fitted 
with a metered Valois VP7 pump
Manufacturer/
source of 
procurement:
GSK
GSK
Method for 
individualizing 
dosage:
N/A
N/A
6.2.
Treatment Assignment
Subjects will be assigned to one of two treatments (either 20 ng GSK2245035 or 
placebo), in accordance with the randomization schedule generated by Clinical Statistics, 
prior to the start of the study, using validated internal GSK software RandAll NG.  The 
randomisation will be stratified by centre and also by exposure state during the treatment 
phase to the allergen selected for BAC (two strata – “Presumed” and “Unknown”).  See 
Section 4.4 for further details regarding allergen exposure.
It is planned that an Interactive Response Technology (IRT) will be used in this study to 
assign randomization and drug containers.  It can also be used to emergency unblind 
subjects if required (see Section 6.3).
Once assigned to a subject a randomization number may not be re-used.
More details of how and when a subject is allocated a randomization number and the 
subject numbering convention will be given in the Study Reference Manual (SRM).


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6.3.
Blinding
This will be a double-blind (sponsor open), study (investigators and subjects are blinded, 
and sponsor will be unblinded).
During the study, there will be an unblinded interim analysis. Some key GSK study team 
members may be unblinded as part of this analysis and review. Initially, only the study 
statistician(s) (and supporting programmers), project physician lead, and medical monitor 
will be unblinded, and if further data reviews are required then details of who were un-
blinded to what data and when will be included in the clinical study report.
On-going safety reviews will be conducted during the course of the study in an unblinded 
manner. Key study team members may be unblinded as part of this review. An external 
consultant, who is not a GSK employee, may also be unblinded to enable independent 
review of emerging safety data.
If the GSK medical monitor deems it necessary to unblind data in order to enhance the 
evaluation of safety and tolerability this will be permitted but also documented and 
discussed in the clinical study report.  The GSK medical monitor will also decide whether 
to un-blind the investigator(s)/site(s) at that time, or just the sponsor study staff.  Details 
of who were un-blinded to what data and when would then be included in the clinical 
study report.
Unblinding would occur using the IRT system.
The following will apply. 
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency OR in the event of a serious medical condition when 
knowledge of the study treatment is essential for the appropriate clinical management or 
welfare of the subject as judged by the investigator. 
Investigators have direct access to the subject’s individual study treatment. 
It is preferred (but not required) that the investigator first contacts the Medical Monitor or 
appropriate GSK study personnel to discuss options before unblinding the subject’s 
treatment assignment. 
If GSK personnel are not contacted before the unblinding, the investigator must notify 
GSK as soon as possible after unblinding, but without revealing the treatment assignment 
of the unblinded subject, unless that information is important for the safety of subjects 
currently in the study. 
The date and reason for the unblinding must be fully documented in the CRF.
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.


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GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with a Serious Adverse Event (SAE). If the SAE 
requires that an expedited regulatory report be sent to one or more regulatory agencies, a 
copy of the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.
One device is dispensed at dosing visit 1 (to use for the first 4 dose administrations), and 
a second device will be dispensed at dosing visit 5 (to use for administration of the fifth 
to eighth doses). Both of these devices will remain in the clinic.  All eight doses will be 
administered to the subjects in the clinic.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.
Only subjects enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment.  All study treatments must be stored in a 
secure environmentally controlled and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator 
and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e. receipt, reconciliation and final disposition records).  
Further guidance and information for final disposition of unused study treatment are 
provided in the SRM. 
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff.  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 GSK study contact.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.


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6.6.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
6.7.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2245035 over the stated maximum of the study treatment 
will be considered an overdose.
GSK does not recommend specific treatment for an overdose. The investigator will use 
clinical judgment to treat any overdose and provide supportive care as appropriate. The 
investigator will inform the GSK Medical Monitor immediately, and will document the 
quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life-threatening or seriously debilitating 
and other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.9.
Challenge Agents
6.9.1.
Bronchial, intranasal and intra-dermal allergen 
challenge/administration
Appropriate allergen extracts will be purchased by the clinical unit(s) or provided.
The specific allergen extract that will be used for the BAC, NAC and ID challenge will 
be selected on the basis of each subject’s skin prick test. The same allergen will be used 
for each method of testing. The NAC and ID challenge are not required for eligibility.
A detailed description of how all of the allergen extracts will be selected, the preparation 
of the allergen extracts and details of the bronchial, intranasal and intradermal allergen 
challenge techniques can be found in the SRM.


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6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions
Dietary restrictions as outlined below will be observed during the time periods specified 
prior to entry to the clinic and dosing.
6.10.2.
Caffeine, Alcohol, and Tobacco

Subjects will abstain from ingesting excessive amounts (more than one cup) of 
caffeine- or xanthine-containing products (e.g. coffee, tea, cola drinks, chocolate) for 
6 hours prior to each dosing. 

During each visit in the clinic, subjects will abstain from alcohol for 24 hours prior 
to entry to the clinic until collection of all assessment is completed.

Subjects will be reminded that all forms of smoking should be avoided during the 
course of the study.
6.10.3.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.
Subjects should refrain from all recreational drugs from screening until the final follow-
up visit.
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Any concomitant medications not specifically permitted will be considered on a case by 
case basis by the investigator and GSK medical monitor. 
Subjects are permitted to take inhaled short-acting β2-agonists (SABA) as rescue 
treatment, but must withhold them for at least 6 hours prior to any study visits with lung 
function assessment or BAC (screening and follow-up visits 1-3).
Medication to control hypertension is permitted, providing it is anticipated to remain 
stable from screening to follow up. Beta blockers are not permitted.
Short term use of anti-histamines is permitted with some limitations as outlined in 
Section 6.11.2; the use of paracetamol and NSAIDS for short-term pain relief is also 
permitted.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Subjects may not receive the following treatments from 4 weeks prior to screening until 
the final follow-up visit:

Intranasal steroids


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
Inhaled corticosteroid (ICS) with or without a long acting beta-2-agonist (LABA)

Non-ICS controller asthma medications (i.e. leukotriene modifier, methylxanthines).
Use of long-acting antihistamines within 7 days’ or short-acting antihistamines within 72 
hours prior to BAC, NAC or ID challenge is prohibited.
Subjects are prohibited from taking systemic corticosteroids within 6 weeks prior to 
screening.
Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) except as described in Section 6.11.1 within 
7 days prior to the first dose of study medication until completion of the follow-up visits, 
unless in the opinion of the investigator and sponsor the medication will not interfere 
with the study.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker assessments may be altered during the 
course of the study based on newly available data to ensure appropriate monitoring. 
Similarly the timing of the post-treatment allergen challenges may change based on 
new information acquired during the course of the study.

Details of the order of planned assessments for each visit and the time windows 
around these visits and assessments will be given in the SRM.

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. 


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
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring scheme
or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.


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7.1.
Time and Events Tables
7.1.1.
Time and Events Table – Screening Visit(s)
Procedure
Screening 
Visit 1 (up to 
Day -28)
Screening Visit 2 
(up to Day -3))
24 hours after 
Screening Visit 2 
(Day -20 to Day -
2)
Notes
There must be a minimum of 48 hours between 
‘Screening Visit 1’ and ‘Screening Visit 2’. This 
ensures adherence to a minimum 3-day window 
between sputum inductions.
There must be a minimum of 48 hours between ‘24 
hours after Screening Visit 2’ and ‘Dosing Visit 1’
Informed consent signing
X
Includes genetics consent
Inclusion and exclusion criteria/eligibility review
X
X
Demographics
X
Medical history (including substance usage and family 
history of premature CV disease)
X
Past and current medical conditions including cardiovascular 
medical history
X
Concomitant medication review
X
Full physical exam including height and weight
X
Urine drug/alcohol screen
X
Urine or serum pregnancy test (all females)
X
No women of childbearing potential are being 
enrolled. However this test is needed to confirm 
pregnancy status at screening.
Serum FSH and estradiol for post-menopausal females
X
HIV, Hep B and Hep C screen
X
Laboratory assessments (including liver chemistries, 
haematology, clinical chemistry and urinalysis)
X
Screening Spirometry assessment
X
To confirm FEV1 >70% predicted
SAE Collection
X
X
X
12-lead ECG
X
Vital signs
X
Skin prick test
X
To confirm eligibility
FeNO measurement
X
X
Collected prior to sputum induction
Saline and incremental BAC challenge plus associated 
spirometry measurements
X
Including pre-procedure FEV1 assessment and 
repeat FEV1 measurements up to 10 hours post BAC


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Procedure
Screening 
Visit 1 (up to 
Day -28)
Screening Visit 2 
(up to Day -3))
24 hours after 
Screening Visit 2 
(Day -20 to Day -
2)
Notes
There must be a minimum of 48 hours between 
‘Screening Visit 1’ and ‘Screening Visit 2’. This 
ensures adherence to a minimum 3-day window 
between sputum inductions.
There must be a minimum of 48 hours between ‘24 
hours after Screening Visit 2’ and ‘Dosing Visit 1’
Sputum induction and processing for BAC associated 
sample collection
X
X
Sputum inductions must be separated by at least 3 
days
Laboratory assessments (haematology only)
X
X
Blood samples should be taken pre-BAC on SV2 
and  on the following day at 24 hrs post BAC
Blood samples for PBMC preparations
X
Blood samples for PBMC preparations (pre-BAC and 
6 hours after BAC at screening visit 2)
Provide diary card, PEF meters, rescue medication and 
thermometers to subjects
X
Only given out to subjects who are eligible following 
the BAC. Thermometers are to be given to record 
temperature as part of capturing AE information.
Nasal lavage
X
Collect nasal lavage to provide a background  
sample. Repeat nasal lavage pre-NAC, then again 5 
minutes and at least 6 hours post-NAC.
Nasal filter collection 
X
Collect nasal filter sample to provide a background 
pre-wash sample, after nasal wash repeat nasal filter 
sampling pre-NAC, then again 5 minutes and at least 
6 hours post-NAC.
NAC
X
Commence after the 24-hour BAC sputum and blood 
biomarker samples have been taken.
Only to be done once subjects have completed a 
successful BAC.
ID challenge
X
ID challenge to be administered after NAC.
Measurements to be made 15 minutes and 6 hours 
post ID challenge. 
Nasal scrape
X
Nasal mucosa sample to be collected at least 
6 hours post-NAC.


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7.1.2.
Time and Events Table – Dosing visit (DV) 1 (Day 1) – DV8 (Week 8) and Early Withdrawal Visit (EW)
Procedure
Pre-dose
Dose
Post-dose
Early-
Withdrawal
Notes
0 hour
20 mins
1 hour
12 hours
24 hours
Outpatient visit
X
X
X
Subjects get discharged 1-2 hours after 
dosing.
Inclusion and 
exclusion 
criteria/eligibility review
X
Only on DV1
Diary card collection 
and review 
X
X
Collect and review diary card at every dosing 
visit 
AE/SAE review
X
X
Concomitant 
medication review
X
X
12-lead ECG
X
X
X
X
Perform on DV1 and DV8 only.
Not required at EW if this occurs during FU
Vital signs (including 
temperature)
X1
X1
X2
X
1 Perform on DV1-8
2 Perform on DV1, 4 and DV8 only.
Not required at EW if this occurs during FU
Laboratory 
assessments (include 
liver chemistries, 
haematology, clinical 
chemistry and 
urinalysis)
X
X
X
Collect samples for laboratory assessments on 
DV1 and DV8,
Not required at EW if this occurs during FU
Blood sample for PK 
analysis
X
X
X
Collect samples on DV1, DV4 and DV8
Genetic sample
X
Take one sample on any of the dosing visits 
after genetics consent.
FeNO measurement
X
Perform FeNO measurements pre-dose on all 
dosing visits 1-8
Nasal examination
X
X
Conducted pre-dose at all study visits and 24 
hours post-dose on DV1, DV4 and DV8


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Procedure
Pre-dose
Dose
Post-dose
Early-
Withdrawal
Notes
0 hour
20 mins
1 hour
12 hours
24 hours
Nasal lavage
X
X
Collect nasal lavage samples pre-dose and 
24hrs post-dose on DV1, DV4 and DV8
Blood sample for 
biomarker analysis
X
X
Collect blood for serum samples and PBMC 
preparations pre-dose and 24 hrs post-dose on 
DV1 and DV8
Blood sample for RNA 
analysis 
X(3)
X(4)
PAX-gene tubes for TLR7/AFFY chip gene 
expression in blood collected pre-dose on 
DV1(3) and 24 hrs after DV8(4)
Call RAMOS
X
Randomisation will occur is at Visit 1 via the 
IRT. Sites should also call RAMOS at DV5.
Dispensing of study 
medication
X
One device will be assigned on DV1. The 
second device will be assigned on DV5.  All 
devices remain in the unit.
Study drug 
administration
X
All doses are administered in the unit.
Sputum induction and 
processing for BAC 
associated sample 
collection
X
Sputum sample is conditional on having 
obtained a sputum sample from the subject at 
screening. Perform sputum induction after 
collection of 24 hour post-dose DV8 blood and 
nasal samples (as pre BAC sample for FUV1).
Follow up phone call
X5
X6
5 Following at least the first two doses of study 
treatment to assess tolerability
6 On DV 2, 3, and 5-7, a follow-up phone call 
will be made approximately 24 hours post-dose 
to check if any CRS events have occurred, and 
if they have, that they have been accurately 
recorded in the diary card and they will then be 
transcribed into the eCRF.
For DV1, 4 and 8 the subjects shall be 
assessed on their return to the unit the 
following day.


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7.1.3.
Time and Events Table – Follow up visits (FUV1 to 3) (Weeks 9 to 20)
Procedure
Follow up Visit 1 
(FUV1)
Follow-up Visit 2 (FUV2)
2 month 
follow-up 
phone 
call
(Week 16)
Follow up Visit 3 (FUV3)
Week 9
(1 week 
after 
DV8)
24 
hours 
later
Week 11
(3 weeks 
after DV8)
Week 12
(4 weeks 
after DV8)
24 
hours 
later
Week 19 
(11 
weeks 
after DV8)
Week 20 
(12 weeks 
after DV8)
24 hours 
later
Notes
AE/SAE review
=========================================
X3
========================
Concomitant 
medication review
=========================================
X3
========================
3 Phone call made to the subject to 
check AEs and concomitant 
medications and confirm availability for 
FUV3
Diarycard collection, 
review and dispensing
X
Review diary card at every visit until 
the end of FUV 2
FeNO measurement
X
X
X
X
X
X
Collect prior to sputum induction
Blood sample for RNA 
analysis
X
PAX tubes for /AFFY chip gene 
expression in blood. Collected prior to 
the bronchial allergen challenge at 
FUV2
Saline and bolus BAC 
challenge plus 
associated spirometry 
measurements
X
X
X
Including pre-procedure FEV1
assessment and repeat FEV1
measurements up to 10 hours post 
BAC
Sputum induction and 
processing for BAC 
associated sample 
collection
X
X
X
X
X
Sputum induction pre-BAC and 24 
hours after BAC
Laboratory 
assessments 
(haematology only)
X
X
X
X
X1
X
Blood samples should be taken pre-
BAC  and  on the following day at 
24hrs post BAC
Blood samples for 
PBMC preparations
X
X
X
Blood samples for PBMC preparations 
(pre-BAC and 6 hours after BAC)


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Procedure
Follow up Visit 1 
(FUV1)
Follow-up Visit 2 (FUV2)
2 month 
follow-up 
phone 
call
(Week 16)
Follow up Visit 3 (FUV3)
Week 9
(1 week 
after 
DV8)
24 
hours 
later
Week 11
(3 weeks 
after DV8)
Week 12
(4 weeks 
after DV8)
24 
hours 
later
Week 19 
(11 
weeks 
after DV8)
Week 20 
(12 weeks 
after DV8)
24 hours 
later
Notes
Nasal lavage
X
X
Collect nasal lavage to provide a
background sample. Repeat nasal 
lavage pre-NAC, then again 5 minutes 
and at least 6 hours post-NAC.
Nasal filter collection
X
X
Collect nasal filter sample to provide a 
background pre-wash sample, after 
nasal wash repeat nasal filter 
sampling pre-NAC, then again 5 
minutes and at least 6 hours post-NA.
NAC
X
X
Commence after the 24-hour BAC 
sputum and blood biomarker  samples 
have been taken at FUV1 and FUV2
ID challenge
X
X
ID challenge to be administered after 
NAC.
Measurements to be made at 15 
minutes and 6 hours post ID 
challenge.
Nasal scrape
X
X
Nasal mucosa sample to be collected 
at least 6 hours post-NAC
Return diary card and 
thermometers
X
Return PEF meters and 
rescue medication
X


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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
7.2.1.
Skin prick testing
Seasonal allergen or perennial allergen-specific skin prick tests will be performed at 
screening to confirm eligibility, and to determine the allergen to be used for each subject 
for subsequent BAC, NAC and ID challenge.
7.3.
Efficacy
7.3.1.
Bronchial allergen challenges and spirometry
BAC will be conducted at screening, and at three follow-up visits (see Time and Events 
Tables in Section 7.1). At the Screening Visit incremental doses of allergen will be 
administered and the total dose inducing an EAR and LAR used to calculate a bolus dose 
for use at the 3 FU visits. A detailed description of the BAC technique and assessments 
can be found in the SRM.  All sites participating in the study will be trained in the same 
methodology to ensure consistency.
Following the final FEV1 measurement, subjects will receive rescue salbutamol until the 
FEV1 returns to within 10% of the pre-saline value. If a subject experiences serious 
discomfort the test will be discontinued and rescue medication administered.
7.3.2.
Intranasal and intra-dermal allergen challenge
NAC and ID challenge will be conducted approximately 24 hours after the bronchial 
allergen challenge at screening and at follow-up visits 1 and 2. 
A detailed description of the NAC and ID challenges can be found in the SRM.
In some regions/countries specific challenges agents may not be approved or available 
for use in ID challenge, in which case this assessment shall be omitted.
7.3.3.
Sputum induction
Hypertonic saline induced sputum samples will be collected.  The sputum induction 
process will follow a standard procedure and GSK will ensure all sites are trained prior to 
study start in order to provide consistency.
At screening, the weight of the sputum sample will be measured to confirm that the 
subject is able to produce an adequate induced sputum sample (must be at least 100 mg).


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If a subject did not induce a successful sputum sample at screening then they will not be 
required to try at the follow up visits.
Further information on induction, collection, processing, storage and shipping procedures 
are provided in the SRM.
7.3.4.
TNSS
Four nasal symptoms: nasal congestion, rhinorrhea, nasal itch and sneezing will be 
evaluated on the morning and evening of each day of the study treatment period, from 
DV1 up until follow-up visit 2 (4 weeks after the end of treatment). These will be 
captured on a diary card every morning and evening.  On dosing days, the morning TNSS 
assessment will be captured pre-dose. The subjects will be asked to rate each of these 
symptoms on a 4-point scale:
0 = None:  No symptom whatsoever; Absent
1 = Mild:  Symptom is present, noticeable but not bothersome 
2 = Moderate:  Symptom is bothersome, but tolerable
3 = Severe:  Symptom which are bothersome, harder to tolerate, desiring relief/treatment
The individual symptom scores will be combined to produce a TNSS.
All data will be transcribed from the diary booklet into the CRF.
7.3.5.
Nasal examination
A brief visual nasal examination will be conducted by a trained physician at the time-
points outlined in the Time and Events Tables (Section 7.1). The physician will examine 
the nostrils using appropriate instrumentation (e.g. a small rounded plastic nasal 
speculum and an auroscope fitted with a wide bore examination probe) for any signs of 
irritancy. Any abnormalities will be documented in the CRF.
7.3.6.
Fractional Exhaled Nitric Oxide (FeNO)
FeNO will be measured using a handheld electronic device.  Measurements will be 
obtained in accordance with the [ATS/ERS Recommendations for Standardized 
Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric 
Oxide and Nasal Nitric Oxide, 2005]. FeNO measurements will be interpreted in 
accordance with the [Official ATS Clinical Practice Guideline: Interpretation of Exhaled 
Nitric Oxide Levels (FeNO) for Clinical Applications, 2011].
Further details will be provided in the SRM.


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7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
The Safety Review Team (SRT) is a GSK cross-functional team reviewing all available 
safety data related to the project, including in-stream data from this study, in an ongoing 
manner. The SRT is an internal GSK requirement put in place to ensure holistic 
evaluation of the safety profile of an investigational product with systematic, periodic and 
documented reviews of available safety data, with the appropriate communication and 
escalation of new findings that have the potential to impact patient safety.  
The SRT for this project will review data from this study in collaboration with an 
independent external (to GSK) expert reviewer.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
Time period and Frequency for collecting AE and SAE information
Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK product will be recorded 
from the time a subject consents to participate in the study up to and including the final 
follow-up visit. 
AEs will be collected from the start of Study Treatment until the final follow-up visit (see 
Section 7.4.1.3), at the time-points specified in the Time and Events Table (Section 7.1).
Medical occurrences that begin prior to the start of study treatment but after obtaining 
informed consent may be recorded on the Medical History/Current Medical Conditions 
section of the CRF.
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 
However, if the investigator learns of any SAE, including a death, at any time after a 
subject has been discharged from the study, and he/she considers the event reasonably 
related to the study treatment or study participation, the investigator must promptly notify 
GSK.


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NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:
“How are you feeling?”
“Have you had any (other) medical problems since your last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 7.4.1.5) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 4.
7.4.1.4.
Cardiovascular and Death Events
Investigators 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
For these cardiovascular events detailed above and for all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be
required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion.


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The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in subjects with mild allergic 
asthma and can be serious/life threatening:

Wheeziness

Chest tightness or chest heaviness

Coughing
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of a SAE).  These events will be recorded 
on the DRE page in the subject’s CRF within 5 working days.
NOTE: However, if either of the following conditions apply, then the event must be 
recorded and reported as an SAE (instead of a DRE): 

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, or

The investigator considers that there is a reasonable possibility that the event was 
related to treatment with the investigational product.
7.4.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator(s) to GSK of SAEs related to study treatment 
(even for non- interventional post-marketing studies) is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a product 
under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.


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7.4.1.7.
Cytokine Related Symptoms (CRS) - Symptoms Grading
In the study, symptoms potentially related to cytokine induction (headache, chills/rigors, 
fever, nausea, vomiting, diarrhoea, arthralgia, myalgia, hypotension) occurring within 24 
hours of dosing will be individually reported as AEs and graded as described in Section 
12.4.2 in Appendix 4. 
7.4.2.
Pregnancy
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of dosing until the final follow-up visit.
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.
7.4.3.
Physical Exams
A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded. 
A brief physical examination will include, at a minimum assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
Investigators should pay special attention to clinical signs related to previous serious 
illnesses
7.4.4.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse rate and respiratory rate. 
Measurements will be made at screening and various occasions throughout the study as 
outlined in the Time and Events Tables (Section 7.1).  Measurements that deviate 
substantially from normal range, according to the opinion of the Investigator(s), will be 
repeated as soon as possible.
7.4.5.
Electrocardiogram (ECG)
Triplicate 12-lead ECGs will be obtained at screening. Single ECGs will be obtained at 
the other determined time points during the study except if according to the opinion of 
the investigator(s) there are abnormal findings and therefore triplicate ECGs should be 
obtained. These measurements will be obtained at each timepoint during the study using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals.  Refer to Section 5.4.2 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.


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7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments must be conducted in accordance with the 
Laboratory Manual, and Protocol Time and Events Schedule. Laboratory requisition 
forms must be completed and samples must be clearly labelled with the subject number, 
protocol number, site/centre number, and visit date. Details for the preparation and 
shipment of samples will be provided by the laboratory and are detailed in the laboratory 
manual. Reference ranges for all safety parameters will be provided to the site by the 
laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory.
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required it is important that the sample for central 
analysis is obtained at the same time. Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
CRF.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 1.


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Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
White Blood Cell (WBC) count 
with Differential:
Red Blood Cell (RBC) 
Count
Mean 
Corpuscular 
Volume 
(MCV)
Neutrophils
Hemoglobin
Mean 
corpuscular 
hemoglobin 
(MCH)
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
Blood Urea 
Nitrogen 
(BUN)
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Urine hCG Pregnancy test 2
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.4.1 and 
Appendix 2.
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.


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7.4.7.
PEF monitoring
Subjects will be given a PEF peak flow meter at screening, along with a diary card. This 
will be used for safety monitoring after the BACS. Subjects will record their PEF 
readings each morning and evening onto the diary card every day from the start of study 
treatment on DV 1 until the 4 week follow-up visit.  
The subject will be instructed to contact the investigator if at any time during the study 
the PEF measurements go outside the normal range for the subject. These instructions 
will be clearly printed on the diary card.
All information from the diary card will be transcribed into the eCRF.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of GSK2245035 will be collected at 
the time points indicated in Section 7.1, Time and Events Tables.  The actual date and 
time of each blood sample collection will be recorded.  The timing of PK samples may be 
altered and/or PK samples may be obtained at additional time points to ensure thorough 
PK monitoring.
Processing, storage and shipping procedures are provided in the SRM.
7.5.2.
Sample Analysis
Plasma analysis will be performed under the control of Platform Technology Sciences 
(PTS)-DMPK/Scinovo, GlaxoSmithKline, the details of which will be included in the 
Study Reference Manual (SRM). Concentrations of GSK2245035 will be determined in 
plasma samples using the currently approved bioanalytical methodology. Raw data will 
be archived at the bioanalytical site (detailed in the SRM).
Once the plasma has been analyzed for GSK2245035, any remaining plasma may be 
analyzed for other compound-related metabolites and the results reported under a 
separate PTS-DMPK/Scinovo, GlaxoSmithKline protocol.
7.6.
Exploratory Biomarkers
7.6.1.
Pharmacodynamic Markers
Details for the collection of samples, processing, storage and shipping procedures for all 
samples are provided in the SRM. Time-points for all sample collections are shown in the 
Time and Events Tables (Section 7.1).
7.6.1.1.
PD blood samples
Blood samples will be collected before and 24 hours post treatment on DV 1 and 8 for 
serum to measure blood PD biomarkers. 


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Blood will be collected before and 24 hours after treatment on DV 1 and 8 and prior to 
bronchial allergen challenges for preparation of peripheral blood mononuclear cells 
(PBMC). These samples may be used for CHIP cytometry for cellular subset 
phenotyping. If this biomarker analysis is performed it may be reported separately.
7.6.1.2.
Blood PAX collection
Blood PAX samples for AFFYCHIP gene expression (mRNA transcriptome) will be 
collected before dosing on DV 1, 24 hours after DV 8 and prior to BAC on FUV2.
7.6.1.3.
PD nasal lavage samples
Nasal lavage samples to measure PD biomarkers will be collected before and 24 hours 
post treatment on DV1, DV4 and DV8.
7.6.1.4.
Bronchial allergen challenge (BAC) associated biomarkers in induced 
sputum samples
Sputum samples will be collected at the time points indicated in the time and events 
tables (see Section 7.1). Sputum sample collection at dosing/follow up visits is 
conditional on having obtained a sputum sample from the subject at screening.
Detailed information on collection, processing, storage and shipping procedures are 
provided in the SRM.
7.6.1.5.
Bronchial allergen challenge (BAC) associated biomarkers in blood 
samples
Blood samples will be collected before, 6 hours and 24 hours after each BAC:

For haematology, (WBC with differential) for blood eosinophil counts (before and 
24 hours after BAC)

To prepare PBMC that may be used for CHIP cytometry (before and 6 hours after 
BAC).  If this biomarker analysis is performed it may be reported separately.
7.6.1.6.
Nasal allergen challenge associated biomarkers in nasal fluid samples
Nasal filter and nasal lavage samples to measure exploratory biomarkers will be collected 
at the timepoints indicated in the Time and Events Tables, Section 7.1.
7.6.1.7.
Cellular profile of nasal mucosa
Nasal scrapes may be collected after NAC following the completion of the collection of 
the 6 hour nasal lavage and nasal filter samples (at screening and at FUV1 and FUV2). 
Samples of suitable quality may be used for cellular analysis for example by CHIP 
cytometry or RNA-sequencing of single cells (if subjects have given informed consent 
for genetic analysis techniques).  If this biomarker analysis is performed it may be 
reported separately.


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7.6.2.
Novel Biomarkers
With the subject’s consent, nasal tissue, nasal fluid, sputum and blood samples will be 
collected during this study and may be used for the purposes of measuring novel 
biomarkers to identify factors that may influence the disease for study treatment, and/or 
medically related conditions, as well as the biological and clinical responses to 
GSK2245035.  If relevant, this approach will be extended to include the identification of 
biomarkers associated with adverse events.
Samples will be collected at the time points indicated in the Time and Events Table 
Section 7.1. The timing of the collections may be adjusted on the basis of emerging 
pharmacokinetic or pharmacodynamic (PD) data from this study or other new 
information in order to ensure optimal evaluation of the PD endpoints.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with asthma or medically related conditions and/or the action of 
GSK2245035 may be identified by application of:

Measurement of the levels of a subset of RNA species on blood and sputum samples.

Proteome analysis of plasma, nasal and sputum samples.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial. 
7.7.
Genetics
Information regarding genetic research is included in Appendix 3.
8.
DATA MANAGEMENT

For this study, subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Paper diary subject data will be collected and transcribed into GSK defined CRFs by 
the site personnel.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug. 

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.


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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
No formal hypotheses will be tested. The primary study objective will assess the effect of 
a weekly dose of 20ng GSK2245035 vs Placebo by precision estimation and credible 
intervals to estimate the magnitude of underlying effect sizes.  A Bayesian approach will 
be utilised to obtain the posterior distribution for the mean treatment effects for the 
endpoints in the study (e.g. posterior distributions for percentage attenuation for the 
endpoint LAR:  minimum FEV1 between 4-10 hours following allergen challenge one 
week after treatment.). 
Other objectives will assess other pharmacodynamic effects and safety and tolerability of 
GSK 2245035.
9.2.
Sample Size Considerations
The following was performed for each of the proposed LAR primary endpoints:

Success criteria: declare endpoint success if the posterior probability of any 
treatment attenuation exceeds 0.7.

The probability of declaring a success has been computed for a range of true percent 
attenuations and sample sizes (n per arm equal allocation). To make the figures 
easier to interpret the “nuisance” parameters of the placebo response and the 
standard deviation have been accounted for as follows:

Eight previous GSK BAC studies (Crossover design) have been re-analysed to obtain
estimates of the average placebo response and the associated estimate of residual 
variability applicable to the proposed Parallel Group design.

These estimates were combined in a random effects meta-analysis to obtain posterior 
distributions for the underlying parameter values (placebo average response, residual 
variability (for an individual subject) and a between study variance component). The 
future placebo response was computed as the sum of random draws from the 
posterior distributions of the placebo average response parameter and a normal 
distribution with mean zero and variance equal to the between study variance 
parameter. The future GSK2245035 response was derived using the simulation 
scenario’s true percentage attenuation. A pooled sample variance value was 
generated using a Chi-Square distribution with degrees of freedom appropriate to the 
simulation scenario and a sampled variance from the meta-analysis posterior 
distribution. Those numbers were entered into the standard formulae for power 
curves. Repeating this process 10,000 times and taking the median of the resulting 
power values constructs “Assurance” operational characteristics for the combination 
of true percent attenuation and sample size under evaluation.


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
These assurance operational curves have been summarised graphically. The x-axis is 
a hypothetical true drug effect that is assumed to be known for experimental design 
purposes.

The simulations can also be used to compute the minimum observed percentage 
attenuations that would result in a successful study outcome. The median (of the 
10,000 simulations) have been derived for a variety of sample sizes and success 
criteria (probability thresholds 0.7, 0.75, 0.8, 0.85, 0.95) and displayed graphically. 
The y-axis is the observed effect from the study data.
Endpoint: LAR:  minimum FEV1 between 4-10 hours following allergen challenge

Figure 1 illustrates the operating characteristics for the proposed design (n=20 
completers per arm) that have a reasonable chance of meeting the definition of 
success. 

The best guess for the true treatment effect comes from the AZ study with AZD8848 
in subjects with mild asthma, which dosed out of the allergen season and observed an 
approximately 18% effect size (Figure 2) [Leaker , 2012].


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Figure 1
LAR:  minimum FEV1 between 4-10 hours following allergen 
challenge: Probability of Success (Assurance) with Success 
threshold of 0.7 (akin to a risk of false positives of 30%)


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Figure 2
LAR:  minimum FEV1 between 4-10 hours following allergen 
challenge: Minimum observed % attenuations needed to declare 
success for a variety of sample sizes and Success thresholds 
(levels of false positive risk)

Endpoint: LAR:  weighted mean FEV1 between 4-10 hours following allergen 
challenge
Figure 3 and Figure 4 are analogous to Figure 1 and Figure 2. The corresponding AZ 
point estimate was 27% attenuation. Similar conclusions can be drawn.


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Figure 3
LAR:  weighted mean FEV1 between 4-10 hours following allergen 
challenge: Probability of Success (Assurance) with Success 
threshold of 0.7 (akin to a risk of false positives of 30%)


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Figure 4
LAR:  weighted mean FEV1 between 4-10 hours following allergen 
challenge: Minimum observed % attenuations needed to declare 
success for a variety of sample sizes and Success thresholds 
(levels of false positive risk)
9.2.1.
Sample Size Assumptions
The sample size assumes that the behaviour of the placebo response and the variability of 
the endpoints in this study are similar to the eight historical GSK studies (Table 2).


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Table 2
Input data for Sample Size Work
LAR Minimum FEV1 between 4-10h
LAR Weighted Mean FEV1 between 
4-10h
GSK 
Internal 
Study ID
Average 
Placebo 
Response
Degrees of 
Freedom
Residual 
Variability
Average 
Placebo 
Response
Degrees of 
Freedom
Residual 
Variability
-1.3975
33.5
0.40571
-0.9462
33.1
0.30417
-1.0864
45.9
0.13063
-0.7093
42.3
0.11430
-1.1238
22.9
0.30521
-0.6916
22.8
0.18820
-0.9006
48.9
0.07344
-0.3749
47.9
0.02191
-0.7309
85.3
0.10717
-0.4662
84.4
0.07528
-0.9027
31.9
0.27740
-0.5502
34.0
0.20925
-1.4484
20.4
0.40528
-0.9817
20.3
0.31342
-0.8129
69.6
0.15866
-0.5260
71.8
0.08695
Assuming the true treatment effect of GSK2245035 is no worse than the results from the 
AstraZeneca study and 20 subjects complete follow up assessments the probability of 
meeting the success criteria for Min LAR and WM LAR are approximately 78% and 81% 
respectively. This is considered sufficient justification for requiring 20 completers.
9.2.2.
Sample Size Sensitivity
Probability of success (Assurance) was determined for all combinations of these three 
factors: success thresholds of 0.95, 0.85, 0.8, 0.75 and 0.7, sample sizes (per arm) of 5, 
10, 15, 20, 25, 30, 35, 40, 45, 50, 100 and Known % attenuations of 0% to 30% by 2% 
increments, 35 to 50% by 5% increments and 60% to 100% by 10% increments. Full 
results are available on file.
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is currently planned for this study beyond that described in 
Section 9.3.2.  However, if during the course of the study, new information becomes 
available about clinically meaningful differences or variability estimates, a sample size 
re-estimation may be conducted.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Subjects who receive at least one dose of study medication will be included in an ‘All 
Subjects’ population.  Furthermore, subjects in the ‘All Subjects’ population who have a 
successful screening sputum sample will be included in the ‘Sputum Producers’ 
population.
PPD


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Additionally, subjects from the All Subjects population who were not on Placebo and 
who provide GSK2245035 pharmacokinetic samples will be included in a ‘PK’ 
population. 
Other populations, such as a Per-protocol population, may be defined in the RAP.
9.3.2.
Interim Analysis
Recruitment into the study would continue whilst the interim analysis is taking place.
The interim analysis will require knowledge of which subjects are in the Placebo arm and 
determine how many of those Placebo subjects failed to meet the screening inclusion 
criteria for LAR in their 1 week follow up visit (i.e. did not show three FEV1 decreases of 
15 % relative to saline baseline between 4 and 10 hours, with two FEV1 decreases 
being at consecutive time points at 1 week follow up).  The number of subjects on 
placebo who do not exhibit an LAR (non-LAR responders) will be determined from the 
available interim data.  This number will be checked against Table 3 to advise whether 
the study should continue or whether further review of the interim analysis data is 
required to assess the impact. For example, if at the time the interim analysis occurs 10 
subjects were on Placebo and 4 of those 10 did not demonstrate an LAR response then 
the interim analysis would recommend reviewing the data further.


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Table 3
Lookup table for Interim Analysis Decision Pathway
Number of non-LAR responders on Placebo
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20
Number of Placebo At Interim
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Continue Study
Data Review
NA
Assessing impact of non-LAR response rate: To evaluate whether recruiting additional 
subjects may counteract the impact of the non-LAR responder alternative version(s) of 
Table 3 would be constructed, but using final sample sizes that range from 20 to 30 
subjects per arm. If any of the resulting estimates for probability of success are within 
10% of the original operating characteristic the study may continue; but requiring 
additional subjects (the smallest number that satisfied the continuation criteria). 
In addition posterior distributions for the percentage attenuation of the primary endpoints 
by GSK2245035 would be constructed from the available interim data. 
Amending protocol / termination of further enrolment (existing subjects would complete 
the study as planned): If the median (point estimate) for the observed treatment effect is 
dramatically different to the assumed effect from the AZ study, the study team may wish 
to predict the probability of success at the end of the study from the interim information 
(details to be provided in the RAP). If this updated probability of success is low then the 
study team may review any of the other available data items at the interim prior to 
amending the protocol / terminating further enrolment (and share these outputs with 
appropriate internal GSK governance boards / senior management). 


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To determine the probability of success in the presence of non-LAR responders (for each 
of the primary endpoints) simulations were performed for each possible combination of 
number of available placebo subjects (n) and number showing no LAR response (r) using 
the AZ point estimates as the true percentage attenuation:
The rate of non-LAR response (p) was assumed to be the same for Placebo and 
GSK2245035 arms. A Beta(0.1, 0.1) prior distribution was assumed for the rate, which 
was updated using conjugate formulae as Beta(0.1 + r, 0.1 + n – r) and a value sampled 
from this posterior distribution. The number of future subjects on placebo with a non-
LAR response was sampled from a Binomial distribution using the sampled value of p 
and (20 – n) observations (the total is a mixture of observed interim data and this sampled 
value). Similarly the number of non-LAR responders on the GSK2245035 arm was 
sampled from a Binomial distribution with the same value of p and 20 observations. Each 
non-responding individual was assigned a constant value for the response, and the 
collection of non-responders were combined with the collection of LAR responders 
(generated in a similar way using the random effects meta-analysis to obtain the expected 
responses). The probability of success was determined for each of the combined datasets 
and the median was derived. If this median was more than 10% smaller than the original 
operating characteristic the recommendation is to further review the data. The 
recommendations from the two endpoints were combined into a single table. Wherever 
there was disagreement between cells the review data decision was chosen.
Sensitivity analyses showed the outcome of this approach is highly dependent on the 
value of the constant used for the non-LAR responses (the further the choice from the 
range of plausible values for LAR responders the more likely the recommendation was to 
review data). The choice of value is arbitrary in nature, but was selected as -0.45 for 
Minimum Change From Saline and -0.2 for Weighted Mean Minimum Change From 
Saline, based upon applying the LAR criteria to seven historical studies and deriving the 
mean responses of all non-LAR responding subjects. Since the decision tables cover all 
interim study possibilities and is pre-specified the consequences of this arbitrary choice 
can be articulated.
9.3.2.1.
Headline results for LAR endpoints at Follow Up 1
The following is conditional on the study not being stopped early by the interim analysis. 
To facilitate internal GSK decision making a data snapshot will be taken when the last 
subject’s BAC FEV1 data (and derived LAR endpoints) from Follow Up 1 are available. 
The associated planned efficacy outputs (to be provided in the RAP) will be produced 
from that (unblinded) snapshot and shared internally with the GSK study team and 
internal GSK governance boards / senior management. This data snapshot will not 
represent a cleaned and locked database and hence its results will not be formally 
reported as they will be superseded by the formal end of study results.


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9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
Statistical models will be fitted separately to each LAR endpoint (weighted mean and 
minimum FEV1).  These parameters will be analysed using analysis of covariance 
(ANCOVA) with treatment and baseline in the model; other covariates such as centre, 
allergen exposure (‘presumed’/’unknown’) (see Section 6.2) and allergen exposure by 
treatment interaction may be included in the model if the observed data support it (the 
default position is not to include the model terms involving the stratification factor).  
Treatment comparisons of GSK2245035 vs Placebo will be presented with results also 
expressed as percentage attenuations to aid clinical interpretation. The posterior 
probability of any percentage attenuation will be obtained along with appropriate 
summary statistics from the posterior distribution (e.g. 95% and 70% equi-tail Credible 
Intervals).
The principle inferences are expected to come from models with non-informative priors. 
Sensitivity analyses using informative priors based on AZ data may be fitted. 
Full details of the BAC analyses will be provided in the RAP.
9.4.2.
Secondary Analyses
Weighted mean and minimum for EAR will be analysed in a similar manner to that of the 
primary analysis described in Section 9.4.1.
9.4.3.
Safety Analyses
Safety and tolerability data, such as rescue medication, PEF, AEs, will be displayed in 
graphical or summary format or listed as appropriate.  Additional details will be provided 
in the RAP.
9.4.4.
Exploratory Analyses
Pharmacokinetic data will be presented in graphical or tabular form and will be 
summarized descriptively.
Other exploratory analyses will be described in detail in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.


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10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent (Subjects who are re-screened are required to 
sign a new ICF)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.


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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 GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.


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10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.


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11.
REFERENCES
An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide 
Levels (FeNO) for Clinical Applications. Am J Respir Crit Care Med. 2011; 184: 
602−615
ATS/ERS Recommendations for Standardized Procedures for the Online and Offline 
Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. Am J 
Respir Crit Care Med. 2005; 171: 912–930
GlaxoSmithKline Document Number 2010N110564_04. GSK2245035 Investigator’s 
Brochure. December 2015.
GlaxoSmithKline Document Number 2011N120740_00. A randomized, single-blind, 
placebo-controlled first time into human study to investigate the safety, tolerability, 
pharmacokinetics and pharmacodynamics of intranasal dosing with GSK2245035, a 
TLR7 agonist, in healthy volunteers and allergic rhinitics. July 2012.
GlaxoSmithKline Document Number 2011N126275_00. A randomised, double-blind, 
placebo-controlled study to investigate the safety, pharmacodynamics and efficacy 
against allergic reactivity of repeat intranasal administration of the TLR7 agonist 
GSK2245035 in subjects with respiratory allergies. January 2012.
GlaxoSmithKline Document Number 2013N174200_00. A randomized, double blind,
placebo-controlled study to investigate the safety, pharmacodynamics and effect on 
allergic reactivity of repeat intranasal administration of the TLR7 agonist GSK2245035 
in subjects with respiratory allergies. August 2015.
Global Initiative for Asthma (GINA). Global Strategy for Asthma management and 
prevention 2015. Available from www.ginasthma.org.
Hankinson J L, Odencrantz, JR; Feden, KB. Spirometric Reference Values from a 
Sample of the General U.S. Population. AM J Respir Crit care Med. 1999;159:179-187.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
Leaker B, Singh D, Lindgren S, et al., editors. The Effects Of The Novel Toll-Like 
Receptor 7 (TLR7) Agonist AZD8848 On Allergen-Induced Responses In Patients With 
Mild Asthma. American Thoracic Society International Conference; 2012; San Francisco, 
California, USA.
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson 
JL, Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative.  Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations.  Eur Respir J. 2012;40:1324-43.


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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AC
Allergen challenge
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
ANOVA
Analysis of Variance
AR
Allergic Rhinitis or Allergic Rhinitics
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
%AUCex
Percentage of AUC(0-) obtained by extrapolation
AUC(0-x)
Area under the concentration-time curve from zero (pre-dose) to some 
fixed nominal time x
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration within a subject across all 
treatments
AUC(0-)
Area under the concentration-time curve over the dosing interval
AZ
AstraZeneca
-HCG
Beta-Human Chorionic Gonadotropin
BAC
Bronchial allergen challenge
BMI
Body mass index
BUN
Blood urea nitrogen
CI
Confidence Interval
CIB
Clinical Investigator’s Brochure
CRF
Case Report Form
CRO
Contract Research Organization
CRS
Cytokine Release Syndrome
CV
Coefficient of variance
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
DRE
Disease Related Event
DV
Dosing Visit
EAR
Early asthmatic response
ECG
Electrocardiogram
eNO
Exhaled Nitric Oxide
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FSH
Follicle Stimulating Hormone
FU
Follow-up
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilence


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GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
HR
Heart rate
HRT
Hormone replacement therapy
HVT
Healthy volunteers
IB
Investigator’s Brochure
IC
Intradermal challenge
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
ICS
Inhaled corticosteroids
IEC
Independent Ethics Committee
IFN
Interferon
Ig
Immunoglobulin
I.N.
Intranasal
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational Product
IP-10
Interferon inducible protein 10
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
Intravenous
Kg
Kilogram
L
Liter
LABA
Long-acting beta2-agonist
LAR
Late asthmatic response
µg
Microgram
µL
Microliter
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
mm
Millimeters
MSDS
Material Safety Data Sheet
msec
Milliseconds
NAC
Nasal allergen challenge
ng
nanogram
NO
Nitric Oxide
NOAEL
No observed adverse event level
OD
Once a day, once daily
PAX
Paired box gene


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PBMC
Peripheral blood mononuclear cell
PBS
Phosphate buffered saline
PD
Pharmacodynamic
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PNIF
Peak Nasal Inspiratory Flow
PTS
Platform Technology Sciences
QC
Quality control
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SABA
Short-acting beta2-agonist
SAE
Serious adverse event(s)
SAR
Seasonal allergic rhinitics
SAS
Statistical Analysis Software
SD
Standard deviation
SOP
Standard Operating Procedure
SRM
Study Reference Manual
T
Time of last observed quantifiable concentration
t½
Terminal phase half-life
Th
T helper cell
Tmax
Time of occurrence of Cmax
TNSS
Total nasal symptoms score
TLR7
Toll like receptor 7
Treg
Regulated T cells
ULN
Upper limit of normal
UK
United Kingdom
US
United States
WBC
White blood cells
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None


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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.


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References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.3.
Appendix 3 - Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 
Response to medicine, including any treatment regimens under investigation in this study 
or any concomitant medicines;
Asthma susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.


