Clinical trial NCT02730351
Conditions: Asthma
Keywords: Fluticasone furoate activity monitoring Vilanterol Cross-over exercise-induced bronchoconstriction exercise challenge double-dummy asthma spirometry fluticasone propionate
Sponsor: GlaxoSmithKline
Start date: 2016-05-25; Completion date: 2017-02-03
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a multicenter, randomized, double-blind, double-dummy, crossover study with two 2-week treatment periods separated by a 2-week wash-out period. Subjects will participate in up to eight study visits and have a follow up phone call approximately a week after the last clinic visit. Visits 1, 2, 3, 5 and 6 are evening visits that will be conducted between 5PM and 11PM. Visit 4 and Visit 7 are also evening visits that will begin between 5PM and 11PM and continue over a period of approximately 24 hours. Subjects will be required to attend three clinic visits during this 24-hour period. An exercise challenge (using a treadmill) will be conducted at Visit 2, Visit 3 and Visit 6 (after 23 hours of the first treatment dose in each Treatment Period); and at 12 and 23 hours post evening dose at Visits 4 and 7. Spirometry will be conducted at specified visits and prior to and after each exercise challenge.

Subjects with symptomatic allergic rhinitis at Visit 1 (screening) may be treated for up to four weeks with intranasal corticosteroids followed by a repeat screening visit to determine eligibility prior to entry into the study.

Eligible subjects at visit 1 will complete a 4-week single blind run-in on FP 250 microgram (mcg) twice daily (BID), followed by 2-week double-blind Treatment Period 1 on randomized treatment, a 2-week single blind washout period on FP 250 mcg BID, 2-week double-blind Treatment Period 2 receiving the alternative treatment, and follow-up contact approximately 7-days after completing Treatment Period 2. The total duration of study participation is approximately 11 weeks; and up to 15 weeks for subjects with Symptomatic Allergic Rhinitis.

The primary objective of the study is to evaluate the protective effect of fluticasone furoate/vilanterol (FF/VI) 100/25 mcg once-daily compared with fluticasone propionate (FP) 250 mcg twice-daily against exercise-induced bronchoconstriction in adolescent and adult subjects aged 12 to 50 with persistent asthma.

ELLIPTA, ACCUHALER, and DISKUS are registered trademarks of the GlaxoSmithKline group of companies.

Detailed description:

Arms: arm 1: Randomised subjects will receive FF/VI 100/25 mcg once daily via ELLIPTA inhaler and placebo twice daily via DISKUS / ACCUHALER for 2 weeks in Period 1. There will be a washout period of 2 weeks between treatment periods in which subjects will receive FP 250 mcg twice daily. Subjects will receive FP 250 mcg twice daily via DISKUS inhaler and placebo once daily via ELLIPTA inhaler for 2 weeks in Period 2. arm 2: Randomised subjects will receive FP 250 mcg twice daily via DISKUS inhaler and placebo once daily via ELLIPTA inhaler for 2 weeks in Period 1. There will be a washout period of 2 weeks between treatment periods in which subjects will receive FP 250 mcg twice daily. Subjects will receive FF/VI 100/25 mcg once daily via ELLIPTA inhaler and placebo twice daily via DISKUS inhaler for 2 weeks in Period 2.
Interventions: intervention 1: Fluticasone furoate/ Vilanterol 100 mcg/25 mcg intervention 2: Fluticasone propionate 250 mcg intervention 3: Placebo via ELLIPTA inhaler intervention 4: Placebo via DISKUS / ACCUHALER
Intervention descriptions: intervention 1: FF/VI 100/25 mcg will be administered via ELLIPTA inhaler once daily in the evening intervention 2: FP 250mcg will be administered via DISKUS inhaler, twice daily, once in the morning and once in the evening intervention 3: Placebo will be administered via ELLIPTA inhaler once daily in the evening intervention 4: Placebo will be administered via DISKUS / ACCUHALER, twice daily, once in the morning and once in the evening

Protocol documents:
Prot_000.pdf: 
2015N231308_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
201832
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
201832: A Randomised, Double-Blind, Double-Dummy,
Crossover Comparison of Fluticasone Furoate/Vilanterol 100/25
mcg Once Daily Versus Fluticasone Propionate 250 mcg Twice
Daily in Adolescent and Adult Subjects with Asthma and
Exercise-Induced Bronchoconstriction
Compound Number:
GW685698+GW642444
Development Phase:
IV
Effective Date:
25-MAY-2016
Protocol Amendment Number:  3
Author (s):
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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2015N231308_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
201832
2
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2015N231308_00
2015-JUL-06
Original
2015N231308_01
2015-AUG-25
Amendment No. 1
This protocol amendment was created to include an additional exercise challenge 
procedure at 23 hours after the first dose of double-blinded study medication in each 
Treatment Period. The purpose is to demonstrate that inhaled Fluticasone 
Furoate/Vilanterol (FF/VI)100/25 mcg provides improved bronchoprotection against 
exercise-induced bronchoconstriction (EIB) compared with Fluticasone Propionate (FP) 
250 mcg after 23 hours of treatment with blinded medication. In addition, it will allow for 
an evaluation of the presence and extent of tachyphylaxis. Separately, the study title was 
revised to indicate the study is a ‘randomised’ study with a ‘crossover’ design. Other 
minor corrections and edits were also made.
2015N231308_02
2015-DEC-16
Amendment No. 2
This protocol is being amended to increase the screen failure rate to 20% (from 10%) and 
the run-in failure rate to 70% (from 55%). This takes into consideration the challenge of 
enrolling EIB subjects with Symptomatic Allergic Rhinitis (SAR) at screening and also 
the challenge for subjects to demonstrate a decrease in FEV1 of ≥20% at one time point 
within 30 minutes of the end of the exercise challenge at Visit 2; after taking fluticasone 
propionate for approximately four weeks during the run-in period. The amendment also 
allows subjects with symptomatic allergic rhinitis at screening to be treated with 
intranasal corticosteroids for up to four weeks, followed by a repeat screening visit to 
determine eligibility prior to entry into the study. Subjects with symptomatic allergic 
rhinitis during the study may be treated with intranasal corticosteroids at a constant dose 
for the duration of the study. 
The time window for the repeat exercise challenge has been extended from 24-48 hours 
to up to one week; taking into consideration the challenge for subjects to return within 48 
hours for a repeat procedure.
The ACT questionnaire has been replaced by the ACQ-5 questionnaire given the 
mismatch between treatment periods of two weeks and the recall period of 4 weeks for 
the ACT.
Tobacco/marijuana use and pregnancy (which were omitted in error in the original 
protocol) have been added as exclusion criteria.
The secondary endpoint for time to recovery has been changed to a binary endpoint 
defining recovery as those subjects who have a 30 minute post-exercise FEV1
measurement that is no more than 5% lower than their pre-exercise FEV1. In addition, the 
statistical testing hierarchy has been changed to prioritise the maximal percentage FEV1
reduction (primary endpoint) and binary recovery endpoints following the 12 hour post-


2015N231308_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
201832
3
dose exercise challenge.
Other minor corrections and edits have been made.
2015N231308_03
2016-MAY-25
Amendment No. 3
This amendment has been written to adjust text to better reflect the intention of the 
protocol with regard to visit timing:
Visit 2 (currently Day 1) redefined as Day 0 and Visit 3 (currently Day 2) redefined as 
Day 1.
Visit window around day 29 removed and footnote added.
Text regarding timing of visits clarified to ensure that the intention of the protocol is 
clearly reflected
Other changes were made as follows:
Subject number will be assigned at Pre-Screening following informed consent rather than 
at Visit 1
Nucala™ added as an example prohibited medication
Rescue medication supply strategy has been removed and the reader referred to the SRM
Confirmation that post exercise vital signs will be immediately post exercise, not after 5 
minutes of rest.


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2015N231308_03
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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 
 
 
Not 
Applicable
Stockley 
Park West, 
1-3 
Ironbridge 
Road, 
Uxbridge, 
Middlesex, 
UB11 1BT, 
United 
Kingdom
Secondary 
Medical 
Monitor
 
5 Moore 
Drive, PO 
Box 13398, 
RTP, NC 
27709-3398, 
United 
States
SAE 
contact  
information 
Medical 
monitor 
as above
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): IND number for FF/VI (077855), IND 
number for FP (IND 044090).
PPD
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PPD
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2015N231308_03
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201832
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


2015N231308_03
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7
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201832......................................................11
2.
INTRODUCTION....................................................................................................16
2.1.
Background ................................................................................................16
2.2.
Study Rationale ..........................................................................................16
2.3.
Brief Background ........................................................................................16
3.
OBJECTIVE ...........................................................................................................17
3.1.
Primary Objective .......................................................................................17
4.
ENDPOINTS ..........................................................................................................17
4.1.
Primary Endpoint ........................................................................................17
4.2.
Secondary Endpoints..................................................................................17
4.3.
Other Endpoints..........................................................................................17
4.4.
Safety Endpoints.........................................................................................18
5.
STUDY DESIGN ....................................................................................................18
5.1.
Overall Design ............................................................................................18
5.2.
Treatment Arms and Duration.....................................................................20
5.3.
Type and Number of Subjects.....................................................................21
5.4.
Design Justification.....................................................................................21
5.5.
Dose Justification........................................................................................21
5.6.
Benefit: Risk Assessment ...........................................................................22
5.6.1.
Risk Assessment .........................................................................23
5.6.2.
Risk assessment for FP 250mcg .................................................30
5.6.3.
Benefit Assessment.....................................................................30
5.6.4.
Overall Benefit: Risk Conclusion..................................................30
6.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............31
6.1.
Screening Criteria.......................................................................................31
6.1.1.
Inclusion Criteria..........................................................................31
6.1.2.
Exclusion Criteria.........................................................................32
6.2.
Randomization Criteria ...............................................................................34
6.2.1.
Inclusion Criteria..........................................................................34
6.2.2.
Exclusion Criteria.........................................................................35
6.3.
Screening/Baseline/Run-in Failures............................................................35
6.4.
Withdrawal/Stopping Criteria.......................................................................36
6.4.1.
Study Specific Withdrawal Criteria ...............................................36
6.4.2.
Reasons for Study Withdrawal.....................................................37
6.4.3.
Lost to Follow up (Non-Attendance).............................................38
6.4.4.
Early Withdrawal Visit ..................................................................38
6.5.
Subject and Study Completion....................................................................39
7.
STUDY TREATMENT ............................................................................................39
7.1.
Investigational Product and Other Study Treatment....................................39
7.2.
Treatment Assignment................................................................................41
7.2.1.
Assignment of Subject Number....................................................41
7.2.2.
Assignment of Treatment Number ...............................................41