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Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  
A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A Blood 
sample is collected at the baseline visit, after the subject has been randomized and 
provided informed consent for genetic research. Instructions for collection and shipping 
of the genetic sample are described in the laboratory manual. The DNA from the blood 
sample may undergo quality control analyses to confirm the integrity of the sample. If 
there are concerns regarding the quality of the sample, then the sample may be destroyed. 
The blood sample is taken on a single occasion unless a duplicate sample is required due 
to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:
Continue to participate in the genetic research in which case the genetic DNA sample is 
retained
Discontinue participation in the genetic research and destroy the genetic DNA sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 


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destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  
Genetic data that has been analyzed at the time of withdrawn consent will continue to be 
stored and used, as appropriate. 
Screen Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.


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


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Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
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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12.4.2.
Definition and Grading of CRS-related Adverse Events
In the study, symptoms potentially related to cytokine induction (headache, chills/rigors, 
fever, nausea, vomiting, diarrhoea, arthralgia, myalgia, hypotension) occurring within 24 
hours of dosing will be individually reported as AEs and graded as described below:


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Cytokine Release Syndrome (CRS) AE grading (continued)
12.4.3.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 


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office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and International Normalised Ratio (INR)** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 2 for the required liver chemistry follow-up instructions


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12.4.4.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.4.5.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.


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12.4.6.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.7.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the GSK Medical Monitor and GSK 
Study Manager

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the GSK 
Medical Monitor and GSK Study Manager by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.5.
Appendix 5: Modified List of Highly Effective Methods for 
Avoiding Pregnancy and Collection of Pregnancy 
Information
12.5.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy
Contraceptive requirements for male subjects with female partners of 
reproductive potential (when applicable).
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until the final follow-up visit.
1.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
2.
Male condom plus partner use of one of the contraceptive options below that meets 
the Standard Operating Procedure (SOP) effectiveness criteria including a <1% rate 
of failure per year, as stated in the product label:

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.5.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study (this may also be a female partner of a male 
subject in the study)

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.


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
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participatingwill discontinue study 
medication and will be withdrawn from the study

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.
12.5.3.
References
CHMP, 2005 - EMA - Guideline on Adjuvants in Vaccines for Human Use, 
(CHMP/VEG/134716/2004), January 2005.
Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy 
tests at the time of missed menses. Am J Ob Gyn 2004(190):100-5.
EMA/CHMP/ICH/449035/2009: General principles to address virus and vector shedding. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002680.pdf Accessed 28 Nov 2014.
EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
Before First Clinical Use of Gene Therapy Medicinal Products [2008]
FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. FDA; 
Feb. 2006. 
FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
(hCG) assays: What laboratorians should know about false-positive results”, 


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http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceS
afety/ucm109390.htm, accessed 17 Nov 2014.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 
Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998]
WHO, 2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants 
and Adjuvanted Vaccines, 2013
World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9.
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.


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12.6.
Appendix 6 - Country Specific Requirements
No country-specific requirements exist.


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12.7.
Appendix 7: Protocol Amendment Changes
AMENDMENT [4]
Where the Amendment Applies
This amendment applies across any site that will be used in the study.
Summary of Amendment Changes with Rationale
Section 4.4 Design Justification, has been updated to permit earlier interim analysis.
Section 5.3, Screening Failures/Re-Screening, has been updated to allow re-screening of 
Subjects screen failed.
Section 7.1.1 Time and Events Table – Screening Visit(s), has been updated to clarify 
timing of screening visits.
Section 10.2 Regulatory and Ethical Considerations, Including the Informed Consent 
Process, to clarify that a new ICF should be completed for each re-screened subject.
List of Specific Changes

Change to text in Section 4.4 Design Justification from Protocol Amendment 3 (26-
May-2017).
PREVIOUS TEXT
4.4
Design Justification

Interim analysis: Previous experience within GSK suggests some individuals 
(approximately 20%) fail to demonstrate a LAR response after the screening visit (i.e. 
they pass the screening criteria but do not demonstrate another LAR response when 
receiving placebo during the on-treatment phase). Those GSK studies were mainly 
crossover designs with a placebo in every sequence, so subjects who did not 
demonstrate a post screening LAR could be retrospectively identified and excluded 
from the statistical analyses. However this study has parallel groups and the profiles 
of a “perfect” drug effect and an inconsistent LAR subject are indistinguishable so 
retrospective exclusions cannot be made for the GSK2245035 arm. If the rate of 
“non-reproducible LAR” subjects is large it will reduce the probability of success. 
The purpose of the interim analysis is to evaluate whether the non-reproducible LAR 
rate is reducing the expected probability of success by more than 10% and, if it is, to 
perform an unblinded review of the observed data to assess the impact and cease 
further recruitment into the study, or enrol additional subjects to counteract the 
effects. Simulations were used to quantify the expected reduction in probability of 
success, using an estimate of the non-responder rate from the placebo arm only. The 
timing of the interim is linked to the enrolment rates and will be triggered by 
whichever occurs first i) Approximately 1 year after the first subject successfully 


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completes the Follow Up 1 assessments or, ii) When 28 subjects have successfully 
completed the Follow Up 1 assessments.
REVISED TEXT
4.4
Design Justification

Interim analysis: Previous experience within GSK suggests some individuals 
(approximately 20%) fail to demonstrate a LAR response after the screening visit (i.e. 
they pass the screening criteria but do not demonstrate another LAR response when 
receiving placebo during the on-treatment phase). Those GSK studies were mainly 
crossover designs with a placebo in every sequence, so subjects who did not 
demonstrate a post screening LAR could be retrospectively identified and excluded 
from the statistical analyses. However this study has parallel groups and the profiles 
of a “perfect” drug effect and an inconsistent LAR subject are indistinguishable so 
retrospective exclusions cannot be made for the GSK2245035 arm. If the rate of 
“non-reproducible LAR” subjects is large it will reduce the probability of success.
The purpose of the interim analysis is to evaluate whether the non-reproducible LAR 
rate is reducing the expected probability of success by more than 10% and, if it is, to 
perform an unblinded review of the observed data to assess the impact and cease 
further recruitment into the study, or enrol additional subjects to counteract the 
effects. Simulations were used to quantify the expected reduction in probability of 
success, using an estimate of the non-responder rate from the placebo arm only. The 
timing of the interim is linked to the enrolment rates and will be triggered by 
whichever occurs first i) Approximately 1 year after the first subject successfully 
completes the Follow Up 1 assessments or, ii) When 28 subjects have successfully 
completed the Follow Up 1 assessments or, iii) At the discretion of the GSK Study 
Team up to the time that 28 subjects have successfully completed the Follow Up 1 
assessment.

Change to text in Section 5.3, Screening Failures/Re-Screening from Protocol 
Amendment 3 (26-May-2017).
PREVIOUS TEXT
5.3
Screening Failures/Re-screening
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.4.1.6).
Re-screening will not be permitted in this study. Sites are encouraged to screen subjects 
who have previously undergone BAC and have demonstrated a LAR. 


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REVISED TEXT
5.3
Screening Failures/Re-screening
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.4.1.6).
Re-screening will be permitted in this study, in discussion with the Medical Monitor. 
Sites are encouraged to screen subjects who have previously undergone BAC and have 
demonstrated a LAR. 
Re-screened subjects should be assigned a separate number from their initial screening 
number and complete a new informed consent form. 

Section 7.1.1 Time and Events Table – Screening Visit(s), has been updated to clarify 
timing of screening visits. Protocol Amendment 3 (26-May-2017).
PREVIOUS TEXT
7.1.1 Time and Events Table – Screening Visit(s)
Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
Informed consent signing
X
Includes genetics consent
Inclusion and exclusion 
criteria/eligibility review
X
X
Demographics
X
Medical history (including substance 
usage and family history of premature 
CV disease)
X
Past and current medical conditions 
including cardiovascular medical 
history
X
Concomitant medication review
X
Full physical exam including height 
and weight
X
Urine drug/alcohol screen
X
Urine or serum pregnancy test (all 
females)
X
No women of childbearing 
potential are being enrolled. 
However this test is needed to 
confirm pregnancy status at 
screening.
Serum FSH and estradiol for post-
menopausal females
X
HIV, Hep B and Hep C screen
X


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Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
Laboratory assessments (including 
liver chemistries, haematology, clinical 
chemistry and urinalysis)
X
Screening Spirometry assessment
X
To confirm FEV1 >70% predicted
SAE Collection
X
X
X
12-lead ECG
X
Vital signs
X
Skin prick test
X
To confirm eligibility
FeNO measurement
X
X
Collected prior to sputum 
induction
Saline and incremental BAC challenge 
plus associated spirometry 
measurements
X
Including pre-procedure FEV1
assessment and repeat FEV1
measurements up to 10 hours 
post BAC
Sputum induction and processing for 
BAC associated sample collection
X
X
Sputum inductions must be 
separated by at least 3 days
Laboratory assessments 
(haematology only)
X
X
Blood samples should be taken 
pre-BAC on SV2 and  on the 
following day at 24 hrs post BAC
Blood samples for PBMC preparations
X
Blood samples for PBMC 
preparations (pre-BAC and 6 
hours after BAC at screening visit 
2)
Provide diary card, PEF meters, 
rescue medication and thermometers 
to subjects
X
Only given out to subjects who 
are eligible following the BAC. 
Thermometers are to be given to 
record temperature as part of 
capturing AE information.
Nasal lavage
X
Collect nasal lavage to provide a 
background  sample. Repeat 
nasal lavage pre-NAC, then 
again 5 minutes and at least 6 
hours post-NAC.
Nasal filter collection 
X
Collect nasal filter sample to 
provide a background pre-wash 
sample, after nasal wash repeat 
nasal filter sampling pre-NAC, 
then again 5 minutes and at least 
6 hours post-NAC.
NAC
X
Commence after the 24-hour 
BAC sputum and blood 
biomarker samples have been 
taken.
Only to be done once subjects 
have completed a successful 
BAC.
ID challenge
X
ID challenge to be administered 
after NAC.
Measurements to be made 15 
minutes and 6 hours post ID 
challenge. 


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Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
Nasal scrape
X
Nasal mucosa sample to be 
collected at least 6 hours post-
NAC.
CURRENT TEXT
7.1.1 Time and Events Table – Screening Visit(s)
Procedure
Screenin
g Visit 1 
(up to 
Day -28)
Screening 
Visit 2 (up to 
Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 to 
Day -2)
Notes 
There must be a minimum of 48 
hours between ‘Screening Visit 
1’ and ‘Screening Visit 2’. This 
ensures adherence to a 
minimum 3-day window between 
sputum inductions.
There must be a minimum of 48 
hours between ‘24 hours after 
Screening Visit 2’ and ‘Dosing 
Visit 1’.
Informed consent signing
X
Includes genetics consent
Inclusion and exclusion 
criteria/eligibility review
X
X
Demographics
X
Medical history (including substance 
usage and family history of premature 
CV disease)
X
Past and current medical conditions 
including cardiovascular medical 
history
X
Concomitant medication review
X
Full physical exam including height 
and weight
X
Urine drug/alcohol screen
X
Urine or serum pregnancy test (all 
females)
X
No women of childbearing 
potential are being enrolled. 
However this test is needed to 
confirm pregnancy status at 
screening.
Serum FSH and estradiol for post-
menopausal females
X
HIV, Hep B and Hep C screen
X
Laboratory assessments (including 
liver chemistries, haematology, clinical 
chemistry and urinalysis)
X
Screening Spirometry assessment
X
To confirm FEV1 >70% 
predicted
SAE Collection
X
X
X
12-lead ECG
X
Vital signs
X


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Procedure
Screenin
g Visit 1 
(up to 
Day -28)
Screening 
Visit 2 (up to 
Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 to 
Day -2)
Notes 
There must be a minimum of 48 
hours between ‘Screening Visit 
1’ and ‘Screening Visit 2’. This 
ensures adherence to a 
minimum 3-day window between 
sputum inductions.
There must be a minimum of 48 
hours between ‘24 hours after 
Screening Visit 2’ and ‘Dosing 
Visit 1’.
Skin prick test
X
To confirm eligibility
FeNO measurement
X
X
Collected prior to sputum 
induction
Saline and incremental BAC challenge 
plus associated spirometry 
measurements
X
Including pre-procedure FEV1
assessment and repeat FEV1
measurements up to 10 hours 
post BAC
Sputum induction and processing for 
BAC associated sample collection
X
X
Sputum inductions must be 
separated by at least 3 days
Laboratory assessments 
(haematology only)
X
X
Blood samples should be taken 
pre-BAC on SV2 and  on the 
following day at 24 hrs post BAC
Blood samples for PBMC preparations
X
Blood samples for PBMC 
preparations (pre-BAC and 6 
hours after BAC at screening 
visit 2)
Provide diary card, PEF meters, 
rescue medication and thermometers 
to subjects
X
Only given out to subjects who 
are eligible following the BAC. 
Thermometers are to be given to 
record temperature as part of 
capturing AE information.
Nasal lavage
X
Collect nasal lavage to provide a 
background  sample. Repeat 
nasal lavage pre-NAC, then 
again 5 minutes and at least 6 
hours post-NAC.
Nasal filter collection 
X
Collect nasal filter sample to 
provide a background pre-wash 
sample, after nasal wash repeat 
nasal filter sampling pre-NAC, 
then again 5 minutes and at 
least 6 hours post-NAC.
NAC
X
Commence after the 24-hour 
BAC sputum and blood 
biomarker samples have been 
taken.
Only to be done once subjects 
have completed a successful 
BAC.
ID challenge
X
ID challenge to be administered 
after NAC.
Measurements to be made 15 
minutes and 6 hours post ID 
challenge. 
Nasal scrape
X
Nasal mucosa sample to be 
collected at least 6 hours post-


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Procedure
Screenin
g Visit 1 
(up to 
Day -28)
Screening 
Visit 2 (up to 
Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 to 
Day -2)
Notes 
There must be a minimum of 48 
hours between ‘Screening Visit 
1’ and ‘Screening Visit 2’. This 
ensures adherence to a 
minimum 3-day window between 
sputum inductions.
There must be a minimum of 48 
hours between ‘24 hours after 
Screening Visit 2’ and ‘Dosing 
Visit 1’.
NAC.

Changes to 10.2 Regulatory and Ethical Considerations, Including the Informed 
Consent Process from Protocol Amendment 3 (26-May-2017).
PREVIOUS TEXT
10.2
Regulatory and Ethical Considerations, Including the Informed 
Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent
CURRENT TEXT
10.2
Regulatory and Ethical Considerations, Including the Informed 
Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.


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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 current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent (Subjects who are re-screened are required to 
sign a new ICF)


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Amendment [3]
Where the Amendment Applies
This amendment applies across any site that will be used in the study.
Summary of Amendment Changes with Rationale
Administrative changes including:

Changes in the Primary Medical Monitor and contact details.

Alignment of contraception requirements, throughout the document, for partners 
of male subjects that are female of reproductive potential.

Inclusion Criteria bullets replaced with numbers. 
List of Specific Changes
Changes in the Primary Medical Monitor and contact details.
PREVIOUS TEXT
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
 
MD
5 Moore 
Drive, PO 
Box 13398, 
RTP, NC 
27709-3398, 
United 
States
Secondary 
Medical 
Monitor 
 
 MD
Gunnels 
Wood Road
Stevenage, 
SG1 2NY
UK
PPD
PPD
PPD
PPD
PPD


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Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
SAE contact  
information 
Medical 
monitor 
as above 
and 
Study 
Manager, 
Gunnels 
Wood Road
Stevenage, 
SG1 2NY
UK
REVISED TEXT
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
 
 
MD
Gunnels 
Wood Road
Stevenage, 
SG1 2NY
UK
Secondary 
Medical 
Monitor 
 
 MD
Gunnels 
Wood Road
Stevenage, 
SG1 2NY
UK
SAE contact  
information 
Medical 
monitor 
as above 
and 
Study 
Manager, 
Gunnels 
Wood Road
Stevenage, 
SG1 2NY
UK
Section 5.1 Inclusion Criteria is now numbered. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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PREVIOUS and REVISED TEXT
5.1 Inclusion Criteria. Bullets replaced with numbers 1-11.
Alignment of contraception requirements, throughout the document, for partners of male 
subjects that are female of reproductive potential.
PREVIOUS TEXT
5.1 Inclusion Criteria
SEX

Male OR female of non-reproductive potential
Males:
Male subjects with female partners of child bearing potential must comply with one of 
the following contraception requirements from the time of first dose of study medication 
until the final follow-up visit.
a.
Vasectomy with documentation of azoospermia. 
b. Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]
This is an all-inclusive list of those methods that meet the following GSK definition of 
highly effective: having a failure rate of less than 1% per year when used consistently and 
correctly and, when applicable, in accordance with the product label. For non-product 
methods (e.g., male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the International 
Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) [ICH M3 (R2) 2009].”
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative [serum or urine] human chorionic gonadotrophin (hCG) test), not lactating, and 
where the following condition applies:
Non-reproductive potential defined as:


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Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment..
REVISED TEXT
SEX
10. Male OR female of non-reproductive potential
Males:
Male subjects with female partners of child bearing potential must comply with the 
contraception requirements in Appendix 5 (Modified List of Highly Effective Methods 
for Avoiding Pregnancy) from the time of first dose of study medication until the final 
follow-up visit.
This is an all-inclusive list of those methods that meet the following GSK definition of 
highly effective: having a failure rate of less than 1% per year when used consistently and 
correctly and, when applicable, in accordance with the product label. For non-product 
methods (e.g., male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the International 
Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) [ICH M3 (R2) 2009].”
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative [serum or urine] human chorionic gonadotrophin (hCG) test), not lactating, and 
where the following condition applies:


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Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
PREVIOUS TEXT
12.5.1       Modified List of Highly Effective Methods for Avoiding Pregnancy
Contraceptive requirements for male subjects with female partners of 
reproductive potential (when applicable).
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until [at least five half-lives of study medication OR for a cycle of spermatogenesis 
following five terminal half-lives] after the last dose of study medication.
REVISED TEXT
12.5.1       Modified List of Highly Effective Methods for Avoiding Pregnancy
Contraceptive requirements for male subjects with female partners of 
reproductive potential (when applicable).
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until the final follow-up visit.


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AMENDMENT [2]
Where the Amendment Applies
This amendment applies across any site that will be used in the study.
Summary of Amendment Changes with Rationale
The protocol title and text have been amended to clarify that while the investigator and 
subjects are blinded the sponsor-is unblinded. 
Details of the procedures required at early withdrawal visits have been added.
Details around the Safety Review Team have been added to include a consultant external 
to GSK.
The inclusion and exclusion criteria have been updated in Section 5.1 and Section 5.2. 
and clarification around prohibited medications has been provided in Section 6.11.2. to 
align with updated exclusion criteria (Section 5.2).
Administrative changes have been made to the T&E table (Section 7.1) and text to ensure 
consistency throughout.
List of Specific Changes
Title: Updated to reflect that the study is sponsor-unblind.
PREVIOUS TEXT
A randomised, double-blind placebo-controlled, parallel group, 8-week treatment study to 
investigate the safety, pharmacodynamics, and effect of the TLR7 agonist, GSK2245035, 
on the allergen-induced asthmatic response  in subjects with mild allergic asthma.
REVISED TEXT
A randomised, double-blind (sponsor open) placebo-controlled, parallel group, 8-week 
treatment study to investigate the safety, pharmacodynamics, and effect of the TLR7 
agonist, GSK2245035, on the allergen-induced asthmatic response  in subjects with mild 
allergic asthma.
This update has been made where necessary throughout the protocol.
Objectives/Endpoints: Updated to clarify what changes in FeNO measurement are 
being assessed; abbreviations for bronchial allergen challenge and nasal allergen 
challenge included. Nasal allergen administration changed to nasal allergen 
challenge for consistency.

To evaluate the induction of TLR7-
associated pharmacodynamic (PD) 

TLR7-induced blood PD biomarkers.

TLR7 induced gene expression changes 


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biomarkers and exhaled nitric oxide 
(FeNO) following treatment with i.n. 
GSK2245035
in blood

TLR7-induced nasal fluid PD biomarkers

FeNO levels 

To evaluate the effect of treatment with 
i.n. GSK2245035 compared to placebo 
on Bronchial Allergen Challenge 
associated allergic biomarkers

Allergic biomarkers in induced sputum

Allergic biomarkers in blood

FeNO levels

To evaluate the effect of treatment with 
i.n. GSK2245035 compared to placebo 
on Nasal Allergen Administration 
associated allergic biomarkers

Allergic biomarkers in nasal fluids

Cellular profile of nasal mucosa
REVISED TEXT

To evaluate the induction of TLR7-
associated pharmacodynamic (PD) 
biomarkers and exhaled nitric oxide 
(FeNO) following treatment with i.n. 
GSK2245035

TLR7-induced blood PD biomarkers.

TLR7 induced gene expression changes 
in blood

TLR7-induced nasal fluid PD biomarkers

Change in FeNO levels during the 
treatment phase

To evaluate the effect of treatment with 
i.n. GSK2245035 compared to placebo 
on Bronchial Allergen Challenge (BAC)
associated allergic biomarkers

Allergic biomarkers in induced sputum

Allergic biomarkers in blood

Change in FeNO levels following BAC

To evaluate the effect of treatment with 
i.n. GSK2245035 compared to placebo 
on Nasal Allergen Challenge(NAC)
associated allergic biomarkers

Allergic biomarkers in nasal fluids

Cellular profile of nasal mucosa
Bronchial Allergen Challenge has been replaced by BAC throughout the protocol and 
Nasal Allergen Challenge/Administration by NAC throughout the protocol. 
Section 4.3. Type and Number of Subjects, Final Paragraph updated
PREVIOUS TEXT
Accounting for replacements and interim analysis recommendations, the total number of 
subjects to be enrolled in this study is not expected to exceed 60


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REVISED TEXT
Accounting for replacements and interim analysis recommendations, the total number of 
subjects to be randomised in this study is not expected to exceed 60
Inclusion Criteria 5 updated to clarify timepoint of assessment
PREVIOUS TEXT
Pre-bronchodilator FEV1 > 70 % predicted normal.
REVISED TEXT
Pre-bronchodilator FEV1 > 70 % predicted normal at Screening Visit 1
Section 5.2. Exclusion Criteria
Two additional exclusion criteria have been added for clarification:

Use of long-acting antihistamines within 7 days’ or short-acting antihistamines 
within 72 hours prior to the screening skin prick test.

Patient known to be intolerant to salbutamol or albuterol
Section 5.4 Withdrawal/Stopping Criteria
PREVIOUS TEXT
Subjects withdrawn from the study while already exposed to IP will be asked to complete 
all safety assessments and the follow-up procedures. Relevant pages of the case report 
form (CRF) should be completed by the investigator.
REVISED TEXT
Subjects withdrawn from the study while already exposed to IP will be asked to complete 
all safety assessments as outlined in the Time and Events Table (Section 7.1.2). Relevant 
pages of the case report form (CRF) should be completed by the investigator.
Section 6.3 Blinding: An additional paragraph has been inserted between 
paragraphs 2 and 3.
PREVIOUS TEXT
This will be a double-blind study (investigators and subjects are blinded, and sponsor will 
be unblinded).
During the study, there will be an unblinded interim analysis. Some key GSK study team 
members may be unblinded as part of this analysis and review. Initially, only the study 
statistician(s) (and supporting programmers), project physician lead, and medical monitor 


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will be unblinded, and if further data reviews are required then details of who were un-
blinded to what data and when will be included in the clinical study report.
If the GSK medical monitor deems it necessary to unblind data in order to enhance the 
evaluation of safety and tolerability this will be permitted but also documented and 
discussed in the clinical study report.  The GSK medical monitor will also decide whether 
to un-blind the investigator(s)/site(s) at that time, or just the sponsor study staff.  Details 
of who were un-blinded to what data and when would then be included in the clinical 
study report.
REVISED TEXT
During the study, there will be an unblinded interim analysis. Some key GSK study team 
members may be unblinded as part of this analysis and review. Initially, only the study 
statistician(s) (and supporting programmers), project physician lead, and medical monitor 
will be unblinded, and if further data reviews are required then details of who were un-
blinded to what data and when will be included in the clinical study report.
On-going safety reviews will be conducted during the course of the study in an unblinded 
manner. Key study team members may be unblinded as part of this review. An external 
consultant, who is not a GSK employee, may also be unblinded to enable independent 
review of emerging safety data.
If the GSK medical monitor deems it necessary to unblind data in order to enhance the 
evaluation of safety and tolerability this will be permitted but also documented and 
discussed in the clinical study report.  The GSK medical monitor will also decide whether 
to un-blind the investigator(s)/site(s) at that time, or just the sponsor study staff.  Details 
of who were un-blinded to what data and when would then be included in the clinical 
study report.
Section 6.10.2. Caffeine, Alcohol, and Tobacco: A third bullet point has been added 
for clarification.
PREVIOUS TEXT

Subjects will abstain from ingesting excessive amounts (more than one cup) of 
caffeine- or xanthine-containing products (e.g. coffee, tea, cola drinks, chocolate) for 
6 hours prior to each dosing. 

During each visit in the clinic, subjects will abstain from alcohol for 24 hours prior 
to entry to the clinic until collection of all assessment is completed. 
REVISED TEXT

Subjects will abstain from ingesting excessive amounts (more than one cup) of 
caffeine- or xanthine-containing products (e.g. coffee, tea, cola drinks, chocolate) for 
6 hours prior to each dosing. 

During each visit in the clinic, subjects will abstain from alcohol for 24 hours prior 
to entry to the clinic until collection of all assessment is completed. 


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
Subjects will be reminded that all forms of smoking should be avoided during the 
course of the study
Section 6.11.2 Permitted Medications and Non-Drug Therapies: Additional wording
has been added to clarify which medications are permitted.
PREVIOUS TEXT
Any concomitant medications not specifically permitted will be considered on a case by 
case basis by the investigator and GSK medical monitor. 
Subjects are permitted to take inhaled short-acting β2-agonists (SABA) as rescue 
treatment, but must withhold them for at least 6 hours prior to study visits with BAC 
(screening and follow-up visits 1-3).
REVISED TEXT
Any concomitant medications not specifically permitted will be considered on a case by 
case basis by the investigator and GSK medical monitor. 
Subjects are permitted to take inhaled short-acting β2-agonists (SABA) as rescue 
treatment, but must withhold them for at least 6 hours prior to any study visits with lung 
function assessment or BAC (screening and follow-up visits 1-3).
Medication to control hypertension is permitted, providing it is anticipated to remain 
stable from screening to follow up. Beta blockers are not permitted.
Section 6.11.2 Prohibited Medications and Non-Drug Therapies. Clarification 
around the time period for which drugs are not permitted is provided.
PREVIOUS TEXT
Subjects may not receive the following treatments within 4 weeks prior to screening:

Intranasal steroids

Inhaled corticosteroid (ICS) with or without a long acting beta-2-agonist (LABA)

Non-ICS controller asthma medications (i.e. leukotriene modifier, 
methylxanthines)
Subjects are prohibited from taking antihistamines within 72 hours prior to the screening 
and follow-up bronchial allergen challenges.

Subjects are prohibited from taking systemic corticosteroids within 6 weeks prior to 
screening
REVISED TEXT
Subjects may not receive the following treatments from 4 weeks prior to screening until 
the final follow-up visit:

Intranasal steroids

Inhaled corticosteroid (ICS) with or without a long acting beta-2-agonist (LABA)


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
Non-ICS controller asthma medications (i.e. leukotriene modifier, 
methylxanthines).
Use of long-acting antihistamines within 7 days’ or short-acting antihistamines within 72 
hours prior to BAC, NAC or ID challenge is prohibited.
Subjects are prohibited from taking systemic corticosteroids within 6 weeks prior to 
screening.
Section 7.1 Time and Events Tables: These have been updated to provide 
consistency and clarification for the sites:
PREVIOUS TEXT
Section 7.1.1. Time and Events Table – Screening Visit(s)
Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
Informed consent signing
X
Includes genetics consent
Inclusion and exclusion 
criteria/eligibility review
X
X
Demographics
X
Medical history (including substance 
usage and family history of premature 
CV disease)
X
Past and current medical conditions 
including cardiovascular medical 
history
X
Concomitant medication review
X
Full physical exam including height 
and weight
X
Urine drug/alcohol screen
X
Urine or serum pregnancy test (all 
females)
X
No women of childbearing 
potential are being enrolled. 
However this test is needed to 
confirm pregnancy status at 
screening.
Serum FSH and estradiol for post-
menopausal females
X
HIV, Hep B and Hep C screen
X
Laboratory assessments (including 
liver chemistries, haematology, clinical 
chemistry and urinalysis)
X
Screening Spirometry assessment
X
To confirm FEV1 > 70% predicted
12-lead ECG
X
Vital signs
X
Skin prick test
X
To confirm eligibility
FeNO measurement
X
X
Collected prior to sputum 
induction
Saline and incremental BAC challenge 
plus associated spirometry 
X
Including baseline FEV1
assessment and repeat FEV1


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Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
measurements
measurements up to 10 hours 
post BAC
Sputum induction and processing for 
BAC associated sample collection
X
X
Sputum induction pre-BAC and 
24 hours after BAC: (must be 
separated by at least 3 days).
Blood sample for assessment of 
allergic biomarkers in blood
X1,2
X2
1 Collect blood samples for 
PBMC preparations (pre-BAC 
and 6 hours after BAC)
2 Collect blood sample for 
haematology (WBC count with 
differential) pre-BAC and 24 
hours after BAC
Provide diary card, PEF meters, 
rescue medication and thermometers 
to subjects
X
Only given out to subjects who 
are eligible following the BAC. 
Thermometers are to be given to 
record temperature as part of 
capturing AE information.
Nasal examination
X
NAC)
X
Commence after the 24-hour 
BAC sputum and blood 
biomarker samples have been 
taken ..
Only to be done once subjects 
have completed a successful 
BAC.
Collect sample for nasal baiomarker 
assessment
X
Collect samples pre-NAC, 5 
minutes and at 6 hours after NAC 
using nasal filters..
Nasal lavage
X
Collect nasal lavage pre-NAC, 5 
minutes and at least 6 hours after 
NAC.
Collect nasal mucosa sample at 
least 6 hours after NAC.
ID allergy testing
X
Intradermal challenge to be 
administered after NAC.
Measurements to be made 15 
minutes and 6 hours post 
intradermal challenge


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Section 7.1.2. Time and Events Table – Dosing visit (DV) 1 (Day 1) – DV8 (Week 8)
Procedure
Pre-
dose
Dos
e
Post-dose
Notes
0 
hour
20 
min
s
1 
ho
ur
12 
hours
24 
hours
Outpatient visit
X
X
Subjects get discharged 1-2 hours after 
dosing.
For DV1, 4, and 8, subjects will return to the 
unit 24 hours after dosing.
Inclusion and 
exclusion 
criteria/eligibility 
review
X
Only on DV1
12-lead ECG
X
X
X
Perform on DV1 and DV8 only
Vital signs (including 
temperature)
X1
X1
X2
1 Perform on DV1-8
2 Perform on DV1, 4 and DV8 only
Laboratory 
assessments 
(include liver 
chemistries, 
haematology, clinical 
chemistry and 
urinalysis)
X
X
Collect samples for laboratory assessments 
on DV1 and DV8
Blood sample for PK 
analysis
X
X
X
Collect samples on DV1, DV4 and DV8
Nasal examination
X
X
Conducted pre-dose and 24 hours post-dose 
on DV1 and DV8
Blood sample for 
biomarker analysis
X
X
Collect blood for serum samples and PBMC 
preparations pre-dose and 24 hrs post-dose 
on DV1 and DV8
Nasal lavage
X
X
Collect nasal lavage samples pre-dose and 
24hrs post-dose on DV1, DV4 and DV8
Blood PAX collection
X(3)
X(4)
PAX tubes for TLR7/AFFY chip gene 
expression in blood collected pre-dose on 
DV1(3) and 24 hrs after DV8(4)
Randomisation via 
IRT
X
Randomisation is on DV1 only
Study drug 
administration
X
All doses are administered in the unit.
Dispensing of study 
medication
X
One device will be assigned on DV1.  The 
second device will be assigned on DV5.  All 
devices remain in the unit.
AE/SAE review
X
Concomitant 
medication review
X
TNSS score (diary 
card) review
X
Captured daily AM and PM from DV1 to FUV2
PEF (diary card) 
review
X
Captured daily AM and PM from DV1 to FUV2
FeNO measurement
X
Perform FeNO measurements pre-dose on all 
dosing visits 1-8
Sputum induction 
and processing for 
BAC associated 
X
Sputum sample is conditional on having 
obtained a sputum sample from the subject at 
screening. Perform sputum induction after 


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Procedure
Pre-
dose
Dos
e
Post-dose
Notes
0 
hour
20 
min
s
1 
ho
ur
12 
hours
24 
hours
sample collection
collection of 24 hour post-dose DV8 blood 
and nasal samples (as pre BAC sample for 
FUV1).
Genetic sample
X
Take one sample on any of the Dosing Visits 
after genetics consent.
Diary card review
X
Review diary card at every dosing visit
Follow up phone call
X5
X6
5 Following at least the first two doses of study 
treatment to assess tolerability
6 On DV 2, 3, and 5-7, a follow-up phone call 
will be made approximately 24 hours post-
dose to check if any CRS events have 
occurred, and if they have, that they have 
been accurately recorded in the diary card 
and they will then be transcribed into the 
eCRF.
For DV1, 4 and 8, subjects will be in the unit 
24 hours after dosing, and any CRS events 
can be assessed and recorded directly by the 
site staff.
Section 7.1.3. Time and Events Table – Follow up visits (FUV1 to 3) (Weeks 9 to 20)
Procedure
Follow up 
Visit 1 
(FUV1)
Follow-up Visit 2 
(FUV2)
2 
mont
h 
follo
w-up 
phon
e call
(Wee
k 16)
Follow up Visit 3 
(FUV3)
Wee
k 9
(1 
wee
k 
afte
r 
DV8
)
24 
hou
rs 
late
r
Week 
11
(3 
week
s 
after 
DV8)
Week 
12
(4 
week
s 
after 
DV8)
24 
hou
rs 
late
r
Week 
19 
(11 
week
s 
after 
DV8)
Week 
20 
(12 
week
s 
after 
DV8)
24 
hour
s 
later
Notes
AE/SAE 
review
==========================
===============
X3
================
========
Concomitant 
medication 
review
==========================
===============
X3
================
========
3 Phone call made to 
the subject to check 
AEs and concomitant 
medications and 
confirm availability for 
FUV3
TNSS scores 
(diary card)
==========================
===============
Captured daily AM and 
PM up until the end of 
FUV 2


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Procedure
Follow up 
Visit 1 
(FUV1)
Follow-up Visit 2 
(FUV2)
2 
mont
h 
follo
w-up 
phon
e call
(Wee
k 16)
Follow up Visit 3 
(FUV3)
Wee
k 9
(1 
wee
k 
afte
r 
DV8
)
24 
hou
rs 
late
r
Week 
11
(3 
week
s 
after 
DV8)
Week 
12
(4 
week
s 
after 
DV8)
24 
hou
rs 
late
r
Week 
19 
(11 
week
s 
after 
DV8)
Week 
20 
(12 
week
s 
after 
DV8)
24 
hour
s 
later
Notes
PEF (diary 
card)
==========================
===============
X
Captured daily AM and 
PM up until the end of 
FUV2, and then 
checked again in the 
unit following the final 
BAC at FUV3
Diary card 
review
X
Review diary card at 
every visit until the end 
of FUV 2.
Blood PAX 
collection
X
PAX tubes for /AFFY 
chip gene expression in 
blood. Collected prior to 
the bronchial allergen 
challenge at FUV2
Saline and 
bolus BAC 
challenge plus 
associated 
spirometry 
measurement
s
X
X
X
Including baseline FEV1
assessment and repeat 
FEV1 measurements up 
to 10 hours post BAC
FeNO 
measurement
X
X
X
X
X
X
Collect prior to sputum 
induction
Sputum 
induction and 
processing for 
BAC 
associated 
sample 
collection of 
allergic 
biomarkers
X
X
X
X
X
Sputum induction pre-
BAC and 24 hours after 
BAC.
BAC 
associated 
sample 
collection of 
allergic 
biomarkers in 
blood
X1,2
X2
X1,2
X2
X1,2
X2
1Blood samples for 
PBMC preparations 
(pre-BAC and 6 hours 
after BAC)
2 Blood sample for 
haematology (WBC 
count with differential) 
pre-BAC and 24 hours 
after BAC


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Procedure
Follow up 
Visit 1 
(FUV1)
Follow-up Visit 2 
(FUV2)
2 
mont
h 
follo
w-up 
phon
e call
(Wee
k 16)
Follow up Visit 3 
(FUV3)
Wee
k 9
(1 
wee
k 
afte
r 
DV8
)
24 
hou
rs 
late
r
Week 
11
(3 
week
s 
after 
DV8)
Week 
12
(4 
week
s 
after 
DV8)
24 
hou
rs 
late
r
Week 
19 
(11 
week
s 
after 
DV8)
Week 
20 
(12 
week
s 
after 
DV8)
24 
hour
s 
later
Notes
Nasal allergen 
challenge/adm
inistration
X
X
Commence after the 
24-hour BAC sputum 
and blood biomarker  
samples have been 
taken at FUV1 and 
FUV2
Nasal filter 
biomarker 
collection
X
X
Collect pre-NAC, 5 
minutes and 6 hours 
after NAC.
Nasal fluid 
biomarker 
collection
X
X
Collect nasal lavage 
pre-NAC, 5 minutes and 
at least 6 hours after 
NAC.
Collect nasal mucosa 
sample at least 6 hours 
after NAC.
Intradermal 
allergy testing
X
X
Intradermal challenge to 
be administered after 
NAC.
Measurements to be 
done at 15 minutes and 
6 hours post 
intradermal challenge.
Return diary 
card, PEF 
meters, 
rescue 
medication 
and 
thermometers
X


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REVISED TEXT
Section 7.1.1. Time and Events Table – Screening Visit(s)
Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
Informed consent signing
X
Inclusion and exclusion 
criteria/eligibility review
X
X
Demographics
X
Medical history (including substance 
usage and family history of premature 
CV disease)
X
Past and current medical conditions 
including cardiovascular medical 
history
X
Concomitant medication review
X
Full physical exam including height 
and weight
X
Urine drug/alcohol screen
X
Urine or serum pregnancy test (all 
females)
X
No women of childbearing 
potential are being enrolled. 
However this test is needed to 
confirm pregnancy status at 
screening.
Serum FSH and estradiol for post-
menopausal females
X
HIV, Hep B and Hep C screen
X
Laboratory assessments (including 
liver chemistries, haematology, clinical 
chemistry and urinalysis)
X
Screening Spirometry assessment
X
To confirm FEV1 > 70% predicted
SAE Collection
X
X
X
12-lead ECG
X
Vital signs
X
Skin prick test
X
To confirm eligibility
FeNO measurement
X
X
Collected prior to sputum 
induction
Saline and incremental BAC challenge 
plus associated spirometry 
measurements
X
Including pre-procedure FEV1
assessment and repeat FEV1
measurements up to 10 hours 
post BAC
Sputum induction and processing for 
BAC associated sample collection
X
X
Sputum inductions must be 
separated by at least 3 days
Laboratory assessments 
(haematology only)
X
X
Blood samples should be taken 
pre-BAC on SV2 and  on the 
following day at 24hrs post BAC
Blood samples for PBMC preparations
X
Blood samples for PBMC 
preparations (pre-BAC and 6 
hours after BAC at screening visit 
2)


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Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
Provide diary card, PEF meters, 
rescue medication and thermometers 
to subjects
X
Only given out to subjects who 
are eligible following the BAC. 
Thermometers are to be given to 
record temperature as part of 
capturing AE information.
NAC
X
Commence after the 24-hour 
BAC sputum and blood 
biomarker samples have been 
taken.
Only to be done once subjects 
have completed a successful 
BAC.
Nasal lavage
X
Collect nasal lavage to provide a 
background  sample. Repeat 
nasal lavage pre-NAC, then 
again 5 minutes and at least 6 
hours post-NAC.
Nasal filter collection 
X
Collect nasal filter sample to 
provide a background pre-wash 
sample, after nasal wash repeat 
nasal filter sampling pre-NAC, 
then again 5 minutes and at least 
6 hours post-NAC.
Nasal scrape
X
Nasal mucosa sample to be 
collected at least 6 hours post-
NAC.
ID challenge
X
ID challenge to be administered 
after NAC.
Measurements to be made 15 
minutes and 6 hours post ID 
challenge


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Section 7.1.2. Time and Events Table – Dosing visit (DV) 1 (Day 1) – DV8 (Week 8) 
and Early Withdrawal Visit (EW)
Procedure
Pre-
dose
Dose
Post-dose
Early-
Withd
rawal
Notes
0 
hour
20 
mins
1 hour
12 
hours
24 
hours
Outpatient 
visit
X
X
X
Subjects get discharged 1-2 
hours after dosing.
Inclusion and 
exclusion 
criteria/eligibil
ity review
X
Only on DV1
Diary card 
collection and 
review 
X
X
Collect and review diary card 
at every dosing visit 
AE/SAE 
review
X
X
Concomitant 
medication 
review
X
X
12-lead ECG
X
X
X
X
Perform on DV1 and DV8 
only
Vital signs 
(including 
temperature)
X1
X1
X2
X
1 Perform on DV1-8
2 Perform on DV1, 4 and DV8 
only
Laboratory 
assessments 
(include liver 
chemistries, 
haematology, 
clinical 
chemistry and 
urinalysis)
X
X
X
Collect samples for laboratory 
assessments on DV1 and 
DV8
Not required at EW if this 
occurs during FU
Blood sample 
for PK 
analysis
X
X
X
Collect samples on DV1, DV4 
and DV8.
Not required at EW if this 
occurs during FU
Genetic 
sample
X
Take one sample on any of 
the dosing visits after 
genetics consent.
Not required at EW if this 
occurs during FU
FeNO 
measurement
X
Perform FeNO 
measurements pre-dose on 
all dosing visits 1-8
Nasal 
examination
X
X
Conducted pre-dose at all 
study visits and 24 hours 
post-dose on DV1, DV4 and 
DV8
Nasal lavage
X
X
Collect nasal lavage samples 
pre-dose and 24hrs post-
dose on DV1, DV4 and DV8


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Procedure
Pre-
dose
Dose
Post-dose
Early-
Withd
rawal
Notes
0 
hour
20 
mins
1 hour
12 
hours
24 
hours
Blood sample 
for biomarker 
analysis
X
X
Collect blood for serum 
samples and PBMC 
preparations pre-dose and 24 
hrs post-dose on DV1 and 
DV8
Blood sample 
for RNA 
analysis 
X(3)
X(4)
PAX-gene tubes for 
TLR7/AFFY chip gene 
expression in blood collected 
pre-dose on DV1(3) and 24 
hrs after DV8(4)
Call RAMOS
X
Randomisation will occur is at 
Visit 1 via the IRT. Sites 
should also call RAMOS at 
DV5.
Dispensing of 
study 
medication
X
One device will be assigned 
on DV1. The second device 
will be assigned on DV5.  All 
devices remain in the unit.
Study drug 
administration
X
All doses are administered in 
the unit.
Sputum 
induction and 
processing 
for BAC 
associated 
sample 
collection
X
Sputum sample is conditional 
on having obtained a sputum 
sample from the subject at 
screening. Perform sputum 
induction after collection of 
24 hour post-dose DV8 blood 
and nasal samples (as pre 
BAC sample for FUV1).
Follow up 
phone call
X5
X6
5 Following at least the first 
two doses of study treatment 
to assess tolerability
6 On DV 2, 3, and 5-7, a 
follow-up phone call will be 
made approximately 24 hours 
post-dose to check if any 
CRS events have occurred, 
and if they have, that they 
have been accurately 
recorded in the diary card 
and they will then be 
transcribed into the eCRF.
For DV1, 4 and 8 the 
subjects shall be assessed 
on their return to the unit the 
following day.


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Section 7.1.3. Time and Events Table – Follow up visits (FUV1 to 3) (Weeks 9 to 20)
Procedure
Follow up 
Visit 1 
(FUV1)
Follow-up Visit 2 
(FUV2)
2 
mont
h 
follo
w-up 
phon
e call
(Wee
k 16)
Follow up Visit 3 
(FUV3)
Wee
k 9
(1 
wee
k 
afte
r 
DV8
)
24 
hou
rs 
late
r
Week 
11
(3 
week
s 
after 
DV8)
Week 
12
(4 
week
s 
after 
DV8)
24 
hou
rs 
late
r
Week 
19 
(11 
week
s 
after 
DV8)
Week 
20 
(12 
week
s 
after 
DV8)
24 
hour
s 
later
Notes
AE/SAE 
review
==========================
===============
X3
================
========
Concomitant 
medication 
review
==========================
===============
X3
================
========
3 Phone call made to 
the subject to check 
AEs and concomitant 
medications and 
confirm availability for 
FUV3
Diarycard 
collection, 
review and 
dispensing
X
Review diary card at 
every visit until the end 
of FUV 2
FeNO 
measurement
X
X
X
X
X
X
Collect prior to sputum 
induction
Blood sample 
for RNA 
analysis
X
PAX tubes for /AFFY 
chip gene expression in 
blood. Collected prior to 
the bronchial allergen 
challenge at FUV2
Saline and 
bolus BAC 
challenge plus 
associated 
spirometry 
measurement
s
X
X
X
Including pre-procedure 
FEV1 assessment and 
repeat FEV1
measurements up to 10 
hours post BAC
Sputum 
induction and 
processing for 
BAC 
associated 
sample 
collection
X
X
X
X
X
Sputum induction pre-
BAC and 24 hours after 
BAC
Laboratory 
assessments 
(haematology 
only)
X
X
X
X
X1
X
Blood samples should 
be taken pre-BAC  and  
on the following day at 
24hrs post BAC
Blood 
samples for 
PBMC 
preparations
X
X
X
Blood samples for 
PBMC preparations 
(pre-BAC and 6 hours 
after BAC)


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Procedure
Follow up 
Visit 1 
(FUV1)
Follow-up Visit 2 
(FUV2)
2 
mont
h 
follo
w-up 
phon
e call
(Wee
k 16)
Follow up Visit 3 
(FUV3)
Wee
k 9
(1 
wee
k 
afte
r 
DV8
)
24 
hou
rs 
late
r
Week 
11
(3 
week
s 
after 
DV8)
Week 
12
(4 
week
s 
after 
DV8)
24 
hou
rs 
late
r
Week 
19 
(11 
week
s 
after 
DV8)
Week 
20 
(12 
week
s 
after 
DV8)
24 
hour
s 
later
Notes
Nasal lavage
X
X
Collect nasal lavage to 
provide a background 
sample. Repeat nasal 
lavage pre-NAC, then 
again 5 minutes and at 
least 6 hours post-NAC.
Nasal filter 
collection
X
X
Collect nasal filter 
sample to provide a 
background pre-wash 
sample, after nasal 
wash repeat nasal filter 
sampling pre-NAC, then 
again 5 minutes and at 
least 6 hours post-NA.
NAC
X
X
Commence after the 
24-hour BAC sputum 
and blood biomarker  
samples have been 
taken at FUV1 and 
FUV2
ID challenge
X
X
ID challenge to be 
administered after NAC.
Measurements to be 
made at 15 minutes and 
6 hours post ID 
challenge.
Nasal scrape
X
X
Nasal mucosa sample 
to be collected at least 
6 hours post-NAC
Return diary 
card and 
thermometers
X
Return PEF 
meters and 
rescue 
medication
X
Section 7.3.1. Bronchial allergen challenges and spirometry: This section has been 
simplified and the detail moved to the SRM
PREVIOUS TEXT
Bronchial allergen challenges will be conducted at screening, and at three follow-up 
visits (see Time and Events Tables in Section 7.1).


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Baseline FEV1 measurements for the challenge will first be taken using saline. The 
highest of the measurements will be taken as the saline baseline value and recorded in the 
eCRF. This value will be the baseline for the allergen challenge. If a fall in FEV1 of 
>10% is observed after saline, the subject will not proceed to allergen inhalation. At 
screening, subjects will inhale increasing concentrations of allergen during the bronchial 
allergen challenge. FEV1 will be measured after each inhalation. The final concentration 
of allergen will be determined when a fall in FEV1 of ≥ 20 % from the saline baseline 
value is achieved. For the subject to be eligible, the screening bronchial allergen 
challenge must demonstrate both an early and late asthmatic response. The early 
asthmatic response must include a fall in FEV1 of 20% from the saline value, on at least 
one occasion, between 5 and 30 minutes after the final concentration of allergen. The late 
asthmatic response must include a fall in FEV1 of 15% from the saline value, on at least 
three occasions, two of which must be consecutive, between 4 and 10 hours after the final 
concentration of allergen. FEV1 measurements will be taken at specified time intervals 
after the final inhalation of allergen up to 10 hours.
Following the final FEV1 measurement, the subject will receive rescue salbutamol until 
the FEV1 returns to within 10% of the pre-saline value. If a subject experiences serious 
discomfort the test will be discontinued and rescue medication administered.
The allergen dose eliciting a fall in FEV1 of ≥ 20 % from the saline baseline value at 
screening will be used for bronchial allergen challenges administered at the follow-up 
visits and FEV1 measurements will be taken at specified time intervals up to 10 hours. 
Detailed description of the bronchial allergen challenge technique and assessments can be 
found in the SRM
REVISED TEXT
BAC will be conducted at screening, and at three follow-up visits (see Time and Events 
Tables in Section 7.1). At the Screening Visit incremental doses of allergen will be 
administered and the total dose inducing an EAR and LAR used to calculate a bolus dose 
for use at the 3 FU visits. A detailed description of the BAC technique and assessments 
can be found in the SRM.  All sites participating in the study will be trained in the same 
methodology to ensure consistency.
Following the final FEV1 measurement, subjects will receive rescue salbutamol until the 
FEV1 returns to within 10% of the pre-saline value. If a subject experiences serious 
discomfort the test will be discontinued and rescue medication administered.
Section 7.3.2. Intranasal and intradermal allergen challenge
PREVIOUS TEXT
Intranasal and intradermal allergen challenges will be conducted approximately 24 hours 
after the bronchial allergen challenge at screening and at follow-up visits 1 and 2. These 
challenges will only be conducted after subjects have completed successful bronchial 
allergen challenges.


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A detailed description of the intranasal and intradermal allergen challenges can be found 
in the SRM.
In some regions/countries specific challenges agents may not be approved or available 
for use in ID challenge, in which case this assessment shall be omitted.
REVISED TEXT
NAC and ID challenge will be conducted approximately 24 hours after the bronchial 
allergen challenge at screening and at follow-up visits 1 and 2. 
A detailed description of the NAC and ID challenges can be found in the SRM.
Section 7.3.4. TNSS: Updated as transcription to CRF does not necessarily have to 
be done by site staff.
PREVIOUS TEXT
All data will be transcribed from the diary card into the CRF by the site staff at each 
clinic visit
REVISED TEXT
All data will be transcribed from the diary booklet into the CRF.
Section 7.3.6. Fractional Exhaled Nitric Oxide (FeNO): Updated to reflect that 
equipment will not be provided centrally.
PREVIOUS TEXT
FeNO will be measured using a handheld electronic device.  Measurements will be 
obtained in accordance with the [ATS/ERS Recommendations for Standardized 
Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric 
Oxide and Nasal Nitric Oxide, 2005].  All sites will use standardised equipment provided 
by a central vendor.  FeNO measurements will be interpreted in accordance with the 
[Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels 
(FeNO) for Clinical Applications, 2011].
REVISED TEXT
FeNO will be measured using a handheld electronic device.  Measurements will be 
obtained in accordance with the [ATS/ERS Recommendations for Standardized 
Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric 
Oxide and Nasal Nitric Oxide, 2005]. FeNO measurements will be interpreted in 
accordance with the [Official ATS Clinical Practice Guideline: Interpretation of Exhaled 
Nitric Oxide Levels (FeNO) for Clinical Applications, 2011].


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Section 7.4. Safety: Updated to describe the role of the SRT and to reflect the 
inclusion of an external consultant.
PREVIOUS TEXT
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring
REVISED TEXT
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
The Safety Review Team (SRT) is a GSK cross-functional team reviewing all available 
safety data related to the project, including in-stream data from this study, in an ongoing 
manner. The SRT is an internal GSK requirement put in place to ensure holistic 
evaluation of the safety profile of an investigational product with systematic, periodic and 
documented reviews of available safety data, with the appropriate communication and 
escalation of new findings that have the potential to impact patient safety.  
The SRT for this project will review data from this study in collaboration with an 
independent external (to GSK) expert reviewer.
Section 7.4.7. PEF monitoring: Final Paragraph updated as transcription to CRF 
does not necessarily have to be done by site staff.
PREVIOUS TEXT
All information from the diary card will be transcribed into the eCRF by the site staff at 
each clinic visit
REVISED TEXT
All information from the diary card will be transcribed into the eCRF.
Section 7.4.7.: PEF monitoring: Text updated to clarify that these are being used for 
safety monitoring at home. Assessment in clinic at FV3 will not be required as 
subject will be attending the clinic the day after their final BAC. 
PREVIOUS TEXT
Subjects will be given a PEF peak flow meter at screening, along with a diary card. 
Subjects will record their PEF readings each morning and evening onto the diary card 
every day from the start of study treatment on Dosing Visit 1 until the 4 week follow-up
visit. Subjects will also have their PEF levels checked in the unit after administration of 
the final bronchial allergen challenge at the 12 week follow-up visit.


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REVISED TEXT
Subjects will be given a PEF peak flow meter at screening, along with a diary card. This 
will be used for safety monitoring after the BACS. Subjects will record their PEF 
readings each morning and evening onto the diary card every day from the start of study 
treatment on DV 1 until the 4 week follow-up visit.  
The subject will be instructed to contact the investigator if at any time during the study 
the PEF measurements go outside the normal range for the subject. These instructions 
will be clearly printed on the diary card.
Section 7.6.1.1. PD blood samples
PREVIOUS TEXT
Blood samples will be collected before and 24 hours post treatment on Dosing Visits 1 
and 8 for serum to measure levels of TLR-7-induced blood PD biomarkers. 
Blood will be collected before and 24 hours after treatment on Dosing Visits 1 and 8 and 
prior to bronchial allergen challenges for preparation of peripheral blood mononuclear 
cells (PBMC). These samples may be used for CHIP cytometry for cellular subset 
phenotyping. If this biomarker analysis is performed it may be reported separately.
REVISED TEXT
Blood samples will be collected before and 24 hours post treatment on DV 1 and 8 for 
serum to measure blood PD biomarkers. 
Blood will be collected before and 24 hours after treatment on DV 1 and 8 and prior to 
bronchial allergen challenges for preparation of peripheral blood mononuclear cells 
(PBMC). These samples may be used for CHIP cytometry for cellular subset 
phenotyping. If this biomarker analysis is performed it may be reported separately.
Section 7.6.1.2. Blood PAX collection
PREVIOUS TEXT
Blood PAX samples for AFFYCHIP gene expression (mRNA transcriptome) will be 
collected before dosing on Dosing Visit 1, 24 hours after Dosing Visit 8 and prior to 
BAC on FUV2.
REVISED TEXT
Blood PAX samples for AFFYCHIP gene expression (mRNA transcriptome) will be 
collected before dosing on DV 1, 24 hours after DV 8 and prior to BAC on FUV2.


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Section 7.6.1.3. PD nasal lavage samples
PREVIOUS TEXT
Nasal lavage samples to measure TLR-7-induced nasal fluid PD biomarkers will be 
collected before and 24 hours post treatment on Dosing Visits 1, 4 and 8.
REVISED TEXT
Nasal lavage samples to measure PD biomarkers will be collected before and 24 hours 
post treatment on DV1, DV4 and DV8.
Section 7.6.1.6. :Nasal allergen challenge associated biomarkers in nasal fluid 
samples
PREVIOUS TEXT
Nasal filter and nasal lavage samples to measure exploratory allergic biomarkers will be 
collected at baseline, then after a nasal wash, samples will be collected before the nasal 
allergen administration (NAC), and at 5 minutes and 6 hours after NAC (at screening and 
at FUV1 and FUV2).
REVISED TEXT
Nasal filter and nasal lavage samples to measure exploratory biomarkers will be collected 
at the timepoints indicated in the Time and Events Tables Section 7.1.
Section 7.6.1.7. Cellular profile of nasal mucosa
PREVIOUS TEXT
Nasal scrapes will be collected after NAC following the completion of the collection of 
the 6 hour nasal lavage and nasal filter samples (at screening and at FUV1 and FUV2). 
Samples of suitable quality may be used for cellular analysis by CHIP cytometry or 
RNA-sequencing of single cells (if subjects have given informed consent for genetic 
analysis techniques).  If this biomarker analysis is performed it may be reported 
separately.
REVISED TEXT
Nasal scrapes may be collected after NAC following the completion of the collection of 
the 6 hour nasal lavage and nasal filter samples (at screening and at FUV1 and FUV2). 
Samples of suitable quality may be used for cellular analysis for example by CHIP 
cytometry or RNA-sequencing of single cells (if subjects have given informed consent 
for genetic analysis techniques).  If this biomarker analysis is performed it may be 
reported separately.


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Section 7.7.1.5.:Bronchial allergen challenge (BAC) associated biomarkers in blood 
samples – Updated to reflect that RNA analysis of single cells will not be performed.
PREVIOUS TEXT
Blood samples will be collected before, 6 hours and 24 hours after each BAC:

For haematology, (WBC with differential) for blood eosinophil counts (before and 
24 hours after BAC)

To prepare PBMC that may be used for CHIP cytometry or RNA sequencing of 
single cells (if patients give informed consent for genetic analysis techniques) before 
and 6 hours after BAC.  If this biomarker analysis is performed it may be reported 
separately.
REVISED TEXT
Blood samples will be collected before, 6 hours and 24 hours after each BAC:

For haematology, (WBC with differential) for blood eosinophil counts (before and 
24 hours after BAC)

To prepare PBMC that may be used for CHIP cytometry (before and 6 hours after 
BAC).  If this biomarker analysis is performed it may be reported separately.


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AMENDMENT [1]
Where the Amendment Applies
This amendment applies across any site that will be used in the study.
Summary of Amendment Changes with Rationale
Section 4.6.1 and Section 7.1.1 have been adjusted slightly to make it clearer that subjects 
will be provided with a thermometer to be able to record temperature as part of capturing 
adverse event (AE) information.
In Section 5.2, exclusion criterion 13 has been updated to reflect the revised 
recommended alcohol consumption guidelines.
List of Specific Changes
Section 4.6.1, Risk assessment table, first paragraph
PREVIOUS TEXT
Each subject will receive a phone call approximately 12 hours following administration 
of at least the first two doses to assess tolerability. They will be provided with a 
thermometer to measure body temperature as needed.
REVISED TEXT
Each subject will receive a phone call approximately 12 hours following administration 
of at least the first two doses to assess tolerability. They will be provided with a 
thermometer to measure body temperature.
Section 5.2, Exclusion criteria, point 13
PREVIOUS TEXT
RELEVANT HABITS
13. 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.
REVISED TEXT
RELEVANT HABITS
13. History of regular alcohol consumption within 6 months of the study defined as: 
An average weekly intake of >14 units for males and 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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Section 7.1.1, Time and Events table, Screening Visit(s)
PREVIOUS TEXT
Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
Informed consent signing
X
Inclusion and exclusion 
criteria/eligibility review
X
X
Demographics
X
Medical history (including substance 
usage and family history of premature 
CV disease)
X
Past and current medical conditions 
including cardiovascular medical 
history
X
Concomitant.medication review
X
Full physical exam including height 
and weight
X
Urine drug/alcohol screen
X
Urine or serum pregnancy test (all 
females)
X
No women of childbearing 
potential are being enrolled. 
However this test is needed to 
confirm pregnancy status at 
screening.
Serum FSH and estradiol for post-
menopausal females
X
HIV, Hep B and Hep C screen
X
Laboratory assessments (including 
liver chemistries, haematology, clinical 
chemistry and urinalysis)
X
Spirometry
X
To confirm FEV1 > 70% predicted
12-lead ECG
X
Vital signs
X
Skin prick test
X
To confirm eligibility
FeNO measurement
X
X
Collected prior to sputum 
induction
BAC and spirometry
X
Including repeat FEV1  
measurements up to 10 hours 
post BAC
Sputum induction and processing for 
BAC associated sample collection
X
X
Sputum induction pre-BAC and 
24 hours after BAC
BAC associated sample collection of 
allergic biomarkers in blood
X1,2
X2
1 Collect blood samples for 
PBMC preparations (pre-BAC 
and 6 hours after BAC)
2 Collect blood sample for 
haematology (WBC count with 
differential) pre-BAC and 24 
hours after BAC
Provide diary card, PEF meters, 
rescue medication and thermometers 
to subjects
X
Only given out to subjects who 
are eligible following the BAC. 
Thermometers are to be given to 


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Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
record temperature as part of 
capturing AE information, if 
needed.
Nasal allergen challenge 
administration (NAC)
X
Commence after the 24-hour 
BAC sputum and blood 
biomarker  samples have been 
taken ..
Only to be done once subjects 
have completed a successful 
BAC.
Nasal filter biomarker collection
X
Collect pre-NAC, 5 minutes and 
at 6 hours after NAC.
Nasal fluid biomarker collection
X
Collect nasal lavage pre-NAC, 5 
minutes and at least 6 hours after 
NAC.
Collect nasal mucosa sample at 
least 6 hours after NAC.
Intradermal allergy testing
X
Intradermal challenge to be 
administered after NAC.
Measurements to be made 15 
minutes and 6 hours post 
intradermal challenge
REVISED TEXT
Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
Informed consent signing
X
Inclusion and exclusion 
criteria/eligibility review
X
X
Demographics
X
Medical history (including substance 
usage and family history of premature 
CV disease)
X
Past and current medical conditions 
including cardiovascular medical 
history
X
Concomitant.medication review
X
Full physical exam including height 
and weight
X
Urine drug/alcohol screen
X
Urine or serum pregnancy test (all 
females)
X
No women of childbearing 
potential are being enrolled. 
However this test is needed to 
confirm pregnancy status at 


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Procedure
Screenin
g Visit 1 
(Day -28 
to Day -
22)
Screening 
Visit 2 (Day -
21 to Day -3)
24 hours 
after 
Screening 
Visit 2 
(Day -20 
to Day -2)
Notes
screening.
Serum FSH and estradiol for post-
menopausal females
X
HIV, Hep B and Hep C screen
X
Laboratory assessments (including 
liver chemistries, haematology, clinical 
chemistry and urinalysis)
X
Spirometry
X
To confirm FEV1 > 70% predicted
12-lead ECG
X
Vital signs
X
Skin prick test
X
To confirm eligibility
FeNO measurement
X
X
Collected prior to sputum 
induction
BAC and spirometry
X
Including repeat FEV1  
measurements up to 10 hours 
post BAC
Sputum induction and processing for 
BAC associated sample collection
X
X
Sputum induction pre-BAC and 
24 hours after BAC
BAC associated sample collection of 
allergic biomarkers in blood
X1,2
X2
1 Collect blood samples for 
PBMC preparations (pre-BAC 
and 6 hours after BAC)
2 Collect blood sample for 
haematology (WBC count with 
differential) pre-BAC and 24 
hours after BAC
Provide diary card, PEF meters, 
rescue medication and thermometers 
to subjects
X
Only given out to subjects who 
are eligible following the BAC. 
Thermometers are to be given to 
record temperature as part of 
capturing AE information.
Nasal allergen challenge 
administration (NAC)
X
Commence after the 24-hour 
BAC sputum and blood 
biomarker samples have been 
taken ..
Only to be done once subjects 
have completed a successful 
BAC.
Nasal filter biomarker collection
X
Collect pre-NAC, 5 minutes and 
at 6 hours after NAC.
Nasal fluid biomarker collection
X
Collect nasal lavage pre-NAC, 5 
minutes and at least 6 hours after 
NAC.
Collect nasal mucosa sample at 
least 6 hours after NAC.
Intradermal allergy testing
X
Intradermal challenge to be 
administered after NAC.
Measurements to be made 15 
minutes and 6 hours post 
intradermal challenge

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205540
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A randomised, double-blind
(sponsor open), placebo-controlled, parallel group, 8-week 
treatment study to investigate the safety, pharmacodynamics, 
and effect of the TLR7 agonist, GSK2245035, on the 
allergen-induced asthmatic response in subjects with mild 
allergic asthma 
Compound Number
:
GSK2245035
Effective Date 
:
27-FEB-2017
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report (CSR) for Protocol 205540.

This RAP is intended to describe the efficacy, biomarker/pharmacodynamics, safety, 
and pharmacokinetics analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
10-FEB-2017
Director (Clinical Statistics)
10-FEB-2017
Principal Statistician (Clinical Statistics)
10-FEB-2017
Director (Clinical Pharmacology)
Approved via email: 
27-FEB-2017
Director (Clinical Statistics)
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD


CONFIDENTIAL
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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 ..........................................................................................11
3.1
Interim Analyses .........................................................................................11
3.2
Headline Analyses Prior to Database Freeze (DBF) ...................................18
3.3
Safety Review Team (SRT) ........................................................................18
3.4
Final Analyses ............................................................................................18
4
ANALYSIS POPULATIONS ...................................................................................19
4.1
Protocol Deviations.....................................................................................20
5
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................21
6
STUDY POPULATION ANALYSES .......................................................................22
6.1
Overview of Planned Analyses ...................................................................22
7
PRIMARY STATISTICAL ANALYSES....................................................................23
7.1
Efficacy Analyses........................................................................................23
7.1.1
Overview of Planned Efficacy Analyses .......................................23
7.1.2
Planned Efficacy Statistical Analyses...........................................24
8
SECONDARY STATISTICAL ANALYSES .............................................................29
8.1
Efficacy Analyses........................................................................................29
8.1.1
Overview of Planned Efficacy Analyses .......................................29
8.1.2
Planned Efficacy Statistical Analyses...........................................30
8.2
Safety Analyses..........................................................................................35
8.2.1
Overview of Planned Adverse Events Analyses...........................35
8.2.2
Overview of Planned Clinical Laboratory Analyses ......................36
8.2.3
Overview of Planned Other Safety Analyses................................36
8.3
Pharmacokinetic Analyses (Exploratory).....................................................38
8.3.1
Overview of Planned Pharmacokinetic Analyses .........................38
8.3.2
Drug Concentration Measures .....................................................38
8.3.3
Pharmacokinetic Parameters.......................................................38
8.3.3.1
Deriving Pharmacokinetic Parameters........................38
8.4
Pharmacodynamic and Biomarker Analyses (Exploratory)..........................39
8.4.1
Overview of Planned Pharmacodynamic and Biomarker 
Analyses......................................................................................39
8.4.2
Planned Pharmacodynamic and Biomarker Statistical 
Analyses......................................................................................53
8.4.2.1
Biomarkers supporting the BAC related 
exploratory objective(s) ..............................................57
8.4.2.1.1
Sputum...................................................57


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8.4.2.1.2
Blood WBC and Differential Cell 
Counts....................................................59
8.4.2.1.3
Blood PBMC...........................................59
8.4.2.1.4
FeNO (Exhaled Nitric Oxide) ..................60
8.4.2.2
Biomarkers Supporting the NAC related 
exploratory objective(s) ..............................................60
8.4.2.2.1
Nasal Lavage Fluid & Nasal 
Lavage Filters.........................................61
8.4.2.2.2
Nasal Scrapes ........................................62
8.4.2.3
Biomarkers supporting the Induction of TLR7 
(target engagement) exploratory objective(s)..............62
8.4.2.3.1
Nasal Lavage .........................................62
8.4.2.3.2
Blood PD (Serum) ..................................63
8.4.2.3.3
Blood PBMC...........................................63
8.4.2.3.4
Blood sample for RNA analysis ..............63
8.4.2.3.5
FeNO (Exhaled Nitric Oxide) ..................64
8.4.2.4
PGx Samples .............................................................64
8.4.3
Multivariate / Composite endpoint analyses.................................64
8.4.3.1
Correlation between Sputum and WBC cell 
differentials.................................................................64
8.4.3.2
Defining responder / non-responder status for 
an individual subject using only their datapoints .........65
8.4.3.3
Multivariate Statistical Analysis Strategy.....................69
9
EXPLORATORY STATISTICAL ANALYSES .........................................................72
9.1
Exploratory Analyses ..................................................................................72
9.1.1
Overview of Planned Exploratory Analyses..................................72
10
REFERENCES.......................................................................................................74
11
APPENDICES........................................................................................................75
11.1
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................76
11.1.1
Exclusions from Per Protocol Population .....................................76
11.2
Appendix 2: Assessment Windows .............................................................77
11.2.1
Definitions of Assessment Windows for Analyses........................77
11.3
Appendix 3: Treatment States and Phases.................................................78
11.3.1
Treatment Phases .......................................................................78
11.3.2
Treatment States .........................................................................78
11.3.2.1
Treatment States for AE (and DRE) Data...................78
11.3.2.2
Treatment States for CRS Events Data ......................79
11.4
Appendix 4: Data Display Standards & Handling Conventions....................80
11.4.1
Study Treatment & Sub-group Display Descriptors......................80
11.4.2
Baseline Definition & Derivations .................................................81
11.4.2.1
Baseline Definitions....................................................81
11.4.2.2
Derivations and Handling of Missing Baseline 
Data ...........................................................................82
11.4.2.3
Imputation for Values Below and Above Limit 
of Quantification .........................................................83
11.4.3
Reporting Process & Standards...................................................83
11.5
Appendix 5: Derived and Transformed Data ...............................................88
11.5.1
General........................................................................................88


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11.5.2
Study Population..........................................................................88
11.5.3
Safety ..........................................................................................89
11.5.4
Efficacy........................................................................................92
11.5.5
Pharmacodynamic and Biomarker ...............................................95
11.5.6
Exploratory Analyses ...................................................................98
11.6
Appendix 6: Premature Withdrawals & Handling of Missing Data .............101
11.6.1
Premature Withdrawals..............................................................101
11.6.2
Handling of Missing Data...........................................................101
11.6.2.1
Handling of Missing Dates........................................101
11.6.2.2
Handling of Partial Dates..........................................102
11.6.2.3
Handling of Missing Data for Statistical 
Analysis....................................................................102
11.7
Appendix 7: Values of Potential Clinical Importance .................................103
11.7.1
Laboratory Values......................................................................103
11.7.2
ECG...........................................................................................104
11.7.3
Vital Signs..................................................................................104
11.8
Appendix 8: Multicentre Studies................................................................105
11.8.1
Methods for Handling Centres ...................................................105
11.9
Appendix 9: Examination of Covariates, Subgroups & Other Strata..........106
11.9.1
Handling of Covariates, Subgroups & Other Strata....................106
11.10 Appendix 10: Multiple Comparisons & Multiplicity .....................................109
11.10.1
Handling of Multiple Comparisons & Multiplicity.........................109
11.11 Appendix 11: Model Checking and Diagnostics for Statistical 
Analyses...................................................................................................110
11.11.1
Statistical Analysis Assumptions................................................110
11.12 Appendix 12 – Abbreviations & Trade Marks ............................................114
11.12.1
Abbreviations.............................................................................114
11.12.2
Trademarks ...............................................................................116
11.13 Appendix 13: List of Data Displays............................................................117
11.13.1
Data Display Numbering............................................................117
11.13.2
Mock Example Shell Referencing ..............................................117
11.13.3
Deliverable [Priority] and Responsibility (including AR 
datasets)....................................................................................117
11.13.4
Study Population Tables............................................................119
11.13.5
Efficacy Tables ..........................................................................121
11.13.6
Efficacy Figures .........................................................................125
11.13.7
Safety Tables.............................................................................132
11.13.8
Safety Figures ...........................................................................136
11.13.9
Pharmacokinetic Tables.............................................................138
11.13.10 Pharmacokinetic Figures ...........................................................138
11.13.11 Pharmacodynamic and Biomarker Tables..................................139
11.13.12 Pharmacodynamic and Biomarker Figures ................................142
11.13.13 Exploratory Tables.....................................................................149
11.13.14 Exploratory Figures....................................................................151
11.13.15 ICH Listings ...............................................................................153
11.13.16 Non-ICH Listings........................................................................158
11.14 Appendix 14: Example Mock Shells for Data Displays ..............................169


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1
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

To describe the planned efficacy, biomarker/pharmacodynamics, safety, and 
pharmacokinetics analyses and output to be included in the Clinical Study 
Report.
Protocol

This RAP is based on the Protocol Amendment 2 (Dated: 17/AUG/2016) of 
Study 205540 (GSK Document No.: 2015N264314_02) and eCRF Version 2.
Primary 
Objective

To evaluate the effect of treatment with i.n. GSK2245035 20 ng once weekly 
(qw) compared to placebo on the allergen-induced late asthmatic response 
(LAR) in subjects with allergic asthma.
Primary 
Endpoint

LAR: minimum FEV1 between 4-10 hours following allergen challenge one week 
after treatment.

LAR: weighted mean (WM) FEV1 between 4-10 hours following allergen 
challenge one week after treatment.
Study 
Design

Randomised (stratified by centre and allergen exposure 
(‘presumed’/’unknown’)), double-blind (sponsor open), placebo-controlled, 
parallel group, 8-week treatment in mild allergic asthmatics
Planned 
Analyses

The planned Interim analysis is detailed within Section 3.1 (including details of 
sample size adjustment).

Pre-Database Freeze (DBF) headline data using FUV1 FEV1 BAC challenge 
results will be produced for internal GSK review/decision making but these
outputs will not be formally reported, since they will be superseded by the final 
analysis.

All decisions regarding final analysis, as defined in this RAP document, will be 
made prior to DBF of the study data.
Analysis 
Populations

Primary analysis:  Per-Protocol Population (comprised of subjects who receive at least 
one dose of study treatment and commence a BAC at follow-up, i.e. mITT subjects who
are not major protocol violators). 

Modified Intent-To-Treat Population / Safety / Sputum Producers & PK are other 
analysis populations that would be used (See Section 4) for full details
Hypothesis

No formal statistical hypotheses are to be tested.  The primary study objective 
will assess the effect of a weekly dose of 20ng GSK2245035 vs Placebo by 
precision estimation and credible intervals to estimate the magnitude of 
underlying effect sizes.  A Bayesian approach will be utilised to obtain the 
posterior distribution for the mean treatment effects for the endpoints in the 
study (e.g. posterior distributions for percentage attenuation for the endpoint 
LAR:  minimum FEV1 between 4-10 hours following allergen challenge one 
week after treatment.). 

Other objectives will assess other pharmacodynamic effects and safety and 
tolerability of GSK2245035.


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Overview
Key Elements of the RAP
Primary 
Analyses

Statistical models will be fitted separately to each LAR endpoint (weighted mean 
and minimum FEV1 change from saline at the FUV1 visit).  These parameters 
will be analysed using a Bayesian version of a mixed effects model (centre as a 
random effect, and baseline as a covariate). A series of nested models will be 
fitted to determine if the allergen strata (and interaction with treatment) are 
necessary.

The principal inferences are expected to come from models with non-informative 
priors. Sensitivity analyses using informative priors based on AZ data may also 
be attempted. 
Secondary 
Analyses

Statistical models will be fitted separately to each EAR endpoint (weighted mean 
and minimum FEV1 change from saline at the FUV1 visit).  These parameters 
will be analysed using the same modelling approach as the Primary analysis.  


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2
SUMMARY OF KEY PROTOCOL INFORMATION
2.1
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the Protocol Amendment 2 (Dated: 17/AUG/2016).
2.2
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the effect of treatment 
with i.n. GSK2245035 compared to 
placebo on the allergen-induced late 
asthmatic response (LAR) in subjects 
with allergic asthma.

LAR:  minimum FEV1 between 4-10 hours following 
allergen challenge one week after treatment.

LAR:  weighted mean FEV1 between 4-10 hours following 
allergen challenge one week after treatment
Secondary Objectives
Secondary Endpoints

To evaluate the effect of treatment 
with i.n. GSK2245035 compared to 
placebo on the allergen-induced early 
asthmatic response (EAR) in subjects 
with allergic asthma.

EAR:  minimum FEV1 between 0-2 hours following 
allergen challenge one week after treatment.

EAR:  weighted mean FEV1 between 0-2 hours following 
allergen challenge one week after treatment.
Safety Objectives
Safety Endpoints

To evaluate the safety and tolerability 
of treatment with eight weekly doses 
of 20 ng i.n. GSK2245035

General safety endpoints including adverse events (AEs), 
peak expiratory flow (PEF), rescue salbutamol use, and 
clinical laboratory parameters
Exploratory Objectives
Exploratory Endpoints

To evaluate the duration of effect of 
treatment with i.n. GSK2245035 
compared to placebo on the allergen-
induced asthmatic responses (LAR 
and EAR) in subjects with allergic 
asthma.

LAR:  minimum and weighted mean FEV1 between 4-10 
hours following allergen challenge approximately 4 and 
12 weeks after treatment.

EAR: minimum and weighted mean FEV1 between 0-2 
hours following allergen challenge approximately 4 and 
12 weeks after treatment.

To evaluate the induction of TLR7-
associated pharmacodynamic (PD) 
biomarkers and exhaled nitric oxide 
(FeNO) following treatment with i.n. 
GSK2245035

TLR7-induced blood PD biomarkers.

TLR7 induced gene expression changes in blood

TLR7-induced nasal fluid PD biomarkers

FeNO levels


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Objectives
Endpoints

To evaluate the effect of treatment 
with i.n. GSK2245035 compared to 
placebo on Bronchial Allergen 
Challenge associated allergic 
biomarkers

Allergic biomarkers in induced sputum

Allergic biomarkers in blood

FeNO levels

To evaluate the effect of treatment 
with i.n. GSK2245035 compared to 
placebo on Nasal Allergen 
Administration associated allergic 
biomarkers

Allergic biomarkers in nasal fluids

Cellular profile of nasal mucosa

To evaluate the effect of treatment 
with i.n. GSK2245035 compared to 
placebo on Intradermal allergen 
challenge

Mean diameter early phase response

Mean diameter late phase response

To evaluate the effect of treatment 
with i.n. GSK2245035 compared to 
placebo on total nasal symptoms

Total nasal symptoms score (TNSS) assessed daily (AM 
and PM) throughout the study treatment phase

To evaluate systemic 
pharmacokinetics (PK) after 
administration of i.n. GSK2245035

Plasma GSK2245035 concentrations


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9
2.3
Study Design
Overview of Study Design and Key Features
Week -4
1       2      3     4     5      6      7      8       9
12 
20
Screening
8 week treatment period
Follow-up
BAC -Bronchial allergen challenge; NAC – Nasal allergen challenge/administration
IC – Intradermalchallenge; DV – Dosing Visit; FU – Follow-up
DV1  DV2 DV3 DV4 DV5 DV6 DV7 DV8   FU1          FU2             FU3
Randomisation
BAC/
NAC/IC
BAC/
NAC/
IC
BAC/
NAC/
IC
BAC
Design
Features

parallel group study comparing GSK2245035 vs Placebo

double-blind, placebo-controlled

randomisation stratified by centre and allergen exposure 
(‘presumed’/‘unknown’)

8-week study treatment 

mild allergic asthmatics

follow-up visits at 1, 4, and 12 weeks after last dose where BAC will be 
conducted
Dosing

GSK2245035 20 ng intranasal spray once weekly (QW) (10 ng actuation per 
nostril making 20 ng total dose)
Treatment 
Assignment

Subjects are centrally block randomised and stratified according to centre and 
type of allergen exposure.  Allergen exposure status is assessed as ‘unknown’ 
or ‘presumed’ during the treatment phase according to whether the subject has 
exposure to that allergen outside of the BAC (see Protocol Section 4.4 for 
further rationale regarding the allergen exposure status).  

The Randomisation Schedule was produced using validated internal software 
RandAll NG and treatment assigned using the interactive voice response 
system (IVRS) RAMOS NG.
Interim 
Analysis

An interim analysis will be conducted to assess how many subjects on placebo 
do not experience an LAR (these subjects will be termed ‘non-LAR 
responders’) as such subjects will reduce the chances of establishing the 
primary objective of this study.  This interim analysis will determine whether: 


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Overview of Study Design and Key Features
i) further recruitment into the trial should continue (i.e. a futility analysis);
or 
ii) additional subjects should be enrolled to counteract the impact of subjects 
who do not experience an LAR on placebo.

The timing of the interim is linked to the enrolment rates and will be triggered 
by whichever occurs first:
i) approximately 1 year after the first subject successfully completes the Follow 
Up 1 assessment;
or 
ii) when 28 subjects have successfully completed the Follow Up 1 
assessments.
Headline 
Analysis

Selected efficacy outputs will be produced once all subjects’ BAC FEV1 at 
Follow-Up 1 are available.  The results will be produced on unblinded data and 
produced before DBF for the purposes of internal decision making.  Ultimately, 
the headline results will be superseded by final end of study results produced 
after DBF.
2.4
Statistical Hypotheses
No formal hypotheses will be tested. The primary study objective will assess the effect 
of a weekly dose of 20 ng GSK2245035 vs Placebo by precision estimation and credible 
intervals to estimate the magnitude of underlying effect sizes.  A Bayesian approach will 
be utilised to obtain the posterior distribution for the underlying treatment effects for the 
endpoints in the study (e.g. posterior distributions of percentage attenuation for the 
endpoint LAR:  minimum FEV1 between 4-10 hours following allergen challenge one 
week after treatment.). 
Other objectives will assess other pharmacodynamic effects and safety and tolerability of 
GSK2245035.


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3
PLANNED ANALYSES
3.1
Interim Analyses
The interim analyses will be undertaken by the study statistician (or designate) and the 
boards/personnel who may be privy to this data are:

key members of the Study Team including Medical Monitor, Clinical Operations 
Representative, Study Statistician(s), Study Programmer(s)
The appropriate internal GSK procedures will be followed to ensure that access to 
unblinded subject level data is restricted to the specific study team members who require
access e.g. storing of data and related outputs in a secure, restricted directory area. Only 
subjects contributing data towards the interim analysis will have their treatment codes 
unblinded.
Recruitment into the study will continue whilst the interim analysis is taking place.
The interim analysis will require knowledge of which subjects are in the Placebo arm and 
determine how many of those Placebo subjects failed to meet the screening inclusion 
criteria for LAR in their follow up 1 visit (i.e. did not show three FEV1 decreases of ≥ 15 
% relative to saline baseline between 4 and 10 hours, with two FEV1 decreases being at 
consecutive time points).  The number of subjects on placebo who do not exhibit an LAR 
(non-LAR responders) will be determined from the available interim data (using the All 
Subjects population at the time of Interim Analysis 1 (IA1)).  This number will be 
checked against Table 1 to advise whether the study should continue or whether further 
review of the interim analysis data is required to assess the impact. For example, if at the 
time the interim analysis occurs 10 subjects were on Placebo and 4 of those 10 did not 
demonstrate an LAR response then the interim analysis would recommend reviewing the 
data further.


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12
Table 1
Lookup table for Interim Analysis Decision Pathway
Assessing impact of non-LAR response rate:
To evaluate whether recruiting additional subjects may counteract the impact of the non-
LAR responders alternative version(s) of Table 1 were constructed using the same 
methodology, but using final sample sizes that range from 20 to 30 subjects per arm. At 
each cell, if the probability of success was within 10% of the original operating 
characteristic for that endpoint (i.e. the characteristics derived under the assumption of 
zero non-LAR responders) the study would continue; but requiring additional subjects 
(the smallest number that satisfied the continuation criteria). These additional tables have 
been compressed into Table 2, which shows the smallest number of subjects (per arm) 
required to continue the study (if the continuation criteria were still not met with 30 
subjects per arm the cell is flagged as recommending further data review).


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Table 2
Lookup Table for Interim decision and revised sample sizes (per 
arm)
Additional analyses / outputs to support the interim analysis decision making
Equivalent versions of the planned summary statistics and figures supporting the primary 
endpoint/analyses.
Posterior distributions for the percentage attenuation of the primary endpoints (WM and 
Minimum LAR at FUV1) by GSK2245035 would be constructed from the available 
interim data using the same methodology as for the planned final analysis; except that a 
simplifying assumption will be used and terms relating to allergen exposure in the model 
will be excluded; since there may not be enough information in each strata at the time of 
the interim to facilitate their estimation (see Section 7 for details of the planned Primary 
analysis). 
Non-binding “Rule of thumb” for amending protocol/termination of further enrolment 
(existing subjects would complete the study as planned)
If either the recommendation of Table 1 and/or Table 2 is for further data review OR the 
model obtained medians (point estimates) for the observed treatment effects are
dramatically different to the assumed effects from the AstraZeneca (AZ) study (27% 
attenuation for WM LAR and 18% attenuation for Minimum LAR) (Leaker, 2012), the 
study team may wish to predict the probability of success at the end of the study for each 
endpoint, using the interim information as a basis for the projection. In the event that this 
probability of success is low (relative to the ~80% operating characteristic from the 
protocol) the study team may decide to review any of the other available data items at the 
interim prior to amending the protocol/terminating further enrolment (and share these 
outputs with appropriate internal GSK governance boards/senior management). Examples 


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of outputs might include the biomarkers of TLR7 target engagement and/or downstream 
allergic reactivity changes.
Technical details for predicting the end of study success using the interim data
For each treatment arm the (joint) posterior predictive distribution of an individual 
subject’s primary endpoints will be obtained (separate Variance Covariance (VCV) 
matrices for each treatment arm are preferred to cover the case where variability is also a 
function of treatment; but there may not be sufficient information in the interim dataset to 
estimate the required parameters, in which case a pooled VCV matrix across treatment 
arms would be acceptable). The predictive distributions will be used to simulate a 
sufficient number of future subjects to achieve the end of study sample size (planned to 
be 20 per arm, but may be revised upwards to a value between 21 and 30 per arm
depending on the observed placebo non-LAR responder rates). Summary statistics 
(sample mean and sample variance covariance matrix) will be derived using each set of 
simulated subjects for each treatment. These summary statistics are used as informative 
prior distributions for the treatment parameters in models fitted to the observed interim 
data (with the simplifying assumption that these models exclude allergen exposure 
covariate(s)). If the resulting posterior probability of any attenuation exceeds 0.7 (for 
either endpoint) the hypothetical end of study result is a success. By repeating the process 
of simulating sets of future subjects (10,000 times); producing informative priors for the 
treatment parameters from those simulated subjects and combining with the (unchanging) 
observed interim dataset in a model to evaluate individual study success an expected 
probability of a successful outcome can be obtained if the study were allowed to continue 
past the interim (i.e. the number of simulated sets flagged as successful / total number of 
simulated sets of subjects).
The advantage of utilising posterior predictive distributions is that they also account for 
the uncertainty in the true values of the parameters (caused by having to estimate them 
using only the interim data). Note: Each simulated subject can be thought of as being 
generated using the average of each of the covariate values. Therefore sample statistics 
are used as priors for the treatment related parameters only in the subsequent modelling 
step. This avoids having to generate covariate values for the simulated subjects (e.g. 
assign them to a centre, or generate a baseline response for them).
Further details are given below:


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15
Interim Analyses to estimate end of study success
Step 1: Obtain posterior predictive distribution for a future subject (separate distribution for 
each treatment arm) 

The endpoints (transformed if necessary) will be assumed to follow a multivariate normal 
(MVN) distribution.  Linear predictors will be derived for each subject (i.e. a vector of means for 
the MVN distribution). Each treatment arm will also have a separate variance covariance 
matrix, i.e.
The linear predictors will consist of mean vectors to capture i) the effect of treatment for each 
endpoint, ii) a continuous baseline for each endpoint and iii) a random centre effect for each 
endpoint (drawn from Normal(0, SDendpoint <x>) distribution). 

Baseline vectors will be fitted as continuous covariates (baseline values should be centered 
prior to inclusion in the model, centering to occur after any transformation of the individual 
subjects responses). 

Non-informative priors will be utilized for each model parameter assigned either as a normal 
distribution centered on 0 with large variance 1E6 or as appropriate to the parameters 
distribution.

The prior for the variance covariance matrices 
Pbo

and 
Act

will be an inverse Wishart 
distribution.  

SAS PROC MCMC will be used to combine the non-informative priors with the observed
interim data to obtain sufficient draws from the posterior distribution (after any thinning) such 
that the MCSE/SD values for parameters of interest are less than 0.01 (anticipated to be in the 
region of ~100,000 draws).  If model convergence is poor then alternative initial parameter 
values should be considered. Note: A SAS coding trick may be required if the MCMC 
procedure does not automatically detect the conjugacy (occurs in SAS v9.3 when fitting 
separate variance covariance structures to treatments in a multivariate normal distribution and 
may occur in SAS v9.4 as well). The trick involves setting up duplicate sets of variables in the 
input dataset with some populated as missing values and having 2x model statements (see 
GSK study statistician for details if required).

The randomization seed used in PROC MCMC should itself be generated with an element of 
randomness - but there is no need to formally document this process (e.g. using Excel function 
RANDBETWEEN [1,9999999] and copying the result into the SAS code)

The following describes the anticipated linear predictor for a hypothetical subject from center 3
(out of 5), on active treatment with centered baseline values of -4.1 and -0.5 for BS1 (WM) and 
BS2 (Min) respectively (Note: although not anticipated additional covariates may be explored 
and added based on the observed data).


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16
Interim Analyses to estimate end of study success


























CentreMin
d
i
i
Min
i
CentreWM
d
i
i
WM
i
Min
A
WM
A
Min
P
WM
P
Min
WM
Min
WM
Min
WM
Min
WM
Min
WM
Min
WM
Min
WM
D
S
N
Centre
D
S
N
Centre
Where
Active
I
Placebo
I
Center
Center
Center
Center
Center
Center
Center
Center
C
I
C
I
C
I
C
I
C
I
S
B
S
B
y
y
ˆ
,0
~
and
ˆ
,0
~
0]
)
I(C
&
)
I(C
),
I(C
),
I(C
and
1
)
I(C
1,
I(Active)
0,
I(Placebo)
[Here
otherwise
zero
and
met 
condition 
if
1
ith value
function w
Indicator 
an 
is
I
ˆ
ˆ
*
ˆ
ˆ
*
Center
Center
2
ˆ
0
0
1
ˆ
5.0
1.4
ˆ
ˆ
.
.
,
.
.
,
5
4
2
1
3
,
,
,
,
,5
,5
,4
,4
,3
,3
,2
,2
,1
,1
5
4
3
2
1
2
1











































Each MCMC iteration will produce values for model parameters

Min
P
WM
P
,
,
ˆ
ˆ


, 


Min
A
WM
A
,
,
ˆ
ˆ


and each of the elements within the 
Pbo

and 
Act

variance covariance 
matrices.

For each MCMC iteration sufficient placebo and active future subjects data will be drawn from 
the following multivariate normal distributions (denoting the number of remaining subjects to be 
Pbo
Nrem
and 
Act
Nrem
):

Placebo: 





Pbo
Min
P
WM
P
MVN
d
i
i
Pbo
fut
Min
WM
y
y





,
ˆ
ˆ
~
,
,
.
.
.
,
2
1



Active: 





Act
Min
A
WM
A
MVN
d
i
i
Act
fut
Min
WM
y
y





,
ˆ
ˆ
~
,
,
.
.
.
,
2
1


Step 2: Compute Sample Statistics and obtain Priors for each treatment arm

The sample mean and sample variance covariance matrices will be derived for each treatment 
arm using the corresponding set of 
Pbo
Nrem
and 
Act
Nrem
subjects (and keeping the 
association with each MCMC iteration)

Placebo: 
Pbo
Min
WM
Min
WM
Pbo
Min
WM
S
S
S
S
S
S
x
x










2
Min
2
WM
2
1
VCV
Sample
Vector
Mean 
Sample

Active: 
Act
Min
WM
Min
WM
Act
Min
WM
S
S
S
S
S
S
x
x










2
Min
2
WM
2
1
VCV
Sample
Vector
Mean 
Sample


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Interim Analyses to estimate end of study success

In the statistical model fitted to the WM endpoint the priors are:







Pbo
Pbo
WM
WM
Pbo
WM
P
Nrem
S
x
N
2
,
,1
,
,
~
ˆ
, 






Act
Act
WM
WM
Act
WM
A
Nrem
S
x
N
2
,
,1
,
,
~
ˆ

In the statistical model fitted to the Min endpoint the priors are







Pbo
Pbo
Min
Min
Pbo
Min
P
Nrem
S
x
N
2
,
,2
,
,
~
ˆ
,






Act
Act
Min
Min
Act
Min
A
Nrem
S
x
N
2
,
,2
,
,
~
ˆ
Step 3: Fit model and flag success or failure

To facilitate easy use of the prior distributions a re-parameterized version of Primary analysis 
Model M3 can be used (Intercept term removed and the zero constraint on the 2nd treatment 
level removed).

Separate models will be fitted to each of the endpoints (WM and Min)

If the posterior probability that 
A
P


ˆ
ˆ

exceeds 0.7 (using the informative prior from the ith 
MCMC iteration) then the ith MCMC iteration is flagged as resulting in a successful end of 
study result.