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7.3.
Blinding.......................................................................................................42
7.4.
Packaging and Labeling..............................................................................42
7.5.
Preparation/Handling/Storage/Accountability..............................................42
7.6.
Investigational Product Malfunction.............................................................43
7.7.
Compliance with Study Treatment Administration.......................................43
7.8.
Treatment of Study Treatment Overdose....................................................43
7.9.
Treatment after the End of the Study ..........................................................44
7.10.
Concomitant Medications and Non-Drug Therapies....................................44
7.10.1.
Permitted Medications and Non-Drug Therapies..........................44
7.10.1.1.
Permitted Asthma Medications ...................................44
7.10.1.2.
Permitted Non-Asthma Medications ...........................44
7.10.2.
Prohibited Medications and Non-Drug Therapies.........................45
7.10.2.1.
Prohibited Non-Asthma Medications...........................46
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................46
8.1.
Time and Events Table...............................................................................47
8.2.
Critical Baseline Assessments....................................................................50
8.3.
Efficacy.......................................................................................................50
8.3.1.
Spirometry ...................................................................................50
8.3.1.1.
Target FEV1 Calculations ...........................................51
8.3.2.
Exercise Challenge Testing .........................................................51
8.3.2.1.
Worsening of Asthma during Exercise 
Challenge...................................................................52
8.3.3.
Key Study Assessments ..............................................................52
8.3.3.1.
Visit 1 (Screening) ......................................................52
8.3.3.2.
Visit 2 (Randomization) ..............................................52
8.3.3.3.
Visit 3 and Visit 6 (23 hours Post First Dose 
Exercise Challenge) ...................................................53
8.3.3.4.
Visit 4 and Visit 7 (Blinded Treatment Exercise 
Challenges) ................................................................54
8.3.3.5.
Visit 5 .........................................................................54
8.3.4.
Physical Activity Monitor ..............................................................54
8.3.5.
Asthma Control Questionnaire-5 (ACQ-5)....................................55
8.4.
Safety .........................................................................................................55
8.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........56
8.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................56
8.4.1.2.
Method of Detecting AEs and SAEs ...........................56
8.4.1.3.
Follow-up of AEs and SAEs........................................57
8.4.1.4.
Cardiovascular and Death Events ..............................57
8.4.1.5.
Regulatory Reporting Requirements for SAEs............57
8.4.2.
Asthma Exacerbations.................................................................58
8.4.3.
Pregnancy ...................................................................................58
8.4.4.
Physical Exams ...........................................................................58
8.4.5.
Vital Signs....................................................................................58
8.4.6.
Electrocardiogram (ECG).............................................................59
8.5.
Genetics .....................................................................................................59
9.
DATA MANAGEMENT ...........................................................................................59
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................60
10.1.
Hypotheses.................................................................................................60


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10.2.
Study Design Considerations......................................................................61
10.2.1.
Sample Size Assumptions ...........................................................61
10.2.2.
Sample Size Sensitivity................................................................62
10.2.3.
Sample Size Re-estimation..........................................................62
10.3.
Data Analysis Considerations .....................................................................63
10.3.1.
Analysis Populations....................................................................63
10.3.2.
Analysis Data Sets.......................................................................63
10.3.3.
Treatment Comparisons ..............................................................63
10.3.3.1.
Primary Comparisons of Interest ................................63
10.3.3.2.
Other Comparisons of Interest....................................63
10.3.4.
Interim Analysis ...........................................................................64
10.4.
Key Elements of Analysis Plan ...................................................................64
10.4.1.
Efficacy Analyses.........................................................................64
10.4.1.1.
Primary Analysis.........................................................64
10.4.1.2.
Secondary Analyses...................................................65
10.4.1.2.1.
Other Efficacy Analyses..........................65
10.4.2.
Safety Analyses...........................................................................66
10.4.2.1.
Extent of Exposure .....................................................66
10.4.2.2.
Adverse Events (AEs) ................................................66
10.4.2.3.
Exacerbations.............................................................66
10.4.3.
Pharmacogenetic Analyses .........................................................66
11. STUDY GOVERNANCE CONSIDERATIONS........................................................66
11.1.
Posting of Information on Publicly Available Clinical Trial Registers............66
11.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................66
11.3.
Quality Control (Study Monitoring) ..............................................................67
11.4.
Quality Assurance.......................................................................................68
11.5.
Study and Site Closure ...............................................................................68
11.6.
Records Retention......................................................................................68
11.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................69
12. REFERENCES.......................................................................................................70
13. APPENDICES........................................................................................................72
13.1.
Appendix 1 – Abbreviations and Trademarks..............................................72
13.2.
Appendix 2: Liver Chemistry Stopping and Increased Monitoring 
Algorithm ....................................................................................................74
13.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................76
13.4.
Appendix 4: Genetic Research ...................................................................80
13.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................83
13.5.1.
Definition of Adverse Events........................................................83
13.5.2.
Definition of Serious Adverse Events...........................................84
13.5.3.
Definition of Cardiovascular Events .............................................86
13.5.4.
Recording of AEs and SAEs ........................................................86
13.5.5.
Evaluating AEs and SAEs............................................................87
13.5.6.
Reporting of SAEs to GSK...........................................................88


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13.6.
Appendix 6: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) and 
Collection of Pregnancy Information ...........................................................90
13.6.1.
Collection of Pregnancy Information ............................................90
13.7.
Appendix 7 - Country Specific Requirements..............................................92
13.8.
Appendix 8 – Protocol Changes..................................................................93
13.8.1.
Protocol Amendment 01 ..............................................................93
13.8.2.
Protocol Amendment 02 ............................................................116
13.8.3.
Protocol Amendment 03 (25-MAY-2016) from Protocol 
Amendment 02 (16-DEC-2015) .................................................162


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1.
PROTOCOL SYNOPSIS FOR STUDY 201832
Rationale
For many patients with symptomatic asthma, physical exertion is often a precipitating 
factor. Although varying in methodology and criteria, early studies showed that as many 
as 90% of asthmatic patients have bronchoconstriction after exercise. In subjects with 
symptoms of persistent asthma, exercise and other forms of physical activity represent 
only one of many triggers that lead to worsening symptoms. 
Chronic treatment with inhaled corticosteroids (ICS) has been shown to reduce the 
severity of asthma associated with exercise. However, some patients continue to 
demonstrate asthma symptoms and a decrease in lung function during exercise even 
while receiving ICS. In patients with persistent asthma, improvements in protection from 
exercise-induced bronchoconstriction (EIB) with ICS/long-acting beta2-agonist (LABA) 
combination product Fluticasone propionate (FP)/salmeterol (ADVAIRTM) have been 
demonstrated. However, differences between FP/salmeterol and FP monotherapy have 
not consistently been observed.  In a study that evaluated the effect of FP/salmeterol 
compared with FP over the 12 hour dosing interval, a large percentage of subjects in both 
the FP/salmeterol (18%) and FP (36% and 33% at Day 1 and Week 4, respectively) 
treatment arms failed to complete the second exercise challenge test 8.5 hours after 
dosing, suggesting loss of protection against EIB towards the end of the 12 hour dosing 
interval. 
FF/VI (Fluticasone furoate/Vilanterol), a new ICS/LABA combination treatment, is 
dosed once daily and has demonstrated significant bronchodilation over 24 hours. The 
purpose of this study is to determine if the once-daily administration of FF/VI 
demonstrates improved protection from EIB over ICS alone (FP) over the 24-hour dosing 
interval.
Objectives
Primary Objective
To evaluate the protective effect of fluticasone furoate/vilanterol (FF/VI) 100/25 mcg 
once-daily compared with fluticasone propionate (FP) 250 mcg twice-daily against 
exercise-induced bronchoconstriction in adolescent and adult subjects aged 12 to 50 with 
persistent asthma 
Primary Endpoint

Maximal percent decrease from pre-exercise FEV1 (Forced Expiratory Volume in 
One Second ) following exercise challenge at 12 hours post evening dose at the end 
of the 2-week treatment period


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Secondary Endpoints

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 
23 hours post evening dose at the end of the 2-week treatment period

Proportion of subjects with a 30 minute post-challenge FEV1 that was no more than 
5% lower than their pre-exercise FEV1 following the exercise challenge at 12 hours 
and 23 hours post evening dose at the end of the 2-week treatment period 

Weighted mean for percentage decrease from pre-exercise FEV1 following exercise 
challenge at 12-hours and 23 hours  post evening dose (weighted mean 0-60 min) at 
the end of the 2-week treatment period
Other Endpoints

Categorical treatment response evaluation of the percentage of subjects who 
demonstrate a decrease from pre-exercise challenge FEV1 (at 12 hours and 23 hours 
post evening dose at the end of the 2-week treatment period) of:
o
<10%, 
o
≥10% to <20%, 
o
≥20% 

Maximal percent decrease from treatment period baseline FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week 
treatment period

Mean change from baseline in Asthma Control Questionnaire-5 (ACQ-5) score at the 
end of the 2-week treatment period.