The overall probability of success is the number of successful MCMC iterations / total number 
of MCMC iterations
Technical details for deriving the individual tables contributing to Table 2  
To determine the probability of success in the presence of non-LAR responders 
simulations were performed for each possible combination of number of available 
placebo subjects (n) and number showing no LAR response (r) using the AZ point 
estimates as the true percentage attenuation (separate procedure for each of the primary 
endpoints):
Let K represent the number of subjects per arm to be evaluated with each value of K 
producing a different table and K ranging from 21 to 30 by 1.
The rate of non-LAR response (p) is assumed to be the same for Placebo and 
GSK2245035 arms. A Beta(0.1, 0.1) prior distribution is assumed for the rate, which is 
updated using conjugate formulae as Beta(0.1 + r, 0.1 + n – r) and a value sampled from 
this posterior distribution. The number of future subjects on placebo with a non-LAR 
response is sampled from a Binomial distribution using the sampled value of p and (K –
n) observations (the total is a mixture of observed interim data and this sampled value).
Similarly the number of non-LAR responders on the GSK2245035 arm is sampled from a 
Binomial distribution with the same value of p and K observations. Each non-responding 
individual is assigned a constant value for the response, and the collection of non-
responders are combined with the collection of LAR responders (values for the LAR 
responders are generated in a similar way to the subjects used in the operating 
characteristics, as described in the protocol, i.e. using the random effects meta-analysis to 
obtain the expected responses). The probability of success is determined for each of the 
combined datasets and the median derived. If this median was more than 10% smaller 
than the original operating characteristic the recommendation is to further review the 
data. The recommendations from the two primary endpoints will be determined 


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separately but combined into a single table. Wherever there is disagreement between 
cells across endpoints the review data decision is chosen.
Table 2 is obtained by examining each cell entry one at a time over all of the additional 
tables and taking the smallest value of K associated with a non-data review outcome.
Sensitivity analyses showed the outcome of this approach is highly dependent on the 
value of the constant used for the non-LAR responses (the further the choice from the 
range of plausible values for LAR responders the more likely the recommendation was to 
review data). As before, the choice of value is arbitrary in nature, but the same value as 
used in the protocol planning stage was selected; namely -0.45 for Minimum Change 
from Saline and -0.20 for Weighted Mean Minimum Change from Saline, based upon 
applying the LAR criteria to seven historical studies and deriving the mean responses of 
all non-LAR responding subjects.
See Section 11.13 for details of the outputs to be produced at the Interim analysis.
3.2
Headline Analyses Prior to Database Freeze (DBF)
The following is conditional on the study not being stopped early by the interim analysis. 
To facilitate internal GSK decision making a data snapshot will be taken when the last 
subject’s BAC FEV1 data (and derived LAR endpoints) from FUV1 are available. The 
associated planned efficacy outputs (see Section 11.13.4-Section 11.13.16) will be 
produced from that (unblinded) snapshot and shared internally with the GSK study team 
and internal GSK governance boards/senior management. As this data snapshot will be 
pre-DBF its results will not be formally reported as they will be superseded by the formal 
end of study results. A separate reporting effort for the headline analyses will be created 
in the HARP system.
3.3
Safety Review Team (SRT)
Safety Review Team meetings are planned for this study as per GSKs standard 
pharmacovigilance policies. The SRT is expected to meet on a regular basis to review 
ongoing safety data, usually via TSCG (Spotfire) and standard TFLs. The SRT meetings 
are beyond the scope of this RAP and will be documented separately as part of their 
operating processes.
3.4
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol i.e., once all subjects 
have completed the last follow-up visit or lost to follow-up.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the (remaining) randomisation codes have been met. 
4.
Randomisation codes have been distributed according to RandAll NG procedures.


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4
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

Comprise of all subjects who were screened 
for inclusion into the study and have any 
value databased in the eCRF.

Study Population
Enrolled1

Comprise of all subjects who were enrolled ie, 
randomised to study treatment.

Only required for ‘Summary of Age Ranges’ 
data display; necessary for disclosure 
purposes to EudraCT and FDAAA.

Demographics
All Subjects

Comprise of all subjects who receive at least 
one dose of study treatment.

This population will be based on the treatment 
the subject actually received.

Study Population

Safety

Biomarkers
Run in failures

Comprise of all subjects who were assigned a 
randomisation number (even if it was assigned 
in error) but did not receive any doses of study 
treatment

Study Population
Modified Intent-
To-Treat (mITT) 

Comprise of all randomised subjects who 
receive at least one dose of study treatment 
and commence a BAC at follow-up.

This population will be based on the treatment 
the subject received.

Any subject who receives a treatment 
randomisation number will be considered to 
have been randomised.

Efficacy
Per-Protocol (PP)

Comprise of all mITT subjects who comply 
with the protocol.

Protocol deviations that would exclude 
subjects from the PP population are defined in 
Section 4.1 (Protocol Deviations) and 
Appendix 1 (Protocol Deviation Management 
and Definition for Per-Protocol Population).

Efficacy
Pharmacokinetic
(PK)

Subjects in the ‘All Subjects’ Population for 
whom a pharmacokinetic sample is obtained 
and analysed.

Pharmacokinetic
Sputum 
Producers 
(Sputum)

Subjects in the ‘All Subjects’ Population for 
whom a viable pre- or post-challenge sputum 
sample is obtained (at Screening).

Sputum Biomarkers
Interim Analysis
(IA1)

Subjects contributing data points used in an 
Interim analysis (Note: The planned headline 
analysis is not counted as an interim analysis)

Study Population


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Population
Definition / Criteria
Analyses Evaluated

If more than one interim analysis occurs then a 
separate population will be created for each 
subsequent interim, using sequential names 
(e.g. IA2, IA3, etc)
NOTES : 

Please refer to Appendix 13: List of Data Displays which details the population to be used for each display being 
generated.
1.
If the ‘All Subjects’ Population contains the same subjects as ‘Enrolled’ Population, the ‘Enrolled’ Population will 
be dropped and ‘All Subjects’ used instead.
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 Deviation 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 on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary/listing will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.


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5
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 3 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 3
Overview of Appendices
Section
Component
11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
11.2
Appendix 2: Assessment Windows
11.3
Appendix 3: Treatment States and Phases
11.4
Appendix 4: Data Display Standards & Handling Conventions
11.5
Appendix 5: Derived and Transformed Data
11.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
11.7
Appendix 7: Values of Potential Clinical Importance
11.8
Appendix 8: Multicentre Studies
11.9
Appendix 9: Examination of Covariates, Subgroups & Other Strata
11.10
Appendix 10: Multiple Comparisons & Multiplicity
11.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
11.12
Appendix 12: Abbreviations and Trade Marks
11.13
Appendix 13: List of Data Displays


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6
STUDY POPULATION ANALYSES
6.1
Overview of Planned Analyses
The study population analyses will be based on the ‘All Subjects’ Population, unless 
otherwise specified.
Table 4 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 13: List of Data Displays.
Table 4
Overview of Planned Study Population Analyses
Endpoint / Parameter / Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition
Y
Screening Status and Reasons for Screen Failure
Y
Y
Subjects by Country and Centre
Y
Subjects by Country and Centre and Allergen Exposure Strata
Y
Reasons for Subject Withdrawal
Y
Subjects for Whom the Treatment Blind was Broken
Y
Planned and Actual Treatments
Y
Protocol Deviations
Important Protocol Deviations
Y
Y[1]
Subjects with Inclusion/Exclusion Criteria Deviations
Y
Populations Analysed
Study Populations and Exclusions
Y
Subjects Excluded from Any Population
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Summary of Age Ranges
Y
Race and Racial Combinations
Y
Y[2]
Skin Prick Test at Screening
Y
Y
Medical Conditions and Prior and Concomitant Medications
Current/Past Medical Conditions
Y
Y
Concomitant Medications
Y
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Y
NOTES :

Y = Yes display generated.
[1] Listing also includes analysis population exclusions.
[2] Listing of race.


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7
PRIMARY STATISTICAL ANALYSES
7.1
Efficacy Analyses
7.1.1
Overview of Planned Efficacy Analyses
The primary efficacy analyses will be based on the PP population, unless otherwise 
specified. As a potential sensitivity analysis the final primary analysis model structure 
(derived using the PP population) may also be run using the mITT population
(conditional on the PP and mITT populations differing).
Table 5 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 5
Overview of Planned Efficacy Analyses
Endpoint
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
LAR
Min and WM FEV1
absolute change from 
saline at Week 9
(FUV1)
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 (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.


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7.1.2
Planned Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)

LAR:  minimum <change from saline baseline> FEV1 between 4-10 hours following allergen 
challenge 1 week after treatment i.e. FUV1.  

LAR:  weighted mean of <change from saline baseline> FEV1 between 4-10 hours following 
allergen challenge 1 week after treatment i.e. FUV1.  
Note: Text in <> added for clarity, since the wording in the protocol and objectives is familiar to 
clinical experts in the field, but may be confusing given there are also absolute FEV1 values 
measured at those times too.

The “raw” data (replicate (absolute) FEV1 values transcribed into the eCRF) require processing 
before the Primary analysis. Each planned timepoint may be associated with replicate FEV1 
values, which need to be condensed down into a single value (giving a single FEV1 value per 
timepoint per subject; the timepoints determine how the data are condensed, i.e. some 
timepoints use the minimum of the replicates others use the maximum). In addition the 
Screening Visit 2 Incremental BAC challenge may also contain additional FEV1 values relating 
to the selection procedure for the bolus BAC concentration. Such FEV1 values are not used in 
the statistical analyses (subjects may differ in the amounts of additional FEV1 data to be 
excluded). Once the single time profile of absolute FEV1 values is available per subject the 
Saline baseline is subtracted from each to leave a time profile of change from saline baseline 
FEV1 values. The minimum and weighted means endpoints are derived from this change from 
saline baseline time profile. Further details are given in Section 11.5.4.

Any transformation of a response variable is also expected to be applied to the corresponding 
baseline variable. Final decisions on transformations will be based on the observed data and 
model diagnostics

Any observations with missing model covariates (e.g. baseline) would be excluded from the 
model fitting process (i.e. also excluding the record from any centering of covariates) 
Model Specification

Each endpoint will be analysed separately using a Bayesian Mixed effects model fitted within
Proc MCMC in SAS using the following approach:

Assume equal variances across treatment arms and use a pooled estimate of residual 
variability (Note: if the posterior predictive distributions produced to support the interim analysis 
suggest this assumption may be invalid then the modelling approach may be modified to 
estimate separate variance terms for each treatment arm). 

Step 1: Fit all three of the following models (report output from each model in the same listing –
along with the DIC values and changes in DIC values between models). Using a combination 
of changes in the DIC criteria, and expert judgment (see Section 11.9.1), select a single 
model.

M1: Intercept + Centre + Treatment + Allergen Exposure + 
Treatment*Allergen Exposure + Baseline

M2: Intercept + Centre + Treatment + Allergen Exposure + Baseline

M3: Intercept + Centre + Treatment + Baseline

See Section 11.4.2 for Baseline definitions (Screening visit 2 BAC endpoint).


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Where in each of the models (M1, M2 and M3) the effects are:
Type
Name (#Levels)
Parameters
Prior(s)
Fixed Categorical
Intercept (1)
#1 Intercept
N (0, Var=1E6)
Treatment (2)
#1 Placebo
N (0, Var=1E6)
#2 20ng
n/a (constraint = 0)
Allergen 
Exposure (2)
#1 Presumed
N (0, Var=1E6)
#2 Unknown
n/a (constraint = 0)
Treatment * 
Allergen 
Exposure (4)
#1 Pbo*P
N (0, Var=1E6)
#2 Pbo*U
n/a (constraint = 0)
#3 20ng*P
n/a (constraint = 0)
#4 20ng*U
n/a (constraint = 0)
Fixed Continuous*
Baseline
Baseline slope
N(0, Var=1E6)
Random
Centre (planned 
6 centres)
Separate value 
per contributing 
centre sampled 
as i.i.d ~ N(0, 
2
Centre

)
2
Centre

~Gamma(Shape=0.
048, Scale=0.830)
Weakly informative prior 
based on 6x in-house GSK 
datasets – same prior for 
both endpoints
*=Centre covariates prior to fitting model (do not use observations that will not contribute 
to the planned model when centering) and if applicable the centering is to occur after any 
transformations have been applied
=If chain is not mixing (i.e. sticking at values close to zero) an additional mixture prior 
may be considered to act as a lower boundary constraint, or the centre term excluded 
from the model.

Step 2 (optional): Explore adding other covariate terms to the Step 1 model (for example, but 
not limited to, Age, Gender, Dose per kg, Blood eosinophil levels). Use expert judgment and 
changes in DIC to determine final model to take to Step 3. Include any Step 2 models in the 
listing output and add the associated DIC / changes in DIC values to those produced in Step 1.

Step 3: For the finally selected model use appropriate combinations of the model parameters 
(back transforming the combination if necessary) to obtain posterior distributions for the 
quantities of interest described in the Model Results Presentation. Binary flag variables can be 
used to evaluate the probability statements, by tracking the instances of the desired event 
happening over each MCMC iteration and taking the mean of the flag variable as the 
probability.
For example, if Model 3 is selected then the posterior distribution for the Placebo can be 


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obtained from adding model parameters Intercept + Treatment[#1] Note: The baseline term is 
centered and drops out of the expression since it is evaluated at its centered mean of zero; 
similarly the random centre effect also has mean zero. 
The treatment difference (Active – Placebo) would be –Treatment[#1] because the 
Treatment[#2] parameter is constrained to be zero and the other model terms cancel out.
The Percentage attenuation would be 100 * (1 – ( Intercept / (Intercept + Treatment[#1]) ) )
The SAS syntax for setting up indicator flags to obtain the probability of any percentage 
attenuation is Myflag = (pctann > 0); where pctann is the variable storing the Percentage 
attenuation.
Programming technical note(s): i) Use of flag variables may result in several error/warning 
messages in the SAS log (for example, but not limited to, warnings about large autocorrelation
and/or zero variance); which should be reviewed but may be safely discounted – if in doubt 
consult the study statistician. ii) To facilitate summary outputs where results from multiple 
models are displayed simultaneously (large) intermediate datasets from Proc MCMC may need 
to be stored to ensure consistency (i.e. no differences due to simulation error between model 
re-runs). Suitable naming conventions should be used to label these files which group related 
items together.

The randomization seed used in PROC MCMC should itself be generated with an element of 
randomness - but there is no need to formally document this process (e.g. using Excel function 
RANDBETWEEN [1,9999999] and copying the result into the SAS code)

In addition posterior probabilities relating to differences and/or percentage attenuations for 
other cut-points (which may be determined upon inspection of the data, or from developing 
business requirements), may also be produced.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Point estimates (median values of the posterior distributions), the standard deviation of the 
posterior distribution (SDs) and 95% & 70% equi-tailed credible intervals will be presented for 
each treatment together with estimated treatment differences relative to Placebo and their
corresponding 95% and 70% credible intervals.  The treatment differences will also be 
expressed as percentage attenuations relative to Placebo (and posterior distribution of the 
percentage attenuation obtained).  The posterior probability of any treatment reduction (any 
percentage attenuation) will also be displayed, along with the posterior probability of the 
percentage attenuation exceeding the corresponding AZ point estimate (27% attenuation for 
WM LAR and 18% attenuation for Minimum LAR) (Leaker, 2012).

Plots of the point estimates for the treatment effects (median values of the corresponding 
posterior distributions) and 95% & 70% credible intervals from the model will be generated for 
each treatment. Additionally, plots of differences and 95% & 70% credible intervals for the 
comparison of GSK2245035 vs Placebo may be generated (for the absolute difference and 
percent attenuation representations).

Note: In the event that Model M1 is selected as final (or the final model includes an interaction 


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term involving treatment and another fixed categorical covariate) the outputs should be 
adjusted accordingly to present treatment comparisons within each level of the covariate. If the 
interaction term involving treatment is with a continuous covariate the mean value of the 
covariate should be used and the outputs clearly labeled that the prediction is made at the 
specified covariate value.
Sensitivity and Supportive Statistical Analyses

A scatterplot of each subject’s two derived primary endpoints (each endpoint is an axis) – with 
appropriate identification of subjects belonging to the four distinct treatment & allergen 
exposure combinations. Include i) the (overall) Pearson correlation coefficient and optionally ii)  
corresponding density estimates for each combination and axis as plot margin panels

As an informal check the weakly informative prior on the variance component of the centre 
effect may be replaced by a non-informative prior and the treatment estimates compared, 
provided both models converge, to confirm the prior is not more informative than was intended 
(outputs from this check do not need to be formally reported)

Informative priors based on AZ published data/effect sizes may be explored for the treatment 
terms. Priors that need to be modified in models M1, M2 and M3 are indicated below (Priors for 
WM LAR endpoint only, and analysis would only be required for PP population):
Type
Name (#Levels)
Parameters
Prior(s)
Fixed Categorical
Intercept (1)
#1 Intercept
N (-0.7081, Var=0.4472^2 / 26)
Treatment (2)
#1 Placebo
N (-0.2619, Var=0.4472^2 * 
(1/25 – 1/26) )
#2 20ng
n/a (constraint = 0)

A sensitivity analysis applying the final model to the mITT population may be performed

Exploration of the relationship between treatment effect sizes and (potential) sub-populations 
based on eosinophil levels in blood: A model building exercise would take place using a similar 
strategy as that used to explore the importance of allergen exposure status. However, the base 
model will start with the simplifying assumption that allergen exposure is not necessary (i.e. 
use the M3 form of model). The base model will be compared to the fit of a model containing 
an additional term for the (log transformed if necessary and centered) absolute blood 
eosinophil from the Baseline visit (SV2, fitted as a continuous covariate). This is similar to 
model form M2 but with the continuous covariate taking the place of the allergen exposure 
term. Additionally the benefit of adding a term for the interaction between treatment and this
continuous covariate will be explored (similar to the M1 form). If any model terms involving 
blood eosinophils are included in the model it will be used to predict the mean response for 
each treatment arm using the following blood eosinophil levels (values presented here may 
require transformation so they are incorporated into the model prediction on the appropriate 
scale): 100 cells/mL and 200 cells/mL. Also the treatment difference at each of those 
eosinophil levels should be evaluated. Non-informative priors would be used for the 
parameters representing these additional term(s). To produce the descriptive summary tables 
the blood eosinophil variable will be grouped and summarized by the categories described in 
Section 11.9.1. Note: If data permit the allergen exposure status may also be added to the 
model (although there may not be sufficient subjects to estimate the required number of model 


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Primary Statistical Analyses
parameters; especially when trying to estimate the multi-way interactions involving treatment, 
allergen exposure and eosinophil levels).


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8
SECONDARY STATISTICAL ANALYSES
8.1
Efficacy Analyses
8.1.1
Overview of Planned Efficacy Analyses
The secondary (and exploratory) efficacy analyses presented in this section will be based 
on the PP population, unless otherwise specified (the exception being the repeated 
measures version of the primary efficacy endpoint analysis which will also be run using 
the mITT population (conditional on the PP and mITT populations differing)). Note: For 
ease of review the exploratory repeated measures analyses for LAR and EAR endpoints 
are also described in this section.
Table 6 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 13: List of Data Displays.
Table 6
Overview of Planned Efficacy Analyses
Endpoint 
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
LAR
Min and WM FEV1
absolute change from 
saline from FUV1, 
FUV2 and FUV3 visits 
(Repeated measures)
Y
Y
Y
Y
Y
Y
Y
EAR
Min and WM FEV1
absolute change from 
saline at Week 9
(FUV1)
Y
Y
Y
Y
Y
Y
Y
Min and WM FEV1
absolute change from 
saline from FUV1, 
FUV2 and FUV3 visits 
(Repeated measures)
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 (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.


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8.1.2
Planned Efficacy Statistical Analyses
Secondary Statistical Analyses: EAR at FUV1
Endpoint(s)

EAR:  minimum <change from saline baseline> FEV1 between 0-2 hours following allergen 
challenge 1 week after treatment i.e. FUV1

EAR:  weighted mean of <change from saline baseline> FEV1 between 0-2 hours following 
allergen challenge 1 week after treatment i.e. FUV1.  

Note: Text in <> added for clarity, since the wording in the protocol and objectives is familiar to 
clinical experts in the field, but may be confusing given there are also absolute FEV1 values 
measured at those times too.
Model Specification

as per Primary Statistical Analysis (see Section 7.1.2).
Model Checking & Diagnostics

as per Primary Statistical Analysis (see Section 7.1.2).
Model Results Presentation

as per Primary Statistical Analysis (see Section 7.1.2).
Sensitivity and Supportive Statistical Analyses

Scatterplots to investigate correlation between endpoints as per Primary Statistical Analysis 
(see Section 7.1.2).

As an informal check the weakly informative prior on the variance component of the centre 
effect may be replaced by a non-informative prior and the treatment estimates compared, 
provided both models converge, to confirm the prior is not more informative than was intended 
(outputs from this check do not need to be formally reported)

Sensitivity analyses exploring blood eosinophil levels as a covariate (see Section 7.1.2).
Exploratory Statistical Analyses: Repeated measures version LAR Primary analysis model
Endpoint(s)

LAR:  minimum <change from saline baseline> FEV1 between 4-10 hours following allergen 
challenge at the three follow up visits (i.e. FUV1, FUV2 and FUV3).  

LAR:  weighted mean of <change from saline baseline> FEV1 between 4-10 hours following 
allergen challenge at the three follow up visits (i.e. FUV1, FUV2 and FUV3).  

Note: Text in <> added for clarity, since the wording in the protocol and objectives is familiar to 
clinical experts in the field, but may be confusing given there are also absolute FEV1 values 
measured at those times too.

Any transformation of a response variable is also expected to be applied to the corresponding 
baseline variable. Final decisions on transformations will be based on the observed data and 
model diagnostics

Any observations with missing model covariates (e.g. baseline) would be excluded from the 
model fitting process (i.e. also excluding the record from any centering of covariates)
Model Specification

Each endpoint will be analysed separately using a Bayesian Mixed effects repeated measures 
model fitted within Proc MCMC in SAS using the following approach:

Assume equal variances across treatment arms and use a pooled estimate of residual 


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Exploratory Statistical Analyses: Repeated measures version LAR Primary analysis model
variability (i.e. a 3x3 Variance Covariance Matrix). Note: if the posterior predictive distributions 
produced to support the interim analysis suggest this assumption may be invalid then the 
modelling approach may be modified to estimate separate variance covariance matrices for 
each treatment arm. 

Step 1: Fit all three of the following models (report output from each model in the same listing –
along with the DIC values and changes in DIC values between models). Using a combination 
of changes in the DIC criteria, and expert judgment (see Section 11.9.1), select a single 
model.

R1: Intercept + Centre + Baseline*Visit + Treatment + Visit + Allergen Exposure + 
Treatment*Visit  + Allergen Exposure*Visit + Treatment*Allergen Exposure + 
Treatment*Allergen Exposure*Visit

R2: Intercept + Centre + Baseline*Visit + Treatment + Visit + Allergen Exposure + 
Treatment*Visit + Allergen Exposure*Visit

R3: Intercept + Centre + Baseline*Visit + Treatment + Visit + Treatment*Visit

See Section 11.4.2 for Baseline definitions (Screening visit 2 BAC endpoint).
Where in each of the models (R1, R2 and R3) the effects are:
Type
Name (#Levels)
Parameters
Prior(s)
Fixed Categorical
Intercept (1)
#1 Intercept
N (0, Var=1E6)
Treatment (2)
#1 Placebo
N (0, Var=1E6)
#2 20ng
n/a (constraint = 0)
Allergen 
Exposure (2)
#1 Presumed
N (0, Var=1E6)
#2 Unknown
n/a (constraint = 0)
Visit (3)
#1 FUV1
N (0, Var=1E6)
#2 FUV2
N (0, Var=1E6)
#3 FUV3
n/a (constraint = 0)
Treatment * 
Allergen 
Exposure (4)
#1 Pbo*P
N (0, Var=1E6)
#2 Pbo*U
n/a (constraint = 0)
#3 20ng*P
n/a (constraint = 0)
#4 20ng*U
n/a (constraint = 0)
Allergen 
Exposure * Visit 
(6)
#1 P*FUV1
N (0, Var=1E6)
#2 P*FUV2
N (0, Var=1E6)


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Exploratory Statistical Analyses: Repeated measures version LAR Primary analysis model
#3 P*FUV3
n/a (constraint = 0)
#4 U*FUV1
n/a (constraint = 0)
#5 U*FUV2
n/a (constraint = 0)
#6 U*FUV3
n/a (constraint = 0)
Treatment * Visit 
(6)
#1 Pbo*FUV1
N (0, Var=1E6)
#2 Pbo*FUV2
N (0, Var=1E6)
#3 Pbo*FUV3
n/a (constraint = 0)
#4 20ng*FUV1
n/a (constraint = 0)
#5 20ng*FUV2
n/a (constraint = 0)
#6 20ng*FUV3
n/a (constraint = 0)
Treatment * 
Allergen 
Exposure * Visit 
(12)
#1 Pbo*P*FUV1
N (0, Var=1E6)
#2 Pbo*P*FUV2
N (0, Var=1E6)
#3 Pbo*P*FUV3
n/a (constraint = 0)
#4 Pbo*U*FUV1
n/a (constraint = 0)
#5 Pbo*U*FUV2
n/a (constraint = 0)
#6 Pbo*U*FUV3
n/a (constraint = 0)
#7 20ng*P*FUV1
n/a (constraint = 0)
#8 20ng *P*FUV2
n/a (constraint = 0)
#9 20ng *P*FUV3
n/a (constraint = 0)
#10 20ng *U*FUV1
n/a (constraint = 0)
#11 20ng *U*FUV2
n/a (constraint = 0)
#12 20ng *U*FUV3
n/a (constraint = 0)
Fixed Categorical / 
Continuous*
Baseline*Visit (3)
#1 Baseline slope 
for FUV1
N(0, Var=1E6)
#2 Baseline slope 
for FUV2
N(0, Var=1E6)
#3 Baseline slope 
N(0, Var=1E6)


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Exploratory Statistical Analyses: Repeated measures version LAR Primary analysis model
for FUV3
Random
Centre (planned 
6 centres)
Separate value per 
contributing centre 
sampled as i.i.d ~ 
N(0, 
2
Centre

)
2
Centre

~Gamma(Shap
e=0.048, Scale=0.830)
Weakly informative 
prior based on 6x in-
house GSK datasets –
same prior for both 
endpoints
*=Centre covariates prior to fitting model (do not use observations that will not contribute 
to the planned model when centering) and if applicable the centering is to occur after any 
transformations have been applied
=If chain is not mixing (i.e. sticking at values close to zero) an additional mixture prior 
may be considered to act as a lower boundary constraint, or the centre term excluded 
from the model

Step 2 (optional): Explore adding other covariate terms to the Step 1 model (for example, but 
not limited to, Age, Gender, Dose per kg, Blood eosinophil levels). Use expert judgment and 
changes in DIC to determine final model to take to Step 3. Include any Step 2 models in the 
listing output and add the associated DIC / changes in DIC values to those produced in Step 1.

Step 3: For the finally selected model use appropriate combinations of the model parameters 
(back transforming the combination if necessary) to obtain posterior distributions for the 
quantities of interest described in the Model Results Presentation. Binary flag variables can be 
used to evaluate the probability statements, by tracking the instances of the desired event 
happening over each MCMC iteration and taking the mean of the flag variable as the 
probability.

Similar MCMC model fitting options and techniques to the Primary Statistical Analysis will be 
employed (see Section 7.1.2).

In addition posterior probabilities of the differences (and/or percentage attenuations) for other 
cut-points (which may be determined upon inspection of the data, or from developing business 
requirements), may also be computed.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.

This analysis can also be used to confirm the results of the Primary Statistical Analysis (see 
Section 7.1.2).  Further investigation should be undertaken if results between the single 
timepoint Bayesian model (Primary) and Bayesian Repeated Measures model at FUV1 are 
inconsistent (a priori the most likely causes would be related to missing data influencing the 
estimates of the respective model’s variance covariance parameters and/or the centre effects 
being a function of all three visits in the repeated measures modeling).
Model Results Presentation

The information derived for each of the three visits would be similar to that presented for the 
Primary Statistical Analysis (see Section 7.1.2) (i.e. focus on comparison of GSK2245035 vs 
Placebo within each visit; except that at FUV2 and FUV3 the additional probability statements 
for the percentage attenuations exceeding AZ estimates are not required).


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Exploratory Statistical Analyses: Repeated measures version LAR Primary analysis model
Sensitivity and Supportive Statistical Analyses

By subject time profiles of the derived endpoints, split by treatment arm with separate 
identifiers (plotting symbols) for the allergen exposure strata

If data permit, the repeated measures equivalent of the models exploring the blood eosinophil 
levels would be attempted (see Sensitivity analysis in Section 7.1.2).This would also make the 
simplifying assumption that allergen exposure terms are not required and build up the 
equivalent of models R1-R3 using (log transformed and visit centered) blood eosinophil values 
in place of the allergen exposure term(s). Predictions would be made for the treatment means 
and differences at each visit using the same set of eosinophil values as Section 7.1.2.
Exploratory Statistical Analyses: EAR Repeated measures model
Endpoint(s)

EAR:  minimum <change from saline baseline> FEV1 between 0-2 hours following allergen 
challenge at the three follow up visits (i.e. FUV1, FUV2 and FUV3).

EAR:  weighted mean of <change from saline baseline> FEV1 between 0-2 hours following 
allergen challenge at the three follow up visits (i.e. FUV1, FUV2 and FUV3).

Note: Text in <> added for clarity, since the wording in the protocol and objectives is familiar to 
clinical experts in the field, but may be confusing given there are also absolute FEV1 values 
measured at those times too.
Model Specification & All other details

As per LAR repeated measures analysis described in this section; including the sensitivity 
analyses exploring blood eosinophil levels as a covariate.


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8.2
Safety Analyses
8.2.1
Overview of Planned Adverse Events Analyses
The safety analyses will be based on the All Subjects Population, unless otherwise 
specified.
Table 7 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 7
Overview of Planned Adverse Event Analyses
Endpoint 
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AEs by SOC and Maximum Grade / Severity
Y
Y
All Drug-Related AEs by SOC Class and Maximum Grade / Severity
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, Preferred Term & Verbatim Text
Y
Disease Related Events (DREs) AEs
All DRE AEs
Y
Cytokine Release Syndrome (CRS) AEs
All CRS AEs by SOC and Maximum Grade / Severity
Y
Y
All CRS AEs by SOC and Maximum Grade / Severity by Week
Y
Y
Frequency of CRS events by Dosing Visit
Y
Frequency of CRS events per Patient
Y
Serious and Other Significant AEs
Non-Fatal Serious AEs
Y
Serious AEs by SOC
Y
Reasons for Considering as a Serious AE
Y
Drug-Related Serious AEs by SOC
Y
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study 
Treatment by Overall Frequency
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.


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8.2.2
Overview of Planned Clinical Laboratory Analyses
The safety analyses will be based on the All Subjects Population, unless otherwise 
specified.
Table 8 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 8
Overview of Planned Clinical Laboratory Analyses
Endpoint 
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Chemistry
Chemistry Changes from Baseline 
Y
Emergent Chemistry Results by PCI Criteria
Y
Chemistry Results of PCI
Y
All Chemistry Results for Subjects with a Value of PCI 
Y
Haematology
Haematology Changes From Baseline
Y
Emergent Haematology Results by PCI Criteria
Y
Haematology Values of PCI
Y
All Haematology Results for Subjects with a Value of PCI 
Y
Urinalysis
Urinalysis Abnormal Laboratory Values
Y
All Urinalysis Results for Subjects with an Abnormal 
Value 
Y
Hepatobiliary (Liver) – Conditional on observed data
Liver Monitoring/Stopping Event Reporting
Y
Medical Conditions for Subjects with Liver Stopping 
Events
Y
Substance Use for Subjects with Liver Stopping Events
Y
All Laboratory
Laboratory Tests and Associated Reference Ranges
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

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.
8.2.3
Overview of Planned Other Safety Analyses
The safety analyses will be based on the All Subjects Population, unless otherwise 
specified.


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Table 9 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 9
Overview of Planned Other Safety Analyses
Endpoint 
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
ECG
ECG Findings 
Y
Change from Baseline in ECG Values by Week
Y
All ECG Values for Subjects with a Value of PCI
Y
ECG Values of PCI
Y
Abnormal ECG Findings
Y
Vital Signs
Change From Baseline in Vital Signs by Week
Y
All Vital Signs for Subjects with a Value of PCI
Y
Vital Sign Values of PCI
Y
Rescue Salbutamol Medication (excluding that given as part of BAC procedure)
Rescue Medication usage
Y
Y
Peak Expiratory Flow (PEF)
Mean PEF Profiles
Y
Y
Mean Morning PEF Profiles
Y
Y
Mean Evening PEF Profiles
Y
Y
Weekly Maximum PEF
Y
Y
Weekly WM PEF
Y
Y
Nasal Examination
Frequency of Abnormalities
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.


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8.3
Pharmacokinetic Analyses (Exploratory)
8.3.1
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the PK Population, unless otherwise
specified.
Table 10 provides an overview of the planned analyses, with full details being presented 
in Appendix 13: List of Data Displays. 
Table 10
Overview of Planned Exploratory PK Analyses
Endpoint
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
PK Concentrations
Y
C
C
NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated, 

C = Conditionally produced if quantifiable concentrations exist for at least 20% of subjects at a particular time 
point, 

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.    
8.3.2
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.3
Reporting Process & Standards).
8.3.3
Pharmacokinetic Parameters
8.3.3.1
Deriving Pharmacokinetic Parameters
Note that there will be no PK Parameters calculated for GSK2245035 due to there being 
too few time points of PK sample collections to adequately define the PK Parameters.  
Additionally, the expectation is that all PK concentrations will be non-quantifiable 
making the derivation of PK Parameters inconsequential. If these assumptions are 
incorrect and further work on PK parameters is performed it will be documented in the 
CPSR.


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8.4
Pharmacodynamic and Biomarker Analyses (Exploratory)
8.4.1
Overview of Planned Pharmacodynamic and Biomarker Analyses
The pharmacodynamic analyses will be based on the All Subjects population, unless 
otherwise specified.
Table 11 and Table 12 provide an overview of the types of biomarkers collected, their 
sampling schemes and how they contribute towards the overall assessment of the effect 
of GSK2245035 on various aspects of immune biology.
Table 13 associates each planned/potential analyte with a higher level grouping (denoted 
“functional class”) and describes the ordering when multiple analytes are to be displayed.
It also indicates which of the analytes the study team strongly expect to be available and 
which may be provided, conditional on other factors.
Full details of data displays being presented can be found in Appendix 13: List of Data 
Displays.


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Table 11
Overview of Biomarkers: Planned sampling scheme and display labelling to use
T&E procedure
“Informal” description 
/ rationale for samples
T&E Timepoints
Data Display Labelling for Statistical 
Modelling activities/outputs
Visit
“T&E” descriptions of 
within Visit Sampling Times
Visit
Planned Time
Sputum induction 
and processing for 
BAC associated 
sample collection
Changes over time (Pre-
BAC timepoint)
Direct BAC changes
(Post Vs Pre BAC)
SV1
Pre-BAC
SV
Pre-BAC
SV2 (24h)
BAC+24h
24h Post BAC
DV8
Dose+24h
FUV1
Pre-BAC
FUV1 (24h)
BAC+24h
24h Post BAC
FUV2 (Wk 11)
Pre-BAC
FUV2
Pre-BAC
FUV2 (24h)
BAC+24h
24h Post BAC
FUV3 (Wk19)
Pre-BAC
FUV3
Pre-BAC
FUV3 (24h)
BAC+24h
24h Post BAC
Laboratory 
assessments 
(haematology only)
Blood (WBC & 
Differentials):
Changes over time (Pre-
BAC timepoint)
Direct BAC changes 
(Post Vs Pre BAC)
SV2
Pre-BAC
SV
Pre-BAC
SV2 (24h)
BAC+24h
24h Post BAC
FUV1 (Wk 9)
Pre-BAC
FUV1
Pre-BAC
FUV1 (24h)
BAC+24h
24h Post BAC
FUV2 (Wk 12)
Pre-BAC
FUV2
Pre-BAC
FUV2 (24h)
BAC+24h
24h Post BAC
FUV3 (Wk 20)
Pre-BAC
FUV3
Pre-BAC
FUV3 (24h)
BAC+24h
24h Post BAC
Blood Samples for 
PBMC preparations
BAC induced allergic 
inflammatory cell 
populations
SV2
Pre-BAC
SV
Pre-BAC
BAC+6h
6h Post BAC
FUV1 (Wk 9)
Pre-BAC
FUV1
Pre-BAC
BAC+6h
6h Post BAC
FUV2 (Wk 12)
Pre-BAC
FUV2
Pre-BAC
BAC+6h
6h Post BAC
FUV3 (Wk 20)
Pre-BAC
FUV3
Pre-BAC
BAC+6h
6h Post BAC


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T&E procedure
“Informal” description 
/ rationale for samples
T&E Timepoints
Data Display Labelling for Statistical 
Modelling activities/outputs
Visit
“T&E” descriptions of 
within Visit Sampling Times
Visit
Planned Time
Nasal lavage
Changes over time 
(Background timepoint)
Direct NAC effects
SV2 (24h)
Background
SV
Background
Pre-NAC
Pre-NAC
NAC+5m
5m Post NAC
NAC+6h
6h Post NAC
FUV1 (24h)
Background
FUV1
Background
Pre-NAC
Pre-NAC
NAC+5m
5m Post NAC
NAC+6h
6h Post NAC
FUV2 (24h)
Background
FUV2
Background
Pre-NAC
Pre-NAC
NAC+5m
5m Post NAC
NAC+6h
6h Post NAC
TLR7 Induced changes 
(confirm target 
engagement)
DV1
Pre-Dose
DV1
Pre-Dose
Dose+24h
24h Post Dose
DV4
Pre-Dose
DV4
Pre-Dose
Dose+24h
24h Post Dose
DV8
Pre-Dose
DV8
Pre-Dose
Dose+24h
24h Post Dose
Nasal filter 
collection
Changes over time 
(Background timepoint)
Direct NAC effects
SV2 (24h)
Background
SV
Background
Pre-NAC
Pre-NAC
NAC+5m
5m Post NAC
NAC+6h
6h Post NAC
FUV1 (24h)
Background
FUV1
Background
Pre-NAC
Pre-NAC
NAC+5m
5m Post NAC
NAC+6h
6h Post NAC


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T&E procedure
“Informal” description 
/ rationale for samples
T&E Timepoints
Data Display Labelling for Statistical 
Modelling activities/outputs
Visit
“T&E” descriptions of 
within Visit Sampling Times
Visit
Planned Time
FUV2 (24h)
Background
FUV2
Background
Pre-NAC
Pre-NAC
NAC+5m
5m Post NAC
NAC+6h
6h Post NAC
Nasal scrape
Changes over time
SV2 (24h)
NAC+6h
SV
6h Post NAC
FUV1 (24h)
NAC+6h
FUV1
6h Post NAC
FUV2 (24h)
NAC+6h
FUV2
6h Post NAC
Genetic sample
PGx
1x at any of DV1-DV8
n/a
n/a
n/a
Blood sample for 
biomarker analysis
TLR7 Induced changes 
(confirm target 
engagement)
DV1
Pre-Dose
DV1
Pre-Dose
Dose+24h
24h Post Dose
DV8
Pre-Dose
DV8
Pre-Dose
Dose+24h
24h Post Dose
Blood sample for 
RNA analysis
TLR7 induced gene 
changes in the periphery
DV1
Pre-Dose
DV1
Pre-Dose
DV8
Dose+24h
DV8
24h Post Dose
FUV2 (Wk 12)
Pre-BAC
FUV2
Pre-BAC
FeNO measurement
Treatment induced 
FeNO changes 
All Dosing Visits 
(DV1 to DV8 
inclusive)
Pre-Dose
DV1, DV2, DV3,
etc..., DV8
Pre-Dose
BAC induced FeNO 
changes
SV1
Prior to Sputum
SV
Pre-BAC
SV2 (24h)
BAC+24h
24h Post BAC
FUV1 (Wk 9)
Pre-BAC
FUV1
Pre-BAC
FUV1 (24h)
BAC+24h
24h Post BAC
FUV2 (Wk 12)
Pre-BAC
FUV2
Pre-BAC
FUV2 (24h)
BAC+24h
24h Post BAC
FUV3 (Wk 20)
Pre-BAC
FUV3
Pre-BAC
FUV3 (24h)
BAC+24h
24h Post BAC


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Table 12
Overview of Biomarkers: Types of samples, data vendors and expected analytes 
T&E 
procedure
“Informal” 
description / 
rationale for 
samples
Matrix
Functional 
Categories
Vendor ()
Analyte(s)
Comments
Anticipated Placebo 
profile
Characteristics of 
Successful drug 
effect
Sputum 
induction and 
processing 
for BAC 
associated 
sample 
collection
Changes 
over time 
(Pre-BAC 
timepoint)
Direct BAC 
changes 
(Post Vs Pre 
BAC)
Cell Pellet
Sputum 
differentials
BIOSPIT
Absolute values 
(Cells/g sputum) and %
(of Total Non-
Squamous Cells) for: 
Eosinophils, 
Neutrophils, 
Lymphocytes, 
Macrophages, 
Bronchial Epithelial 
Cells & Total Non-
Squamous Cells
BAC may increase 
Sputum EOS 
(Absolute values and 
%)
Reduced Sputum 
EOS (Absolute values 
and/or %) relative to 
Placebo for  i) 
Baseline (Pre-BAC) 
or ii) BAC induced 
increase (Post/Pre 
ratio)
PBS 
Wash
Inflammatory 
mediators
GSK 
(Stevenage)
IL-5, IL-13
Conditional: IL-16, IL-
33, TSLP, Eotaxin, 
MDC, TARC, ECP
BAC may increase 
inflammatory 
mediator levels e.g. 
IL-5 & IL-13
Reduced sputum 
TH2 mediators (IL-
5 & IL-13) relative 
to Placebo for i) 
Baseline (Pre-BAC)
or ii) BAC induced 
increase (Post/Pre 
ratio)
Cell Pellet 
RNA
Inflammatory 
gene 
expression
Expression 
Analysis
Affy CHIP 
Note: Data generation  
conditional on sufficient 
cells remaining in 
BAC may increase 
inflammatory gene 
expression
Reduction or 
change in nature of 
BAC induced gene 
expression 


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T&E 
procedure
“Informal” 
description / 
rationale for 
samples
Matrix
Functional 
Categories
Vendor ()
Analyte(s)
Comments
Anticipated Placebo 
profile
Characteristics of 
Successful drug 
effect
sample and sufficient 
sputum producers
(Post/Pre) or the 
Baseline (pre BAC)
gene expression
Laboratory 
assessments 
(haematology 
only)
Blood (WBC 
& 
Differentials):
Changes 
over time 
(Pre-BAC 
timepoint)
Direct BAC 
changes 
(Post Vs Pre 
BAC)
Blood
Blood WBC 
and 
differentials
Q2
Absolute values (Cell 
counts) and % (of Total 
WBC) for: Eosinophils, 
Neutrophils, 
Lymphocytes, 
Monocytes, Basophils, 
& Total WBC
Note: Neutrophils refers 
to Total Neutrophils 
(Segs + Bands), as 
described in dataset 
manager codelists
Blood EOS may 
increase (either 
Absolute counts or 
%) after the BAC
Reduction  in (Pre-
BAC) blood EOS 
(as absolute count 
or %) from SV 
and/or Reduction in 
BAC induced 
increase in blood 
EOS after 
treatment 
compared to pbo
Blood 
Samples for 
PBMC 
preparations
BAC induced 
allergic 
inflammatory 
cell 
populations
Blood 
PBMC
n/a
ZKW
Conditional on other 
study endpoints 
showing positive 
signals
Reported outside of 
CPSR as data 
generation may take a 
long time
To be defined, 
analysis of BAC 
induced allergic 
inflammatory 
populations in 
PBMC. 
To be defined, 
reduction in BAC 
induced allergic 
inflammatory 
populations in 
PBMC. 