Percentage of subjects controlled, defined as an ACQ-5 score ≤0.75, at the end of the 
2-week treatment period. 

Percentage of subjects achieving an improvement of ≥0.5 or greater in ACQ-5 score 
at the end of the 2-week treatment.

Change in physical activity measures as assessed by a biosensor (SenseWear 
Armband) in terms of physical activity endpoints (e.g. daily step count, Metabolic 
Equivalent of Tasks (METs), sleep duration)

Proportion of subjects with a 5 minute post-challenge FEV1 that was no more than 
5% lower than their pre-exercise FEV1 following the exercise challenge at 12 hours 
and 23 hours post evening dose at the end of the 2-week treatment period. Repeat for 
the 10,15,45 and 60 minute time points. 
Safety Endpoints

Adverse events 


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Overall Design
This is a multicenter, randomized, double-blind, double-dummy, crossover study with 
two 2-week treatment periods separated by a 2-week wash-out period.  Subjects will 
participate in up to eight study visits (Visit 0 to Visit 7) over the course of the study and a 
follow up phone call approximately a week after Visit 7. Visits 1, 2, 3, 5 and 6 are 
evening visits that will be conducted between 5PM and 11PM. Visit 4 and Visit 7 are also 
evening visits that will begin between 5PM and 11PM and continue over a period of 
approximately 24 hours. Subjects will be required to attend three clinic visits during this 
24-hour period.
Standardized exercise challenge testing (using a treadmill) will be conducted at Visit 2 
for eligibility determination, Visit 3 and Visit 6 (after 23 hours of the first treatment dose 
in each Treatment Period); and at 12 and 23 hours post evening dose at Visits 4 and 7. 
Spirometry will be conducted at Screening (Visit 1), and pre-dose at Visit 5, and prior to 
each exercise challenge at Visits 2, 3, 4, 6 and 7. Serial spirometry (6 time points over 60 
minutes) as FEV1 only will be conducted after each exercise challenge test. At Visit 2, 
subjects must demonstrate a decrease in FEV1 of ≥20% when compared to the FEV1
obtained immediately pre-exercise for at least one of the post-exercise spirometry efforts 
obtained within 30 minutes post-challenge.  Subjects who achieve a decrease in FEV1 of 
15% to <20% may continue taking their daily run-in medication and repeat the eligibility 
exercise challenge and associated procedures once within a week of the original 
procedure. Subjects should be monitored until they reach a recovery level where their 
FEV1 value represents a 95% recovery of the pre-exercise FEV1 result.  Additional 
spirometry and rescue medication may be used as needed during recovery.
A Pre-Screening Visit (Visit 0) is included to obtain a signed Informed Consent, 
demography and to review concomitant medications, and may be conducted on the same 
day as Visit 1, if appropriate. 
At Visit 1, subjects meeting eligibility criteria and will enter a 4 week single-blinded run-
in period on fluticasone propionate (FP) 250 mcg twice daily (BD). Subjects with 
symptomatic allergic rhinitis at Visit 1 (screening) may be treated for up to four weeks 
with intranasal corticosteroids followed by a repeat screening visit to determine eligibility 
prior to entry into the study. Only one repeat screening visit will be performed following 
treatment with intranasal corticosteroids. Subjects that continue to be symptomatic after 
up to four weeks of treatment will be excluded. Eligible subjects will enter the run-in 
period. Subjects who are asymptomatic at screening, who become symptomatic during 
the study will remain in the study and may be treated with intranasal corticosteroids at a 
constant dose for the duration of the study.
Albuterol/salbutamol will be issued for rescue use during the run-in, wash-out and 
treatment periods as needed.  Subjects will be instructed to contact the site if they develop 
worsening asthma.  
All subjects will be given a paper diary during the run-in, washout and treatment periods 
to record any medical problems experienced during the study, any medications taken, and 
rescue medication usage.


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A screening electrocardiogram (ECG) and a complete physical examination will be 
conducted at Visit 1. Vital signs including pulse rate and systolic and diastolic blood 
pressure will be obtained at each clinic visit, including any Early Withdrawal visit. At all 
time points where both vital signs and spirometry are performed, vital signs will be done 
before the spriometry measurement. At visits where the exercise challenge is performed, 
vitals will be measured before (prior to the pre-exercise spirometry) and after the exercise 
challenge. 
Asthma control will be assessed using the ACQ-5 at Visits 2, 4, 5 and 7.
Physical activity levels will be monitored to assess activity outside the clinic with the use 
of a physical activity monitor (SenseWear Armband accelerometer) worn for 7 days prior 
to Visit 2 (baseline), for 7 days prior to Visit 4 (during the last week of Treatment Period 
1), for 7 days prior to Visit 5, and for 7 days prior to Visit 7 (during the last week of 
Treatment Period 2).  Subjects unwilling or unable to participate in daily physical activity 
monitoring may still participate in the study, if appropriate.
A follow up phone call will be conducted approximately 7 days after Visit 7.
Treatment Arms and Duration
Two treatment arms will be employed for the study: 

FF/VI 100/25 mcg QD via ELLIPTA + Placebo BD via Diskus

FP 250 mcg BD via Diskus + Placebo QD via ELLIPTA
As this is a 2-period cross-over study, all randomized subjects will receive both 
treatments in the study, either in Treatment Period 1 or Treatment Period 2. Also, each 
subject will receive a Diskus and ELLIPTA inhaler in Treatment Period 1 and Treatment 
Period 2.
Subjects will complete a 4-week single blind run-in on FP 250 mcg BID, followed by 2-
week double-blind Treatment Period 1 on randomized treatment, a 2-week single blind 
washout period on FP 250 mcg BID, 2-week double-blind Treatment Period 2 receiving 
the alternative treatment, and follow-up contact approximately 7-days after completing 
Treatment Period 2. The total duration of study participation is approximately 11 weeks; 
and up to 15 weeks for subjects with SAR at screening who may need to be treated with 
intranasal corticosteroids followed by a repeat screening visit.
Type and Number of Subjects
Approximately 275 subjects with persistent asthma with evidence of EIB and current use 
of a low- to moderate-dose inhaled corticosteroid (ICS) will be screened in order to 
randomize 66 subjects, assuming a 20% screen failure rate and 70% run-in failure rate. 
This is to achieve 56 evaluable subjects completing the exercise challenges and the FEV1
evaluations at the end of both treatment periods. This calculation assumes a 15% 
withdrawal rate during the study.  


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Analysis
The primary treatment comparison will be between the FF/VI combination and FP and 
will be performed using the intent-to-treat (ITT) Population. Demonstration of efficacy 
for the treatments will be based on a hypothesis testing approach whereby the null 
hypothesis is that there is no difference between the population treatment groups and the 
alternative hypothesis is that there is a difference between the population treatment 
groups.  
The primary endpoint will be defined as the maximal percent decrease from pre-exercise 
FEV1 at 12 hours post-evening dose at the end of the 2-week treatment period. Pre-
exercise FEV1 will be defined as the FEV1 value collected prior to the exercise challenge 
test at 12 hours post-dose. Maximal percent decrease will be defined as the percent 
change from the pre-exercise FEV1 value to the minimum FEV1 collected within one 
hour following exercise challenge at 12 hours post-dose. Mean post-exercise minimum 
FEV1 measurements and mean maximal percent decrease from pre-exercise values will 
be summarized with descriptive statistics by treatment group. A linear mixed model will 
be fitted that includes the following covariates: treatment, subject-level mean of the FEV1 
period baselines (mean of the 2 period baselines per subject), centered period-level 
baseline FEV1 (period baselines centered using subject-level mean of the FEV1 period 
baselines), gender, age and treatment period as fixed effects, and a random intercept for 
each subject.
A 2-sided 5% probability associated with incorrectly rejecting the null hypothesis 
(significance level) is considered acceptable for this study.  In order to account for 
multiplicity, the primary hypothesis test on the primary endpoint for the ITT population 
will act as a gatekeeper for all other hypothesis tests using the secondary endpoints, 
where these tests will proceed in a pre-defined order. If a given statistical test fails to 
reject the null hypothesis of no population treatment group difference at the significance 
level of 0.05, then all tests lower down the hierarchy will be interpreted as descriptive 
only.  


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2.
INTRODUCTION
2.1.
Background
For many patients with symptomatic asthma, physical exertion is often a precipitating 
factor. Although varying in methodology and criteria, early studies showed that as many 
as 90% of asthmatic patients have bronchoconstriction after exercise [McFadden, 1994; 
Poppius, 1970]. In subjects with symptoms of persistent asthma, exercise and other forms 
of physical activity represent only one of many triggers that lead to worsening symptoms. 
Chronic treatment with inhaled corticosteroids (ICS) has been shown to reduce the 
severity of asthma associated with exercise. However, some patients continue to 
demonstrate asthma symptoms and a decrease in lung function during exercise even 
while receiving ICS. The addition of a long-acting beta2-agonist (LABA) to ICS has been 
considered as a possible treatment in these cases. International guidelines such as those 
issued by the Global Initiative for Asthma (GINA) [GINA, 2015] and the National Heart 
Lung and Blood Institute (NHLBI) [NIH, 2007] advocate the use of inhaled LABA in 
combination with ICS as maintenance therapy in asthma for subjects who remain 
symptomatic on low- to mid-dose ICS. 
2.2.
Study Rationale
In patients with persistent asthma, improvements in protection from exercise-induced 
bronchoconstriction (EIB) with ICS/LABA combination product Fluticasone propionate
(FP)/salmeterol (Advair™) have been demonstrated [Murray, 2011; Pearlman, 2009; 
Weiler, 2005]. However, differences between FP/salmeterol and FP monotherapy have 
not consistently been observed [Murray, 2011; Weiler, 2005]. In a study that evaluated 
the effect of FP/salmeterol compared to FP over the 12 hour dosing interval [Weiler, 
2005], a large percentage of subjects in both the FP/salmeterol (18%) and FP (36% and 
33% at Day 1 and Week 4, respectively) treatment arms failed to complete the second 
exercise challenge test 8.5 hours after dosing, suggesting loss of protection against EIB 
towards the end of the 12 hour dosing interval. 
FF/VI, a new ICS/LABA combination treatment, is administered once daily and has 
demonstrated significant bronchodilation over 24 hours. The purpose of this study is to 
determine if the once-daily administration of FF/VI demonstrates improved protection 
from EIB over ICS alone (FP) over the entire 24-hour dosing interval.
2.3.
Brief Background
Fluticasone furoate (FF) is a novel glucocorticoid approved in the US for use as a once-
daily inhaled treatment for asthma.  
Vilanterol (VI) is an orally inhaled LABA. The inhaled fixed-dose combination of once-
daily VI and FF is approved in the US for the maintenance treatment of asthma in adults 
aged 18 and older, and in the European Union and other regions in adults and adolescents 
≥12 years of age. The FF/VI 100/25 mcg combination is being developed globally as a 