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T&E 
procedure
“Informal” 
description / 
rationale for 
samples
Matrix
Functional 
Categories
Vendor ()
Analyte(s)
Comments
Anticipated Placebo 
profile
Characteristics of 
Successful drug 
effect
Nasal lavage
Changes in 
time 
(Background 
timepoint)
Direct NAC 
effects
Lavage
Immuno-
globulins
Eosinophil 
mediators
GSK 
(Stevenage)
Background
Pre-NAC & 6h Post
NAC samples only
(Allergens are “Birch”, 
“House Dust Mite”, 
“Cat” and “Grass” –
Expecting one result 
per subject using the 
allergen they were 
challenged with – but 
re-label to “Allergen 
Specific IgA” for 
displays; only German 
sites expected to 
provide Birch Allergen 
data)
ECP, Allergen Specific 
IgA
NAC should 
increase 
inflammatory 
mediators
Treatment related 
changes compared 
to screening of 
either background 
levels or the NAC 
induced increase at 
6 hrs (6h/Pre-NAC 
ratio)
Eosinophil 
mediators should 
go down or not 
increase on NAC if 
drug is working &
IgA should increase
Mast Cell 
mediators
GSK 
(Stevenage)
Pre-NAC & 5m Post 
NAC samples only
Histamine Tryptase 
Conditional: 
Mast cell mediators 
should increase in 5 
min post NAC 
sample
Reduction in the 
NAC (5 min/pre-
NAC ratio) induced 
response after 
treatment 


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T&E 
procedure
“Informal” 
description / 
rationale for 
samples
Matrix
Functional 
Categories
Vendor ()
Analyte(s)
Comments
Anticipated Placebo 
profile
Characteristics of 
Successful drug 
effect
Prostaglandin D2
compared to the SV
TLR7 
Induced 
changes 
(confirm 
target 
engagement)
Lavage
“TLR7” 
Target 
engagement
GSK 
(Stevenage)
IP-10
Within visit ratio (24h / 
Pre-dose) should be 
approximately one
Increase in within visit 
fold changes to 
confirm target 
engagement. 
Investigate whether 
the magnitude of fold 
changes at DV4 and 
DV8 are similar
Nasal filter 
collection
Changes in 
time 
(Background 
timepoint)
Direct NAC 
effects
Nasal 
Lining 
fluid
Inflammatory 
mediators
GSK 
(Stevenage)
Background
Pre-NAC & 6h Post 
NAC samples only
IL-5
IL-16
Conditional: IL-13, IL-
33, TSLP, Eotaxin, 
MDC, TARC, IL-10, 
IFNg
NAC should 
increase 
inflammatory 
mediators
Treatment related 
reduction 
(compared to 
screening) of either 
background and or 
reduction of NAC 
6h induced 
response.
Th2 cytokines 
should all go down 
if drug is working
Th1/Treg cytokines 
should increase


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T&E 
procedure
“Informal” 
description / 
rationale for 
samples
Matrix
Functional 
Categories
Vendor ()
Analyte(s)
Comments
Anticipated Placebo 
profile
Characteristics of 
Successful drug 
effect
Mast Cell 
mediators
GSK 
(Stevenage)
Pre-NAC & 5m Post 
NAC samples only
Histamine, Tryptase, 
Conditional:Prostagland
in D2
Note: Data generation 
conditional on sufficient 
sample remaining. 
Would only be assayed 
if mast cell mediators 
cannot be detect in 
Nasal lavage fluid
samples
Mast cell mediators 
should increase in 5 
min post NAC 
sample
Reduction in the 
NAC (5min/pre-
NAC ratio) induced 
response after 
treatment 
compared to the SV


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T&E 
procedure
“Informal” 
description / 
rationale for 
samples
Matrix
Functional 
Categories
Vendor ()
Analyte(s)
Comments
Anticipated Placebo 
profile
Characteristics of 
Successful drug 
effect
Nasal scrape
Changes in 
time
Nasal 
Cells
n/a
ZKW
Samples to be held by 
ZKW, if we are able to 
get good samples and 
study is positive will be 
analysed. Reported 
outside of CPSR as 
data generation may 
take a long time
n/a
n/a
Genetic 
sample
PGx
Blood
Whole blood
GSK 
(Stevenage)
Stored for genomic 
DNA can only be used 
if individual consent is 
signed, could be used 
to see why someone is 
a non-responder
n/a
n/a
Blood sample 
for biomarker 
analysis
TLR7 
Induced 
changes 
(confirm 
Serum
“TLR7” 
Target 
engagement
Q2
IP-10, IFNa, IFNb, IL-
1b, IL-6, TNFa, MCP-1
Within visit ratio (24h / 
Pre-dose) should be 
approximately one
Increase in within visit 
fold changes to 
confirm target 
engagement


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T&E 
procedure
“Informal” 
description / 
rationale for 
samples
Matrix
Functional 
Categories
Vendor ()
Analyte(s)
Comments
Anticipated Placebo 
profile
Characteristics of 
Successful drug 
effect
target 
engagement)
PBMC
n/a
ZKW
To be used in 
association with 
Haematology cell 
counts to define which 
populations of cells are 
changing post dose i.e. 
in more detail that just 
“Lymphocytes”. . Can 
also use pre BAC 
samples at FUV1 and 
FUV2 to see if 
(“Lymphocyte”) 
phenotype is restored 1 
and 4 weeks after 
treatment.
Reported outside of 
CPSR as data 
generation may take a 
long time
n/a
n/a


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T&E 
procedure
“Informal” 
description / 
rationale for 
samples
Matrix
Functional 
Categories
Vendor ()
Analyte(s)
Comments
Anticipated Placebo 
profile
Characteristics of 
Successful drug 
effect
Blood sample 
for RNA 
analysis
TLR7 
induced gene 
changes in 
the periphery
PAX-gene 
tubes for 
TLR7/AFF
Y chip 
gene 
expressio
n in blood
Whole blood 
RNA
Expression 
Analysis
Affy CHIP
No changes
Change from pre DV1 
of TLR7  induced 
gene expression in 
blood 24h after 8th
dose and do they 
return to baseline 4 
weeks after treatment
FeNO 
measurement
Treatment 
induced 
FeNO 
changes
eCRF 
data


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T&E 
procedure
“Informal” 
description / 
rationale for 
samples
Matrix
Functional 
Categories
Vendor ()
Analyte(s)
Comments
Anticipated Placebo 
profile
Characteristics of 
Successful drug 
effect
BAC induced 
FeNO 
changes
eCRF 
data
Notes: () Vendors provided to indicate likely packages/deliverables for pre-programming “ZKW” = Zellkraftwerk, “Q2” = Quest and Quintiles, “BIOSPIT” = Quintiles 
(BIOSPIT), “GSK (Stevenage)” = 
 team, “<TBC>” = To be confirmed
PPD


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Table 13
Functional Categories of Analytes and Display Orders (irrespective 
of originating matrix) for anticipated analytes at RAP writing
Functional Category
(Direction supporting further drug 
development)
Analyte
Display 
order within 
Category
Data 
Availability*
“TLR7” Target engagement (Increases 
indicative of target pathway 
engagement)
IP-10
1
E
MCP-1
2
E
IFNa
3
E
IFNb
4
E
IL-1b
5
E
IL-6
6
E
TNFa
7
E
Sputum Differentials (Absolute and %)
(Decreases in Eosinophils desired)
Eosinophils
1
E
Neutrophils
2
E
Lymphocytes
3
E
Macrophages
4
E
Bronchial Epithelial 
Cells
5
E
Total Non-Squamous 
Cells
6
E
Blood WBC and Differentials (Absolute 
and %)
(Decreases in Eosinophils desired)
Eosinophils
1
E
Neutrophils
2
E
Lymphocytes
3
E
Monocytes
4
E
Basophils
5
E
Total WBC
6
E
Immunoglobulins (Increases)
Allergen Specific IgA
1
E
Mast Cell & Eosinophil Mediators 
(Decreases)
Histamine 
1
E
Tryptase
2
E
Prostaglandin D2
3
C
ECP
4
E
Inflammatory Mediators
TH1/Treg Panel (Increases)
IFNg
1
C
IL-10
2
C
TH2 Panel
(Decreases)
Cytokines
IL-5
1
E
IL-13
2
Sput’:E, Lav’:C
IL-16
3
Sput’:C, Lav’:E
IL-33
4
C
TSLP
5
C
Chemokines
Eotaxin
1
C
MDC
2
C
TARC
3
C
*: E = Expected to be available at final reporting; C = Conditional – not guaranteed to be in final data 
package (e.g. reasons for absence of analyte may include, but not be limited to  i) responses (or lack of) in 
other data or ii) satisfactory completion of lab assay development by the time of sample processing)
=Neutrophils refers to Total Neutrophils (Segs. + Bands)


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8.4.2
Planned Pharmacodynamic and Biomarker Statistical Analyses
Individual biomarkers referred to in the RAP were correct at time of writing, but may not 
represent the final / definitive list of analytes. The structure / framework of the univariate 
statistical analyses will be described for a generic biomarker of a given class & proposed 
sampling scheme. Additional biomarkers would be assigned to the appropriate class & 
sampling scheme and would be analysed using a similar methodology. 
The proposed multivariate analyses / composite endpoints would be modified accordingly 
if new biomarkers/analytes are assayed and deemed relevant for inclusion.
Additional analyses would use the next available output numbering and changes 
(additions / planned analyses that were not performed) would be documented in the 
CPSR.
Several biomarker sampling types will be collected and stored and reporting performed 
outside of the CPSR and/or SAC deliverable. These have been captured here for 
completeness and any details on methodology / comparisons would be included in the 
respective reporting processes.
Pharmacodynamic/Biomarker
General Considerations

Imputations described in Section 11.4.2.3 would be applied to the response variables prior to 
any further activities.

Listings should also display original and any imputed versions of the response variable.

Unless otherwise stated all planned analyses will use the imputed response variable.  If the 
baseline value is imputed then the imputed value will be included in the statistical analyses (and 
any change from baseline responses will be computed as the change from imputed baseline). 
Only if there are many time points and dose levels with imputed values will sensitivity analyses 
be performed (e.g. by re-fitting the statistical model without the imputed data points). Any 
sensitivity analyses will be described in the CPSR (separate outputs from these sensitivity 
analyses may not be included in the final CPSR if the conclusions from the original statistical 
analysis do not change).

Each of the biomarkers will be examined to determine if a log transformation should be applied 
prior to any statistical analyses (no outputs will be produced from this step).  Log base 2 will be 
used unless otherwise stated (including on any Figures requiring a logarithmic y-axis). Based 
on previous experience with biomarker data the default assumption will be that the variable will 
require a Log base 2 transformation.

If a transformation is necessary then the transformation should be applied to any associated 
baseline responses prior to them being centred (applies when fitting models using SAS PROC 
MCMC).

Transformations of the response variable and/or alternative analysis techniques will be explored 
on an as needed basis if model assumptions appear invalid (these techniques would be 
documented in the CPSR).

Use will be made of the recommendations contained in the internal DB – Respiratory guidance 
document on handling PK values below the limit of quantification when summarising the PD 
data.  For the purposes of this study a “large” amount of missing data is defined as ≥75% of 


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values.  For example if the experimental design has 8 potential values for a given time-point 
and 6 or more are LLQ then selected summary statistics (mean, SD, geometric mean and 95% 
CI for geometric mean, SD logs and CVb(%) will be set to NA).

Default sets/layouts of descriptive Summary Tables and Figures will be produced for each 
biomarker where data permit (these are based on the raw data values and not on statistical 
model outputs); layouts described below.

Subsequent statistical analyses will only be performed if the study statistician (or delegate) 
deems that such analysis may provided additional information / value over and above the 
descriptive Figures and summary tables (for example, if the majority of responses for biomarker 
X were below Limit of Quantification on all treatment arms, further statistical modelling are not 
likely to provide much information and would not be attempted).

Unless otherwise stated model checking will include examination of Studentised residual plots 
and Q-Q plots for frequentist based statistical analyses and utilise the techniques in Section 
11.11 for Bayesian based analyses. 

Panel plots of selected posterior distributions (using groupings and layouts appropriate to the 
data being summarised) may also be attempted to bring together the results of (Bayesian) 
statistical modelling to facilitate easier review to obtain an idea of the behaviour of 
GSK2245035. These would take the next available display numbers but would not be labelled 
as post-hoc in their titles because they are summarising existing analyses (the exception to this 
would be if any of their content utilised modelling results from a post-hoc model). 

Exploratory scatter plots involving different combinations of endpoints (and time points) may be 
produced to investigate possible correlation structures and biological activity (for example, 
relating Visit 1 IP-10 fold changes in nasal lavage supernatant to post allergen challenge IL-5 
levels at follow up visits).  It is not possible to pre-specify these in advance (they will be guided 
by the observed data).  These exploratory scatter plots need not be formally reported unless 
they are required to support statements made in the CPSR (in which case they would be 
assigned the next available free number and be labelled as post-hoc). Any subsequent 
statistical analyses resulting from the exploratory figures would be described in the CPSR and 
also labelled as post-hoc.
Descriptive data summaries (Figures and Tables)
Figures

PD_F1: Displaying Individual Subject level data: Aim to achieve one page per analyte and 
treatment combination, containing panels of individual subject data (use judgement on the best 
layout; expected to be 4 columns and 5 rows but it is allowable to use more than one page if 
necessary to maintain readability). The x-axis and y-axis ranges should be common across all 
subjects within the analyte (i.e. Placebo page uses same x-axis and y-axis range as 20ng 
GSK2245035 page to allow comparability; but different analytes can have different y-axis 
ranges). The x-axis should be discrete and ordered chronologically. Responses within a visit 
should be joined but there should be gaps between data points from different visits. Use the 
colour scheme for the treatment and allergen stratum combination described in Section 11.4.3
for each subject (but do not include a legend). The y-axis should be spaced on an appropriate 
scale (e.g. Log 2) but the labels can be the untransformed values to allow for greater clinical 
interpretability. The imputed responses should be displayed. If necessary use abbreviations for 
labelling visit/time combinations, and footnote accordingly. LLQs and ULQs should be displayed 
as horizontal dashed lines whenever appropriate (e.g. do not put the LLQ line on if none of the 
subjects values are near the LLQ value, as it will only extend the y-axis range and make the 


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subjects data harder to distinguish). However the corresponding LLQ (and the ULQ if defined) 
can be displayed in the sub-title (or by line) associated with the graph, even if the reference 
lines are omitted. Display the analytes in the order given by Table 13. Arrange the subject 
panels so that they are grouped by allergen exposure stratum, centre and subject ID (if space is 
constrained each panel label should contain the allergen exposure (P or U) and the subject ID
as centre information is implied by the ranges of subject ID numbers). Omit unscheduled data 
points from these figures (only add an appropriate footnote when required, e.g. “Note: 
Unscheduled data excluded – see corresponding listing for values”) 

PD_F2: Displaying Individual Subject level data grouped by treatment arm (all timepoints): Aim 
to achieve one page per analyte; using a grid layout (Placebo 1st row, 20ng GSK2245035 2nd
row). Each column is a visit, arranged chronologically from left to right (try to get all visits on the 
same page but use more than one page to display visits if necessary). The x-axis and y-axis 
ranges should be common within each analyte. The x-axis should be discrete and ordered 
chronologically. Use the colour scheme for the treatment and allergen stratum combination 
described in Section 11.4.3 for each subject. Overlay the means and approximate 95% CI from 
the corresponding summary tables in thicker lines with different colours; sufficiently offsetting 
their x-axis values from the individual subject data so that the 95% Cis do not obstruct the 
individual data markers and/or the other means (if no CI is available due to n* being too low 
then just plot the mean); i.e. a total of three items to be overlaid; giving the most emphasis to 
the overall treatment mean. The summary statistics selected should be appropriate to the 
planned transformations (e.g. if the endpoint is to be log transformed then the mean and 
associated Cis should be for the geometric mean but if no transformation is planned then they 
can be for the arithmetic mean). For the individual subject data display the imputed responses 
using only the planned time-points (omit any unscheduled data). The criteria for y-axis 
scale/labels, footnotes, LLQ/ULQs and display ordering are the same as PD_F1. The legend 
should include both i) individual subjects data symbols/line types and ii) the sets of overlaid 
items (3x means and associated 95% Cis). If the lower and/or upper bound of any CI is 
negative and the y-axis involves a log transformation then the negative value should be 
replaced with a suitable small constant (e.g. 10% of the LLQ) and an appropriate footnote 
added to the display to indicate some of the Cis are altered for display purposes.

PD_F3: Displaying Individual Subject level data grouped by treatment arm (Background or Pre-
Challenge (or Pre-Dose) timepoints only): This will use the same principles as PD_F2, except 
that there are not separate panels (columns) for visits. Instead Visit will form the x-axis 
categories (ordered chronologically from left to right) and the column label will be the timepoint 
within the visit (e.g. “Background” or “Pre-Challenge” or “Pre-Dose”). 

PD_F4: Displaying Individual Subject Fold changes grouped by treatment arm (for analytes 
unrelated to demonstrating TLR7 target engagement): Aim to achieve one page per analyte, 
containing panels of individual subject fold-change data; with one panel for each visit/timepoint 
combination (ordered chronologically from left to right). Within each panel the x-axis is the 
treatment arm (categorical – ascending dose levels; offset the points by the Stratum level if 
possible). Use a grid layout; rows contain the reference timepoint (denominator in the fold 
change ratio) and columns are the visit/timepoint combinations (numerators in the fold change 
ratio). For example, there may only be one row, which might be labelled as “Pre-BAC for the 
Visit” and four columns “SV 24h Post BAC”, “FUV1 24h Post BAC”, “FUV2 24h Post BAC” and 
“FUV3 24h Post BAC”. Use the colour scheme for the treatment and allergen stratum 
combination described in Section 11.4.3 for each subjects fold change value (include this 


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information in a legend). Draw a horizontal dashed reference line at 1. If necessary use a log 
base y-axis.

PD_F5: Displaying Individual Subject Fold changes grouped by treatment arm (for analytes 
related to demonstrating TLR7 target engagement): This will use the same principles as PD_F4
but will consist of two rows (1st row showing fold changes relative to the true baseline (i.e. 
before the 1st dose was administered (DV1 Pre-Dose)) and the 2nd row showing fold changes 
relative to the pre-dose baseline associated with that visit. Note: If i) the timepoint (column) is 
the reference value in row 2 or ii) no pre-dose value was taken at the corresponding timepoint 
then the row 2 panel can be left blank/empty.
Tables

Analytes should be presented in the order described in Table 13. For each analyte the summary 
statistics should be derived and presented for i) the overall treatments (Placebo and 20ng 
GSK2245035) and then by ii) the Treatment and Allergen exposure strata combinations 
(Placebo Presumed, Placebo Unknown, 20ng GSK2245035 Presumed and 20ng GSK2245035 
Unknown); each visit and planned time combination (ordered chronologically) within the 
treatment grouping. The descriptive summary statistics to be presented are detailed in Section 
11.4.3. Most biomarkers would require log transformations (i.e. the associated tables will also 
include the geometric means etc). The tables should be modified to include the n* column (see 
the internal DB – Respiratory guidance document on handling PK values below the limit of 
quantification). To facilitate presentation with the same layouts use “Overall” for the stratum 
value when presenting the overall treatment means.
Default approach for Bayesian MCMC Modelling output
Items and Comparisons of interest and required Probability statements for each 
comparison

Assuming that the final model is not of the “R1” form (See Section 11.9.1) then treatment 
comparisons of interest are the equivalents to the frequentist counterpart LSMeans estimates 
for Treatment*Visit in a model fitted in SAS PROC MIXED. The posterior distributions of these 
quantities will be obtained and the median and 95% credible interval (equi-tail) will be tabulated
and displayed graphically. Additionally, appropriate combinations of model parameters will be 
constructed to obtain the posterior distributions of the ratio of Active / Placebo for each planned 
time point (equivalent to extracting out relevant back transformed LSmean diffs from a PROC 
MIXED call for a log-transformed response variable). The posterior probabilities that the ratios 
at each planned timepoint exceeded the cut-points described Table 14 will be computed, along 
with the median and 95% credible interval (equi-tail) of the distribution. The posterior 
distributions for the ratios will be displayed graphically and the aforementioned items tabulated. 
Note: These posterior probabilities relate to events in the current study, and the mean 
responses on the treatment arms. Predictions relating to i) an individual subject in a future trial 
and ii) the mean response in a future trial with N subjects per arm will not be produced as part 
of the reporting of this study, but may be obtained as part of experimental design activities for 
any future clinical trials involving GSK22454035.

If the model is of the “R1” form (See Section 11.9.1) then the approach will be modified to 
obtain and display LSMean equivalents of Treatment*Visit*Allergen and the comparisons would 
be the ratio of Active/Placebo within each Allergen strata within each visit. The same set of 
default posterior probability cut points will be used for each comparison.


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Table 14
Default Posterior Probability (PP) cut-points of interest for 
Pharmacodynamic/Biomarkers analyses
Item
X = Treatment ratio (Active / Placebo) at each planned time point
1
PP(X<0.10) “More than a 90% reduction in mean response relative to Placebo”
2
PP(X<0.25) “More than a 75% reduction in mean response relative to Placebo”
3
PP(X<0.50) “More than a 50% reduction in mean response relative to Placebo”
4
PP(X<0.75) “More than a 25% reduction in mean response relative to Placebo”
5
PP(X<0.90) “More than a 10% reduction in mean response relative to Placebo”
6
PP(X<1.00) “Any reduction in mean response relative to Placebo”
7
PP(X1.00) “Any increase in mean response relative to Placebo”
8
PP(X>1.10) “More than a 10% increase in mean response relative to Placebo”
9
PP(X>1.25) “More than a 25% increase in mean response relative to Placebo”
10
PP(X>1.50) “More than a 50% increase in mean response relative to Placebo”
11
PP(X>2.00) “More than a 2-fold increase in mean response relative to Placebo”
12
PP(X>10) “More than a 10-fold increase in mean response relative to Placebo”
Note: If the response is untransformed then the cut-points will be computed using the median of 
the posterior (adjusted) distribution for Placebo and the above ratios to determine the equivalent 
absolute difference (e.g. If Pbo median = 76 then Item 1 would be PP(Difference (A-P) < -68.4 ) )
Note: Shortened versions of the labels may be used in the TLFs as appropriate (e.g. PP(X<0.10) 
or PP(Any Reduction c.f. Pbo))
8.4.2.1
Biomarkers supporting the BAC related exploratory objective(s)
8.4.2.1.1
Sputum
Analyses described in Section 8.4.2.1.1 will use the Sputum producers population. If this 
population is deemed too small (e.g. less than 3 evaluable subjects per treatment 
arm/strata combination) a review of each of the planned modelling activities may take 
place to determine which (if any) of them would be attempted.
Cell Pellet: Sputum Differential cell counts
These analysis models assume all of the required data manipulation steps have been 
completed and that two response variables are derived per subject; namely a (derived)
Total count (in Cells/g sputum – sometimes referred to as Absolute counts in display 
titles) and a Percentage (% of the Total Non-Squamous Cells). It is expected that a large 
proportion of subjects may not produce samples and/or viable/evaluable samples at all of 
the planned timepoints. Inspection of the amount and pattern of missing data will be 
conducted, to determine if any form of statistical modelling should take place. Note: 
The data manipulation steps add on a small constant in the eventuality that zero counts 
were recorded for a cell type so there should be no value that cannot be subjected to a log 
transformation.


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Descriptive summary tables will be produced for “%” and Absolute count versions of the 
endpoints.
Figures of type PD_F1 and PD_F2 should be produced for each combination of response 
variable (absolute and %) and the cell type (Eosinophils, Neturophils, etc) using all of the 
available timepoints.
The most pertinent of the differential cell types are the Eosinophils; although the same 
modelling process would be attempted for the other cell types (Neutrophils, 
Lymphocytes, Macrophages, Bronchial Epithelial Cells and Total Non-Squamous cells).
Statistical analysis of “Pre-BAC” Samples

Additional Figures of type PD_F3

Separate Bayesian repeated measures mixed effect models (per response variable and cell 
differential type), with non-informative priors for all model parameters, will be fitted to each 
transformed response over the planned post Screening time points (FUV1, FUV2 and FUV3). 

Baseline: (Transformed) SV Pre-BAC 

The additional terms to include in the chosen “R” model (see Section 11.9.1) are:
Fixed Categorical:  Intercept
Fixed Continuous Covariates:  Baseline*Visit  

The repeated measures term is Visit (Subject = Subject), with an Unstructured variance 
covariance matrix common to each treatment arm (3x3).
Statistical analysis of “Direct BAC effect” Samples (All Samples)

Additional Figures of type PD_F4

Separate Bayesian repeated measures mixed effect models (per response variable and cell 
differential type), with non-informative priors for all model parameters, will be fitted to each of 
the transformed responses collected from an individual subject (i.e. 8 data points per subject; 
the combinations of Visit and Sample times SV Pre-BAC, SV 24 Post BAC, FUV1 Pre-BAC, 
FUV1 24h Post BAC, FUV2 Pre-BAC, FUV2 24h Post BAC, FUV3 Pre-BAC and FUV3 24h 
Post BAC).

For the purposes of assessing models R1 to R3 (see Section 11.9.1) consider “Visit” in those 
models to be a eight level term covering the data recorded per subject with these additional 
terms:
Fixed Categorical:  Intercept
The repeated measures term is Visit (Subject = Subject), with an Unstructured variance 
covariance matrix common to each treatment arm (8x8). 

In this model parameterization the usual “Baseline” timepoints (Pre-BACs) are modeled as 
response variables and not covariates. Therefore posterior distributions for the quantities of 
interest; namely treatment effect on “within visit fold changes (Post/Pre) adjusted for the 
screening visit and placebo fold changes”; use fold changes representing the mean predicted 
response at the timepoint (and not the average of the individual subjects fold changes).


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
The model can provide several layers of useful information that should be presented instead of 
the default set of comparisons. The following should be modified if the model form is “R1”. The 
Back transformed predicted response for each treatment arm (x2) and visit (x8) combination 
should be produced. The next stage is to determine the fold change of the predicted response 
(Predicted Post BAC / Predicted Pre-BAC) within each of the four visits (SV, FUV1, FUV2 and 
FUV3) for each treatment. For each treatment arm its respective SV fold change can be 
subtracted from the FUV1, FUV2 and FUV3 visits. This quantity can then be compared across 
the treatment arms (within each of FUV1, FUV2 and FUV3); to provide an estimate of the 
screening visit and placebo adjusted change in BAC induced response.
PBS Wash: Allergic Mediators
A similar approach to the analysis of Sputum Differential Cell Counts data will be used 
for each of the available inflammatory mediators; with the exception being the direction 
of interest (increases or decreases) may change depending upon which analyte is being 
modelled (see Table 13 for which direction to prioritise for the biomarker classes).
Cell Pellet RNA
NOT PART OF SAC DELIVERABLE: Conditional on sufficient sample remaining
(priority is Cell Pellet and PBS wash data). If available it would produce Affy CHIP data, 
which would be analysed in a similar fashion to Section 8.4.2.3.4.
8.4.2.1.2
Blood WBC and Differential Cell Counts
As with sputum, the emphasis is on the Eosinophils. These are expected to increase upon 
BAC challenge (i.e. increases on Placebo c.f. pre-BAC values), and GSK2245035 should 
“blunt” this increase (a priori it is not certain if the treatment effect is sufficiently strong 
that it causes decreases, rather than a reduced level of increase c.f. Placebo).
The analysis approach is similar to Section 8.4.2.1.1; except that the All Subjects 
population is to be used and the list of differential cell types from the Blood Haematology 
samples is different (no Macrophages, BEC or Total Non-Squamous Cells but Monocytes 
and Basophils are expected). Also and if present in the source data only the total 
Neutrophils should be descriptively summarised/analysed (not Segs and Bands). Total 
WBC should also be modelled.
8.4.2.1.3
Blood PBMC
NOT PART OF SAC DELIVERABLE: These samples will be stored and further 
processing would be subject to study outcome determined from the other endpoints 
(statistical analyses would be reported separately and methods documented in the 
corresponding write up / report). The Statistical analysis methodology depends upon what 
methodology is used to process the samples, as the data structure/content will depend on 
that choice.


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8.4.2.1.4
FeNO (Exhaled Nitric Oxide)
This section has been written assuming that FeNO response will require a log 
transformation. If it is not the case then appropriate modification should be made (e.g. 
comparisons expressed as differences rather than ratios (fold changes)).
Statistical Analysis of “Direct BAC effect” FeNO Samples

Tables of descriptive summary statistics and Figures of type PD_F1, PD_F2 and PD_F4

A Bayesian repeated measures mixed effect model, with non-informative priors for all model 
parameters, will be fitted to each of the transformed responses collected from an individual 
subject (i.e. 8 data points per subject; the combinations of Visit and Sample times SV Pre-BAC, 
SV 24 Post BAC, FUV1 Pre-BAC, FUV1 24h Post BAC, FUV2 Pre-BAC, FUV2 24h Post BAC, 
FUV3 Pre-BAC and FUV3 24h Post BAC).

For the purposes of assessing models R1 to R3 (see Section 11.9.1) consider “Visit” in those 
models to be a eight level term covering the data recorded per subject with these additional 
terms:
Fixed Categorical:  Intercept
The repeated measures term is Visit (Subject = Subject), with an Unstructured variance 
covariance matrix common to each treatment arm (8x8). 

In this model parameterization the usual “Baseline” timepoints (Pre-BACs) are modeled as 
response variables and not covariates. Therefore posterior distributions for the quantities of 
interest; namely treatment effect on “within visit fold changes (Post/Pre) adjusted for the 
screening visit and placebo fold changes”; use fold changes representing the mean predicted 
response at the timepoint (and not the average of the individual subjects fold changes).

The model can provide several layers of useful information that should be presented instead of 
the default set of comparisons. The following should be modified if the model form is “R1”. The 
Back transformed predicted response for each treatment arm (x2) and visit (x8) combination 
should be produced. The next stage is to determine the fold change of the predicted response 
(Predicted Post BAC / Predicted Pre-BAC) within each of the four visits (SV, FUV1, FUV2 and 
FUV3) for each treatment. For each treatment arm its respective SV fold change can be 
subtracted from the FUV1, FUV2 and FUV3 visits. This quantity can then be compared across 
the treatment arms (within each of FUV1, FUV2 and FUV3); to provide an estimate of the 
screening visit and placebo adjusted change in BAC induced response.
8.4.2.2
Biomarkers Supporting the NAC related exploratory objective(s)
The Background samples should be analysed separately from the others as their intent is 
to capture changes in condition over the season (longer term changes).
The Pre-NAC, 5min and 6 hours are designed to measure the direct (within day) impact 
of the NAC procedure. The pre-wash (applied as part of the process to obtain the 
background sample) should also make the pre-NAC values more consistent (essentially 
zero) and should ensure that subjects should begin from a similar nasal condition (i.e. 
with a clean nose). Thus challenge related changes should be more consistent as 
mediators induced by the challenge should be the dominant items detected.


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However, although all post NAC samples may be collected, not all of the biomarker types
will be evaluated in the first instance. Pre-NAC samples will be evaluated for all 
biomarker types (mast cell mediators and inflammatory mediators).  Mast cell mediators 
will also be evaluated from the 5min sample and Inflammatory mediators will be also be 
evaluated for the 6h sample.  
Whilst the statistical analysis may split the data initial summaries will be produced using 
the complete dataset (i.e. a “PD_F1” format Figure and summarised in descriptive 
tables).
8.4.2.2.1
Nasal Lavage Fluid & Nasal Lavage Filters
Nasal Lavage Fluid samples are expected to provide the Mast Cell Mediator results (plus 
ECP and allergen specific IgA). Nasal Filters are expected to provide the Inflammatory 
mediators (chemokines and cytokines).
Statistical Analysis of “Background” Samples

Additional Figures of type PD_F3

Separate Bayesian repeated measures mixed effect models (per analyte), with non-informative 
priors for all model parameters, will be fitted to each transformed response over the planned 
post Screening time points (FUV1 and FUV2). 

Baseline: (Transformed) SV Background 

The additional terms to include in the chosen “R” model (see Section 11.9.1) are:
Fixed Categorical:  Intercept
Fixed Continuous Covariates:  Baseline*Visit  
The repeated measures term is Visit (Subject = Subject), with an Unstructured variance 
covariance matrix common to each treatment arm (2x2). 
Statistical Analysis of “Direct NAC effect” Samples

Additional Figures of type PD_F2 and PD_F4

Separate Bayesian repeated measures mixed effect models (per analyte), with non-informative 
priors for all model parameters, will be fitted to each of the transformed responses collected 
from an individual subject (i.e. 6 data points per subject; the combinations of Visit and Sample 
times SV Pre-NAC, SV Post NAC, FUV1 Pre-NAC, FUV1 Post NAC, FUV2 Pre-NAC and 
FUV2 Post NAC; where Post-NAC is either 5m or 6h depending whether the biomarker is a 
mast cell mediator (5m) or inflammatory (6h)).

For the purposes of assessing models R1 to R3 (see Section 11.9.1) consider “Visit” in those 
models to be a six level term covering the data recorded per subject with these additional 
terms:
Fixed Categorical:  Intercept
The repeated measures term is Visit (Subject = Subject), with an Unstructured variance 
covariance matrix common to each treatment arm (6x6). 


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
In this model parameterization the usual “Baseline” timepoints (Pre-NACs) are modeled as 
response variables and not covariates. Therefore posterior distributions for the quantities of 
interest; namely treatment effect on “within visit fold changes (Post/Pre) adjusted for the 
screening visit and placebo fold changes”; use fold changes representing the mean predicted 
response at the timepoint (and not the average of the individual subjects fold changes).

The model can provide several layers of useful information that should be presented instead of 
the default set of comparisons. The following should be modified if the model form is “R1”. The 
Back transformed predicted response for each treatment arm (x2) and visit (x6) combination 
should be produced. The next stage is to determine the fold change of the predicted response 
(Predicted Post NAC / Predicted Pre-NAC) within each of the three visits (SV, FUV1, and 
FUV2) for each treatment. For each treatment arm its respective SV fold change can be 
subtracted from the FUV1 and FUV2 visits. This quantity can then be compared across the 
treatment arms (within each of FUV1 and FUV2); to provide an estimate of the screening visit 
and placebo adjusted change in NAC induced response.
8.4.2.2.2
Nasal Scrapes
NOT PART OF SAC DELIVERABLE: These samples will be stored and further 
processing would be subject to study outcome determined from the other endpoints 
(statistical analyses would be reported separately and methods documented in the 
corresponding write up / report). Note: Nasal scrape data are not going to be processed as 
in previous GSK2245045 studies (i.e. not planning to obtain a gene expression panel); 
samples may be analysed by CHIP-Cytometry.
8.4.2.3
Biomarkers supporting the Induction of TLR7 (target engagement)
exploratory objective(s)
8.4.2.3.1
Nasal Lavage

Tables of descriptive summary statistics and Figures of type PD_F1, PD_F2 and PD_F5

Separate Bayesian repeated measures mixed effect models (per analyte), with non-informative 
priors for all model parameters, will be fitted to each of the transformed post DV1 baseline 
responses collected from an individual subject (i.e. 5 data points per subject; the combinations 
of Visit and Sample times excluding DV1 Pre-Dose; namely DV1 24h Post Dose, DV4 Pre-
Dose, DV4 24h Post Dose, DV8 Pre-Dose and DV8 24h Post Dose).

Baseline: (Transformed) DV1 Pre-Dose

For the purposes of assessing models R1 to R3 (see Section 11.9.1) consider “Visit” in those 
models to be the five level effect covering the data recorded per subject (excluding DV1 Pre-
Dose) with these additional terms:
Fixed Categorical: Intercept
Fixed Continuous Covariates: Baseline*Visit
The repeated measures term is Visit (Subject = Subject), with an Unstructured variance 
covariance matrix common to each treatment arm (5x5).

Only items 6 and 7 from the default set of cut-points (Table 14) should be evaluated for the 
each of the default within visit treatment comparisons.

Appropriate combinations of the model parameters should be used to evaluate the following 
two additional comparisons of interest (all cut point items from Table 14 should be applied to 


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the posterior distributions obtained for these additional comparisons and also this one:
Posterior Probability the quantity (X) is {NOT[(0.8 X 1.25)]})
o
24h response at DV4 vs DV1 for the 20ng GSK2245035 arm (adjusting for equivalent 
changes on Placebo). This is equivalent to 
“[20ng Post at DV4 / 20ng Post at DV1] / [Pbo Post at DV4 / Pbo Post at DV1]”
o
Analogous comparison for DV8 Vs DV1 
o
The above additional comparisons are investigating if there is any evidence for gross 
amplification or tolerisation of the TLR7 induced responses after 4 and 8 weeks of 
weekly dosing, using the placebo data to adjust for any drift in the biomarker changes 
that may be caused by other factors (e.g. seasonal changes in allergen exposure).
8.4.2.3.2
Blood PD (Serum)
A similar approach to Section 8.4.2.3.1 will be used, except that “Visit” is a three level 
term (DV1 24h Post Dose, DV8 Pre-Dose and DV8 24h Post Dose) and only the 
additional comparison involving DV8 is relevant. Baseline is still DV1 Pre-Dose.
8.4.2.3.3
Blood PBMC
NOT PART OF SAC DELIVERABLE: These samples will be stored and further 
processing would be subject to study outcome determined from the other endpoints 
(statistical analyses would be reported separately and methods documented in the 
corresponding write up / report). Possible processing would involve CHIP-cytometry 
with an interest in characterising differences in cell populations (e.g. B cells and T-cells) 
between the treatment arms after dosing with drug.
8.4.2.3.4
Blood sample for RNA analysis
Gene expression (Affy CHIP) data. Standard GSK processes for QC of each CHIP and 
the normalisation procedure will be employed (e.g. using Array Studio software). 
The model to be fitted to each probeset will be a repeated measures model (this may be 
fitted in SAS PROC MIXED). It will be based on the appropriate “R” model (See Section 
11.9.1) using (transformed) DV1 Pre-Dose as Baseline, Visits are DV8 and FUV2 with 
the following additional terms.
Fixed Categorical:  Intercept
Fixed Continuous Covariates:  Baseline*Visit
The repeated measures term is Visit (Subject = Subject), with an Unstructured variance 
covariance matrix common to each treatment arm (2x2). 
Back transformed adjusted within visit Treatment comparisons (fold changes) and p-
values (from a null hypothesis that the fold change=1) would be provided to the 
Computational Biology group within GSK for each probeset. That group will follow its 
processes (e.g. apply an appropriate false discovery rate correction (and possibly a 
threshold on the magnitude of fold change)) and place the resulting subset of genes into a
pathway analysis. The Computational Biologist (or designate) would contribute directly 
to the corresponding CPSR sections with the interpretation of the pathway analysis 
outcome(s); and to describe any additional methodologies.


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8.4.2.3.5
FeNO (Exhaled Nitric Oxide)
This section has been written assuming that FeNO response will require a log 
transformation. If it is not the case then appropriate modification should be made (e.g. 
comparisons expressed as differences rather than ratios (fold changes)).
Statistical Analysis of “Treatment induced changes” FeNO Samples

Tables of descriptive summary statistics and Figures of type PD_F1 (but modified to use the 
PD_F3 axis layouts; i.e. one panel per subject with visit as the x-axis category and join the pre-
dose values together for each subject across visits) and PD_F3.

A Bayesian repeated measures mixed effect model, with non-informative priors for all model 
parameters, will be fitted to each of the post DV1 transformed responses collected from an 
individual subject (i.e. 7 data points per subject; the Pre-Dose values for DV2 to DV8 inclusive).

Baseline: (Transformed) DV1 Pre-Dose

The additional terms to include in the chosen “R” model (see Section 11.9.1) are:
Fixed Categorical: Intercept
Fixed Continuous Covariates:  Baseline*Visit
The repeated measures term is Visit (Subject = Subject), with an Unstructured variance 
covariance matrix common to each treatment arm (7x7). 
8.4.2.4
PGx Samples
These samples will be stored and further processing would be subject to study outcome 
determined from the other endpoints (statistical analyses would be reported separately 
and methods documented in the corresponding write up / report). 
8.4.3
Multivariate / Composite endpoint analyses
Given the exploratory nature and timing in the overall clinical development program of 
this study, it is anticipated that further post-hoc analyses would be conducted on the data 
beyond those specified in this section. However, these would be data driven and difficult 
to pre-specify. Any post-hoc analyses would be labelled as such in their title, take the 
next available display number(s) and be described in the CPSR.
8.4.3.1
Correlation between Sputum and WBC cell differentials
Using the Sputum population scatterplots of BAC Sputum and WBC Differential cell 
results (both absolute counts and percentage variables) will be produced for each cell 
differential evaluated that is comparable over both sampling matrices. Simple linear 
regression lines may be overlaid onto the plot for i) each individual treatment arm and ii) 
all data combined (i.e. these would be simple regressions that do not account for the 
repeated measures on individuals when estimating the regression parameters and are 
intended to act as a rough indicator for how translatable conclusions drawn from analyses 
of WBC Differentials may be to the lung (BAC Sputum)). The plots will display all of 
the available data from all visits.


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8.4.3.2
Defining responder / non-responder status for an individual subject 
using only their datapoints
For each subject the criteria in Table 15 will be evaluated. If the endpoint relating to a 
question is missing then the subject’s response will be set to missing and they would not 
contribute to the denominator when deriving any proportions.


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Table 15
Criteria to be derived/applied at an individual subject level
ID
Area
Question(s)
Statistical 
Population
Endpoint(s)
Criteria / Responder algorithm
(for non-missing endpoints)
Expected rate on Pbo 
Arm
A1
Target 
Engagement
Sustained 
activation of 
GSK2245035 
target pathway?
Per 
Protocol
Within visit fold change in 
Nasal Lavage IP-10 (24h / 
Pre-Dose) at DV1 and 
DV8
Yes: Fold change >= 2 for BOTH 
DV1 and DV8 visits
No: Any other outcome
<5% from 3x Previous 
studies (TL7114450, 
TL7116392, TL7116958)
B1 
(FUV1)
B2 
(FUV2)
B3 
(FUV3)
Clinical BAC 
endpoint(s)
At least 20% 
attenuation of 
LAR Response 
c.f. SV?
Per 
Protocol
FUV1: WM and Min LAR 
FEV1 absolute change 
from saline
FUV2: WM and Min LAR 
FEV1 absolute change 
from saline
FUV3: WM and Min LAR 
FEV1 absolute change 
from saline
Derive Separately for each FU 
Visit 
Yes: >=20% Attenuation (c.f. SV) 
observed for either WM or Min 
LAR endpoint
No: Any other outcome
~40% from 8x Historical 
GSK Allergen challenge 
studies (EL110002, 
HZA113126, INO102141, 
IPA101985, LPA111834, 
RES104385, 
RES114748 and 
SIG110762)
C1 
(FUV1)
C2 
(FUV2)
C3 
(FUV3)
Clinical BAC 
endpoint(s)
At least 20% 
attenuation of 
EAR Response 
c.f. SV?
Sputum 
Producer
FUV1: WM and Min EAR 
FEV1 absolute change 
from saline
FUV2: WM and Min EAR 
FEV1 absolute change 
from saline
FUV3: WM and Min EAR 
FEV1 absolute change 
from saline
Derive Separately for each FU 
Visit 
Yes: >=20% Attenuation (c.f. SV) 
observed for either WM or Min 
EAR endpoint
No: Any other outcome
~50% from 8x Historical 
GSK Allergen challenge 
studies
D1 
(FUV1)
D2 
(FUV2)
D3 
Pre-BAC 
Endpoint(s)
Any Reduction 
in Pre-BAC 
Sputum EOS 
c.f. SV
Sputum 
Producer
Pre-BAC Sputum EOS 
(%) for FUV1, FUV2 and 
FUV3
Derive Separately for each FU 
Visit 
Yes: FU visit Sputum EOS % < 
corresponding SV %
No: Any other outcome
~50% (Assumption of no 
underlying change)


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ID
Area
Question(s)
Statistical 
Population
Endpoint(s)
Criteria / Responder algorithm
(for non-missing endpoints)
Expected rate on Pbo 
Arm
(FUV3)
E1 
(FUV1)
E2 
(FUV2)
E3 
(FUV3)
BAC 
Induced 
Changes in  
Endpoint(s)
Reduced Fold 
change in 
Sputum EOS 
(24h Post 
BAC/Pre-BAC) 
c.f. SV
Sputum 
Producer
Within Visit fold change in 
Sputum EOS (%) [24h 
Post BAC / Pre-BAC] at 
FUV1, FUV2 and FUV3
Derive Separately for each FU 
Visit 
Yes: FU visit Fold change < 
corresponding SV fold change
No: Any other outcome
~50% (Assumption of no 
underlying change)
F1 
(FUV1)
F2 
(FUV2)
F3 
(FUV3)
Pre-BAC 
Endpoint(s)
Any Reduction 
in Pre-BAC 
Blood EOS c.f. 
SV
Sputum 
Producer
Pre-BAC Blood EOS (%) 
for FUV1, FUV2 and 
FUV3
Derive Separately for each FU 
Visit 
Yes: FU visit Blood EOS % < 
corresponding SV %
No: Any other outcome
~50% (Assumption of no 
underlying change)
G1 
(FUV1)
G2 
(FUV2)
G3 
(FUV3)
BAC 
Induced 
Changes in  
Endpoint(s)
Reduced Fold 
change in 
Blood EOS 
(24h Post 
BAC/Pre-BAC) 
c.f. SV
Per 
Protocol
Within Visit fold change in 
Blood EOS (%) [24h Post 
BAC / Pre-BAC] at FUV1, 
FUV2 and FUV3
Derive Separately for each FU 
Visit 
Yes: FU visit Fold change < 
corresponding SV fold change
No: Any other outcome
~50% (Assumption of no 
underlying change)
H1 
(FUV1)
H2 
(FUV2)
Pre-NAC 
Endpoint(s)
Any Reduction 
in Pre-NAC 
Nasal Lavage 
IL-5 c.f. SV
Per 
Protocol
Pre-NAC Nasal Lavage IL-
5 for FUV1 and FUV2
Derive Separately for each FU 
Visit 
Yes: FU visit NL IL-5 < 
corresponding SV value
No: Any other outcome
~50% (Assumption of no 
underlying change)
I1 (FUV1)
I2 (FUV2)
NAC 
Induced 
Changes in  
Endpoint(s)
Reduced Fold 
change in 
Nasal Lavage 
IL-5 (6h Post 
NAC/Pre-NAC) 
Per 
Protocol
Within visit fold change in 
Nasal Lavage IL-5 [6h 
Post NAC / Pre-NAC] at 
FUV1 and FUV2
Derive Separately for each FU 
Visit 
Yes: FU visit Fold change < 
corresponding SV fold change
No: Any other outcome
~50% (Assumption of no 
underlying change)


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ID
Area
Question(s)
Statistical 
Population
Endpoint(s)
Criteria / Responder algorithm
(for non-missing endpoints)
Expected rate on Pbo 
Arm
c.f. SV
J1 (FUV1)
J2 (FUV2)
Pre-NAC 
Endpoint(s)
Any Reduction 
in Pre-NAC 
Nasal Lavage 
ECP c.f. SV
Per 
Protocol
Pre-NAC Nasal Lavage 
ECP for FUV1 and FUV2
Derive Separately for each FU 
Visit 
Yes: FU visit NL ECP < 
corresponding SV value
No: Any other outcome
~50% (Assumption of no 
underlying change)
K1 
(FUV1)
K2 
(FUV2)
NAC 
Induced 
Changes in  
Endpoint(s)
Reduced Fold 
change in 
Nasal Lavage 
ECP (6h Post 
NAC/Pre-NAC) 
c.f. SV
Per 
Protocol
Within visit fold change in 
Nasal Lavage ECP [6h 
Post NAC / Pre-NAC] at 
FUV1 and FUV2
Derive Separately for each FU 
Visit 
Yes: FU visit Fold change < 
corresponding SV fold change
No: Any other outcome
~50% (Assumption of no 
underlying change)
L1 (FUV1)
L2 (FUV2)
*
Pre-NAC 
Endpoint(s)
Any Reduction 
in Pre-NAC 
Nasal Filter 
Eotaxin c.f. SV
Per 
Protocol
Pre-NAC Nasal Filter ECP 
for FUV1 and FUV2
Derive Separately for each FU 
Visit 
Yes: FU visit NF ECP < 
corresponding SV value
No: Any other outcome
~50% (Assumption of no 
underlying change)
M1 
(FUV1)
M2 
(FUV2)
*
NAC 
Induced 
Changes in  
Endpoint(s)
Reduced Fold 
change in 
Nasal Filter 
Eotaxin (6h 
Post NAC/Pre-
NAC) c.f. SV
Per 
Protocol
Within visit fold change in 
Nasal Filter Eotaxin [6h 
Post NAC / Pre-NAC] at 
FUV1 and FUV2
Derive Separately for each FU 
Visit 
Yes: FU visit Fold change < 
corresponding SV fold change
No: Any other outcome
~50% (Assumption of no 
underlying change)
* = Only included if the Nasal Filter Eotaxin biomarker was processed / evaluated


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A subject level listing will be produced to display the results of each question in Table 15
(and any additional post-hoc data driven questions). The proportion of individuals in the 
Yes category will be derived for each treatment arm and question, using both the main 
and alternative set of treatment descriptors (i.e. derive a separate proportion for each 
descriptor). These proportions will be listed and also displayed on starcharts (sometimes 
called radar plots), with a separate spoke per question and a separate chart per visit, with 
the treatment profiles overlaid on the individual panels (answers to questions which do 
not naturally have a visit structure will be duplicated across each visit/starchart). Aim to 
get all visits on the same page and align question B to the top spoke and present the 
questions in the following clockwise order: B, C, D, F, H, E, G, I, J, K, L, M and A. If 
possible use the same axis scale for each spoke, but question A may produce a wide 
range of proportions and therefore it is acceptable to present some questions on a 
different spoke axis scale to aid interpretation of any questions where smaller treatment 
differences are observed. To allow for (data driven) modifications to the number and/or 
ordering of the question a listing linking the abbreviated IDs to the actual 
questions/criteria will also be produced and any new questions/criteria not in Table 15
should be appropriately identified (e.g. using a lower case “p” as a suffix to the new 
question ID). 
8.4.3.3
Multivariate Statistical Analysis Strategy
The following is a top level description of the (exploratory) analysis strategy; further 
refinements may be required once the number of endpoints and their distribution are 
known (i.e. data driven modifications to the planned analysis may be made during study 
reporting). Please consult the GSK study statistician for further details if required. Further 
details of the methodology used would be included in the CPSR. 