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once-daily therapy for the long-term maintenance treatment of asthma in adults and 
children ≥5 years of age. The inhaled fixed-dose combination of FF and VI is 
administered via the ElliptaDry Powder Inhaler (DPI).  
Information on the physical, chemical, and pharmaceutical properties of FF alone, VI 
(GW642444) alone, and FF/VI in combination may be found in the respective 
Investigator Brochures (IB).
3.
OBJECTIVE
3.1.
Primary Objective
To evaluate the protective effect of fluticasone furoate/vilanterol (FF/VI) 100/25 mcg 
once-daily compared with fluticasone propionate (FP) 250 mcg twice-daily against 
exercise-induced bronchoconstriction in adolescent and adult subjects aged 12 to 50 with 
persistent asthma.
4.
ENDPOINTS
4.1.
Primary Endpoint

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 
12 hours post evening dose at the end of the 2-week treatment period
4.2.
Secondary Endpoints

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 
23 hours post evening dose at the end of the 2-week treatment period

Proportion of subjects with a 30 minute post-challenge FEV1 that was no more than 
5% lower than their pre-exercise FEV1 following the exercise challenge at 12 hours 
and 23 hours post evening dose at the end of the 2-week treatment period 

Weighted mean for percentage decrease from pre-exercise FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose (weighted mean 0-60 min) at 
the end of the 2-week treatment period
4.3.
Other Endpoints

Categorical treatment response evaluation of the percentage of subjects who
demonstrate a decrease from pre-exercise challenge FEV1 (at 12 hours and 23 hours 
post evening dose at the end of the 2-week treatment period) of:
o
<10%, 
o
≥10% to <20%, 
o
≥20% 


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
Maximal percent decrease from treatment period baseline FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week 
treatment period.

Mean change from baseline in Asthma Control Questionnaire -5 (ACQ-5) score at 
the end of the 2-week treatment period. 

Percentage of subjects controlled, defined as an ACQ-5 score ≤0.75, at the end of the 
2-week treatment period. 

Percentage of subjects achieving an improvement of ≥0.5 or greater in ACQ-5 score 
at the end of the 2-week treatment. 

Change in physical activity measures as assessed by a biosensor (SenseWear 
Armband) in terms of physical activity endpoints (e.g. daily step count, Metabolic 
Equivalent of Tasks (METs), sleep duration).

Proportion of subjects with a 5 minute post-challenge FEV1 that was no more than 
5% lower than their pre-exercise FEV1 following the exercise challenge at 12 hours 
and 23 hours post evening dose at the end of the 2-week treatment period. Repeat for 
the 10, 15, 45 and 60 minute time points. 
4.4.
Safety Endpoints

Adverse events 
5.
STUDY DESIGN
5.1.
Overall Design
This is a multicenter, randomized, double-blind, double-dummy, crossover study with 
two 2-week treatment periods separated by a 2-week wash-out period. Subjects will 
participate in up to eight study visits (Visit 0 to Visit 7) over the course of the study and a 
follow up phone call approximately a week after Visit 7. Visits 1, 2, 3, 5 and 6 are 
evening visits that will be conducted between 5PM and 11PM. Visit 4 and Visit 7 are also 
evening visits that will begin between 5PM and 11PM and continue over a period of 
approximately 24 hours. Subjects will be required to attend three clinic visits during this 
24-hour period.
Standardized exercise challenge testing (using a treadmill) will be conducted at Visit 2 
for eligibility determination, Visit 3 and Visit 6 (after 23 hours of the first dose in each 
Treatment Period); and at 12 and 23 hours post evening dose at Visits 4 and 7. 
Spirometry will be conducted at Screening (Visit 1), and pre-dose at Visit 5 and prior to 
each exercise challenge at Visits 2, 3, 4, 6 and 7. Serial spirometry (6 time points over 60 
minutes) as FEV1 only will be conducted after each exercise challenge test. At Visit 2, 
subjects must demonstrate a decrease in FEV1 of ≥20% when compared to the FEV1
obtained immediately pre-exercise for at least one of the post-exercise spirometry efforts 
obtained within 30 minutes post-challenge.  Subjects who achieve a decrease in FEV1 of 
15% to <20% may continue taking their daily run-in medication and repeat the eligibility 


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exercise challenge and associated procedures once within a week of the original 
procedure. Subjects should be monitored until they reach a recovery level where their 
FEV1 value represents a 95% recovery of the pre-exercise FEV1 result.  Additional 
spirometry and rescue medication may be used as needed during recovery. 
A Pre-Screening Visit (Visit 0) is included to obtain a signed Informed Consent (ICF), 
demography and to review concomitant medications, and may be conducted on the same 
day as Visit 1, if appropriate. 
At Visit 1, subjects meeting eligibility criteria will enter a 4-week single-blinded run-in 
period on fluticasone propionate (FP) 250 mcg twice daily (BD). Subjects with 
symptomatic allergic rhinitis at Visit 1 (screening) may be treated for up to four weeks 
with intranasal corticosteroids followed by a repeat screening visit to determine eligibility 
prior to entry into the study. Only one repeat screening visit will be performed following 
treatment with intranasal corticosteroids. Subjects that continue to be symptomatic after 
up to four weeks of treatment will be excluded. Eligible subjects will enter the run-in 
period. Subjects who are asymptomatic at screening, who become symptomatic during 
the study will remain in the study and may be treated with intranasal corticosteroids at a 
constant dose for the duration of the study.
Albuterol/salbutamol will be issued for rescue use during the run-in, wash-out and 
treatment periods as needed.  Subjects will be instructed to contact the site if they develop 
worsening asthma.  
All subjects will be given a paper diary during the run-in, washout and treatment periods 
to record any medical problems experienced during the study, any medications taken, and 
rescue medication usage.


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A screening electrocardiogram (ECG) and a complete physical examination will be 
conducted at Visit 1. Vital signs including pulse rate and systolic and diastolic blood 
pressure will be obtained at each clinic visit, including any Early Withdrawal visit. At all 
time points where both vital signs and spirometry are performed, vital signs will be done 
before the spirometry measurement. At visits where the exercise challenge is performed, 
vitals will be measured before (prior to the pre-exercise spirometry) and after the exercise 
challenge. 
Asthma control will be assessed using the ACQ-5 at Visits 2, 4, 5 and 7.
Physical activity levels will be monitored to assess activity outside the clinic [Mitchell, 
2014] using a physical activity monitor (SenseWear Armband accelerometer) worn for 7 
days prior to Visit 2 (baseline), for 7 days prior to Visit 4 (during the last week of 
Treatment Period 1), for 7 days prior to Visit 5, and for 7 days prior to Visit 7 (during the 
last week of Treatment Period 2). Subjects unwilling or unable to participate in daily 
physical activity monitoring may still participate in the study, if appropriate. See Study 
Reference Manual (SRM) for additional details.
A follow up phone call will be conducted approximately 7 days after Visit 7.
Re-screening of subjects is not allowed in this study with the exception of subjects with 
symptomatic allergic rhinitis at screening who may have a repeat screening visit after 
treatment with intranasal corticosteroids.
There are no plans to routinely provide any of the study treatments for compassionate use 
following study completion, as asthma treatments including ICS/LABA combination 
products are available worldwide.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the SRM. The SRM will provide the site personnel with administrative and 
detailed technical information that does not impact subject safety.
5.2.
Treatment Arms and Duration
Two treatment arms will be employed for the study: 

FF/VI 100/25 mcg QD via ELLIPTA + Placebo BD via Diskus

FP 250 mcg BD via Diskus + Placebo QD via ELLIPTA
As this is a 2-period cross-over study, all randomized subjects will receive both 
treatments in the study either in Treatment Period 1 or Treatment Period 2. Also, each 
subject will receive a Diskus and ELLIPTA inhaler in Treatment Period 1 and Treatment 
Period 2.
Subjects will complete a 4-week single blind run-in on FP 250 mcg twice daily, followed 
by 2-week double-blind Treatment Period 1 on randomized treatment, a 2-week single 
blind washout period on FP 250 mcg twice daily, 2-week double-blind Treatment Period 
2 receiving the alternative treatment, and follow-up contact approximately 7-days after 
completing Treatment Period 2. The total duration of study participation is approximately 


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11 weeks; and up to 15 weeks for subjects with SAR at screening who may need to be 
treated with intranasal corticosteroids followed by repeat screening visit.
5.3.
Type and Number of Subjects
Subjects must have been diagnosed with persistent asthma with evidence of EIB and have 
been using a low- to moderate-dose ICS as a part of their asthma maintenance treatment.
Assuming a 20% screen failure rate and 70% run-in failure rate, approximately 275 
subjects will be screened in order to randomize 66 subjects in this study and ultimately 
achieve 56 evaluable subjects who have completed both the exercise challenges and 
spirometric evaluations at the end of both treatment periods. This calculation assumes a 
15% withdrawal rate during the study.  
5.4.
Design Justification
The study design is based on the practice parameters for assessing EIB developed by the 
Joint Task Force on Practice Parameters for Allergy and Immunology [Weiler, 2010], 
American Thoracic society clinical practice guideline [Parsons, 2013], EMA (European 
Medicines Agency) Note on Guidance on Clinical Investigation of Medicinal Products 
for Treatment of Asthma [EMA, 2013] and FDA Draft Guidance for the Development of 
Drugs for Exercise-Induced Bronchospasm [FDA Guidance for Industry, 2002].  
A randomized, double-blind, double dummy, cross-over design is a well-validated means 
to assess the efficacy and safety of two treatment groups. A cross-over design was chosen 
to reduce the impact of confounding variables, and allow for between and within group 
comparisons. The expectation that mild to moderate patients with EIB would already be 
using an ICS necessitated standardization of baseline ICS therapy and eliminates the need 
for use of a placebo comparator.  Considering a 4-week run-in period on FP, two weeks 
of treatment with FF/VI followed by exercise challenge is considered adequate to observe 
a treatment effect for this within-subject comparison. A two-week washout period is 
adequate to wash out the LABA, VI, prior to Treatment Period 2.
FP was chosen as the “gold standard” ICS active comparator as its ability to prevent EIB 
has been previously characterized and FF is not currently commercially available outside 
of the US.
The primary endpoint of maximal percent decrease from pre-exercise baseline FEV1 is a 
well-established measure of EIB and is consistent with agency guidance and established 
practice parameters. Exercise challenge testing at 12, and 23 hours post-dose at the end of 
each Treatment Period will allow for assessment of the duration of protective effect for 
the interventions.
5.5.
Dose Justification
The inhaled FF/VI 100/25 mcg dose combination corresponds to the dose approved in the 
US (adults) and EU (adults and adolescents) for the treatment of asthma corresponding to 
low to moderate ICS/LABA asthma therapy. FF100 is deemed a low/mid strength ICS.


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5.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with FF 
(GW685698)/VI (GW642444) can be found in the corresponding Investigator’s Brochure 
and in the RELVAR/BREO™ ELLIPTA Prescribing Information for countries in which 
FF/VI is approved for marketing. For the FP section, information is taken from the label 
of FLOVENT ACCUHALER/DISKUS.
The following section outlines the risk assessment and mitigation strategy for this 
protocol: 


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5.6.1.
Risk Assessment
For FF/VI the following risks and the mitigation strategy as applicable to asthma patients were taken from the summary of safety concerns 
in the European Union – Risk Management Plan (EU-RMP). For FF/VI the data/rationale for the risk were derived from the 2014 
Investigator’s Brochure, from an integrated analysis of key RELVAR studies (Integrated Summary of Safety for Fluticasone 
Furoate/Vilanterol v02 DBL 31 Jan 2014), from the RMP version 6.2 and in the RELVAR/BREO ELLIPTA Prescribing Information for 
countries in which FF/VI is approved for marketing.
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [FF/VI] 
Pneumonia in patients with asthma
The incidence of pneumonia in patients with 
asthma was uncommon. The incidence (adjusted 
for exposure) seen with FF/VI 100/25 microgram 
strength (8.5/1000 patient years) was similar to 
placebo (9.3/1000 patient years). No risk factors 
were identified.
In an analysis performed on the 18 key studies in 
subjects with asthma pneumonia  was reported 
by 0.5% (13 of 2369) of subjects who received 
FF/VI 100/25 subjects and 0.2% (2 of 1070) of 
subjects who received placebo.a
The risk of pneumonia in asthma patients is very 
low and is consistent with the risk of other ICS.  
Subjects are not at an increased risk in this 
study, since they enter the study stable on an 
existing ICS treatment. Subjects are alerted to 
the potential risk of pneumonia in the informed 
consent. Investigators are informed of the risk in 
Section 1.2.3 (Asthma Clinical Studies) and 
Section 5.3.3 (Safety in Asthma Clinical Studies) 
of the IB. Subjects with concurrent respiratory 
disease are excluded from the study.
Asthma related intubations and deaths
This is a class effect of LABA in asthma. This 
has not been observed for FF/VI.
An FDA meta-analysis of LABA vs. no LABA 
(60,954 patients in 110 trials) by age group on a 
composite endpoint of asthma-related deaths, 
intubations, and hospitalizations (asthma 
Subjects with a history of life-threatening asthma 
are excluded from the study. 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
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composite index) showed a statistically 
significant difference among age groups.  The 
composite event incidence difference for all ages 
was 6.3 events per 1000 patient-years (95% 
confidence interval [CI]: 2.2-10.3) with LABAs 
compared with no LABA use. Among the 15,192 
patients with concurrent ICS use, the incidence 
difference was 0.4 events per 1000 patient-years 
(95% CI: -3.8 to 4.6).  The authors noted a trend 
of greater excess risk with LABA among the 
younger age groups [McMahon, 2011].
Serious cardiovascular events
In an analysis performed on the 18 key studies in 
subjects with asthma, eight serious 
cardiovascular events have been reported in 
patients exposed to FF/VI. Seven events in FF/VI 
100/25 and one event in FF/VI 200/25. This 
represents an incidence less than 1% in the 
asthmatic patients exposed to FF/VI.a
The events reported include atrial fibrillation, 
acute coronary syndrome, coronary artery 
disease, hypertension, myocardial ischemia, 
tachyarrhythmia and tachycardia.
Subjects with existing serious cardiovascular 
disease and/or abnormal ECG findings are 
excluded from the study. Investigators are made 
aware of the potential class effects of LABAs and 
are advised to exercise caution for subjects with 
existing serious cardiovascular disease (Section 
6.3 [Warnings and Precautions] of the IB).
Hypersensitivity
No FF/VI drug related hypersensitivity was noted 
in clinical trials.
Spontaneous reports of hypersensitivity 
reactions have been reported in post-marketing 
Subjects will be informed about the risk of 
hypersensitivity in the informed consent. 
Subjects will be advised to seek medical 
treatment if any signs of hypersensitivity occur.
Subjects with milk protein allergy or known 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
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data for FF/VI. A possible causal association 
cannot be ruled out based on the temporal 
association between drug administration and 
hypersensitivity events including anaphylactic 
reaction, angioedema, urticaria, pruritis and rash.
hypersensitivity to FF, VI, the classes ICS or 
beta-agonist or any ingredient of the IP 
preparation will be excluded from participating in 
the study. Investigators are informed of the risk 
in Section 6.2 (Contraindications) of the IB.
Decreased bone mineral density and associated 
fractures
Risk of fracture has been associated with oral 
corticosteroids. It is unclear if inhaled 
corticosteroids carry the same risk. 
There were few events associated with bone 
disorders or fractures reported during the asthma 
development program. These events tended to 
be those associated with trauma. 
Currently the risk of reduced bone mineral 
density has not been observed in the asthma 
population [Jones, 2002]. In addition specific 
assessments in adolescents with asthma have 
not demonstrated an effect on bone mineral 
density, when controlled for growth [König, 1993; 
Turpeinen, 2010].
In an analysis performed on the 18 key studies in 
subjects with asthma bone fractures were 
reported by <1% (16 of 2369) of subjects who 
received FF/VI 100/25.a
Subjects will be informed about the risk of 
decreased bone mineral density and bone 
fractures in the informed consent. Investigators 
are made aware of the potential for this ICS 
class effect. Subjects will be advised to seek 
medical treatment if any signs of decreased bone 
mineral density or fractures occur.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Adrenal Suppression
This is considered a class effect of ICS. 
Preclinical studies showed that FF effects are 
comparable with other corticosteroids. No 
studies have shown a clinically relevant effect of 
FF/VI on the hypothalamic-pituitaryadrenal axis 
(HPA) at the 100/25 strength. This includes a 
formal HPA study (HZA106851), using 24-hour 
serum cortisol measurements, and multiple 
studies with chronic obstructive pulmonary 
disorder (COPD) and asthma subjects which 
monitored urinary cortisol.
Subjects will be informed about the risk of 
adrenal suppression in the informed consent. 
Investigators are made aware of the potential for 
this class effect in Section 6.3 (Warnings and 
Precautions) of the IB. If systematic symptoms
appear, investigators should implement an 
appropriate treatment while observing the 
subject’s’ asthma symptoms.
Corticosteroid associated eye disorders
This is considered a class effect of ICS. 
Preclinical studies showed FF at high dose 
comparable to other high dose corticosteroids. In 
study HZA106839 (FF/VI, FF and FP in subjects 
with asthma), formal ophthalmic assessments 
were conducted (including LOCS III evaluations 
for ocular opacities) throughout the study. This 
study showed no apparent effects on lens 
opacification, compared to baseline. During 
studies in both subjects with asthma and COPD, 
no associated affect on ocular disorders was 
observed.
Subjects will be informed about the risk of
corticosteroid associated eye disorders in the 
informed consent. Subjects will be advised to 
seek medical treatment if any signs of eye 
disorder occur. Investigators are made aware of 
the potential for this class effect in Section 
5.3.3.7 (Ophthalmic Effects) of the IB.
Study Design and Procedures
Exercise-induced bronchoconstriction following 
exercise challenge testing
This study specifically recruits a study population 
which demonstrates a minimal level of exercise-
Exercise challenges may be stopped at any time 
during the assessment for worsening asthma. 
(Guidelines for treatment are provided in the 