Whenever possible, to preserve the maximum amount of information contained 
within them, continuous variables should not be dichotomised.

Imputed biomarker responses would be used in this analysis (e.g. responses below 
LLQ would be assigned ½ LLQ).

Missing data / covariate values: Given the exploratory nature and relatively small 
number of subjects strong simplifying assumptions will be made. A missing at 
random assumption will be made for response variables. Initially for simplicity, 
covariates that are missing would be replaced with the corresponding treatment 
arm mean. A possible extension may use multiple imputation methodology to 
sample 5 sets of complete cases (via MCMC sampling methodology since the 
missingness patterns are not expected to be monotonic), analyse each of the 5 
datasets separately and combine them using Rubin’s rules (e.g. via SAS PROC 
MI and PROC MIANALYZE). This extension would be considered if the number 
of missing covariates is deemed large by the GSK study statistician.

Two approaches would be attempted each aiming to explore the magnitude and 
duration of any GSK2245035 drug related as assessed using a range of endpoints. 
If the observed data do not permit their use or their assumptions are unlikely to be 
valid these methods may not be attempted.


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o
Profile regression (via the PReMiuM R package) – see Liverani (2015). 

Response variable: BAC LAR outcomes (continuous Primary 
endpoint(s)). Separate modelling for each of the two primary 
endpoints

For simplicity, the repeated measures aspect will be ignored and 
data from each visit for an individual will be assumed to be 
independent.

For display purposes the endpoints will be grouped by (biomarker) 
functional category listed in Table 13; with the option to explore 
the inclusion of other variables via additional functional categories; 
for example but not limited to FeNo and diary card WM TNSS 
value(s). 

If necessary biomarkers from a functional category may be omitted 
if there appears to be a larger amount of multicolinearity.

Log transformed data used, individual variables may be 
standardised prior to model fitting.

Treatment and visit information would not be provided to the 
model fitting process.

A desirable outcome is if the number of clusters roughly matches
the treatment and visit combinations (approximately 6) and/or that 
individuals from the same treatment arms are consistently 
clustering together. Also it is desirable that the expected response 
associated with any “GSK2245035 clusters” is lower than “placebo 
clusters”. 
o
Unsupervised clustering of individuals and visits followed by Canonical 
Correspondence analysis / Principal co-ordinates analysis to identify 
patterns when grouping results by treatment and visit – See Valles (2014)

The strategy described in Valles (2014) would be modified to 
reflect the continuous data in this study (rather than binary 
presence/absence in their data). 

Each variable may be standardised prior to model fitting.

For each subject and visit combination their associated two 
primary response variables and the potential set of biomarkers 
described above for profile regression (plus the option to include 
other variables, for example but not limited to FeNo and diary card 
WM TNSS value(s)) would be put through an unsupervised 
clustering algorithm and the resulting dendrogram would also 
identify the timepoint and treatment associated with each sample 


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as well as colour coding by the standardised absolute values (see 
Fig 3 of the Valles (2014) paper).

Additionally Canonical Correspondence analysis / Principal co-
ordinates analysis would be used to explore patterns in samples 
belonging to the same treatment and visit. As in Fig 4 of Valles
(2014) convex hulls may be drawn around the data points relating 
to samples from each treatment and timepoint combination and the 
areas of overlap determined and compared. Separately for each 
treatment arm and taking its respective Screening visit convex hull 
area as a reference, the area of overlap from the follow up visits 
would be expressed as a percentage of screening. Additionally and 
separately for each visit the convex hull area of GSK2245035 
would be expressed relative to the Placebo convex hull area. The 
relative changes in these areas can potentially inform on magnitude 
and duration of treatment effects.

Desirable outcomes would be distinct clusters by treatment arm(s) 
and lasting changes (across FUV1, FUV2 and FUV3) in convex 
hull areas on active that are not observed on the placebo.


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9
EXPLORATORY STATISTICAL ANALYSES
9.1
Exploratory Analyses
9.1.1
Overview of Planned Exploratory Analyses
The exploratory analyses will be based on different populations depending on what the 
endpoint is.  
Table 16 provides an overview of the planned exploratory analyses, with further details 
of data displays being presented in Appendix 13: List of Data Displays.
Table 16
Overview of Planned Exploratory Analyses
Endpoint 
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
TNSS
WM TNSS by Week
Y
Y
Y
Y
Y
Y
WM Individual 
Components of TNSS
by Week
C
C
C
C
C
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated, C=Display conditional on other results.

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.
Intradermal Allergen 
Challenge
Log 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
Mean Diameter Early Phase Response (15m)
Wheal/Flare data
C
C
C
Y
Y
Y
Y
Y
Mean Diameter Late Phase Response (6h)
Wheal/Flare data
C
C
C
Y
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated, C=Display conditional on other results.

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.
Weighted Mean TNSS
The weighted means of the TNSS values (AM and PM values combined into an overall
daily score prior to deriving WM) will be derived for each diary card week. They will be 
analysed using a similar model to FeNO (Section 8.4.2.3.5) except the response is not 
anticipated to require any transformation, so the model should be modified to examine 
differences and not ratios and to account for the additional Follow Up Visit timepoints.


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Baseline would be the Day 1 AM TNSS value and Visit would be the week (of each 
weighted mean).
Conditional on the above output the following may be attempted (and would be assigned 
the next available output number):
Modelling repeated as above for AM and PM weighted means (derived separately; with 
Baseline being Day 1 AM TNSS in both models)
Each individual TNSS component may have weekly Weighted Means determined and 
modelled (for overall and separate AM and PM endpoints; with baseline term being the 
respective TNSS component from Day 1 AM).
Intradermal Allergen Challenge
Summary statistics for the absolute and change from baseline values will be produced, 
along with a Figure of the change from baseline values. Further Statistical modelling is 
conditional on i) review of these summary outputs and ii) other study results / outcomes 
and would be similar to the other repeated measures models fitted in this study (main aim 
to compare the treatment effects within each visit). Further details of any statistical 
modelling would be provided in the CPSR.
Note: Intradermal Allergen Challenge test procedures will not be performed on subjects if 
the allergen manufacturer is “Allergopharma” (i.e. no data for those individuals). This 
manufacturer is being used as a solution in response to anticipated supply issues during 
the clinical study, and may impact on a number of individuals. If the proportion of 
missing data is large then statistical modelling may not take place.


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10
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GSK2245035, on the allergen-induced asthmatic response in subjects with mild 
allergic asthma, 27-Feb-2017.

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Effects Of The Novel Toll-Like Receptor 7 (TLR7) Agonist AZD8848 On Allergen-
Induced Responses In Patients With Mild Asthma. American Thoracic Society 
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Liverani S., Hastie D I, Azizi, L., Papathomas, M., Richardson, S. PReMiuM: An R 
Package for Profile Regression Mixture Models Using Dirichlet Processes. Journal of 
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Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, Culver B, Enright P, Hankinson J, 
M lp, Zheng J, Stocks J. Multi-Ethnic Reference Values for Spirometry for the 
3-95 yr Age Range: The Global Lung Function 2012 Equations. European 
Respiratory Journal, 2012.

Spiegelhalter, D. J, Best, N. G., Carlin, B. P., Van der Linde, A. Bayesian Measures 
of Model Complexity and Fit, Journal of the Royal Statistical Society, Series B, 
64(4), 583–616, with discussion, 2002.

Valles Y, Artacho A, Pascual-Garcia A, Ferrus ML, Gosalbes MJ, Abellán 
JJ, Francino MP Microbial Succession in the Gut: Directional Trends of Taxonomic 
and Functional Change in a Birth Cohort of Spanish Infants. PLoS Genet 10(6): 
e1004406. Doi:10.1371/journal.pgen.1004406, 2014.


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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: Assessment Windows
Section 11.3
Appendix 3: Treatment States & Phases
Section 11.4
Appendix 4: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 11.5
Appendix 5: Derived and Transformed Data

General, Study Population & Safety

Efficacy

Pharmacokinetic

Pharmacodynamic and or Biomarkers
Section 11.6
Appendix 6: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 11.7
Appendix 7: Values of Potential Clinical Importance

Laboratory Values

ECG

Vital Signs
Section 11.8
Appendix 8: Multicentre Studies
Section 11.9
Appendix 9: Examination of Covariates and Subgroups
Section 11.10
Appendix 10: Multiple Comparisons and Multiplicity
Section 11.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 11.12
Appendix 12: Abbreviations & Trade Marks
Section 11.13
Appendix 13: List of Data Displays
Section 11.14
Appendix 14: Example Mock Shells for Data Displays (see separate document: 
RAP-Mock Tables-205540.doc)


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11.1
Appendix 1: Protocol Deviation Management and Definitions
for Per Protocol Population
11.1.1
Exclusions from Per Protocol Population
The Protocol Deviation Management Plan (PDMP) contains more detail on the specific 
items that may cause subjects to be excluded from the per protocol population. In general 
a subject meeting any of the following criteria is expected to be excluded from the Per 
Protocol population (as described in the PDMP reviews and decisions will occur on a 
case by case basis):
Number
Exclusion Description
01
Failure of any inclusion/exclusion criteria, but subject is still enrolled.
02
Subject took short-acting beta-agonist (SABA) more than 2 days per week on average.
03
Subject did not receive all 8 doses of planned medication (Placebo or GSK2245035).
04
Subject did not receive the same allergen dose during study period as that determined at 
Screening (except for cases where the dose was reduced for safety reasons- in which case 
the same (reduced) dose must be used at all follow up challenges (otherwise the individual 
should be excluded)).


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11.2
Appendix 2: Assessment Windows
11.2.1
Definitions of Assessment Windows for Analyses
Data Management are responsible for documenting and implementing the visit windows 
in this study. If an item is within its visit window it should be transferred to statistics and 
programming using the corresponding timeslicing key (items that fall outside of the 
window may be transferred using unscheduled timeslicing keys with the corresponding 
planned items containing no data). In addition this should also be captured in the protocol 
deviations dataset. For the purposes of AE, DRE and CRS assignments the algorithms 
described in Section 11.3.2 should be used.


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11.3
Appendix 3: Treatment States and Phases
11.3.1
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
dosing.
Treatment Phase
Definition
Pre-Treatment 
Date/Time < Study Treatment Start Date/Time
On-Treatment*
Study Treatment Start Date/Time ≤ Date/Time ≤ Study Treatment Stop Date/Time+7
Post-Treatment*
Date/Time+7 > Study Treatment Stop Date/Time
NOTES: 

* Treatment phase assumes that the effects of study treatment duration will last a week.

Study Treatment Start relates to the 1st dose received by the individual and the Study Treatment Stop relates to 
the final dose received by the individual  
11.3.2
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment.
11.3.2.1
Treatment States for AE (and DRE) Data
Treatment State
Definition
Pre-Treatment
AE Start Date/Time < Study Treatment Start Date/Time
On-Treatment*
If AE onset date/time is on or after treatment start date/time & on or before treatment 
stop date/time.
Study Treatment Start Date/Time ≤ AE Start Date/Time ≤ Study Treatment Stop 
Date/Time + 7
Post-Treatment*
If AE onset date is after the treatment stop date.
AE Start Date > Study Treatment Stop Date + 7
Onset Time  
Since 1st 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.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on eCRF OR value is missing
NOTES: 

* Treatment phase assumes that the effects of study treatment duration will last a week.

Study Treatment Start relates to the 1st dose received by the individual and the Study Treatment Stop relates to 
the final dose received by the individual. If the study treatment stop date is missing then the AE will be considered 
to be On-Treatment.

=Not applicable/required for DRE


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11.3.2.2
Treatment States for CRS Events Data
Treatment State
Definition
Pre-Treatment
CRS Start Date/Time < Study Treatment Start Date/Time
On-Treatment 
Week i
i=1, 2, 3, …, 7
If CRS Start Date/Time is on or after ith dose of treatment start date/time & on or before 
(i+1)th dose of treatment stop date/time.
Ith Study Treatment Dose Start Date/Time  ≤ CRS Start Date/Time ≤ (i+1)th Study 
Treatment Start Date/Time
Post-Treatment*
If CRS onset date is after the last dose of treatment start date/time + 7 ie, 
CRS Start Date/Time > Study Treatment Stop Date/Time + 7.
Onset Time  
Since 1st Dose 
(Days)
If Treatment Start Date ˃  CRS Onset Date = CRS Onset Date – Treatment Start Date
If Treatment Start Date ≤ CRS Onset Date = CRS Onset Date – Treatment Start Date 
+ 1
Missing otherwise.
Duration (Days) 
CRS Resolution Date – CRS Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on eCRF OR value is missing
NOTES: 

* Treatment phase assumes that the effects of study treatment duration will last a week.

If the study treatment stop date is missing then the CRS event will be considered to be On-Treatment during 
Week 1.


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11.4
Appendix 4: Data Display Standards & Handling 
Conventions
11.4.1
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions (Main / default)
RandAll NG 
Data Displays for Reporting 
Code
Description
Description [1]
Order [2]
A
Placebo intranasal once weekly
Placebo
1
B
GSK2245035 20ng i.n. once weekly
20 ng GSK2245035 i.n. once weekly
2
NOTES:
1.
Abbreviated versions of the treatment descriptions are also permissible if space is restricted e.g., 20ng 
GSK2245035.
2.
Order represents treatments being presented in TFL, as appropriate.
Alternative Treatment Group Descriptions #1
RandAll NG 
Data Displays for Reporting 
Description
Stratum
Description [1]
Order [2]
Placebo
Presumed Allergen
Placebo: Presumed Allergen
1
Unknown Allergen
Placebo: Unknown Allergen
2
20 ng GSK2245035 i.n. 
once weekly
Presumed Allergen
20 ng GSK2245035 i.n. once 
weekly: Presumed Allergen
3
Unknown Allergen
20 ng GSK2245035 i.n. once 
weekly: Unknown Allergen
4
NOTES:
1.
Abbreviated versions of the treatment descriptions are also permissible if space is restricted e.g., 20ng 
GSK2245035: Pres, 20ng GSK2245035: Unk; or Pbo P, Pbo U, 20ng P, 20ng U
2.
Order represents treatments being presented in TFL, as appropriate.


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11.4.2
Baseline Definition & Derivations
11.4.2.1
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/ 
Analysis
Screening 
Visit 1
Screening 
Visit 2
24H After 
Screening 
Visit 2
Day 
1
Pre-
dose
Pre-Dose on 
Corresponding 
Dosing Visit
Efficacy
LAR 
Minimum 
FEV1
X
Screening Visit 
2
LAR: WM 
FEV1
X
Screening Visit 
2
EAR 
Minimum 
FEV1
X
Screening Visit 
2
EAR: WM 
FEV1
X
Screening Visit 
2
Laboratory
Chemistry
X
Day 1 Pre-dose
Haematology
X
Day 1 Pre-dose
Safety
ECG
X
Day 1 Pre-dose
Vital Signs 
(excluding 
body 
temperature)
X
Day 1 Pre-dose
Nasal 
Examination
X
Day 1 Pre-dose
Body 
Temperature
X
DV<x> Pre-
Dose
Pharmacodynamic and Biomarker (including FeNO)
(See Specific model details in Section 8.4.2)
Other Exploratory Endpoints (excluding Diary Card data)
IAC 
Wheal/Flare 
Early Phase
X (15M)
Screening Visit 
2 (15M)


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Parameter
Study Assessments Considered As Baseline
Baseline Used 
in Data 
Display/ 
Analysis
Screening 
Visit 1
Screening 
Visit 2
24H After 
Screening 
Visit 2
Day 
1
Pre-
dose
Pre-Dose on 
Corresponding 
Dosing Visit
IAC 
Wheal/Flare 
Late Phase
X (6H)
Screening Visit 
2 (6H)
NOTES :
1.
Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point. 
11.4.2.2
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Saline1
=Highest Challenge Value – Highest Saline Value
% Change from Saline1
= 100 x [(Highest Challenge Value – Highest Saline Value) / 
Highest Saline Value]
% Attenuation of Reference 
Response
= 100 x [1-(Test Mean/Reference Mean)]
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given time point
   and determine the maximum change
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 11.4.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition should be footnoted on all change from baseline displays.
1.
Example of calculations of Change and % Change from Saline in the BAC:
                                                                         FEV1 Change
Challenge           Planned                      Max       from Max
concentration      relative      FEV1      FEV1         Saline
(squ/mL)                   time      (L)         (L)        (L)      (%)
Saline                      2 M      3.79       4.02
                                3 M       4.02
                                  4 M     3.83
45250                       5 M   
4.11       4.11        0.09     2.2
                                10 M    4.08       4.08     0.06     1.5
                               15 M    3.86     3.86    -0.16    -4.0
                               20 M      3.97      3.97      -0.05   -1.2
                              30 M       4.16      4.16       0.14    3.5
                                45 M     4.12      4.12      0.10      2.5
                    1 H-READ 1     4.14       4.14      0.12      3.0
                    1 H-READ 2     3.76


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11.4.2.3
Imputation for Values Below and Above Limit of Quantification
PD responses which are below the assay’s respective lower limit of quantification (LLQ)
will be imputed using half of the LLQ value.
PD responses which are above the assay’s respective upper limit of quantification (ULQ)
will be imputed using the ULQ value.
In the event that multiple LLQ/ULQ values are present the minimum for that analyte (for
LLQ) and maximum for that analyte (ULQ) should be used in the imputations. If any
LLQ values are zero then a suitable small constant may be used in place, to allow the data
to be log transformed (for example half of the smallest observed non-zero value).
11.4.3
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS and S-Plus software will be used.
Reporting Area
HARP Server
uk1salx00175
HARP Area*
\arprod\gsk2245035\mid205540\final (for CSR)
\arprod\gsk2245035\mid205540\headline (for Headline Results) 
\arprod\gsk2245035\mid205540\interim (for Interim Analysis)
QC Spreadsheet
\arwork\gsk2245035\mid205540\final\documents (for CSR)
\arwork\gsk2245035\mid205540\headline\documents (for Headline Results) 
\arwork\gsk2245035\mid205540\interim\documents (for Interim Analysis)
*=upcoming functionality change in HARP v7 may impose naming conventions which would supersede these 
suggestions for reporting effort names
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards 
Intermediate Datasets

The Bayesian framework necessitates the storage of intermediate outputs datasets 
(convention dictates that they be stored in the dddata folder of the reporting effort). It is 
strongly recommended that a file naming convention be adopted across all MCMC 
analyses to allow easy grouping/location of associated items. The naming convention has 
to follow the SAS dataset length rules, and any HARP naming conventions imposed in the 
upcoming v7 release and existing limitations on special characters, but the following is 
proposed (it may be modified as necessary/appropriate):

The file name is made up of components joined by underscores. This should allow items to 
automatically group/sort when viewed as a list. 
Component 
ID
Description
Examples
Clarification
1
Three letters aligning item to 
its closest study objective
BAC
NAC
TL7
Bronchial Allergen Challenge
Nasal Allergen Challenge
Target engagement


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Reporting Process
IDX
Intradermal Challenge
2
Single letter if the response 
variable was Univariate or 
Multivariate
U
M
Univariate
Multivariate
3
Three letters for the sample 
matrix
FEV
SPU
NLS
NLF
SRM
FEV1 (Lung data)
Sputum
Nasal Lavage Fluid
Nasal Lavage Filters
Serum
4
Up to 5 letters for the 
Item/Analyte (can exceed 5 if 
BICATCD values are longer)
LARWM
LARMI
EARWM
EARMI
<Bicat 
code>
LAR WM 4-10h CFB FEV1
LAR Min CFB FEV1
EAR WM 0-2h CFB FEV1
EAR Min CFB FEV1
<Taken from SI.BIOMARK 
and/or dataset manager>
5
Single digit Population code
1
2
3
4
etc
All Subjects
Per Protocol
mITT
Sputum Producers
(Statistician will need to track 
assignments)
6
Single digit Model ID 
(may vary depending on the 
analysis, so model 1 can have 
different meanings across 
objectives/sample 
matricies/endpoints)
1
2
etc
Pre-BAC Samples only
All BAC Samples
(Statistician will need to track 
assignments on a per 
objectives/sample 
matricies/endpoint basis)
7
Double digit Analysis ID
(specific to the modelling, can 
be used to store the R1-R3 
outputs and models fitted 
whilst covariate building or the 
models with informative priors)
01
02
03
04
etc
Statistician will need to track 
on a per item basis
8
MCMC related item
dsetin
poall
pokdein
+ Others as 
required
The dataset that was passed to 
MCMC
Posterior Summary Stats 
(processed and ready for 
display)
Posterior samples

Example for the input dataset passed to PROC MCMC for the Primary analysis of 
LAR WM4-10h CFB Saline Baseline using the PP population (analysis ID 01): 


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Reporting Process
“BAC_U_FEV_LARWM_2_1_01_dsetin”

Example for the Output statistics (Medians and credible intervals) for the Background samples 
of Nasal Lavage IL-5 using the All Subjects population: “NAC_U_NLS_IL5_1_1_01_poall” 

The above naming convention (excluding item 8) can also be used to name the respective 
reporting effort SAS programs / macros that implement the different analyses
Generation of RTF Files

RTF files will be generated for all reporting efforts.
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.


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Reporting Standards
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.

Where possible the following colour scheme will be adopted noting that treatment comparisons 
against Placebo will utilise the style of GSK2245035 treatment:
Treatment
Colour
Plotting Symbol
Line Style
Placebo once weekly
Blue
Circle, Solid
Solid
20 ng GSK2245035 i.n. 
once weekly
Orange
Triangle (up), Solid
Solid
If applicable, eg individual subject profile plots, a different line style can be applied to distinguish 
Allergen Exposure in the Efficacy Figures.
Treatment
Allergen 
Exposure 
Strata
Colour
Plotting Symbol
Line Style
Placebo once weekly
Presumed
Blue
Circle, Solid
Solid
Unknown
Blue
Circle, Hollow
ShortDash
20 ng GSK2245035 i.n. 
once weekly
Presumed
Orange
Triangle (up), Solid
Solid
Unknown
Orange
Triangle (up), Hollow
ShortDash
In some displays the visits need to be distinguished, in which case the following colour scheme 
should be used whenever possible


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Reporting Standards
Visit
Colour
(SAS Syntax)
Plotting Symbol
Line Style
Screening Visit 1
bioy
Circle, Solid
Solid
Screening Visit 2
green
Diamond, Solid
Solid
Dosing Visit 1
pink
Circle, Solid
LongDash
Dosing Visit 2
brown
Diamond, Solid
LongDash
Dosing Visit 3
dep
HomeDown, Solid
Solid
Dosing Visit 4
lime
Square, Solid
LongDash
Dosing Visit 5
parp
Star, Solid
LongDash
Dosing Visit 6
salmon
Triangle, Solid
Solid
Dosing Visit 7 
vlib
TriangleDown, 
Solid
Solid
Dosing Visit 8
magenta
TriangleLeft, Solid
Solid
Follow Up Visit 1
red
Star, Solid
Solid
Follow Up Visit 2
cyan
Square, Solid
Solid
Follow Up Visit 3
purple
TriangleRight,
Solid
Solid
Note: If there is a need to also distinguish the allergen exposure strata then use of 
Solid/Hollow symbols and Solid/ShortDashed lines can be made, as in the above treatment 
example (with any LongDash mapping to Dot)


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11.5
Appendix 5: Derived and Transformed Data
11.5.1
General
Multiple Measurements at One Time Point

Generally, mean of the measurements will be calculated, unless replicate FEV1 or PEF
measurements exist in which case the maximum will be utilised, 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 

Ref Date < Randomisation Date   → Study Day = Ref Date – Randomisation Date    

Ref Data ≥ Randomisation Date   → Study Day = Ref Date – (Randomisation Date) + 1    
11.5.2
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Date and month will be imputed as ‘30th June’ for every subject.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg)/Height (m)2
Predicted FEV1

Calculated using (Quanjer, 2012), the website www.ers-education.org/guidelines/global-lung-
function-initiative has resources such as a SAS macro and an Individual Subject Excel 
Spreadsheet downloadable from the Tools section of the website that will be provided to the 
sites (see SRM).
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Number of Weekly Doses

Subjects who were randomised but did not report a treatment start date and stop date will be 
categorised as having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of Total Weekly Doses


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11.5.3
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 
Fridericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as : 
Adverse Events

MedDRA version 19.0 or later will be used for coding of AE’s.
Disease Related Events

The following DREs are common in subjects with mild allergic asthma and can be serious/life 
threatening:

wheeziness

chest tightness or chest heaviness

coughing
The start and stop date/time would be recorded for each DRE. The time since 1st dose and 
time since most recent dose should be computed for each DRE.
Cytokine Release Syndrome (CRS)

CRS events will be captured on a modified version of GSK’s standard non-serious AE eCRF 
page. The modification captures whether the item is a CRS event and, if it is, its CRS grading 
score.

For the purposes of summarising data the GSK AE preferred terms (as coded by the dictionary 
groups using the latest version of MEDDRA) will be mapped to the CRS categories as shown 
below:


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CRS 
Category
Examples of GSK AE (Verbatim) 
Terms that might be mapped to each 
CRS category via MEDDRA
MEDDRA Preferred terms (Codes)
Note: Should be cross checked at 
time of analysis since codes may be 
superseded if MEDDRA version 
changes
Headache
Headache
Headache (10019211)
Sinus headache (10040744)
Fever
High temperature, feeling hot and cold 
& shivering
Pyrexia (10037660)
Body temperature increased 
(10005911)
Feeling hot (10016334)
Hyperhidrosis (10020642)
Chills/Rigors
Shivering & trembling
Chills (10008531)
Feeling cold (10016326)
Influenza like illness (10022004)
Nausea
Feeling sick
Nausea (10028813)
Vomiting
Being sick
Vomiting (10047700)
Diarrhoea
Loose stools & frequent bowel 
movements
Diarrhoea (10012735)
Arthralgia 
Arthralgia 
Arthralgia (10003239)
Musculoskeletal stiffness (10052904)
Myalgia
Achy Muscles
Myalgia (10028411)
Back pain (10003988)
Neck pain (10028836)
Pain (10033371)
Pain in extremity (10033425)
Hypotension
Low blood pressure
Hypotension (10021097)
Note: The above may not be an exhaustive list. Therefore, prior to unblinding the medical monitor 
shall review a list of distinct AE preferred terms observed in the study and ensure that they are all 
assigned/mapped to a single CRS category (if the preferred term does not relate to a CRS 
category then it can be mapped as non-CRS; further queries may be raised with the sites if a term 
was not marked by the site as a CRS event but maps to a CRS category via its MEDDRA coding). 


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
In the event that multiple terms with different CRS grading scores are mapped to the same 
CRS category the worst case score (highest severity) should be used in any TLFs.

For each CRS category the total number of occasions (visits) each subject experienced any 
non-zero grade of CRS event should be derived (should range between 0 and 8 if the subject 
completed all dosing visits as planned). This should also be expressed as a proportion of the 
actual dosing visits attended by the subject.

For each subject and dosing visit combination the number of different CRS event categories 
should be derived (where the subjects reported any non-zero grade event); e.g. Subject  
experienced 3 different CRS event types at dosing visit 1, 0 CRS event types at dosing visit 2, 
4 CRS event types at dosing visit 3, etc.
Rescue Medication
Rescue medication (e.g. Salbutamol) administered as part of the BAC procedures will not be 
reported separately (it may be reported as part of the con med listings).
Prior to DBF the medical monitor should review the unique medications in the con med dataset to 
flag any items that should be classified as rescue medications.
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    
P


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11.5.4
Efficacy
LAR and EAR
Schematic
Weighted Mean is defined using the area under the curve divided by the duration of the 
interval (details below).
100
Mean
Adjusted
Reference
Mean
Adjusted
Test
1
sponse
Re
Reference
of
Percentage








n
Attenuatio
LAR
General Considerations

FEV1 measurements taken following the administration of saline will be used as the 
time zero assessment. 

In the event that the administration of saline was repeated for safety reasons (saline 
values must be within 10% of the pre-saline values) the latest saline FEV1 values prior 
to the administration of allergen will be used.

Pre-saline FEV1 values and the FEV1 values recorded as part of the allergen 
concentration selection phase in the Incremental BAC challenge (Screening visit 2) are 
not expected to be used in the statistical analysis of the BAC data but will be included 
in the subject listings if available (e.g. should the coasting procedure occur then it is 
only planned to database the FEV1 values associated with the final outcome but any 
repeat pre-saline values may be captured).
Weighted Mean LAR

Weighted mean will be calculated for FEV1 using the linear trapezoidal rule (see 
formula below).  

Actual relative times will be used for the calculation except where actual times are 
missing.  If any actual times are missing, planned relative time will be used for these 


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LAR and EAR
observations.  Actual relative time will be the time relative to the last inhalation stop 
time.  

The weighted mean will be calculated as the AUC(tf – tl) divided by the tf- tl hrs time 
interval for each subject (tf = time of first observation, tl = time for last observation).












l
f
l
f
i
i
i
i
t
t
t
t
C
C
l
f
1
1
2
1
)
(
Mean 
Weighted
where, 
Ci = highest FEV1 value at planned relative time point I
ti = actual time for planned relative time point i
i = planned relative time of assessment relative to challenge (i.e. 4 hrs, 4.5 hrs, 5
hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs and 10 hrs)
f = first I
l = last I

If an observation is missing between two non-missing observations, the AUC will be 
linearly interpolated between the two non-missing values i.e., the subject’s profile will 
be assumed to be linear between the two available values.  No imputation will be made 
if either the first or last observation is missing. 

If the number of missing values is considered to be substantial, or if the data is not 
considered to be missing at random, a sensitivity analysis will be carried out with 
respect to methods of handling missing data in the calculation of the weighted mean.

The weighted mean will be set to missing for the relevant challenge if any of the 
following occurs:

A short-acting inhaled β-agonist is taken within 8 hours at any time prior to the 
challenge

The dose of allergen administered is different to that of the Screening dose.  Note 
that the dose of allergen used during the treatment period may be modified from the 
total dose received at screening, for safety reasons, at the discretion of the 
investigator.  However, in this case, the modified dose used must be consistent for 
all follow up visits.  [In these cases the baseline will be set to missing.]

The weighted mean LAR will be set to missing if the subject took rescue medication 
prior to the LAR period i.e., between 0 and 4 hours post-saline. 

If rescue medication is administered during the LAR period prior to the completion of 
the 10 hour FEV1 assessment, all FEV1 values recorded after the administration of 
rescue medication for that challenge will be set to the last recorded FEV1 value prior 
to the administration of rescue medication.  The LAR does not have the same natural 
recovery as the EAR, hence this is the most appropriate derivation for the LAR.  The 
weighted mean LAR will then be calculated as above, using the imputed data set. 

If the use of rescue medication is widespread and/or appears to follow a trend, 
appropriate sensitivity analyses to examine the impact of the derivations may be
conducted.  For example, if a large number of subjects are rescued at around 8 hours, 
the weighted mean LAR over 4-8 hours may be derived and analysed as a sensitivity 
analysis.  All sensitivity analyses will be documented in the CPSR.

There may be other conditions that effect the LAR response.  In such situations it may 
be necessary to set the respective response to missing.  Such scenarios will be 


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LAR and EAR
identified and documented before unblinding or DBF.  Appropriate, sensitivity 
analyses may be conducted if other situations are noted following unblinding or DBF.
Minimum LAR

Minimum FEV1 over 4-10 hrs post–saline challenge will be the minimum value of all 
the post-saline time points between 4 to 10 hours post-allergen challenge, inclusive of 
4 hrs and 10 hrs time points i.e., minimum over 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 
6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs and 10 hrs.

Note that the maximum FEV1 value at each planned relative time point will be derived, 
where replicates are taken, for every subject and period, before the minimum values are 
calculated over the specified time period above.

The minimum will be set to missing for the relevant challenge if either of the following 
occurs:

The subject did not receive the correct dose of study medication at any of the 
8-weekly visits.

A short-acting inhaled β-agonist is taken within 8 hours at any time prior to the 
challenge.

If subject took rescue medication prior to the LAR period i.e. between 0 and 4 
hours post-saline administration.

The incorrect dose of allergen is administered for the respective BAC. Note that the 
dose of allergen used during the treatment period may be modified from the total dose 
received at screening for safety reasons at the discretion of the investigator.  However, 
in this case, the modified dose used must be consistent for all follow up visits. In 
these cases only the baseline value will be set to missing (essentially removing the 
subject from any statistical modelling that has the baseline term as a covariate).
There may be other conditions that affect the LAR response.  In such situations it may be 
necessary to set the respective response to missing.  Such scenarios will be identified and 
documented before unblinding.  Appropriate, sensitivity analyses may be conducted if 
other situations are noted following unblinding.
EAR
Weighted Mean EAR

Weighted mean EAR will be calculated for FEV1 using the linear trapezoidal rule as 
per LAR (see above) except using the appropriate EAR time points (i.e., 0 m, 5 m, 
10 m, 15 m, 20 m, 30 m, 45 m, 1 hr, 1.5 hrs and 2 hrs).

In the event that rescue medication is administered prior to the completion of the 
2 hour FEV1 assessment, the weighted mean will be calculated using only FEV1 values 
up to the point of administration of rescue medication. This is considered the most 
appropriate derivation, given the natural self-limiting profile of the EAR. 
Minimum EAR

Minimum EAR will be calculated for FEV1 as per LAR (see above) except using the 
appropriate EAR time points (see above) ie, 0-2 hrs post-saline challenge will be the 
minimum value of all the post-allergen challenge time points up to and including 2 
hours post-allergen challenge i.e., minimum over 5 m, 10 m, 15 m, 20 m, 30 m, 45 m 
and 1 hr, 1.5 hrs and 2 hrs.  Note, saline time point (i.e. 0 hr value) will not be included 
in this calculation. 


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11.5.5
Pharmacodynamic and Biomarker
Pharmacodynamic/Biomarker
TRL7 Induced Blood PD Biomarkers

Fold changes should be computed relative to the Visit 1 pre-dose response (DV1 Pre-Dose), and 
if applicable, to the corresponding pre-dose value from that dosing visit (one value per subject 
per visit and time point combination). Fold changes should be computed using the imputed 
responses.
Sputum Differential Cell Counts
This section is based on understanding of the process and expected data items at time of RAP 
writing. Please consult with GSK Study Statistician at reporting time to confirm what manipulation 
steps are required, as process details may be changed in-stream as experience is gained 
(modifications wouldn’t be captured via a formal RAP amendment but would be documented by the 
GSK study statistician via a note to file - if no changes are required then there will be no related note 
to file).
The following will be provided as source data from the eCRF.  The vendor counting the slides would 
not have access to these values, hence why additional data manipulation is required by GSK Stats 
and Programming. 

‘Total Cell Count (Total Non-Squamous Cells in sample)’
[Equation 4 in the Sputum processing worksheet]

‘Total Leukocytes Count (Total Non-Squamous Cells) per Gram of Selected Sputum Cells’
[Equation 6 in the Sputum processing worksheet]

‘% Viable Leukocytes (% Viability of non-squamous cells)’ 
[Equation 1 in the Sputum processing worksheet] 
Pertinent information to the planned data manipulations that the vendor counting the slides would 
return to GSK data management is:

Was the slide rejected (Y/N) (and if Y the reasons for rejection)

For each slide reader (up to three readers possible): Cell counts of the following types: 
eosinophils, neutrophils, macrophages, lymphocytes, BEC (bronchial epithelial cells) and 
squamous cells. These counts are from a representative set of cells counted on each slide
(vendor expect to count a maximum of ~600 cells to get a minimum of ~400 non-squamous 
cells on each slide). 

The actual numbers of cells counted on the slide are also provided as “Total Cell Count”
(sum of all cell types) and “Total non-squamous cell count” (sum of cell types; eosinophils, 
neutrophils, macrophages, lymphocytes and BEC). As a sanity check the supplied slide
totals (per reader) should match those slide totals derived by hand using the individual cell 
type count results.
Only two readers per slide are expected but the vendor may provide readings from a third reader if 
the results of the initial two readers are sufficiently different (according to the vendor’s standard 


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Pharmacodynamic/Biomarker
operating procedure, currently > 10% for the major cell types eosinophils, macrophages and 
neutrophils). When >2 readers are supplied whichever pair of readers are closest to each other would 
be used in the subsequent derivations but data from all readers would be listed (and the reader pair 
indicated , e.g. R1R3 if Reader1 and Reader 3 used or R1R2 if Reader 1 and Reader 2 used).
The percentage of each leukocyte cell type observed on the slide will be derived for the ith reader as 
follows (leukocyte cells are eosinophils, neutrophils, macrophages, lymphocytes and BEC)
i
Count
Cell
Squamous
-
Non
Total
Absolute
i
Type
Cell
Leukocyte
of
Number
Absolute

i
Slide
on 
Type
Cell
Leukocyte
%
Prior to statistical analysis the results for each reader and slide would be “scaled up” to reflect the 
counts for the sample the slide was constructed with. This requires [Equation 6] information from the 
eCRF page.
The Absolute Leukocyte Cell Types Counts per gram of sputum for the ith reader are derived as
6]
Equation 
[
*
i
Slide
on 
Type
Cell
%Leukocyte
i
sputum
g
 / 
cells
6
 x10
Type
Cell
Leukocyte
Absolute

The geometric mean of the (two) readers would be derived and used in the statistical analyses that 
refer to the Absolute Cells/g sputum endpoint (separate variable for each cell type).
A new total non-squamous cell count variable will be created as the sum of the geometric mean’s of 
the Leukocyte cell types. This total would be used to derive the percentage of each leukocyte cell 
type in the sample (ensures the percentages will sum to 100%) as 
“(Geo Mean Abs Leuk Cell Count / Total) * 100”.
These % endpoints would be used in statistical analyses (separate variable for each cell type)
The following scenarios may result in a sample being deemed as non evaluable (even if the vendor 
provided data back):

Slide not read or rejected

If the value entered in the eCRF for [Equation 1] 70% (implying more than 30% of the non-
squamous cells were not viable). Note: This threshold is study specific and may be altered upon 
review of the complete dataset in consultation with the GSK biology group

> 50% squamous cells of the proportion counted

< 200 total cells counted on the slide

Note: When zero counts are observed for a cell type it complicates the derivation of the 
geometric means. A constant should be added onto all results in the dataset prior to deriving the 
reader geometric mean (separate value for the constant for each cell type). The constant should 
be set to half the smallest observed non-zero scaled up absolute count in the entire dataset for 


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Pharmacodynamic/Biomarker
that cell type, and if all values are zero in the dataset for the cell type then the variable would not 
be analysed but the means would be set to zero.

The following is a worked example for two visits for the same subject.
Values entered on eCRF: 
Visit
% Viable Leukocytes 
(% Viability of non-
squamous cells)
[Equation 1]
Total cell count (106 cells) 
(Total non-squamous cells in 
sample)
[Equation 4]
Total  Leukocytes count 
(Total non-squamous cell 
count) per gram of selected 
sputum (106 cells/g)
[Equation 6]
1  
85
1.062
7.080
2
74
1.11744
6.984
Values supplied by vendor
Visit
Reader
Eos
Neut
Mac
Lym
BEC
Squamous
Tot 
Non-
Squ
Total 
cells
1
1
2
371
38
0
0
96
411
507
1
2
0
348
43
0
0
109
391
500
2
1
4
342
42
0
2
111
390
501
2
2
0
290
50
0
0
160
340
500
Derived % on slides
Visit
Reader
Eos
Neut
Mac
Lym
BEC
1
1
0.49
90.27
9.25
0.00
0.00
1
2
0.00
89.00
11.00
0.00
0.00
2
1
1.03
87.69
10.77
0.00
0.51
2
2
0.00
85.29
14.71
0.00
0.00
Cell counts scaled up to sample and small constant added on to each to allow for zeros (e.g. Add to 
all scaled up BEC values the constant of 0.0178092 = 0.5 * 0.0051 * 6.984)
Visit
Reader
Eos
Neut
Mac
Lym
BEC
1
1
0.052038
6.391116
0.6549
0.00
0.018054
1
2
0.017346
6.3012
0.7788
0.00
0.018054
2
1
0.089281
6.12427
0.752177
0.00
0.053428
2
2
0.017346
5.956654
1.027346
0.00
0.017809


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Pharmacodynamic/Biomarker
Geometric Means and Percentages used in statistical analyses (Lym has imputed Geo mean of zero)
Visit
Item
Eos
Neut
Mac
Lym
BEC
Tot Non-
Squ
1
Abs 
(106
cells/g 
sputum)
0.030044
6.345999
0.714168
0
0.017809
7.108265
1
%
0.42
89.28
10.05
0
0.25
2
Abs
(106
cells/g 
sputum)
0.039353
6.03988
0.87906
0
0.030846
6.98914
2
%
0.56
86.42
12.58
0
0.44
WBC Differentials

Note: When zero percentages are observed the corresponding cell count is also zero. Therefore 
if the count data require log transformations the constant to add on should be set at half the 
smallest observed non-zero count in the corresponding dataset
11.5.6
Exploratory Analyses
Intradermal Allergen Challenge
Wheal/Flare Derivations

The wheal and flare derived value to be used in the summaries and figures will be 
calculated as follows:

At each planned timepoint both the Wheal (also referred to as Induration in some 
study documents) and Flare components will have two measurements databased; 
namely the longest and orthogonal diameters. The mean diameter for each component 
is the average of these two values. For display purposes the label “Wheal” should be 
used rather than “Induration”. An example is illustrated below


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Intradermal Allergen Challenge

Mean Diameter (Wheal) = (A1+A2) / 2

Mean Diameter (Flare) = (B1+B2) / 2

For each subject and planned sampling time the Mean Diameter Wheal values for each 
allergen should be compared to the corresponding Negative control value as an 
additional data validation check. A flag variable should capture if the Mean Diameter 
Wheal response on Challenge not at least 3mm larger than the corresponding Negative 
control value (i.e. flag if Wheal Mean Diameter Challenge – Wheal Mean Diameter 
Negative Control Challenge <= 3mm). 
Total Nasal Symptom Score (Diary card)
Daily Score Derivation (TNSS and its individual components) – daily scores sometimes 
referred to as “Overall”

The Daily Score is calculated as the mean of the (non-missing) respective AM and PM 
assessments (e.g. Daily TNSS = Mean of AM TNSS and PM TNSS values; Daily 
nasal congestion score = Mean of AM nasal congestion score and PM nasal 
congestion score, etc. A daily score would only be recorded as missing if both the AM 
and PM assessment are missing on that day.
Weekly Weighted Mean Derivation

Each diary card week begins on the planned day of dosing (relative to the date of 
dosing at DV1) and contains 7 days of data, i.e. Week 1 contains days 1 to 7 inclusive, 
Week 2 contains days 8 to 14 inclusive etc.

The weekly weighted means are derived from the 7 days of data using a similar 
approach to the BAC endpoints. The exceptions are i) no actual time, but only planned 
times, starting at 1 and ending at 7 for each weeks worth of data, ii) the first and last 
values (day 1 and 7 within the week) may be missing and a valid WM derived (the 


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Total Nasal Symptom Score (Diary card)
WM would only not be derived if 4 or more days within the week were missing; in 
which case the Weekly WM would also be set to missing) and iii) No BAC specific 
rules e.g. setting WM means to missing based on rescue medication, SABA or 
incorrect BAC allergen administration.

If the number of missing WM values is considered to be substantial, or if the data is 
not considered to be missing at random, a sensitivity analysis may be carried out with 
respect to methods of handling missing data in the calculation of the weighted mean.


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11.6
Appendix 6: Premature Withdrawals & Handling of Missing 
Data
11.6.1
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as one 
who has completed all phases of the study including all of the follow-up visits.

Withdrawn subjects may be replaced in the study.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
11.6.2
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.
11.6.2.1
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 as per Appendix
3: Treatment States and Phases.
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.


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Element
Reporting Detail

Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied.
11.6.2.2
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 this 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.
11.6.2.3
Handling of Missing Data for Statistical Analysis
The SAS PROC MCMC framework automatically assumes/implements a missing at 
random / multiple imputation approach if any of the supplied response variables are 
missing. This is deemed to be sufficient given the exploratory nature of the study. 
However, if a large proportion of data are missing then alternative approaches may be 
considered. 
Several analyses are specified as being conditional on there being sufficient non-missing 
data to take place (e.g. Sputum and biomarkers with large proportions of LLQ values).
If model covariates are missing (e.g. Baseline) then the best approach will be selected on 
a case by case basis, but may involve omitting the record or imputing a response based on 
other data prior to fitting the observation model. 
Given the exploratory nature of this study and the large number of endpoints it is not 
possible to pre-specify/cover all eventualities but any missing data approaches 
investigated would be documented in the CPSR and if deemed important included in the 
outputs as sensitivity analyses.


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11.7
Appendix 7: Values of Potential Clinical Importance
11.7.1
Laboratory Values
Hematology Analyte
Effect
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
White Blood Cell Count 
0.67
1.82
Neutrophil Count
0.83
Lymphocytes
0.81
Hemoglobin
Male
1.03
Female
1.13
Hematocrit
Male
1.02
Female
1.17
Platelet Count
0.67
1.57
Absolute – Low
Absolute – High
MCV (fL)
< 80
> 100
MCH (pg/cell)
< 25.78
> 34
Monocytes (K/mL)
< 0.1
> 0.9
Eosinophils (K/mL)
< 0
> 0.6
Basophils (K/mL)
< 0
> 0.9
Chemistry Analyte
Effect
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
Albumin (mmol/L)
0.86
Calcium (mmol/L)
0.91
1.06
Glucose (mmol/L)
0.71
1.41
Potassium (mmol/L)
0.86
1.10
Sodium (mmol/L)
0.96
1.03
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2×ULN
AST/SGOT 
U/L
High
2×ULN
Alkaline Phosphatase
U/L
High
2×ULN
Total Bilirubin 
µmol/L
High
1.5×ULN
Total Bilirubin + ALT
µmol/L
High
1.5×ULN Total Bilirubin
+
U/L
2×ULN ALT


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Note: The following lab tests are being collected in this study but have not had PCI 
ranges defined: RBC Count, BUN, Creatinine, Direct Bilirubin and Total Protein. The 
maximum and minimum observed values will be reported as part of the lab summary 
tables and this is deemed sufficient to identify potentially extreme values which would 
then be investigated further if required.
11.7.2
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450
Absolute PR Interval
msec
< 110
> 220
Absolute QRS Interval
msec
< 75
> 110
Change from Baseline
Increase from Baseline QTc
msec
> 60
11.7.3
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
Body Temperature
°C
< 36.0
> 37.5
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
Clinical Concern Range
Lower
Upper
Body Temperature
°C
< -1
> +1


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11.8
Appendix 8: Multicentre Studies
11.8.1
Methods for Handling Centres

See Section 11.9.1 for details of how centres will be handled in the statistical 
modelling.