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induced bronchoconstriction (≥20% decrease 
from their pre-exercise FEV1). However, more 
severe bronchoconstriction is possible following 
exercise challenge testing.
study reference manual [SRM].) 
If a subject's FEV1 decreases to ≥40% from 
their pre-exercise FEV1 following exercise 
challenge, he/she must receive rescue therapy. If 
he/she requires rescue therapy with anything 
other than MDI (Metered Dose Inhaler )or 
nebulized albuterol/salbutamol or ipratropium 
(secondarily) following the exercise challenge 
assessment, he/she will not be allowed to 
continue in the study. 
Subjects will be monitored until their FEV1 
reaches ≥95% of their pre-exercise FEV1. 
Rescue Albuterol/salbutamol may be given 
during recovery.
Cardiovascular stress resulting from exercise
Rigorous exercise can lead to heart attack, 
stroke and even death. 
Subjects with existing serious cardiovascular 
disease and abnormal ECG findings are 
excluded from the study. Investigators are made 
aware of the potential class effects of LABAs and 
are advised to exercise caution for subjects with 
existing serious cardiovascular disease (Section 
6.3 [Warnings and Precautions] of the IB).
Musculoskelatal injury resulting from exercise 
challenge testing
Musculoskelatal injury is a risk of exercise on a 
treadmill.
The exercise challenge will begin gradually to 
allow the subject to warm up over 2 minutes, and 
end with a gradual stop.
Falls or other injuries resulting from exercise 
Exercise challenge testing will be conducted on a Front and side handrails will be in place in order 
to prevent a fall. Subjects will be instructed to 


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challenge testing
treadmill, with an air mask and heart rate 
monitor. Subjects unfamiliar with treadmill usage 
or with wearing equipment while on the treadmill 
could become unbalanced and fall.
refrain from holding on to the support railings 
during the challenge. At least one staff member 
will be behind and within reach of the
subject throughout the challenge. It is 
recommended that 3 staff members should 
facilitate the challenge procedures.
Unknown risks to an embryo, fetus (unborn 
baby) or nursing infant
There are no studies with FF/VI or the individual 
components (FF and VI) in pregnant women.
As specified in the protocol:
Women who are pregnant, lactating or are 
planning on becoming pregnant during the 
study are not eligible to participate in this 
study.
Female subjects must be postmenopausal or 
using a highly effective method for avoidance 
of pregnancy while in this study.
If a female subject becomes pregnant during 
the study, she should let the study doctor 
know immediately. The study medication will 
be stopped.
For women of child-bearing potential, a urine 
pregnancy test will be performed at Screening 
(Visit 1). For enrolled subjects, a urine 
pregnancy test will be performed at 
Screening, randomization, Visit 4 and at 
home at the Follow-Up contact. The result will 
be reported to the site study staff during the 


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Potential Risk of Clinical Significance
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Follow-Up Phone Contact.
Asthma symptoms may worsen during the study
As specified in the protocol:
The use of certain asthma medications is 
excluded prior to and during the study.
After Visit 1, the use of rescue medication 
(albuterol/salbutamol) must be withheld for at 
least 6 hours prior to and during each clinic 
visit.
Patients will be placed on an ICS alone 
treatment during the run-in period and 
possibly during the treatment period.
The informed consent advises the subject to:
Talk to the study doctor about the excluded 
medications before deciding and consenting 
to participate in the study.
Use the rescue medication 
(albuterol/salbutamol) if asthma symptoms 
worsen.
Notify the study doctor or staff if his/her 
asthma symptoms worsen or do not get better 
after using the rescue medication.
Go immediately to the emergency 
department/seek medical attention if the 
symptoms are severe.
Shortness of breath, coughing, lightheadedness 
or fainting, and/or chest tightness during the 
spirometry measurements
None.
As specified in the informed consent form for this 
study, if any of these symptoms should happen 
to the subject, he/she will receive medical 
treatment.
a.
RELVAR studies summarized include FFA109684, FFA109685, FFA109687, B2C109575, HZA106827, HZA106829, HZA113091, HZA113714, HZA113719, HZA116863, 
HZA106837, HZA106839, HZA106851, FFA112059, FFA114496, FFA115283, FFA115285, B2C112060.


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5.6.2.
Risk assessment for FP 250mcg
FLOVENT/FLIXOTIDE is a marketed drug that contains the ICS fluticasone propionate
(FP 250 mcg). A similar profile of undesirable effects as reported for ICS may occur with 
FP. Since FLOVENT/FLIXOTIDE contains an ICS (FP), the risk mitigation strategies 
for FF (ICS) as mentioned in Section 5.6.1 will be applicable.
Please refer to the authorized product label for further information about the risks of 
using FP. In this study, FP will be used in line with the recommendations provided in the 
product label.
5.6.3.
Benefit Assessment
Combined treatment with ICS and LABA has been shown to be more effective than the 
individual components in asthma, leading to the development of fixed dose combination 
inhalers. The use of ICS/LABA combinations is now well established in international 
treatment guidelines for moderate to severe persistent asthma patients for whom 
treatment with ICS alone is not sufficient. 
In patients with persistent asthma, improvements in protection from EIB with ICS/LABA 
combination product FP/salmeterol (Advair) have been demonstrated [Murray, 2011; 
Pearlman, 2009; Weiler, 2005].  Once-daily FF/VI 100/25 mcg is hypothesized to 
provide protection from EIB throughout the dosing period.
FP 250 mcg is a commercially available product for the treatment of persistent asthma 
and has a recognized safety profile. 
5.6.4.
Overall Benefit: Risk Conclusion
GlaxoSmithKline (GSK) has assessed this study for any potential risks that a subject may 
experience. The investigational product (IP) FF/VI has an acceptable safety profile for 
clinical use and there are no significant associated risks. This conclusion is supported by 
the results of previously performed clinical studies with the products in healthy 
volunteers and subjects with Asthma and COPD. The ICS (FP) described above will be 
used at a dose and frequency that is approved for the treatment of Asthma and has an 
acceptable safety profile for use. This conclusion is supported by the results of previously 
performed clinical studies and post-marketing experience (see local label).
Adverse effects that could be associated with the use of FF/VI and FP will be closely 
monitored. A safety criterion outlining details for subject withdrawal is included in the 
protocol (Section 6.4, Withdrawal Criteria). A thorough summary and evaluation of the 
available pre-clinical data can be found in the IB. Routine safety analysis of this study 
will be conducted by the company.
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with FF/VI and FP are justified by the 
anticipated benefits that may be afforded to patients with asthma.


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6.
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 product label or IB/IB 
supplement(s).
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.
6.1.
Screening Criteria
6.1.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Informed consent: Subjects must give their signed and dated written informed 
consent to participate prior to commencing any study related activities.
2. Age Range:  12 to 50 years of age, inclusive, at Visit 1 (Screening).  
3. Diagnosis:  A diagnosis of asthma, as defined by the National Institutes of Health 
[NIH, 2007], for at least 12 weeks prior to Visit 1. 
4. Asthma Severity: Subjects must have a pre-bronchodilator FEV1 of ≥70% of the 
predicted normal value. Predicted values will be based upon Global Lung 
Function Initiative (GLI) [Quanjer, 2012] equations for spirometry reference 
values.
5. Evidence of EIB: Subjects must answer “Yes” to at least 2 of the following 3 
questions reflecting on the previous 12 months:

Are you short of breath during exercise or other physical exertion?

Do you wheeze after exercise or other physical exertion?

Do you cough after exercise or other physical exertion?
6. Concurrent Anti-Asthma Therapy:  Subjects must be taking low- to moderate-
dose inhaled steroids for 12 weeks prior to Visit 1 in order to participate with no 
change in dose for the 4 weeks prior to Visit 1.  Example dosages considered 
appropriate for study participation are outlined in the SRM.
7. Gender: Subjects may be male or an eligible female. 
A female is eligible to enter and participate in the study if she is of:
Non-child bearing potential (i.e., physiologically incapable of becoming 
pregnant, including any female who is post-menopausal or surgically sterile). 
Surgically sterile females are defined as those with a documented hysterectomy 


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and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are 
defined as being amenorrhoeic for greater than 1 year with an appropriate clinical 
profile, e.g., age appropriate, > 45 years, in the absence of hormone replacement 
therapy.
OR
Child bearing potential, has a negative pregnancy test at screening, and agrees to 
acceptable contraceptive methods approved in their local country, when used 
consistently and correctly (i.e., in accordance with the approved product label and 
the instructions of the physician for the duration of the study – screening to 
follow-up contact). See Appendix 5. 
8. Albuterol/salbutamol Use:  All subjects must be able to replace their current 
short-acting beta2-agonist (SABA) with albuterol/salbutamol, to be used only on 
an as-needed basis for the duration of the study.  Each subject must be judged 
capable of withholding albuterol/salbutamol for at least 6 hours prior to 
performing spirometric evaluations.
9. Physical Capacity: Each subject must be physically able to perform the exercise 
challenges on a treadmill when bronchodilators have been withheld.
6.1.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Intermittent Asthma, Seasonal Asthma, or Exercise-Induced 
Bronchoconstriction Only:  Subjects with only intermittent or seasonal asthma 
or only exercise-induced asthma are excluded from participation in this study.
2.
History of Life-threatening Asthma:  Defined for this protocol as an asthma 
episode that required intubation and/or was associated with hypercapnia, 
respiratory arrest or hypoxic seizures within the last 10 years. 
3.
Asthma Exacerbation:  Any asthma exacerbation requiring oral corticosteroids 
within 12 weeks of Visit 1 or that resulted in an overnight hospitalization 
requiring additional treatment for asthma within 6 months prior to Visit 1.
4.
Symptomatic Allergic Rhinitis:  Subjects with symptomatic allergic rhinitis at 
Visit 1 may be treated for up to four weeks with intranasal corticosteroids 
followed by a repeat screening visit to determine eligibility prior to entry into the 
study. Subjects that continue to be symptomatic after up to four weeks of 
treatment will be excluded. 
5.
12-Lead Electrocardiogram (ECG):  A subject is not eligible if he/she has an 
abnormal, clinically significant ECG as determined by the investigator at the 
Screening Visit. 
6.
Pregnancy: Women who are pregnant or lactating or are planning on becoming 
pregnant during the study.