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11.9
Appendix 9: Examination of Covariates, Subgroups & Other 
Strata
11.9.1
Handling of Covariates, Subgroups & Other Strata

The following is a list of covariates that may be used in descriptive summaries and
statistical analyses, some of which may also be used for subgroup analyses.

Additional covariates of clinical interest may also be considered. 

If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial.  

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.

To avoid parameter estimation problems caused by the small sample size (i.e. empty 
cells in the possible combinations of centre, treatment and allergen exposure) the 
default approach (unless specified otherwise) for fitting centre in statistical models is 
to handle it as a random effect (Normally distributed with mean zero and a SD 
appropriate to the endpoint). Where possible historical data would be used to form a 
weakly informative prior for the SD, with the specific value described in the 
corresponding RAP section. If historical data are not available then the distribution 
for the random centre effects would use a SD value of 1000.

For analyses without repeated measures over visit, the output from fitting three 
nested models (M1-M3) to each statistical analysis should be available (e.g. listing 
form); but inferences (summary tables and figures) would be produced from the final 
chosen model only. The three models represent possible combinations of centre 
(fitted as a random effect), treatment and allergen exposure status (fitted as fixed 
effects). The models may include other terms appropriate to the analysis, but any
further covariate exploration activity would start using the selected model (M1, M2 
or M3) as its base:

M1: Centre + Treatment + Allergen Exposure + Treatment*Allergen Exposure 
+ <other terms>

M2: Centre + Treatment + Allergen Exposure + <other terms>

M3: Centre + Treatment + <other terms>
Where Treatment = “Placebo” or “20ng GSK2245035”, Allergen Exposure = 
“Presumed allergen” or “Unknown allergen” and Centre is the random effect 
drawn from the N(0, SD) distribution.

The DIC criteria (which may be overruled by expert judgement) would be used 
to select from Models M1-M3 (see Section 11.11.1). To aid review DIC values 
from models M1 to M3 should also be summarised in one location in the listing. 
Examples of expert judgement would be rejecting model M1, even if the DIC 


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suggested otherwise, if the effect size was deemed to be too small to be 
clinically important/relevant (i.e. differences in the point estimates for the 
presumed and unknown allergen exposure responses are clinically unimportant). 
Other examples of expert judgement include making an overarching decision on 
the model structure based on all endpoints of a similar nature (e.g. choosing a 
model form (M1, M2 or M3) for both primary endpoints, or for all serum 
biomarkers measuring TLR7 induction).

An analogous set of three models should be used when comparisons of treatment 
within multiple visits are of interest:

R1: Centre + Treatment + Visit + Allergen Exposure + Treatment*Visit  + 
Allergen Exposure*Visit  + Treatment*Allergen Exposure + 
Treatment*Allergen Exposure*Visit + <other terms>

R2: Centre + Treatment + Visit + Allergen Exposure + Treatment*Visit + 
Allergen Exposure*Visit + <other terms>

R3: Centre + Treatment + Visit + Treatment*Visit + <other terms>

If any of the models M1-M3 (or R1-R3) cannot be fitted then the formal process to 
select models described above is not possible and the default approach should be to 
use the simplest model form that has acceptable model convergence. 
Category
Covariates and / or Subgroups
Centre
One level per site contributing evaluable data to the analysis. 
Sites may be grouped by country for display purposes.
If pooling of centres is deemed necessary the strategy would be 
to pool centres within the same country before attempting to 
pool centres over different countries.
Country
Currently planned to be either “UK” or “Germany” but other 
countries may be utilised.
Allergen Exposure
“Presumed allergen” or “Unknown allergen”
Blood Eosinophil Levels 
(Cells/mL)
Although the planned statistical modelling will fit this term as a 
continuous covariate the following categorical variables may be 
derived based on 
i)
Baseline (SV2) Blood Eosinophils: 
<150 Cells/mL and >= 150 Cell/mL
ii)
BAC visit Blood Eosinophil Levels: 
<150 Cells/mL and >= 150 Cell/mL
Sputum Eosinophil Levels (%)
Note: Only if data are available
Although only derivable for subjects/timepoints where sputum 
samples were produced and were viable the following variables 
should be created for use as potential categorical covariates 
based on 
i)
Baseline (SV2) Sputum Eosinophils: <= 2% and > 2%
ii)
BAC visit Sputum Eosinophils: <= 2% and > 2%
iii) Baseline (SV2) Sputum Eosinophils: <= Median of 
Observed values and > Median of Observed values


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Category
Covariates and / or Subgroups
iv) BAC visit Sputum Eosinophils: <= Median of Observed 
values and > Median of Observed values
FeNo (Ppb)
Potential categorical covariate based on
i)
<= 25 ppb and > 25 ppb


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11.10
Appendix 10: Multiple Comparisons & Multiplicity
11.10.1
Handling of Multiple Comparisons & Multiplicity
Due to the extensive use of a Bayesian framework and the early phase / exploratory 
medicine nature of this study there will be no explicit multiplicity adjustments.


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11.11
Appendix 11: Model Checking and Diagnostics for 
Statistical Analyses
11.11.1
Statistical Analysis Assumptions
Endpoint(s)

All which are modelled using a Bayesian framework
Analysis

Bayesian (Proc MCMC)
General Considerations for Bayesian Analyses (PROC MCMC):
The following points are for guidance and illustration and do not guarantee a successful 
model convergence. They cannot cover all eventualities and do not remove the 
requirement to do what is best for the specific set of observed data being modelled.
Priors:
Unless otherwise specified the following would be the default approach to selecting prior 
distributions:

Non-informative priors of the form Normal(0, Var=1E6) would be assigned to each fixed effect 
in the proposed statistical model.

Non-informative Inverse-gamma priors of the form IGamma(0.001,0.001) would be assigned to 
stand-alone variance parameters that are not expected to take values near zero (e.g. for the 
residual variance rather than a random effect variance component)

For stand-alone variance parameters that may take values close to zero a non-informative 
prior of the form Uniform(0, XXX) may be assigned for the SD

For repeated measures models non-informative Inverse-Wishart priors will be assigned for the 
Variance Covariance matrix (VCV). They would use degrees of freedom equal to the 
dimension of the VCV matrix and an Identity matrix (of the same dimension).

If there are issues with those variance parameters then the Identitity matrix may be replaced 
with a diagonal matrix that uses best guesses for the residual variance at each repeated 
measure time point (or the residual estimates from fitting simple models)

It is good practice to ensure that each prior distribution is visualised to ensure it appears 
sensible and allows clinically plausible response values, whilst not allowing impossible values 
to be drawn with high probability and that if it is intended to be non-informative it is doing so 
over the region of the likelihood function.
Note: There is no requirement to formally report these visualisation outputs. 
Initial Values:
Unless otherwise specified initial parameter values of zero would be used for the fixed 
effect parameters and for remaining model parameters initial values may be drawn at 
random from their respective prior distribution. If model converge is problematic then 
alternative estimates, more suited to the particular dataset being modelled, may be used 
(for example, these could be based on visual inspection of the raw data and/or parameter 
estimates from fitting simpler models).
Checking Convergence and Other Diagnostics:
The key model diagnostic output is the MCSE/SD ratio for each parameter:

Adequate values for the number of MCMC samples / thinning / number of burn in 


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samples should be chosen to ensure that the MCSE/SD for the key parameters is 
below 0.01 (e.g. key parameters those associated with treatment, or as pre-specified 
comparisons of interest) in each final model.

For other model parameters, try to get the MCSE/SD values as close to 0.01 as 
possible, but if there is significant autocorrelation then values below 0.05 would be 
considered acceptable.

In addition, the number of tuning units and maximum number of tuning iterations 
may be increased to find a better multivariate normal approximation to the 
parameters, which in turn may reduce the MCSE/SD values

Where possible the code should be written to allow the SAS compiler to identify and 
use conjugate sampling, since this can greatly reduce the corresponding MCSE/SD 
values

Models selected with MCSE/SD values above 0.01 (for key parameters) or 0.05 (for 
other parameters) would need a brief remark/justification added to the QC log and/or 
CPSR to clarify why it was not possible to reach the targets and why it is believed the 
subsequent model still has utility.
Use of the default SAS PROC MCMC diagnostic plots should be made and where 
possible:

Autocorrelation should decline rapidly and show no oscillation patterns

Worm plots should show the chain appears to be stationary and mixing, i.e. 
o Constant mean, constant variance
o Moving around the parameter space freely (not getting “stuck” at similar values 
for a large number of iterations before moving on again)   
o Moving rapidly between extremes

The posterior density should look reasonable for each parameter (e.g. for posterior 
parameters expected to follow a normal distribution the density plot should not appear 
bi-modal, but for parameters acting as binary flags then bi-modal is acceptable)
Use of a bespoke GSK utility macro “%ScatterHist” is encouraged to examine correlation 
structures between relevant posterior parameters (and/or parameters in each PARMS 
block). This can provide information about what potential issues may be and also what 
corrective action(s) may be worthwhile attempting. 
(SAS macro code of the most up to date version including any refinements would be 
available from GSK internal training course materials – modifications may be made to 
improve axis scales and legibility as required).
Possible corrective actions:
Possible corrective actions include but are not limited to:

Moving parameters (or combinations of parameters) onto separate PARMS statements (to 
form blocks that are updated independently in the MCMC algorithms)

Increasing the number of MCMC draws from the posterior distributions

Increasing the length of the burn in period

Increasing the thinning parameter (to reduce the autocorrelation)

Centring covariates (to reduce correlations between the posterior parameters)

Re-parameterising the model (e.g. using log-normal prior distributions to stop values being 


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sampled that are below zero)

Re-scaling the parameters (e.g. if one parameter takes values orders of magnitudes different 
to the other model parameters then dividing it by a suitable constant but back transforming the 
rescaled parameter prior to its use in any subsequent manipulations)

Visualising the likelihood function of the dataset to determine if there are more appropriate 
starting estimates (or profiled versions of the likelihood for subsets of model parameters where 
difficulties are being encountered if it is a high dimensionality problem)

Consulting with internal GSK experts to resolve the issues
Model selection / Criteria for assessing covariates:
The following is a “rule of thumb” only; the study statistician’s expert judgment based on the 
observed data / context of the endpoint / scientific & biological rationale for including a covariate 
may override this:

Changes in Deviance Information Criterion (DIC) may be used to compare models that have 
been fitted to the same dependent variable (endpoint). In general the model with the lowest 
DIC would be preferred; although the simpler models would be selected if the differences in 
DIC were sufficiently small (see below for guidance on what constitutes sufficiently small).

Since most of the proposed MCMC modeling is undertaken using non-informative priors the 
DIC approximates Akaike Information Crikteria (AIC) and therefore the AIC “rules of thumb” 
may be used to guide the selection as follows: Suppose there are R candidate models. Let 
DIC1, DIC2, …, DICR be the Deviance Information Criteria for each model and let DICmin be the 
minimum of these values.  

“Models receiving DIC within 1–2 of the ‘best’ (DICmin) deserve consideration, and models 
within 3–7 have considerably less support” (Spiegelhalter, 2002). These boundaries have been 
modified so that there are no gaps as follows: if the difference in DIC is < 1 then choose the 
simpler model, refine the “deserve consideration” range to be 1< Diff DIC <= 2.5 and the “less 
support” range to be 2.5 < Diff DIC <=7. Models receiving DIC in excess of 7 from DICmin
should not be considered unless there is sufficient scientific/biological rationale for favoring the 
additional model / covariates.
Utilising the posterior distributions:

In the relevant statistical analysis sections pre-specified quantities of interest are 
supplied to be obtained from the posterior distribution (e.g. Table 14). These lists 
should not be considered exhaustive and may be amended as further information 
becomes available (for example, but not limited to, if competitors publish results that 
set a new benchmark then GSK2245035 may be compared to that benchmark by 
adding it to the list of cut points). Results from any additions should appear after the 
pre-specified quantities in the corresponding outputs.

Equi-tail credible intervals should be used, since they are invariant under 
transformation of the parameter space (unlike Highest Posterior Density).

In addition, truncation of the x-axis ranges for posterior distributions may be 
necessary if there are a small number of extreme value posterior samples that would 
otherwise inhibit interpretation of where the bulk of the distribution lies. Appropriate 
footnotes should indicate whether axes have been truncated and give an indication of 
the level of truncation (e.g. 5 values are truncated, or less than 0.1% of posterior 
samples are truncated).


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
To facilitate review the posterior distributions may be grouped into lattice plots to 
move more towards the “big picture on one page”. SAS PROC MCMC uses the 
density statement in GTL to produce its internal diagnostic figures from the dataset of 
posterior samples; hence it is possible to re-produce and add customisations to those 
density plots (such as displaying them in a lattice layout); although it may require on 
the fly combinations of several of the temporary datasets that store the individual 
MCMC samples. 


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11.12
Appendix 12 – Abbreviations & Trade Marks
11.12.1
Abbreviations
Abbreviation
Description
A&R
Analysis and Reporting 
Act
Active Drug in this study 20 ng GSK2245035 i.n. once weekly
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
ALQ
Above Limit of Quantification
ALT/SGPT
Alanine Amino Transferase / Serum Glutamic-Pyruvic Transaminase
AST/SGOT
Aspartate Amino Transferase / Serum Glutamic Oxaloacetic 
Transaminase
AZ
AstraZeneca
BAC
Bronchial Allergen Challenge
BEC
Bronchial Epithelial Cells
BLQ
Below Limit of Quantification
BUN
Blood Urea Nitrogen
CB / CFB
Change from Baseline
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
CPMS
Clinical Pharmacology Modelling & Simulation
CrI
Credible interval (may also be denoted CI if context is clear that it refers 
to an interval)
CRS
Cytokine Release Syndrome
CS
Clinical Statistics
CSR / CPSR
Clinical Study Report / Clinical Pharmacology Study Report (terms can 
be used interchangeably)
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DIC
Deviance Information Criterion
DOB
Date of Birth
DP
Decimal Places
DVx
xth Dosing Visit (x = 1 to 8)
EAR
Early Asthmatic Response
eCRF
Electronic Case Record Form
EudraCT
European Clinical Trials Database
FDAAA
Food and Drug Administration Amendments Act
FeNO
Fractional exhaled Nitric Oxide
FEV1
Forced Expiratory Volume in 1 Second
FUVx
xth Follow Up Visit (x = 1 to 3)
GSK
GlaxoSmithKline


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Abbreviation
Description
GUI
Guidance
HARP
Harmonisation for Analysis of the Reporting Program
IA
Interim Analysis
IAC and/or 
IAD
Intradermal Allergen Challenge
IC and/or ID
Intradermal Challenge
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
IVRS
Interactive Voice Response System
LAR
Late Asthmatic Response
LLQ
Lower Limit of Quantification
LOC
Last Observation Carries Forward
Max
Maximum
MCMC
Markov Chain Monte Carlo
Min
Minimum
mITT
Modified Intent-To-Treat
MMRM
Mixed Model Repeated Measures
MVN
Multivariate normal distribution
NAC
Nasal Allergen Challenge
Pbo
Placebo
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PP
Per-Protocol
PP
Posterior Probability
QC
Quality Control
QTcB
Bazett’s QT Interval Corrected for Heart Rate
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
RAMOS (NG)
Randomization & Medication Ordering System (Next Generation)
RAP
Reporting & Analysis Plan
SABA
Short-acting beta-agonist
SAC
Statistical Analysis Complete
SAS
Statistical Analysis System
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SE
Standard Error
SOC
System Organ Class
SOP
Standard Operation Procedure
SVx
xth Screening Visit
TA
Therapeutic Area


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Abbreviation
Description
TFL
Tables, Figures & Listings
TLR7
Toll Like Receptor 7
TNSS
Total Nasal Symptom Score
TSCG
TIBCO Spotfire Clinical Graphics
ULQ
Upper Limit of Quantification
VCV
Variance Co-Variance
WM
Weighted Mean
11.12.2
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
TSCG


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11.13
Appendix 13: List of Data Displays
11.13.1
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Pharmacokinetic
4.1 to 4.n
4.1 to 4.n
Pharmacodynamic and / or Biomarker
5.1 to 5.n
5.1 to 5.n
Exploratory
6.1 to 6.n
6.1 to 6.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
11.13.2
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example
mock-up displays provided in Appendix 14: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic and Biomarker
PD_Fn
PD_Tn
PD_Ln
Exploratory
EXP_Fn
EXP_Tn
EXP_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
11.13.3
Deliverable [Priority] and Responsibility (including AR datasets)
Delivery [Priority] [1]
Description
IA [X]
Interim Analysis 
HR [X]
Headline Results During Study (i.e., in-stream data review)
SAC [X]
Final Statistical Analysis Complete
NOTES: 
1: Indicates priority (i.e. order) in which displays will be generated for the reporting effort [1] = Highest priority, [2] 
= 2nd highest priority, etc.


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Unless indicated otherwise GSK will be responsible for producing each planned output. 
Outputs marked “FSP” in the “Deliverable Priority” column should be produced by the 
associated Full Service Provider.
The FSP should discuss with GSK whether they are also responsible for the associated 
analysis and reporting dataset (AR dataset) if it is not obvious. For example, the ECG 
outputs are solely the responsibility of the FSP and thus the AR ECG dataset would 
naturally be their responsibility too, but some outputs can be split between organisations 
and it may be that additional variables are requested for a common AR dataset by either 
organisation. For example, the AE dataset has to be modified to contain the study specific 
CRS related variables, and it is likely that GSK will assume responsibility for the 
production and QC of this modified AR AE dataset as they will produce it to allow in 
stream reviews by the Safety Review Team and the production of the related CRS 
outputs; but that this same dataset will be used by the FSP to produce the standard AE 
Tables and Listings using the standard macros. The (shared study) QC spreadsheet will 
document these agreements on the number/names of the AR datasets required to report 
the study and the associated accountability and QC duties (preliminary discussions / 
assignments to occur at the GSK and FSP study kick off meeting).
In some instances additional outputs may be required. To avoid GSK and the FSP(s) re-
using the same number the (shared study) QC spreadsheet will be the definitive source of 
output numbers for the study that are not already pre-specified in the RAP. It should be 
consulted and a record added to allocate/reserve the next available number(s) before 
creating new display(s) in the HARP system.


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11.13.4
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
All Subjects
ES1
Summary of Subject Disposition
ICH E3, GSK CTR, FDAAA, EudraCT
IA 1, HR 1, SAC 
1
1.2.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
Used with Summary of Study 
Populations and Summary of Subject 
Disposition to create Consort diagram.
FSP: SAC 1
1.3.
All Subjects
NS1
Summary of Number of Subjects by Country and Centre
EudraCT
IA 1, HR 1, SAC 
1
1.4.
All Subjects
NS1
Summary of Number of Subjects by Country, Centre and 
Allergen Exposure Strata
IA 1, HR 1, SAC 
1
Protocol Deviation
1.5.
All Subjects
DV1
Summary of Important Protocol Deviations
ICH E3
IA 1, HR 1, SAC 
1
Population Analysed
1.6.
Screened
SP1 and SP2
Summary of Study Populations and Exclusions
Use IDSL terminology
Combine the SP1 and SP2 
structures into the same display. 
Summary table may not be 
necessary if there are few study 
populations (e.g., only Safety 
and PK, and the sample sizes 
are apparent from other outputs).
IA 1, HR 1, SAC 
1


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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
1.7.
All Subjects
DM1
Summary of Demographic Characteristics
ICH E3, GSK CTR, FDAAA, EudraCT
IA 1, HR 1, SAC 
1
1.8.
Enrolled
DM11
Summary of Age Ranges
FDAAA, EudraCT
FSP: SAC 1
1.9.
All Subjects
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
IA 1, HR 1, SAC 
1
1.10.
All Subjects
POP_T1
Summary of the Selected Allergen from the Skin Prick Tests at 
Screening
IA 1, HR 1, SAC 
1
Prior and Concomitant Medications
1.11.
All Subjects
MH4
Summary of Past Medical Conditions
ICH E3
FSP: SAC 2
1.12.
All Subjects
MH4
Summary of Current Medical Conditions
ICH E3
FSP: SAC 2
1.13.
All Subjects
CM1
Summary of Concomitant Medications
ICH E3
FSP: SAC 2


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11.13.5
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
LAR
2.1.
PP
EFF_T1 
(also see 
gw685698_gw6
42444 Study 
hza113126 final 
reporting effort 
Table 10.1)
Summary of Bronchial Allergen Challenge Minimum and 
Weighted Mean LAR Absolute Change from Saline by Visit
Include an additional column for Visit 
between the Shell columns “Treatment” 
& “N” (group items by treatment then 
visit)  and modify Parameter names as 
appropriate to the information being 
displayed 
IA 1, HR 1, SAC 
1
2.2.
PP
EFF_T1
Sensitivity Analysis: Summary of Bronchial Allergen Challenge 
Minimum and Weighted Mean LAR Absolute Change from 
Saline by Visit and Blood Eosinophil Level
As per main summary table with 
additional column for the Blood 
Eosinophil group (arranged so that 
groups from the same visit appear in
consecutive rows)
SAC 2


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.3.
PP
EFF_T2 
(also see 
gsk2245035 
mid204509 final 
Table 5.2)
Summary of Posterior Distributions and Posterior Probability 
statements - Bronchial Allergen Challenge Primary Analysis 
Minimum and Weighted Mean LAR Absolute Change from
Saline at Week 9 (FUV1)
Four (or Three part Table if no baseline 
terms). 1st Part: Raw Baseline values 
and Baseline covariate value 
predictions made at. Also add values 
used to determine predictions for any 
other covariates included in final model.  
2nd part “Model Adjusted” predictions for 
Treatment and Timepoint combinations; 
3rd part Summarises the posterior 
distributions for each comparison and 
4th part lists the posterior probabilities
evaluated from each comparison
Include the SD from the posterior 
distribution inbetween the “Median” and 
“95% CrI” columns (Parts 2 and 3).
Also include the 70% CrI (Parts 2 and 
3)
Also present the results as percentage 
attenuations in the Comparisons and 
Probability statements parts
Replace/relabel Analyte(units) to be the 
Parameter/response from the 
modelling. Add column for Allergen 
Strata after the “Treatment” column if 
the final model used for inferences 
requires it.
IA 1, HR 1, SAC 
1
2.4.
mITT
EFF_T2
Summary of Posterior Distributions and Posterior Probability 
statements - Bronchial Allergen Challenge Minimum and 
Weighted Mean LAR Absolute Change from Saline at Week 9 
(FUV1)
Conditional on PP and mITT 
populations differing.
As per PP equivalent
SAC 1


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.5.
PP
EFF_T2
Sensitivity Analysis: Summary of Posterior Distributions and 
Posterior Probability statements - Bronchial Allergen Challenge 
Minimum and Weighted Mean LAR Absolute Change from 
Saline at Week 9 (FUV1) using Informative Priors
Sensitivity analysis: Display priors as 
footnotes / or as appropriate in the 
output
HR 2, SAC 2
2.6.
PP
EFF_T2
Sensitivity Analysis: Summary of Posterior Distributions and 
Posterior Probability statements - Bronchial Allergen Challenge 
Minimum and Weighted Mean LAR Absolute Change from 
Saline at Week 9 (FUV1) using Blood Eosinophil level as a 
covariate
Modify Table structure to also indicate 
which value of esoinophils the 
prediction/item is associated with 
SAC 2
2.7.
PP
EFF_T2
Summary of Repeated Measures Posterior Distributions and 
Posterior Probability statements - Bronchial Allergen Challenge 
Minimum and Weighted Mean LAR Absolute Change from 
Saline 
As per single timepoint version (the 
Planned Time column should contain 
the Visit and Timepoints within visits, 
e.g. FUV1, FUV2)
SAC 2
2.8.
mITT
EFF_T2
Summary of Repeated Measures Posterior Distributions and 
Posterior Probability statements - Bronchial Allergen Challenge 
Minimum and Weighted Mean LAR Absolute Change from 
Saline
Conditional on PP and mITT 
populations differing. 
As per PP equivalent version
SAC 2
2.9.
PP
EFF_T2
Sensitivity Analysis Summary of Repeated Measures Posterior 
Distributions and Posterior Probability statements - Bronchial 
Allergen Challenge Minimum and Weighted Mean LAR Absolute 
Change from Saline using Blood Eosinophil level as a covariate
As per PP equivalent version but 
modify Table structure to also indicate 
which value of esoinophils the 
prediction/item is associated with
SAC 2
EAR
2.10.
PP
EFF_T1
Summary of Bronchial Allergen Challenge Minimum and 
Weighted Mean EAR Absolute Change from Saline by Visit
As per LAR equivalent
SAC 1
2.11.
PP
EFF_T1
Sensitivity Analysis: Summary of Bronchial Allergen Challenge 
Minimum and Weighted Mean EAR Absolute Change from 
Saline by Visit and Blood Eosinophil Level
As per LAR equivalent
SAC 2


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12.
PP
EFF_T2
Summary of Posterior Distributions and Posterior Probability 
statements - Bronchial Allergen Challenge Minimum and 
Weighted Mean EAR Absolute Change from Saline at Week 9 
(FUV1)
As per LAR equivalent
SAC 1
2.13.
PP
EFF_T2
Sensitivity Analysis: Summary of Posterior Distributions and 
Posterior Probability statements - Bronchial Allergen Challenge 
Minimum and Weighted Mean EAR Absolute Change from 
Saline at Week 9 (FUV1) using Blood Eosinophil level as a 
covariate
As per LAR equivalent
SAC 2
2.14.
PP
EFF_T2
Summary of Repeated Measures Posterior Distributions and 
Posterior Probability statements - Bronchial Allergen Challenge 
Minimum and Weighted Mean EAR Absolute Change from 
Saline 
As per LAR equivalent
SAC 2
2.15.
PP
EFF_T2
Sensitivity Analysis: Summary of Repeated Measures Posterior 
Distributions and Posterior Probability statements - Bronchial 
Allergen Challenge Minimum and Weighted Mean EAR Absolute 
Change from Saline using Blood Eosinophil level as a covariate
As per LAR equivalent
SAC 2


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11.13.6
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
LAR
2.1.
PP
EFF_F2
Boxplots of derived LAR endpoints By Visit and 
Treatment/Allergen Strata Combinations
Overlay individual data points next to 
boxes (but do not obscure key features 
such as mean/median symbols and 
whiskers/outliers)
Use default SAS boxplot type
Deviate from treatment/strata colour 
schemes if necessary to  display all 
information types (e.g. use different box 
fill colours/patterns for presumed and 
unknown allergen strata)
IA 1, HR 1, SAC 
1
2.2.
PP
EFF_F7
By Subject time profiles of derived LAR endpoints grouped by 
Treatment/Allergen Strata Combinations
Separate Page per endpoint
Separate spaghetti plots for each 
treatment arm/allergen strata (arrange 
in lattice with treatment as columns and 
allergen strata as rows). Join individual 
subjects visits (use separate 
colours/symbols/line styles for each 
subject) but use same legend across 
both endpoints. If space permits include 
the subject IDs in a legend (however it 
is anticipated that there will not be 
sufficient space and the legend would 
be omitted). Use same y-axis and x-
axis range for each of the panels on a 
page 
IA 1, HR 1, SAC 
1


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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.3.
PP
EFF_F3 and 
EFF_F4
Bronchial Allergen Challenge Scatterplots of Minimum Vs 
Weighted Mean LAR Absolute Change from Saline by Visit
One page per BAC visit.
1st set of 4 pages should use Main 
treatment descriptors (EFF_F3) and 2nd
set of 4 pages should use Alternative 
treatment descriptors (EFF_F4)
Diagonal reference line (y=x)
Marginal panels are Kernel Density 
Estimate smoothers, Pearson 
correlation coefficient for overall dataset 
(not split by treatments)
IA 1, HR 1, SAC 
1
2.4.
PP
EFF_F5
Bronchial Allergen Challenge Point estimates and Credible 
Intervals (70% and 95%) from the Primary Analysis of LAR 
Minimum and Weighted Mean LAR Absolute Change from 
Saline endpoints at Week 9 (FUV1)
Display results from Primary analysis 
(i.e. not repeated measures model 
output) Median plus 70% & 95% CrI
If final model uses allergen strata then 
split the treatments by strata and 
present comparisons within strata
Separate page per endpoint (WM and 
Min) and confidence level for the 
credible intervals (70% and 95%); i.e. 
four pages in total
To facilitate production of presentations 
/ publications include each individual 
panel on its own page at the end of the 
display.
IA 1, HR 1, SAC 
1


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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.5.
PP
EFF_F6
& Fig12.135 
(idslfinal 
reporting effort 
of GSK2245035 
TL7116958 
study)
Bronchial Allergen Challenge Posterior Distribution Density Plots 
from the Primary Analysis of LAR Minimum and Weighted Mean 
LAR Absolute Change from Saline endpoints at Week 9 (FUV1)
Display results from Primary analysis 
(i.e. not repeated measures model 
output) for the quantities of interest 
presented in the corresponding point 
estimate figure. 
One page per density curve, if 
necessary truncate the density curve 
(e.g. if outliers distort axis scales) – but 
indicate how much truncation has 
occurred. Use appropriate x-axis/by-line 
labels to identify the items.
Display “Absolutes”, then “differences in 
absolutes” and then “% Attenuations”, 
sorting by chronological order (visits) 
and treatment/allergen strata within 
each of these types.
When the item is a comparison (vs 
Pbo) use vertical reference lines to 
indicate when equality occurs (i.e. zero 
for a difference, one for a ratio)
IA 1, HR 1, SAC 
1
2.6.
mITT
EFF_F5
Bronchial Allergen Challenge Point estimates and Credible 
Intervals (70% and 95%) from the analysis of LAR Minimum and 
Weighted Mean LAR Absolute Change from Saline endpoints at 
Week 9 (FUV1)
Conditional on PP and mITT 
populations differing.
As per PP Version
SAC 1
2.7.
mITT
EFF_F6
Bronchial Allergen Challenge Posterior Distribution Density Plots 
from the analysis of LAR Minimum and Weighted Mean LAR 
Absolute Change from Saline endpoints at Week 9 (FUV1)
Conditional on PP and mITT 
populations differing.
As per PP Version
SAC 1


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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
PP
EFF_F5
Sensitivity Analysis: Bronchial Allergen Challenge Point 
estimates and Credible Intervals (70% and 95%) from the 
analysis of LAR Minimum and Weighted Mean LAR Absolute 
Change from Saline endpoints at Week 9 (FUV1) using 
Informative Priors
Sensitivity analysis: Display priors as 
footnotes / or as appropriate in the 
output
HR 2, SAC 2
2.9.
PP
EFF_F6
Sensitivity Analysis: Bronchial Allergen Challenge Posterior 
Distribution Density Plots from the analysis of LAR Minimum and 
Weighted Mean LAR Absolute Change from Saline endpoints at 
Week 9 (FUV1) using Informative Priors
Sensitivity analysis: Display any 
corresponding prior on each item (or 
the implied prior if item is a combination 
of model parameters which had priors 
put on them). Also display the likelihood 
function derived from the observed data 
(but scale it to have AUC of 1 to allow 
comparability with the probability 
distributions and appropriately indicate 
it is a scaled likelihood in any legends)
HR 2, SAC 2
2.10.
PP
EFF_F5
Sensitivity Analysis: Bronchial Allergen Challenge Point 
estimates and Credible Intervals (70% and 95%) from the 
analysis of LAR Minimum and Weighted Mean LAR Absolute 
Change from Saline endpoints at Week 9 (FUV1) using Blood 
Eosinophil level as a covariate
Modify x-axis labels/groups as 
appropriate to incorporate the value of 
eosinophils the precition/item is 
associated with
SAC 2
2.11.
PP
EFF_F6
Sensitivity Analysis: Bronchial Allergen Challenge Posterior 
Distribution Density Plots from the analysis of LAR Minimum and 
Weighted Mean LAR Absolute Change from Saline endpoints at 
Week 9 (FUV1) using Blood Eosinophil level as a covariate
Modify x-axis labels/groups as 
appropriate to incorporate the value of 
eosinophils the precition/item is 
associated with
SAC 2
2.12.
PP
EFF_F5
Bronchial Allergen Challenge Point estimates and Credible 
Intervals (70% and 95%) from the Repeated Measures analysis 
of LAR Minimum and Weighted Mean LAR Absolute Change 
from Saline endpoints
Notes as for the FUV1 timepoint
version, but within each sub-panel 
present the results by visit
SAC 2


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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.13.
PP
EFF_F6
Bronchial Allergen Challenge Posterior Distribution Density Plots 
from the Repeated Measures analysis of LAR Minimum and 
Weighted Mean LAR Absolute Change from Saline endpoints
Notes as for the FUV1 timepoint 
version
SAC 2
2.14.
mITT
EFF_F5
Bronchial Allergen Challenge Point estimates and Credible 
Intervals (70% and 95%) from the Repeated Measures analysis 
of LAR Minimum and Weighted Mean LAR Absolute Change 
from Saline endpoints
Conditional on PP and mITT 
populations differing.
As per PP repeated measures version
SAC 2
2.15.
mITT
EFF_F6
Bronchial Allergen Challenge Posterior Distribution Density Plots 
from the Repeated Measures analysis of LAR Minimum and 
Weighted Mean LAR Absolute Change from Saline endpoints
Conditional on PP and mITT 
populations differing.
As per PP repeated measures version
SAC 2
2.16.
PP
EFF_F5
Sensitivity Analysis: Bronchial Allergen Challenge Point 
estimates and Credible Intervals (70% and 95%) from the 
Repeated Measures analysis of LAR Minimum and Weighted 
Mean LAR Absolute Change from Saline endpoints using Blood 
Eosinophil level as a covariate
As per PP equivalent version but 
modify structure to also indicate which 
value of esoinophils the prediction/item 
is associated with
SAC 2
2.17.
PP
EFF_F6
Sensitivity Analysis: Bronchial Allergen Challenge Posterior 
Distribution Density Plots from the Repeated Measures analysis 
of LAR Minimum and Weighted Mean LAR Absolute Change 
from Saline endpoints using Blood Eosinophil level as a 
covariate
As per PP equivalent version but 
modify structure to also indicate which 
value of esoinophils the prediction/item 
is associated with
SAC 2
EAR
2.18.
PP
EFF_F2
Boxplots of derived EAR endpoints By Visit and 
Treatment/Allergen Strata Combinations
See notes for LAR boxplot figure
IA 1, HR 1, SAC 
1
2.19.
PP
EFF_F3 and 
EFF_F4
Bronchial Allergen Challenge Scatterplots of Minimum Vs 
Weighted Mean EAR Absolute Change from Saline by Visit
See notes for EAR scatterplot figure
IA 1, HR 1, SAC 
1
2.20.
PP
EFF_F7
By Subject time profiles of derived EAR endpoints grouped by 
Treatment/Allergen Strata Combinations
See notes for EAR equivalent figure
IA 1, HR 1, SAC 
1


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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.21.
PP
EFF_F5
Bronchial Allergen Challenge Point estimates and Credible 
Intervals (70% and 95%) from the analysis of EAR Minimum and 
Weighted Mean EAR Absolute Change from Saline endpoints at 
Week 9 (FUV1)
As per LAR equivalent  (except no AZ 
benchmark)
SAC 1
2.22.
PP
EFF_F6
Bronchial Allergen Challenge Posterior Distribution Density Plots 
from the analysis of EAR Minimum and Weighted Mean EAR 
Absolute Change from Saline endpoints at Week 9 (FUV1)
As per LAR equivalent
SAC 1
2.23.
PP
EFF_F5
Sensitivity Analysis: Bronchial Allergen Challenge Point 
estimates and Credible Intervals (70% and 95%) from the 
analysis of EAR Minimum and Weighted Mean EAR Absolute 
Change from Saline endpoints at Week 9 (FUV1) using Blood 
Eosinophil level as a covariate
As per LAR equivalent (except no AZ 
benchmark)
SAC 2
2.24.
PP
EFF_F6
Sensitivity Analysis: Bronchial Allergen Challenge Posterior 
Distribution Density Plots from the analysis of EAR Minimum 
and Weighted Mean EAR Absolute Change from Saline 
endpoints at Week 9 (FUV1) using Blood Eosinophil level as a 
covariate
As per LAR equivalent
SAC 2
2.25.
PP
EFF_F5
Bronchial Allergen Challenge Point estimates and Credible 
Intervals (70% and 95%) from the Repeated Measures analysis 
of EAR Minimum and Weighted Mean EAR Absolute Change 
from Saline endpoints
As per LAR equivalent (except no AZ 
benchmark)
SAC 2
2.26.
PP
EFF_F6
Bronchial Allergen Challenge Posterior Distribution Density Plots 
from the Repeated Measures analysis of EAR Minimum and 
Weighted Mean EAR Absolute Change from Saline endpoints
As per LAR equivalent
SAC 2


CONFIDENTIAL
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.27.
PP
EFF_F5
Sensitivity Analysis: Bronchial Allergen Challenge Point 
estimates and Credible Intervals (70% and 95%) from the 
Repeated Measures analysis of EAR Minimum and Weighted 
Mean EAR Absolute Change from Saline endpoints using Blood 
Eosinophil level as a covariate
As per LAR equivalent (except no AZ 
benchmark)
SAC 2
2.28.
PP
EFF_F6
Sensitivity Analysis: Bronchial Allergen Challenge Posterior 
Distribution Density Plots from the Repeated Measures analysis 
of EAR Minimum and Weighted Mean EAR Absolute Change 
from Saline endpoints using Blood Eosinophil level as a 
covariate
As per LAR equivalent
SAC 2
Bronchial Allergen Challenge
2.29.
All Subjects
EFF_F1
By Subject plots of Bronchial Allergen Challenge Absolute 
Change from Saline FEV1 time profiles by Visit
Order pages by Country, Centre 
Treatment (Pbo 1st) and Allergen Strata 
(Presumed 1st).
Use same y-axis range for all panels. 
Use the plotting symbols in 11.4.3
Choose appropriate number of subject 
panels per page to minimise “wasted 
space”
Shell provides structure/layout; labels 
and text etc should be modified as 
appropriate to the data presented.
IA 1, HR 1, SAC 
1
2.30.
All Subjects
EFF_F1
By Subject plots of Bronchial Allergen Challenge Absolute FEV1
time profiles by Visit
Use Programming notes from above 
figure of change from saline baseline 
FEV1 and same layout/structure
IA 1, SAC 1


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11.13.7
Safety Tables
Safety: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
All Subjects
CP_AE1p
Summary of All Adverse Events by System Organ Class
ICH E3
FSP: SAC 1
3.2.
All Subjects
CP_AE1p
Summary of All Drug-Related Adverse Events by System Organ 
Class
GSK CTR
FSP: SAC 1
3.3.
All Subjects
AE5
Summary of All Adverse Events by System Organ Class and 
Maximum Grade / Severity
ICH E3
FSP: SAC 1
3.4.
All Subjects
AE5
Summary of All Drug-Related Adverse Events by System Organ 
Class and Maximum Grade / Severity
GSK CTR
FSP: SAC 1
3.5.
All Subjects
AE15
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
FDAAA, EudraCT
FSP: SAC 1
Cytokine Release Syndrome (CRS) Events
3.6.
All Subjects
SAFE_T2
(Also see 
GSK2245035 
TL7116958 
idslfinal Table 
10.104)
Summary of Cytokine Release Syndrome Events
Create two versions of the Table 
within the output. The 1st uses the 
Main Treatment descriptors and the 
2nd uses the Alternative Treatment 
descriptors (Pbo P, Pbo U, 20ng P, 
20ng U). 
SAC 1


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Safety: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.7.
All Subjects
SAFE_T3
(Also see 
GSK2245035 
TL7116958 
idslfinal Table 
10.105)
Summary of the Consistency of Cytokine Release Syndrome 
Events Reporting by Individuals over Dosing Visits
Create two versions of the Table 
within the output. The 1st uses the 
Main Treatment descriptors and the 
2nd uses the Alternative Treatment 
descriptors (Pbo P, Pbo U, 20ng P, 
20ng U). 
Sort by CRS Category, Treatment
Add footnotes about set interval 
notation for category boundaries
SAC 1
Serious and Other Significant Adverse Events
3.8.
All Subjects
CP_AE1p
Summary of Serious Adverse Events by System Organ Class
Only produce if more than 5 events
IDSL / GSK CTR
FSP: SAC 1
3.9.
All Subjects
CP_AE1p
Summary of Drug-Related Serious Adverse Events by System 
Organ Class
Only produce if more than 5 events
GSK CTR
FSP: SAC 1
Laboratory: Chemistry 
3.10.
All Subjects
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
Include (absolute) Baseline values 
summarised as a row in the table and 
then the change from baseline for each 
visit below. Do  not include Screening 
visit 1 values
FSP: SAC 2
3.11.
All Subjects
LB4
Summary of Emergent Chemistry Results by Normal Range
Criteria
ICH E3
Planned times should be each post-visit 
timepoint (e.g. DV1 24h, DV8 pre-dose, 
DV8 24h). Do not include screening 
visit 1 values. 
Use Normal Ranges for Lab tests rather 
than PCI ranges to determine criteria.
FSP: SAC 2


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Safety: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Haematology
3.12.
All Subjects
LB1
Summary of Haematology Changes From Baseline
ICH E3
As per Lab Chemistry equivalent
FSP: SAC 2
3.13.
All Subjects
LB4
Summary of Emergent Haematology Results by Normal Range 
Criteria
ICH E3
As per Lab Chemistry equivalent
FSP: SAC 2
Laboratory: Hepatobiliary (Liver)
3.14.
All Subjects
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IDSL
FSP: SAC 2
ECG
3.15.
All Subjects
EG1
Summary of ECG Findings 
IDSL
FSP: SAC 2
3.16.
All Subjects
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
Include (absolute) Baseline values as 
the first record. Do not include 
Screening visit 1 values
FSP: SAC 2
Vital Signs
3.17.
All Subjects
VS1
Summary of Change From Baseline in Vital Signs by Visit
ICH E3
Include (absolute) Baseline values as
the first record. Do not include 
Screening visit 1 values
FSP: SAC 2
Medications
3.18.
All Subjects
CP_CM1
Summary of Concomitant Medications by Generic Term
FSP: SAC 2
Rescue Medication
3.19.
All Subjects
Table 10.112 
TL7116958
Summary of Rescue Medication Usage
Include reasons (if easily condensed to 
a handful of terms). Exclude any rescue 
medication given as part of the BAC 
procedure(s) and add this as an 
explanatory footnote.
FSP: SAC 2


CONFIDENTIAL
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Safety: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PEF
3.20.
All Subjects
EFF_T1
Summary of Weekly Maximum PEF by Visit
Calculate the maximum PEF for the 
week per subject
Add Appropriate Visit Column to Shell
FSP: SAC 2
3.21.
All Subjects
EFF_T1
Summary of Weekly Weighted Mean PEF by Visit
Add Appropriate Visit Column to Shell
FSP: SAC 2
Nasal Examination
3.22.
All Subjects
SAFE_T1
Summary of Nasal Examination Data by Visit
Count as yes any entries in the free text 
field for Signs of Bleeding.
FSP: SAC 2
3.23.
All Subjects
SAFE_T4
Shift Tables of Nasal Examination Status from Pre-Dose DV1 to 
24h Post Dose DV8
Count as yes any entries in the free text 
field for Signs of Bleeding.
Separate page per category/domain
FSP: SAC 2


CONFIDENTIAL
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11.13.8
Safety Figures
Safety: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PEF
3.1.
All Subjects
Figure 10.107 
TL7116958
Unadjusted Mean Peak Expiratory Flow vs Time Profiles by 
Treatment (with approx 95% CI Bands)
Display the raw Treatment means 
for each day and connect each (1st
page uses main treatment 
descriptors and 2nd page uses 
Alternative descriptors). Do not add 
individual CIs for each day, but 
instead display them as a band plot. 
X-axis is continuous (Week) with 
tick marks every 7 days (1st Dose is 
Week 0)
Add vertical reference lines for the 
1st and 8th planned dose
FSP: SAC [2]
3.2.
All Subjects
Figure 10.107 
TL7116958
Unadjusted Mean AM Peak Expiratory Flow vs Time Profiles by 
Treatment (with approx 95% CI Bands)
As per Mean PEF Figure
FSP: SAC [2]
3.3.
All Subjects
Figure 10.107 
TL7116958
Unadjusted Mean PM Peak Expiratory Flow vs Time Profiles by 
Treatment (with approx 95% CI Bands)
As per Mean PEF Figure
FSP: SAC [2]


CONFIDENTIAL
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Safety: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.4.
All Subjects
SAFE_F1
Frequency of Cytokine Release Syndrome Events (within 
individuals) over the Eight Planned Dosing Visits
Try to get all CRS events on one 
page. Do not distinguish between 
CRS severity grades in this display.
1st Page should be Placebo and 
20ng treatments (two bars per CRS 
category)
2nd Page should use 
Placebo/Allergen stratum 
combinations (four bars per CRS 
category)
Footnote each subsection of each 
bar when individuals did not 
complete all 8 visits fall.
If possible consider patterns/fill 
types that can display in black and 
white (but revert to example shell 
(colours only) if patterns result in 
confusing figure details)
SAC [1]


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11.13.9
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentrations
4.1.
PK
pkct1
Summary of GSK2245035 Plasma Concentration-time Data by 
Dose
Only to be produced if at least 20% 
quantifiable values at any time point.
SAC [3]
11.13.10
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentrations
4.1.
PK
pkcf1
Individual Subject GSK2245035 Concentration-time Plot (Linear 
and Semi-log) by Subject
Only to be produced if at least 20% 
quantifiable values at any time point.
SAC [3]
4.2.
PK
pkcf2
Mean GSK2245035 Concentration-time Plot (Linear and Semi-
log) 
Only to be produced if at least 20% 
quantifiable values at any time point.
SAC [3]