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7.
Respiratory Infection: Culture-documented or suspected bacterial or viral 
infection of the upper or lower respiratory tract, sinus or middle ear that is not 
resolved within 4 weeks of Visit 1 and led to a change in asthma management or, 
in the opinion of the investigator, is expected to affect the subject’s asthma status 
or the subject’s ability to participate in the study. 
8.
Concurrent Respiratory Disease: A subject must not have current evidence of: 
a.
Atelectasis 
b.
Bronchopulmonary dysplasia 
c.
Chronic bronchitis 
d.
Chronic obstructive pulmonary disease (current or past diagnosis including 
asthma/COPD overlap)
e.
Pneumonia 
f.
Pneumothorax 
g.
Interstitial lung disease 
h.
Or any evidence of concurrent respiratory disease other than asthma 
9.
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.
The list of additional excluded conditions/diseases includes, but is not limited to, 
the following:
Table 1
Excluded Conditions/Diseases
Addison's disease
hypertension1 (uncontrolled)
aortic aneurysm (clinically significant)
immunologic compromise
cardiac arrhythmia (clinically significant)
malignancy2 (current)
congestive heart failure
peptic ulcer (recent or poorly controlled)
coronary heart disease (clinically significant)
renal disease
Cushing's disease
stroke within 3 months of Visit 1
diabetes mellitus (uncontrolled)
thyroid disorder (uncontrolled)
drug or alcohol abuse (recent history)
tuberculosis (current or untreated3)
hematological disease
1.
Two or more measurements with systolic pressure >160mmHg or diastolic pressure >100mmHg
2.
A history of malignancy is acceptable only if subject has been in remission for one year prior to Visit 1 
(remission = no current evidence of malignancy and no treatment for the malignancy in the 12 months 
prior to Visit 1)
3.
Subjects with a history of tuberculosis infection who have completed an appropriate course of 
antituberculosis treatment may be suitable for study entry provided that there is no clinical suspicion of 
active or recurrent disease.


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10. Investigational Medications:  A subject must not have used any investigational 
drug within 30 days prior to Visit 1 or within five half-lives (t½) of the prior 
investigational study, whichever is longer of the two periods. 
11. Allergies:
a) Drug Allergy:  Any adverse reaction including immediate or delayed 
hypersensitivity to any beta2-agonist, sympathomimetic drug, or any 
intranasal, inhaled, or systemic corticosteroid therapy, or excipients used with 
FF/VI 100/25 or FP 250 (i.e., drug, lactose or magnesium stearate).
b) Milk Protein Allergy: History of severe milk protein allergy.
c) Latex Allergy: History of allergy or sensitivity to latex that in the opinion of 
the investigator contraindicates the subject’s participation in the study.
12. Concomitant Medication:  Administration of prescription or non-prescription 
medication that would significantly affect the course of asthma, or interact with 
study drug (see Prohibited Medication Section 7.10 for a list of prohibited 
medications and washout times required prior to Visit 1).
13. Immunosuppressive Medications: A subject must not be using or require the 
use of immunosuppressive medications during the study.
14. Compliance:  A subject will not be eligible if he/she or his/her parent or legal 
guardian has any infirmity, disability, disease, or geographical location which 
seems likely (in the opinion of the investigator) to impair compliance with any 
aspect of this study protocol
15. Tobacco/Marijuana Use: Current tobacco smoker or has a smoking history of 
≥10 pack-years (20 cigarettes/day for 10 years). A subject may not have used 
inhaled tobacco products or inhaled marijuana within the past 3 months (e.g., 
cigarettes, cigars, electronic cigarettes, or pipe tobacco).
16. Affiliation with Investigator’s Site:  A subject will not be eligible for this study 
if he/she is an immediate family member of the participating investigator, sub 
investigator, study coordinator or an employee of the participating investigator.
6.2.
Randomization Criteria
At the end of the run-in period, a subject will be eligible for Randomization to double-
blinded study treatment if he/she meets all the following criteria at Visit 2. 
6.2.1.
Inclusion Criteria
1.
Physical Capacity: All subjects must be physically able to perform the exercise 
challenges on a treadmill with specific consideration of any health changes since 
Visit 1.
2.
FEV1 Target: Subjects must demonstrate a decrease in FEV1 of 20% at one 
time point within 30 minutes of the end of a standardized exercise challenge.  
Subjects who achieve a decrease in FEV1 of 15% to <20% may continue taking 


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their daily run-in medication and repeat the eligibility exercise challenge and 
associated procedures once within a week of the original procedure.
6.2.2.
Exclusion Criteria
1.
Pregnancy: Positive urine pregnancy test at Visit 2.
2.
Asthma Medication Changes:  Changes in asthma medication after Visit 1 
(excluding albuterol/salbutamol inhalation aerosol provided at Visit 1) are not 
permitted.
3. Prohibited Medication:  Use of any prohibited medications (Section 7.10.2) 
during the run-in period or at Visit 2.
4. Respiratory Infections:  Occurrence of a culture-documented or suspected 
bacterial or viral infection of the upper or lower respiratory tract, sinus or middle 
ear during the run-in period that led to a change in asthma management or, in the 
opinion of the investigator, is expected to affect the subject’s asthma status or the 
subject’s ability to participate in the study.
5. Asthma Exacerbation:  Evidence of a severe exacerbation, defined as 
deterioration of asthma requiring the use of systemic corticosteroids (tablets, 
suspension, or injection) for at least 3 days or an in-patient hospitalization or 
emergency department (ED) visit due to asthma that required systemic 
corticosteroids between Visits 1 and 2.
6.3.
Screening/Baseline/Run-in Failures
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 reason details, Eligibility Criteria, and 
any Serious Adverse Events.
A subject who is assigned a subject number, has signed the informed consent, and has 
completed at least one study procedure, but does not enter the run-in period of the study 
is considered a ‘screen failure’.  
A subject who completes the screening visit and is dispensed FP 250 mcg, 
albuterol/salbutamol for rescue use, and a medical conditions diary card is considered to 
have entered the run-in period.  A subject who has entered the run-in period, but is not 
randomized to study treatment medication, is classified as a ‘run-in failure’.  
At a minimum, the following information will be collected for subjects who fail 
screening or run-in:
1.
Demographic information for race, age and gender
2.
Reason for screen/run-in failure (screen/run-in failure eCRF page, 
inclusion/exclusion criteria eCRF page, and randomization criteria eCRF page 
[if applicable])


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3.
SAE information
4.
Investigator signature page
Re-screening of subjects is not allowed in this study with the exception of subjects with 
symptomatic allergic rhinitis at screening who may have a repeat screening visit after 
treatment with intranasal corticosteroids.
6.4.
Withdrawal/Stopping Criteria
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. Once withdrawn from the investigational product a subject will be 
considered withdrawn from the study. Subjects who are withdrawn from the study may 
be replaced at the discretion of the Sponsor.  The primary reason for withdrawal will be 
recorded in the eCRF.
6.4.1.
Study Specific Withdrawal Criteria
A Subject will be withdrawn from the study if any of the following withdrawal criteria 
are met:
1.
Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping 
criteria (see Appendix 2).
Liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment 
with the FDA premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM174090.pdf
If the liver chemistry stopping criteria are met by any subject participating in this 
study, treatment restart or rechallenge is not permitted.
2.
Severe Asthma Exacerbation
Subjects who experience a severe asthma exacerbation at any time during the study must 
be withdrawn from the study.  A severe exacerbation is defined as deterioration of asthma 
requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 
3 days or an in-patient hospitalization or Emergency Department visit due to asthma that
required systemic corticosteroids during the study. 
3.
Worsening of Asthma requiring additional treatment
Subjects requiring rescue therapy with anything other than MDI or nebulized 
albuterol/salbutamol or ipratropium (secondarily) following the exercise challenge 
assessment should be withdrawn.
NOTE: If a subject's FEV1 decreases to ≥40% from their pre-exercise FEV1
following exercise challenge, he/she must receive rescue therapy. If he/she 
requires rescue therapy with anything other than MDI or nebulized 


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albuterol/salbutamol or ipratropium (secondarily) following the exercise 
challenge assessment, he/she is not allowed to continue in the study
Subjects who experience asthma worsening outside of the exercise challenges 
which, in the opinion of the investigator, requires additional asthma treatment 
other than study medication or study supplied albuterol/salbutamol should be 
withdrawn. 
4.
Pregnancy: Positive urine pregnancy test
5.
ECG: Discontinuation is required if any of the following ECG criteria are met 
during the study:
QTcF>500 msec or uncorrected QT>600 msec 
Change from baseline: QTcF> 60msec
For patients 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 

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.  
Details on performing ECG assessments can be found in Section 8.4.6.
6.4.2.
Reasons for Study Withdrawal
The primary reason for Study Withdrawal will be recorded in the eCRF and any data 
collected up until the point of withdrawal will be used in the data analyses.