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11.13.11
Pharmacodynamic and Biomarker Tables
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarkers supporting the BAC related exploratory objective(s)
5.1.
Sputum 
Producers
PD_T1
Sputum Cell Pellet: Summary of data availability by Treatment 
and selected visits
Little n’s relate to the number of 
subjects with evaluable samples 
satisfying the header criteria. The % 
relate to the big N of the corresponding 
treatment/strata combination. “Overall” 
displays the treatment arms ignoring 
strata. Complete profile represents all 
eight planned timepoints.
SAC [2]
5.2.
Sputum 
Producers
PD_T2
Sputum Cell Pellet: Summary of Absolute Cell Counts
Absolute relates to the derived Total 
cells/g values and not the raw counts 
provided by the vendor.
Cells/g sputum
SAC [2]
5.3.
Sputum 
Producers
PD_T2
Sputum Cell Pellet: Summary of Percentage Cell Counts
SAC [2]
5.4.
Sputum 
Producers
EFF_T2
Sputum Cell Pellet: Summary of Posterior Distributions and 
Posterior Probability statements from the Analysis of Absolute 
Cell Count Pre-BAC Samples
Conditional on sufficient evaluable data 
points.
SAC [2]
5.5.
Sputum 
Producers
EFF_T2
Sputum Cell Pellet: Summary of Posterior Distributions and 
Posterior Probability statements from the Analysis of all Absolute 
Cell Count Samples
Conditional on sufficient evaluable data 
points.
SAC [2]
5.6.
Sputum 
Producers
EFF_T2
Sputum Cell Pellet: Summary of Posterior Distributions and 
Posterior Probability statements from the Analysis of Percentage 
Cell Counts Pre-BAC Samples
Conditional on sufficient evaluable data 
points.
SAC [2]
5.7.
Sputum 
Producers
EFF_T2
Sputum Cell Pellet: Summary of Posterior Distributions and 
Posterior Probability statements from the Analysis of all 
Percentage Cell Counts Samples
Conditional on sufficient evaluable data 
points.
SAC [2]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.8.
All Subjects
PD_T2
PBS Wash: Summary of Concentration data
SAC [2]
5.9.
All Subjects
EFF_T2
PBS Wash: Summary of Posterior Distributions and Posterior 
Probability statements from the Analysis of Pre-BAC Samples
SAC [2]
5.10.
All Subjects
EFF_T2
PBS Wash: Summary of Posterior Distributions and Posterior 
Probability statements from the Analysis of all Samples
SAC [2]
5.11.
All Subjects
PD_T2
Blood Differentials: Summary of Absolute Counts
SAC [2]
5.12.
All Subjects
PD_T2
Blood Differentials: Summary of Percentages
SAC [2]
5.13.
All Subjects
EFF_T2
Blood Differentials: Summary of Posterior Distributions and 
Posterior Probability statements from the Analysis of Absolute 
Count Pre-BAC Samples
SAC [2]
5.14.
All Subjects
EFF_T2
Blood Differentials: Summary of Posterior Distributions and 
Posterior Probability statements from the Analysis of all Absolute 
Count Samples
SAC [2]
5.15.
All Subjects
EFF_T2
Blood Differentials: Summary of Posterior Distributions and 
Posterior Probability statements from the Analysis of 
Percentages Pre-BAC Samples
SAC [2]
5.16.
All Subjects
EFF_T2
Blood Differentials: Summary of Posterior Distributions and 
Posterior Probability statements from the Analysis of all 
Percentages Samples
SAC [2]
5.17.
All Subjects
PD_T2
FeNO: Summary of All FeNO Data
Include BAC and Dosing Visit samples 
in the same table.
SAC [2]
5.18.
All Subjects
EFF_T2
FeNO: Summary of Posterior Distributions and Posterior 
Probability statements from the Analysis of BAC Visit FeNO data
SAC [2]
Biomarkers supporting the NAC related exploratory objective(s)
5.19.
All Subjects
PD_T2
Nasal Lavage: Summary of Fluid and Filter Concentration data 
(All NAC associated Timepoints)
Include all data from all NAC visit 
planned timepoints in this listing (i.e. 
Background, Pre-NAC, 5m Post NAC 
and 6h Post NAC for SV, FUV1, FUV2)
SAC [2]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.20.
All Subjects
EFF_T2
Nasal Lavage: Summary of Posterior Distributions and Posterior 
Probability statements from the Analysis of NAC Background 
Samples
SAC [2]
5.21.
All Subjects
EFF_T2
Nasal Lavage: Summary of Posterior Distributions and Posterior 
Probability statements from the Analysis of Direct NAC Samples
SAC [2]
Biomarkers supporting the Induction of TLR7 (target engagement) exploratory objective(s)
5.22.
All Subjects
PD_T2
Nasal Lavage: Summary of Fluid and Filter Concentration data 
(All Dosing Visit associated Timepoints)
Include all data from all Dosing Visit 
planned timepoints in this listing (i.e. 
Pre-Dose and 24h Post Dose for DV1, 
DV4 and DV8)
SAC [2]
5.23.
All Subjects
EFF_T2
Nasal Lavage: Summary of Posterior Distributions and Posterior 
Probability statements from the Analysis of Dosing Visit Samples
SAC [2]
5.24.
All Subjects
PD_T2
Serum: Summary of Concentration data
SAC [2]
5.25.
All Subjects
EFF_T2
Serum: Summary of Posterior Distributions and Posterior 
Probability statements from the Analysis of Dosing Visit Samples
SAC [2]
5.26.
All Subjects
EFF_T2
FeNO: Summary of Posterior Distributions and Posterior 
Probability statements from the Analysis of Dosing Visit FeNO 
data
SAC [2]
Multivariate / Composite
5.27.
All Subjects
n/a
Multivariate Approach 1 - Profile Regression Summary Tables
SAC [2]
5.28.
All Subjects
n/a
Multivariate Approach 2 – Summary Tables
SAC [2]


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11.13.12
Pharmacodynamic and Biomarker Figures
Pharmacodynamic and Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarkers supporting the BAC related exploratory objective(s)
5.1.
Sputum 
Producers
PD_F1
Sputum Cell Pellet: By Subject profiles of Absolute Cell Counts
SAC 2
5.2.
Sputum 
Producers
PD_F2
Sputum Cell Pellet: Summary profiles of Absolute Cell Counts by 
Visit
SAC 2
5.3.
Sputum 
Producers
PD_F3
Sputum Cell Pellet: Summary profiles of Absolute Cell Counts by 
Planned Sampling Time
SAC 2
5.4.
Sputum 
Producers
PD_F6
Sputum Cell Pellet: Point estimates and 95% Credible Intervals 
from the Analysis of Absolute Cell Count Pre-BAC Samples
Conditional on sufficient evaluable data 
points.
SAC 2
5.5.
Sputum 
Producers
EFF_F6
Sputum Cell Pellet: Posterior Distribution Density Plots from the 
Analysis of Absolute Cell Count Pre-BAC Samples
Conditional on sufficient evaluable data 
points.
SAC 2
5.6.
Sputum 
Producers
PD_F4
Sputum Cell Pellet: Summary profiles of Fold Changes in 
Absolute Cell Counts (24h Post BAC /Pre-BAC)
SAC 2
5.7.
Sputum 
Producers
PD_F7
Sputum Cell Pellet: Point estimates and 95% Credible Intervals 
from the Analysis of all Absolute Cell Count Samples
Conditional on sufficient evaluable data 
points.
SAC 2
5.8.
Sputum 
Producers
EFF_F6
Sputum Cell Pellet: Posterior Distribution Density Plots from the 
Analysis of all Absolute Cell Count Samples
Conditional on sufficient evaluable data 
points.
SAC 2
5.9.
Sputum 
Producers
PD_F1
Sputum Cell Pellet: By Subject profiles of Percentage Cell 
Counts
SAC 2
5.10.
Sputum 
Producers
PD_F2
Sputum Cell Pellet: Summary profiles of Percentage Cell Counts 
by Visit
SAC 2
5.11.
Sputum 
Producers
PD_F3
Sputum Cell Pellet: Summary profiles of Percentage Cell Counts 
by Planned Sampling Time
SAC 2


CONFIDENTIAL
205540
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Pharmacodynamic and Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.12.
Sputum 
Producers
PD_F6
Sputum Cell Pellet: Point estimates and 95% Credible Intervals 
from the Analysis of Percentage Cell Counts Pre-BAC Samples
Conditional on sufficient evaluable data 
points.
SAC 2
5.13.
Sputum 
Producers
EFF_F6
Sputum Cell Pellet: Posterior Distribution Density Plots from the 
Analysis of Percentage Cell Counts Pre-BAC Samples
Conditional on sufficient evaluable data 
points.
SAC 2
5.14.
Sputum 
Producers
PD_F4
Sputum Cell Pellet: Summary profiles of Fold Changes in 
Percentage Cell Counts (24h Post BAC /Pre-BAC)
SAC 2
5.15.
Sputum 
Producers
PD_F7
Sputum Cell Pellet: Point estimates and 95% Credible Intervals 
from the Analysis of all Percentage Cell Counts Samples
Conditional on sufficient evaluable data 
points.
SAC 2
5.16.
Sputum 
Producers
EFF_F6
Sputum Cell Pellet: Posterior Distribution Density Plots from the 
Analysis of all Percentage Cell Counts Samples
Conditional on sufficient evaluable data 
points.
SAC 2
5.17.
All Subjects
PD_F1
PBS Wash: By Subject profiles of Concentration data
SAC 2
5.18.
All Subjects
PD_F2
PBS Wash: Summary profiles of Concentration data by Visit
SAC 2
5.19.
All Subjects
PD_F3
PBS Wash: Summary profiles of Concentration data by Planned 
Sampling Time
SAC 2
5.20.
All Subjects
PD_F6
PBS Wash: Point estimates and 95% Credible Intervals from the 
Analysis of Pre-BAC Samples
SAC 2
5.21.
All Subjects
EFF_F6
PBS Wash: Posterior Distribution Density Plots from the 
Analysis of Pre-BAC Samples
SAC 2
5.22.
All Subjects
PD_F4
PBS Wash: Summary profiles of Fold Changes (24h Post BAC 
/Pre-BAC)
SAC 2
5.23.
All Subjects
PD_F7
PBS Wash: Point estimates and 95% Credible Intervals from the 
Analysis of all Samples
SAC 2
5.24.
All Subjects
EFF_F6
PBS Wash: Posterior Distribution Density Plots from the 
Analysis of all Samples
SAC 2
5.25.
All Subjects
PD_F1
Blood Differentials: By Subject profiles of Absolute Counts
SAC 2


CONFIDENTIAL
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Pharmacodynamic and Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.26.
All Subjects
PD_F2
Blood Differentials: Summary profiles of Absolute Counts by 
Visit
SAC 2
5.27.
All Subjects
PD_F3
Blood Differentials: Summary profiles of Absolute Counts by 
Planned Sampling Time
SAC 2
5.28.
All Subjects
PD_F6
Blood Differentials: Point estimates and 95% Credible Intervals 
from the Analysis of Absolute Count Pre-BAC Samples
SAC 2
5.29.
All Subjects
EFF_F6
Blood Differentials: Posterior Distribution Density Plots from the 
Analysis of Absolute Count Pre-BAC Samples
SAC 2
5.30.
All Subjects
PD_F4
Blood Differentials: Summary profiles of Fold Changes in 
Absolute Counts (24h Post BAC /Pre-BAC)
SAC 2
5.31.
All Subjects
PD_F7
Blood Differentials: Point estimates and 95% Credible Intervals 
from the Analysis of all Absolute Count Samples
SAC 2
5.32.
All Subjects
EFF_F6
Blood Differentials: Posterior Distribution Density Plots from the 
Analysis of all Absolute Count Samples
SAC 2
5.33.
All Subjects
PD_F1
Blood Differentials: By Subject profiles of Percentages
SAC 2
5.34.
All Subjects
PD_F2
Blood Differentials: Summary profiles of Percentages by Visit
SAC 2
5.35.
All Subjects
PD_F3
Blood Differentials: Summary profiles of Percentages by 
Planned Sampling Time
SAC 2
5.36.
All Subjects
PD_F6
Blood Differentials: Point estimates and 95% Credible Intervals 
from the Analysis of Percentages Pre-BAC Samples
SAC 2
5.37.
All Subjects
EFF_F6
Blood Differentials: Posterior Distribution Density Plots from the 
Analysis of Percentages Pre-BAC Samples
SAC 2
5.38.
All Subjects
PD_F4
Blood Differentials: Summary profiles of Fold Changes in 
Percentages (24h Post BAC /Pre-BAC)
SAC 2


CONFIDENTIAL
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145
Pharmacodynamic and Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.39.
All Subjects
PD_F7
Blood Differentials: Point estimates and 95% Credible Intervals 
from the Analysis of all Percentages Samples
SAC 2
5.40.
All Subjects
EFF_F6
Blood Differentials: Posterior Distribution Density Plots from the 
Analysis of all Percentages Samples
SAC 2
5.41.
All Subjects
PD_F1
FeNO: By Subject profiles of BAC Visit FeNO data
SAC 2
5.42.
All Subjects
PD_F2
FeNO: Summary profiles of BAC Visit FeNO data by Visit
SAC 2
5.43.
All Subjects
PD_F4
FeNO: Summary profiles of Fold Changes in BAC Visit FeNO 
data (24h Post BAC /Pre-BAC)
SAC 2
5.44.
All Subjects
PD_F7
FeNO: Point estimates and 95% Credible Intervals from the 
Analysis of BAC Visit FeNO data
SAC 2
5.45.
All Subjects
EFF_F6
FeNO: Posterior Distribution Density Plots from the Analysis of 
BAC Visit FeNO data
SAC 2
Biomarkers supporting the NAC related exploratory objective(s)
5.46.
All Subjects
PD_F1
Nasal Lavage: By Subject profiles of NAC associated Fluid and 
Filter Concentration data
SAC 2
5.47.
All Subjects
PD_F3
Nasal Lavage: Summary profiles of NAC associated Background
Samples
SAC 2
5.48.
All Subjects
PD_F6
Nasal Lavage: Point estimates and 95% Credible Intervals from 
the Analysis of NAC associated Background Samples
SAC 2
5.49.
All Subjects
EFF_F6
Nasal Lavage: Posterior Distribution Density Plots from the 
Analysis of NAC associated Background Samples
SAC 2
5.50.
All Subjects
PD_F2
Nasal Lavage: Summary profiles of Direct NAC Samples by Visit
Do not include Background timepoints 
from each visit
SAC 2


CONFIDENTIAL
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Pharmacodynamic and Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.51.
All Subjects
PD_F4
Nasal Lavage: Summary profiles of Fold Changes in Direct NAC 
Samples (relative to the respective visits Pre-NAC)
Do not include Background timepoints.
Panel structure/layout can change 
across biomarkers (e.g. If a biomarker 
has data at both the 5m and 6h 
timepoints then there should be two 
columns per visit). However most 
biomarkers are only expected to have 
either the 5m or the 6h timepoint so 
there would only be one column per 
visit.
SAC 2
5.52.
All Subjects
PD_F7
Nasal Lavage: Point estimates and 95% Credible Intervals from 
the Analysis of Direct NAC Samples
SAC 2
5.53.
All Subjects
EFF_F6
Nasal Lavage: Posterior Distribution Density Plots from the 
Analysis of Direct NAC Samples
SAC 2
Biomarkers supporting the Induction of TLR7 (target engagement) exploratory objective(s)
5.54.
All Subjects
PD_F1
Nasal Lavage: By Subject profiles of Dosing Visit associated 
Fluid and Filter Concentration data
SAC 2
5.55.
All Subjects
PD_F2
Nasal Lavage: Summary profiles of Dosing Visit associated Fluid 
and Filter Concentration data by Visit
SAC 2
5.56.
All Subjects
PD_F5
Nasal Lavage: Summary profiles of Fold Changes in Dosing 
Visit associated Fluid and Filter Concentration data
SAC 2
5.57.
All Subjects
PD_F8
Nasal Lavage: Point estimates and 95% Credible Intervals from 
the Analysis of Dosing Visit Samples
SAC 2
5.58.
All Subjects
EFF_F6
Nasal Lavage: Posterior Distribution Density Plots from the 
Analysis of Dosing Visit Samples
SAC 2
5.59.
All Subjects
PD_F1
Serum: By Subject profiles of Dosing Visit associated 
Concentration data
SAC 2


CONFIDENTIAL
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Pharmacodynamic and Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.60.
All Subjects
PD_F2
Serum: Summary profiles of Dosing Visit associated 
Concentration data by Visit
SAC 2
5.61.
All Subjects
PD_F5
Serum: Summary profiles of Fold Changes in Dosing Visit 
associated Concentration data
SAC 2
5.62.
All Subjects
PD_F8
Serum: Point estimates and 95% Credible Intervals from the 
Analysis of Dosing Visit Samples
SAC 2
5.63.
All Subjects
EFF_F6
Serum: Posterior Distribution Density Plots from the Analysis of 
Dosing Visit Samples
SAC 2
5.64.
All Subjects
PD_F1
FeNO: By Subject profiles of Dosing Visit FeNO data
Modify PD_F1 structure to use PD_F3 
axis layouts (i.e. one panel per subject 
with visit as x-axis category and points 
joined)
SAC 2
5.65.
All Subjects
PD_F3
FeNO: Summary profiles of Dosing Visit FeNO data by Visit
Only require one column (Pre-Dose)
SAC 2
5.66.
All Subjects
PD_F6
FeNO: Point estimates and 95% Credible Intervals from the 
Analysis of Dosing Visit FeNO data
SAC 2
5.67.
All Subjects
EFF_F6
FeNO: Posterior Distribution Density Plots from the Analysis of 
Dosing Visit FeNO data
SAC 2


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Pharmacodynamic and Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Multivariate / Composite
5.68.
Sputum 
Producers
n/a
Exploratory: Scatterplots of Sputum and WBC Cell Differentials
One page per figure. Order pages by 
the display orders in Table 13 for 
variables common to each sampling 
method. Present absolute variable 1st
(then percentage). Suggestion to use 
the SAS SGxxx procedures so that the 
derivation and display of the required 
regression line(s) is one step; and 
display the resulting parameters and 
goodness of fit (r squared) next to their 
corresponding line
X axis: WBC, Y axis Sputum
Use Main treatment descriptor colours 
for plotting symbols and regression 
lines and a contrasting colour for the 
overall regression line (e.g. solid black)
SAC [2]
5.69.
All Subjects
n/a
Multivariable responder/non-responders: Starcharts of the 
Proportion of responders for each Question ID by Treatment
To Save space use the abbreviated 
question IDs (e.g. A1, B1, N1p etc) and 
add footnote referring the reader to the 
Output with the link to the full 
text/criteria (i.e. the listing number that 
is used at time of reporting)
Produce versions using the main and 
alternate sets of treatment descriptors 
and see Section 8.4.3.2 for more 
details.
SAC [2]
5.70.
All Subjects
n/a
Multivariate Approach 1 - Profile Regression Summary Figures
SAC [2]
5.71.
All Subjects
n/a
Multivariate Approach 2 – Summary Figures
SAC [2]


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11.13.13
Exploratory Tables
Exploratory: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
TNSS
6.1.
All Subjects
EFF_T1
Summary Statistics of Weighted Mean TNSS by Week
Separate Tables within the output for 
Overall TNSS and the AM and PM WM 
endpoints
FSP: SAC 2
6.2.
All Subjects
EFF_T2
WM TNSS: Summary of Posterior Distributions and Posterior 
Probability statements from the Analysis of Weekly WM TNSS
data
FSP: SAC [2]
6.3.
All Subjects
EFF_T1
Summary Statistics of TNSS component Weighted Means by 
Week
Conditional
FSP: SAC 2
6.4.
All Subjects
EFF_T2
WM TNSS: Summary of Posterior Distributions and Posterior 
Probability statements from the Analysis of Weekly WM TNSS 
component data
Conditional
FSP: SAC [2]


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Exploratory: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Intradermal Allergen Challenge
6.5.
All Subjects
EFF_T1
Intradermal Allergen Challenge: Summary Statistics of Mean 
Diameter Early/Late Phase Wheal/Flare Response by Visit and 
Treatment/Allergen Strata Combinations
Include an additional column for Visit 
(SV, FUV1 and FUV2) between the 
Shell columns “Treatment” & “N” (group 
items by treatment then visit)  and 
modify Parameter names as 
appropriate to the information being 
displayed; namely “Challenge” and 
“Negative control” and have additional 
columns “Item” to capture if its Wheal or 
Flare and “Phase” to capture Early 
(15m) or Late (6h)
Create two versions of the Table 
within the output. The 1st uses the 
Main Treatment descriptors and the 
2nd uses the Alternative Treatment 
descriptors (Pbo P, Pbo U, 20ng P, 
20ng U).
FSP: SAC [2]
6.6.
All Subjects
EFF_T1
Intradermal Allergen Challenge: Summary Statistics of Mean 
Change from Baseline Diameter Early/Late Phase Wheal/Flare 
Response by Visit and Treatment/Allergen Strata Combinations
As per main summary table except SV 
(baseline) visit not included.
FSP: SAC [2]


CONFIDENTIAL
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11.13.14
Exploratory Figures
Exploratory: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Intradermal Allergen Challenge
6.1.
All Subjects
EFF_F2
Intradermal Allergen Challenge: Boxplots of derived Change 
from Baseline in Mean Diameter Early/Late Phase Wheal/Flare 
By Visit and Treatment/Allergen Strata Combinations
Overlay individual data points next to 
boxes (but do not obscure key features 
such as mean/median symbols and 
whiskers/outliers)
Use default SAS boxplot type
Deviate from treatment/strata colour 
schemes if necessary to  display all 
information types (e.g. use different box 
fill colours/patterns for presumed and
unknown allergen strata)
Response variable is the derived 
change from baseline (SV)
Separate page for Wheal and Flare 
responses
Row categories are Early phase (15m 
timepoint) and Late phase (6h 
timepoint)
Columns are Visits (FUV1 and FUV2)
Add horizontal ref line(s) at zero
FSP: SAC 2


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Exploratory: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Weighted Mean Total Nasal Symptom Score (TNSS)
6.2.
All Subjects
PD_F3
WM TNSS: Summary profiles of Weekly WM TNSS data by 
Week
Separate Figure/Page for Overall TNSS 
and the AM and PM versions.
Do not include the mean and 95% CI 
profiles for the allergen exposure strata 
(grey lines in shell)
If necessary to improve 
clarity/readability of figure display CIs 
for a subset of the timepoints (e.g. 
Week 1, 4, 8, FUV1, FUV2)
FSP: SAC [2]
6.3.
All Subjects
PD_F6
WM TNSS: Point estimates and 95% Credible Intervals from the 
Analysis of Weekly WM TNSS data
FSP: SAC 2
6.4.
All Subjects
EFF_F6
WM TNSS: Posterior Distribution Density Plots from the Analysis 
of Weekly WM TNSS data
FSP: SAC 2
6.5.
All Subjects
PD_F3
WM TNSS: Summary profiles of Weekly WM TNSS component 
data by Week
Conditional. As per TNSS equivalent
FSP: SAC [2]
6.6.
All Subjects
PD_F6
WM TNSS: Point estimates and 95% Credible Intervals from the 
Analysis of Weekly WM TNSS component data
Conditional. As per TNSS equivalent
FSP: SAC 2
6.7.
All Subjects
EFF_F6
WM TNSS: Posterior Distribution Density Plots from the Analysis 
of Weekly WM TNSS component data
Conditional. As per TNSS equivalent
FSP: SAC 2


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11.13.15
ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
Only include failures
FSP: SAC 1
2.
Enrolled
ES2
Listing of Reasons for Study Withdrawal
ICH E3
IA 1, HR 1, SAC 
1
3.
All Subjects
BL1 
Listing of Subjects for Whom the Treatment Blind was Broken
ICH E3
IA 1, HR 1, SAC 
1
4.
All Subjects
TA1 / CP_RD1x
Listing of Planned and Actual Treatments
IDSL
Also include Allergen Strata as an 
additional column
IA 1, HR 1, SAC 
1
Protocol Deviations
5.
All Subjects
DV2
Listing of Important Protocol Deviations 
ICH E3
IA 1, HR 1, SAC 
1
6.
All Subjects
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
IA 1, HR 1, SAC 
1
Populations Analysed
7.
Enrolled
SP3
Listing of Subjects Excluded from All Subjects, mITT, PP, PK, 
Sputum Populations
ICH E3
Include subjects who are randomised.  
If ‘Enrolled’ and ‘All Subjects’ 
Populations are the same, use 
population ‘All Subjects’ label and 
change title to ‘Listing of Subjects 
Excluded from mITT, PP, PK, Sputum 
Populations.’
IA 1, HR 1, SAC 
1


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
8.
All Subjects
DM2
Listing of Demographic Characteristics
ICH E3
IA 1, HR 1, SAC 
1
9.
All Subjects
DM9
Listing of Race
ICH E3
IA 1, HR 1, SAC 
1
Medical Conditions and Prior and Concomitant Medications
10.
All Subjects
MH2
Listing of Past and Current Medical History
FSP: SAC 2
11.
All Subjects
CP_CM3
Listing of Concomitant Medications
IDSL
FSP: SAC 2
Exposure and Treatment Compliance
12.
All Subjects
EX3
Listing of Exposure Data
ICH E3
GSK may have coded AR Exposure 
dataset to support IA
FSP: SAC 2
Adverse Events
13.
All Subjects
CP_AE8
(Also see 
GSK2245035 
TL7116958 
idslfinal Listing 
111) 
Listing of All Adverse Events
ICH E3
Add columns for the CRS Category and 
CRS Grading
FSP: SAC 1
14.
All Subjects
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
FSP: SAC 1
15.
All Subjects
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
FSP: SAC 1


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Cytokine Release Syndrome (CRS) Events
16.
All Subjects
CP_AE8 
(Also see 
GSK2245035 
TL7116958 
idslfinal Listing 
113)
Listing of Cytokine Release Syndrome Events
List all CRS events (even ones that 
map to the same CRS category but 
a lower grade)
SAC 1
17.
All Subjects
SAFE_L2 
(Also see 
GSK2245035 
TL7116958 
idslfinal Listing 
115)
Listing of worst case Cytokine Release Syndrome (CRS) Score 
by subject and dosing visit
Also add the allergen stratum to the 
Treatment when setting the page by 
line.
Handle subjects who withdraw early 
like Subject 
 in the example shell
SAC 1
18.
All Subjects
AE7
(Also see 
GSK2245035 
TL7116958 
idslfinal Listing 
114)
Listing of Subject Numbers for Individual Cytokine Release 
Syndrome Events
ICH E3
SAC 1
19.
All Subjects
AE2
Listing of Relationship Between Cytokine Release Syndrome
Event and associated AE System Organ Classes, Preferred 
Terms, and Verbatim Text
IDSL
SAC 1
Serious and Other Significant Adverse Events
20.
All Subjects
CP_AE8a
Listing of Serious Adverse Events
ICH E3
FSP: SAC 1
21.
All Subjects
SAE Reasons
Listing of Reasons for Considering as a Serious Adverse Event
FDA
Note: IDSL shell in development.
FSP: SAC 1
PP


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
22.
All Subjects
CP_AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
FSP: SAC 1
Hepatobiliary (Liver)
23.
All Subjects
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
IDSL
FSP: SAC 2
24.
All Subjects
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
IDSL
FSP: SAC 2
Laboratory – Haematology
25.
All Subjects
LB5
Listing of All Haematology Laboratory Data for Subjects with 
Values of Potential Clinical Importance
ICH E3
FSP: SAC 2
26.
All Subjects
CP_LB5
Listing of Haematology Laboratory Data Values of Potential 
Clinical Importance
FSP: SAC 2
Laboratory – Chemistry
27.
All Subjects
LB5
Listing of All Chemistry Laboratory Data for Subjects with Values 
of Potential Clinical Importance
ICH E3
FSP: SAC 2
28.
All Subjects
CP_LB5
Listing of Chemistry Laboratory Data Values of Potential Clinical 
Importance
FSP: SAC 2
Laboratory – Urinalysis
29.
All Subjects
UR2a
Listing of All Urinalysis Laboratory Data for Subjects with 
Abnormal Values of Potential Clinical Concern
ICH E3
Abnormal values are any Positive 
dipstick result and/or greater than or 
equal to 1+ in the urine blood test 
and/or greater than equal to 1+ in the 
urine protein test
FSP: SAC 2
30.
All Subjects
UR2a
Listing of Urinalysis Laboratory Data Abnormal Values 
Only include abnormal values (see 
above)
FSP: SAC 2


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
All Laboratory 
31.
All Subjects
LB13
Listing of Laboratory Tests and Associated Reference Ranges
Split into separate listings by chemistry, 
hematology, urinalysis, etc.
FSP: SAC 2
ECG
32.
All Subjects
CP_EG3
Listing of ECG Values for Subjects with Values of Potential 
Clinical Importance
IDSL
FSP: SAC 2
33.
All Subjects
CP_EG3
Listing of ECG Values of Potential Clinical Importance
IDSL
FSP: SAC 2
34.
All Subjects
CP_EG5
Listing of Abnormal ECG Findings
IDSL
FSP: SAC 2
Vital Signs
35.
All Subjects
CP_VS4
Listing of Vital Signs for Subjects with Values of Potential 
Clinical Importance
IDSL
FSP: SAC 2
36.
All Subjects
CP_LB5
Listing of Vital Sign Values of Potential Clinical Importance
IDSL
FSP: SAC 2


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11.13.16
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
37.
All Subjects
See 
GW685968_G
W642444
HZA113126 
final Listing 4
Listing of Skin Prick Test at Screening
Modify Example Shell Columns for 
Parallel group design
FSP: SAC 2
38.
All Subjects
PFT10
Listing of FEV1 and Percent Predicted FEV1 Data at
Screening
Modify Shell for Parallel group design
Include columns for site
Footnote [1] Values have been 
recalculated from raw data using 
equations in Quanjer, 2012
FSP: SAC 2
Allergen Challenge
39.
All Subjects
See 
GW685968_G
W642444 
HZA113126 
final Listing 6
Listing of Allergen Challenge FEV1
Modify Example Shell Columns for 
Parallel group design
IA 1, HR 1, SAC 
1
LAR/EAR
40.
All Subjects
EFF_L1
Listing of Subjects Treated with Placebo Who Did Not 
Experience a Late Asthmatic Response at Week 9 (LAR Non-
Responder at FUV1)
SAC 1


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
41.
All Subjects
See 
GSK2190915
LPA111834
final Listing 8
Bronchial Allergen Challenge Listing of Minimum and Weighted 
Mean LAR and EAR absolute Change from Saline
Modify Example Shell Columns for 
Parallel group design
Omit the Placebo Difference column 
Have Absolute (L), Change (L) and 
Change (%) columns for each Derived 
endpoint (Min and WM)
Make “Treatment” the leftmost column. 
Period column becomes Visit.
IA 1, HR 1, SAC 
1
42.
PP
n/a
Raw SAS Output for the Statistical Analysis - Bronchial Allergen 
Challenge Primary Analysis Minimum LAR Absolute Change 
from Saline at Week 9 (FUV1)
IA 1, HR 1, SAC 
1
43.
PP
n/a
Raw SAS Output for the Statistical Analysis - Bronchial Allergen 
Challenge Primary Analysis Weighted Mean LAR Absolute 
Change from Saline at Week 9 (FUV1)
IA 1, HR 1, SAC 
1
44.
mITT
n/a
Raw SAS Output for the Statistical Analysis - Bronchial Allergen 
Challenge Minimum LAR Absolute Change from Saline at Week 
9 (FUV1)
Conditional on PP and mITT 
populations differing.
IA 1, HR 1, SAC 
1
45.
mITT
n/a
Raw SAS Output for the Statistical Analysis - Bronchial Allergen 
Challenge Weighted Mean LAR Absolute Change from Saline at 
Week 9 (FUV1)
Conditional on PP and mITT 
populations differing.
IA 1, HR 1, SAC 
1
46.
PP
n/a
Sensitivity Analysis: Raw SAS Output for the Statistical Analysis 
- Bronchial Allergen Challenge Minimum LAR Absolute Change 
from Saline at Week 9 (FUV1) using Informative Priors
Sensitivity analysis: Display priors as 
footnotes / or as appropriate in the 
output
HR 2, SAC 2
47.
PP
n/a
Sensitivity Analysis: Raw SAS Output for the Statistical Analysis 
- Bronchial Allergen Challenge Weighted Mean LAR Absolute 
Change from Saline at Week 9 (FUV1) using Informative Priors
Sensitivity analysis: Display priors as 
footnotes / or as appropriate in the 
output
HR 2, SAC 2


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
48.
PP
n/a
Sensitivity Analysis: Raw SAS Output for the Statistical Analysis 
- Bronchial Allergen Challenge Minimum LAR Absolute Change 
from Saline at Week 9 (FUV1) using Blood Eosinophil level as a 
covariate
SAC 2
49.
PP
n/a
Sensitivity Analysis: Raw SAS Output for the Statistical Analysis 
- Bronchial Allergen Challenge Weighted Mean LAR Absolute 
Change from Saline at Week 9 (FUV1) using Blood Eosinophil 
level as a covariate
SAC 2
50.
PP
n/a
Raw SAS Output for the Repeated Measures Statistical Analysis 
- Bronchial Allergen Challenge Minimum LAR Absolute Change 
from Saline
SAC 2
51.
PP
n/a
Raw SAS Output for the Repeated Measures Statistical Analysis 
- Bronchial Allergen Challenge Weighted Mean LAR Absolute 
Change from Saline
SAC 2
52.
mITT
n/a
Raw SAS Output for the Repeated Measures Statistical Analysis 
- Bronchial Allergen Challenge Minimum LAR Absolute Change 
from Saline
Conditional on PP and mITT 
populations differing. 
SAC 2
53.
mITT
n/a
Raw SAS Output for the Repeated Measures Statistical Analysis 
- Bronchial Allergen Challenge Weighted Mean LAR Absolute 
Change from Saline
Conditional on PP and mITT 
populations differing. 
SAC 2
54.
PP
n/a
Sensitivity Analysis: Raw SAS Output for the Repeated 
Measures Statistical Analysis - Bronchial Allergen Challenge 
Minimum LAR Absolute Change from Saline using Blood 
Eosinophil level as a covariate
SAC 2


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
55.
PP
n/a
Sensitivity Analysis: Raw SAS Output for the Repeated 
Measures Statistical Analysis - Bronchial Allergen Challenge 
Weighted Mean LAR Absolute Change from Saline using Blood 
Eosinophil level as a covariate
SAC 2
56.
PP
n/a
Raw SAS Output for the Statistical Analysis - Bronchial Allergen 
Challenge Minimum EAR Absolute Change from Saline at Week 
9 (FUV1)
SAC 1
57.
PP
n/a
Raw SAS Output for the Statistical Analysis - Bronchial Allergen 
Challenge Weighted Mean EAR Absolute Change from Saline at 
Week 9 (FUV1)
SAC 1
58.
PP
n/a
Sensitivity Analysis: Raw SAS Output for the Statistical Analysis 
- Bronchial Allergen Challenge Minimum EAR Absolute Change 
from Saline at Week 9 (FUV1) using Blood Eosinophil level as a 
covariate
SAC 2
59.
PP
n/a
Sensitivity Analysis: Raw SAS Output for the Statistical Analysis 
- Bronchial Allergen Challenge Weighted Mean EAR Absolute 
Change from Saline at Week 9 (FUV1) using Blood Eosinophil 
level as a covariate
SAC 2
60.
PP
n/a
Raw SAS Output for the Repeated Measures Statistical Analysis 
- Bronchial Allergen Challenge Minimum EAR Absolute Change 
from Saline
SAC 2
61.
PP
n/a
Raw SAS Output for the Repeated Measures Statistical Analysis 
- Bronchial Allergen Challenge Weighted Mean EAR Absolute 
Change from Saline
SAC 2


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
62.
PP
n/a
Sensitivity Analysis: Raw SAS Output for the Repeated 
Measures Statistical Analysis - Bronchial Allergen Challenge 
Minimum EAR Absolute Change from Saline using Blood 
Eosinophil level as a covariate
SAC 2
63.
PP
n/a
Sensitivity Analysis: Raw SAS Output for the Repeated 
Measures Statistical Analysis - Bronchial Allergen Challenge 
Weighted Mean EAR Absolute Change from Saline using Blood 
Eosinophil level as a covariate
SAC 2
Other Safety Parameters
64.
All Subjects
CP_CM3
Listing of Rescue Medication  (excluding that given as part of 
BAC procedures)
Rescue medications include 
Salbutamol (review with medical 
monitor prior to DBF the conmeds 
and/or any diary card data to determine 
if any other rescue medications exist)
FSP: SAC 2
65.
All Subjects
n/a
Listing of Disease Related Events
By Subject listing of the information 
collected and the derived time since 1st
dose and time since most recent dose
FSP: SAC 2
66.
All Subjects
SAFE_L3
Listing of Peak Expiratory Flow (PEF) 
Also display the Max and WM summary 
measure. Study day does not reset 
when it gets to a new week.
FSP: SAC 2
67.
All Subjects
SAFE_L1
Listing of Nasal Examination Data
Use “-“ when the item was normal / not 
present. Wrap free text from Signs of 
bleeding field. Slot in any unscheduled 
data using the date/time of 
observations.
FSP: SAC 2
Pharmacokinetic
68.
PK
pkcl1p
Listing of GSK2245035 Plasma Concentration-time Data
SAC [3]


CONFIDENTIAL
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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacodynamic and Biomarker
Biomarkers supporting the BAC related exploratory objective(s)
69.
Sputum 
Producers
PD_L1
Sputum Cell Pellet: Listing of evaluable data by Subject
For a sample to be evaluable it must 
have been both sent and viable (read 
without any quality issues)
Order to display individuals (within each 
treatment): Complete profiles at top of 
list, then subjects with Pre-BAC SV 
timepoint missing, then 24h Post-BAC 
SV timepoint missing and finish by 
displaying remaining subjects by the 
(ascending) number of missing 
timepoints. In the event of identical 
profiles order by Allergen Strata and 
then subject ID.
SAC [2]
70.
Sputum 
Producers
PD_L2
Sputum Cell Pellet: Listing of Collection information
CONDITIONAL: Content may need 
revising when the precise nature of the 
sputum data transfer is agreed. The 
intent of this display is to provide the 
eCRF data, and whether sample sent 
for processing and whether it was 
subsequently rejected (non-viable)
SAC [2]
71.
Sputum 
Producers
PD_L3
Sputum Cell Pellet: Listing of Absolute Counts from each Slide 
Reader provided by the Vendor
CONDITIONAL: Content may need 
revising when the precise nature of the 
sputum data transfer is agreed. The 
intent of this display is to show the 
vendor provided “raw data”. It may not 
be required
SAC [2]


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
72.
Sputum 
Producers
PD_L4
Sputum Cell Pellet: Listing of Sputum Percentage data
CONDITIONAL: Content may need 
revising when the precise nature of the 
sputum data transfer is agreed. The 
intent of this display is to provide the 
raw data used in subsequent stats 
analyses
SAC [2]
73.
Sputum 
Producers
PD_L5
Sputum Cell Pellet: Listing of Absolute Cell Counts/g sputum 
data
CONDITIONAL: Content may need 
revising when the precise nature of the 
sputum data transfer is agreed. The 
intent of this display is to provide the 
raw data used in subsequent stats 
analyses
SAC [2]
74.
Sputum 
Producers
n/a
Sputum Cell Pellet: Raw SAS Output for the Statistical Analysis 
of Absolute Cell Count Pre-BAC Samples
Conditional on sufficient evaluable data 
points.
SAC [2]
75.
Sputum 
Producers
n/a
Sputum Cell Pellet: Raw SAS Output for the Statistical Analysis 
of all Absolute Cell Count Samples
Conditional on sufficient evaluable data 
points.
SAC [2]
76.
Sputum 
Producers
n/a
Sputum Cell Pellet: Raw SAS Output for the Statistical Analysis 
of Percentage Cell Counts Pre-BAC Samples
Conditional on sufficient evaluable data 
points.
SAC [2]
77.
Sputum 
Producers
n/a
Sputum Cell Pellet: Raw SAS Output for the Statistical Analysis 
of all Percentage Cell Counts Samples
Conditional on sufficient evaluable data 
points.
SAC [2]
78.
All Subjects
PD_L6
PBS Wash: Listing of concentration data
SAC [2]
79.
All Subjects
n/a
PBS Wash: Raw SAS Output for the Statistical Analysis of Pre-
BAC Samples
Separate analysis for each
inflammatory mediator
SAC [2]
80.
All Subjects
n/a
PBS Wash: Raw SAS Output for the Statistical Analysis of all 
Samples
Separate analysis for each 
inflammatory mediator
SAC [2]
81.
All Subjects
PD_L6
Blood Differentials: Listing of Absolute count data
SAC [2]
82.
All Subjects
PD_L6
Blood Differentials: Listing of Percentages data
SAC [2]


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
83.
All Subjects
n/a
Blood Differentials: Raw SAS Output for the Statistical Analysis 
of Absolute Count Pre-BAC Samples
SAC [2]
84.
All Subjects
n/a
Blood Differentials: Raw SAS Output for the Statistical Analysis 
of all Absolute Count Samples
SAC [2]
85.
All Subjects
n/a
Blood Differentials: Raw SAS Output for the Statistical Analysis 
of Percentages Pre-BAC Samples
SAC [2]
86.
All Subjects
n/a
Blood Differentials: Raw SAS Output for the Statistical Analysis 
of all Percentages Samples
SAC [2]
87.
All Subjects
PD_L7
FeNO: Listing of All FeNO data
Include BAC and Dosing Visit samples 
in the same listing.
SAC [2]
88.
All Subjects
n/a
FeNO: Raw SAS Output for the Statistical Analysis of BAC Visit 
FeNO data
SAC [2]
Biomarkers supporting the NAC related exploratory objective(s)
89.
All Subjects
PD_L8
Nasal Lavage: Listing of Fluid and Filter Concentration data (All 
NAC associated Timepoints)
Include all data from all NAC visit 
planned timepoints in this listing (i.e. 
Background, Pre-NAC, 5m Post NAC 
and 6h Post NAC for SV, FUV1, FUV2)
SAC [2]
90.
All Subjects
n/a
Nasal Lavage: Raw SAS Output for the Statistical Analysis of 
NAC Background Samples
Separate analysis for each biomarker 
(Fluid and Filters)
SAC [2]
91.
All Subjects
n/a
Nasal Lavage: Raw SAS Output for the Statistical Analysis of 
Direct NAC Samples
Separate analysis for each biomarker 
(Fluid and Filters)
SAC [2]
Biomarkers supporting the Induction of TLR7 (target engagement) exploratory objective(s)
92.
All Subjects
PD_L8
Nasal Lavage: Listing of Fluid and Filter Concentration data (All 
Dosing Visit associated Timepoints)
Include all data from all Dosing Visit 
planned timepoints in this listing (i.e. 
Pre-Dose and 24h Post Dose for DV1, 
DV4 and DV8)
SAC [2]


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
93.
All Subjects
n/a
Nasal Lavage: Raw SAS Output for the Statistical Analysis of 
Dosing Visit Samples
Separate analysis for each biomarker
SAC [2]
94.
All Subjects
PD_L8
Serum: Listing of Concentration data
Drop the volume of sample column.
SAC [2]
95.
All Subjects
n/a
Serum: Raw SAS Output for the Statistical Analysis of Dosing 
Visit Samples
Separate analysis for each biomarker
SAC [2]
96.
All Subjects
n/a
FeNO: Raw SAS Output for the Statistical Analysis of Dosing 
Visit FeNO data
SAC [2]
Multivariate / Composite
97.
All Subjects
n/a
Multivariable responder/non-responders: Listing of Question IDs 
and their associated text / criteria
Note: Data may drive the addition or 
removal of questions/criteria. Any new 
post hoc additions (but not counting re-
ordering of items in Table 15) should be 
indicated using a lowercase p as a 
suffix, e.g. N1p, N2p 
SAC [2]
98.
All Subjects
n/a
Multivariable responder/non-responders: Listing of Individual 
subjects responder status to each Question ID
To Save space use the abbreviated 
question IDs (e.g. A1, B1, N1p etc) and 
add footnote referring the reader to the 
Output with the link to the full 
text/criteria (i.e. the listing number that 
is used at time of reporting)
Note: Individual questions may use 
different analysis populations and the 
All Subjects has been specified here 
because it should encompass all of 
them.
SAC [2]


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
99.
All Subjects
n/a
Multivariable responder/non-responders: Listing of the 
Proportion of responders for each Question ID by Treatment
To Save space use the abbreviated 
question IDs (e.g. A1, B1, N1p etc) and 
add footnote referring the reader to the 
Output with the link to the full 
text/criteria (i.e. the listing number that 
is used at time of reporting)
Derive separate proportions for the 
main and alternate sets of treatment 
descriptors.
SAC [2]
100.
All Subjects
n/a
Multivariate Approach 1 - Profile Regression Raw Output
SAC [2]
101.
All Subjects
n/a
Multivariate Approach 2 – Raw Output
SAC [2]
Exploratory
102.
All Subjects
Base around 
principles of 
gsk2245035 
mid204540 final 
listing 13
Listing of Total Nasal Symptom Score (TNSS)
Include individual components and 
total. Include column for the overall 
daily score (akin to the BAC FEV1 
repeat measures from a timepoint being 
modelled using their max value)
FSP: SAC [2]
103.
All Subjects
Base around 
principles of 
gsk2245035 
mid204540 final 
listing 14 & 15
Listing of Weighted Mean Total Nasal Symptom Score (TNSS)
Include WMs derived for individual 
components and total for each study 
week
FSP: SAC [2]
104.
All Subjects
EXP_L1
Listing of Intradermal Allergy Testing – Wheal/Flare data
List Negative control and Challenge 
(Allergen) data on same row if 
possible. 
FSP: SAC [2]


CONFIDENTIAL
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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
105.
All Subjects
EXP_L2
Listing of Intradermal Allergy Testing – Change from Baseline 
Mean Diameter Wheal/Flare data
List Negative control and Challenge 
(Allergen) data on same row if 
possible. Include SV2 absolute 
value (baseline) as a row and then 
the change from baselines as 
record per visit underneath
FSP: SAC [2]
Interim Analysis Specific
106.
All Subjects 
(at the time 
of IA1)
EFF_L1
Interim Analysis: Listing of Subjects Treated with Placebo Who 
Did Not Experience a Late Asthmatic Response at Week 9 (LAR 
Non-Responder at FUV1)
1st Section: Table of how many non-
LAR responders there were on Placebo 
at FUV1
2nd Section: Lists the non-LAR 
responders (if any) and which item(s) 
they failed on
IA [1]
107.
All Subjects 
(at the time 
of IA1)
EFF_L2
Interim Analysis: Raw SAS output from predicting the probability 
of achieving end of study success
Conditional on observed data at time of 
interim (Consult GSK Study statistician 
to determine whether to produce)
IA [1]


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11.14
Appendix 14: Example Mock Shells for Data Displays
See separate document: RAP-Mock Tables-205540.doc