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General reasons for withdrawal may include: 
1.
Adverse event 
2.
Withdrew consent
3. Lost to follow-up 
4. Protocol deviation impacting safety
5. Lack of efficacy
6. Subject reached protocol-defined withdrawal criteria
Liver function
Asthma Exacerbation
Asthma Worsening
Pregnancy
ECG
7. Non-compliance 
8. Injury during the exercise challenge
9. Study closed/terminated
6.4.3.
Lost to Follow up (Non-Attendance)
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”. 
6.4.4.
Early Withdrawal Visit
Subjects may withdraw or be withdrawn from the study for any reason. If withdrawal 
occurs, the investigator must make every effort to have the subject return to the clinic as 
soon as possible after the subject stopped study medication for an Early Withdrawal 
(EW) Visit (ideally within 24 hours).  At withdrawal, all study medications and other 


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study-related materials should be returned to the site by the subject (Time and Events 
Table Table 3).  In the event a subject withdraws at, or during, a scheduled visit, an Early 
Withdrawal Visit is not required.  However, all study procedures scheduled at an Early
Withdrawal Visit must be performed at this visit instead.  A follow-up phone contact 
should be made 7 days (± 2 days) after the Early Withdrawal Visit.
Following completion of these procedures, the subject will be discharged from the study.  
Upon completion of the Early Withdrawal Visit, each subject may resume any asthma 
medications deemed appropriate by the investigator for the management of the subject.
In the event that a subject is withdrawn from the study due to an adverse event, the 
investigator must attempt to follow the subject until the adverse event has either resolved 
or has become clinically insignificant.
6.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up phone contact. 
The end of the study is defined as the last subject’s last contact.
7.
STUDY TREATMENT
7.1.
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.
Albuterol/salbutamol will be given to all subjects to use throughout the study to treat 
acute asthma symptoms as needed per product label. Only study-supplied 
albuterol/salbutamol should be used for rescue during the study. Rescue usage will be 
recorded once daily in the subject’s paper diary. Do not record albuterol/salbutamol 
use in the eCRF.
Albuterol/salbutamol inhalation aerosol will be supplied as detailed in the SRM.


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Study Treatment
Product name:
Fluticasone Furoate/
Vilanterol
100/25 mcg
Fluticasone Propionate
250 mcg
Placebo ELLIPTA
Placebo DISKUS/ 
ACCUHALER
Formulation:
First strip: FF 100 mcg 
blended with lactose
Second strip: VI 25 
mcg blended with 
lactose and magnesium 
stearate
FP 250 mcg blended 
with lactose.
First strip: lactose
Second strip: blend of 
lactose and magnesium 
stearate 
Lactose
Dosage form:
ELLIPTA –
30 doses per device
DISKUS/
ACCUHALER – 60 
doses per device
ELLIPTA –
30 doses per device
DISKUS/
ACCUHALER – 60 
doses per device
Unit dose 
strength(s)/Dosage 
level(s):
100/25 mcg per 
actuation
250 mcg per actuation
NA
NA
Route of Administration
Inhaled
Inhaled
Inhaled
Inhaled
Dosing instructions:
Once daily in the 
evening
Twice daily; once in the 
morning and once in 
the evening
Once daily in the 
evening
Twice daily; once in the 
morning and once in 
the evening
FF= fluticasone furoate; VI = vilanterol; FP = fluticasone propionate; mcg = micrograms; NA = not applicable


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7.2.
Treatment Assignment
Subjects will be assigned in a 1:1 ratio to the following treatment sequences (Table 2) in 
accordance with the randomization schedule generated by Clinical Statistics, prior to the 
start of the study, using validated internal software:
Table 2
Treatment Assignment
Treatment 
Sequence
Treatment Period 1
Washout
Treatment Period 2
1
FF/VI 100/25 mcg QD 
via Ellipta + Placebo 
BD via Diskus
FP 250 mcg BD
FP 250 mcg BD via 
Diskus + Placebo QD via 
Ellipta
2
FP 250 mcg BD via 
Diskus + Placebo QD 
via Ellipta
FP 250 mcg BD
FF/VI 100/25 mcg once 
daily (QD) via Ellipta + 
Placebo BD via Diskus
7.2.1.
Assignment of Subject Number
At the Pre-screen Visit, a unique Subject Number (CRF number) will be assigned to any 
subject who has given informed consent. The unique Subject Number will be used to 
identify individual subjects during the course of the study. 
All subjects that have a repeat screening visit following treatment for symptomatic 
allergic rhinitis will continue to use the same subject number assigned at the original 
screening visit.
7.2.2.
Assignment of Treatment Number
Subjects meeting the randomization eligibility criteria at Visit 2 will be randomized to a 
treatment group through an Interactive Response Technology (IRT). The IRT will 
confirm the subject’s CRF number (Subject Number) and provide two additional 
numbers:

A randomization number will be assigned from a randomization schedule 
generated by Clinical Statistics, prior to the start of the study, using validated 
internal software. Once assigned, this number must not be reassigned to any 
other subject in the study.

Two treatment pack numbers will be provided that identifies the single blinded 
study medication (Diskus) and double-blind study medication (ELLIPTA and 
Diskus) that should be dispensed to the subject from the investigator’s inventory


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7.3.
Blinding
Subjects will be single blinded to the study medication given in the run-in and washout 
periods. Investigators and site staff will be unblinded to the run-in and washout 
medication. 
The treatment periods will be double-blind, double-dummy study and the following will 
apply: 

The investigator or treating physician may unblind a subject’s treatment
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the eCRF 

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.
7.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
7.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required. Eligible subjects will be taught 
proper use of the Diskus inhaler and administer their first dose of inhaled FP 250 mcg at 
Visit 1. Randomized subjects will be taught proper use of the ELLIPTA inhaler at Visit 2 
and administer their first doses from each inhaler (active and placebo) at the visit. 

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 


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(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.
7.6.
Investigational Product Malfunction
Any investigational product inhaler that fails to function properly must be identified to 
GSK personnel for return to GSK for testing. Details of the failure will be documented in 
the eCRF. The subject should return the inhaler to the clinic as soon as possible to avoid 
missing any doses. The site will then contact GSK’s internal IVRS (also known as the 
Registration and Medication Ordering System [RAMOS] NG) and obtain a new 
treatment pack number for this subject and dispense a new study medication kit from the 
site's investigational product supply, as instructed per the IVRS. 
7.7.
Compliance with Study Treatment Administration
Subject compliance with study medication will be assessed at all visits (including at Early 
Withdrawal) via review of the dose counters on the ELLIPTA and DISKUS inhalers. 
This information will be recorded in the eCRF. Subjects who are not compliant with run-
in medication administration or study drug administration should be counselled on 
appropriate dosing of study drug and this counselling should be noted in the source 
documentation. Subjects who demonstrate <80% compliance may be withdrawn from the 
study upon consultation with the Sponsor. 
7.8.
Treatment of Study Treatment Overdose
For this study, an overdose will be defined as the subject receiving any amount of 
investigational product greater than the maximum dose permitted by the protocol, which 
results in clinical signs or symptoms.
GSK does not recommend specific treatment for an overdose. 


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In the event of an overdose the investigator [or treating physician] should use their 
discretion as to whether other treatment is warranted and contact the Medical Monitor. 
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.
7.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study as other treatment options are available for persistent asthma. 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. At the end of Visit 7, investigators should prescribe asthma medication 
appropriate to the severity of the subject’s asthma in accordance with asthma guidelines 
[GINA, 2015; NIH, 2007]. Do not record asthma medications started on or after the 
final clinic visit in the eCRF.
7.10.
Concomitant Medications and Non-Drug Therapies
The names, doses, and regimens of the asthma medications taken during the 12 weeks 
prior to Visit 1 must be recorded in the Concomitant Medications section in the eCRF.
All concomitant medications taken during the study will be recorded in the eCRF. The 
minimum requirement is for the reporting of the drug name and dates of administration. 
Study provided albuterol/salbutamol should NOT be recorded in the eCRF.
Asthma medications taken after the final clinic visit will not be recorded in the eCRF.
7.10.1.
Permitted Medications and Non-Drug Therapies
7.10.1.1.
Permitted Asthma Medications
1.
Short-acting β2-Agonist: Subjects will receive albuterol/salbutamol inhalation 
aerosol at Visit 1 for rescue use throughout the run-in, washout and treatment 
periods. Subjects should be able to withhold albuterol/salbutamol at least 6 hours 
prior to spirometry at each visit. 
2.
Anticholinergic Rescue: Ipratropium is permitted as a secondary treatment for 
rescue purposes at the exercise challenges. All other anticholinergic use is prohibited 
during the study.
7.10.1.2.
Permitted Non-Asthma Medications
The following non-asthma medications are permitted. This list is not all inclusive. For 
any questions contact the Medical Monitor.


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
Cardioselective beta-blockers (stable dose) and ophthalmic beta-blockers: 
Administer with caution as they may block bronchodilatory effects of beta-agonists 
and produce severe bronchospasm.

Strong cytochrome P450 3A4 inhibitors (e.g. ketoconazole, ritonavir, 
clarithromycin): Use with caution. May cause systemic corticosteroid and 
cardiovascular effects.

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs):
Administer with extreme caution as they may potentiate the effects of beta-
agonists on the vascular system.

Diuretics: Caution is advised in the co-administration of beta-agonists with non 
potassium–sparing diuretics.

Decongestants: Subjects may take decongestants during the study except during the 
24 hours prior to ECG measurements.

Antihistamines: Short-acting and long-acting antihistamines are allowed to control 
symptoms of allergic disorders, however are not permitted the week prior to 
exercise testing. In addition, antihistamine eye drops are allowed during the study. 
Subjects should be reminded to avoid taking any antihistamines a week before 
each exercise challenge procedure.

Intranasal corticosteroids: Subjects may take intranasal corticosteroids to control 
symptoms of allergic disorders as long as the dose remains constant for the duration 
of the study.

Topical corticosteroids: Subjects may use topical corticosteroids (≤ 1% 
hydrocortisone) for dermatological diseases.

Influenza and/or pneumonia vaccination.

All medications for other disorders as long as the dose remains constant wherever 
possible and their use is not expected to affect the subjects’ lung function or safety 
assessments.
7.10.2.
Prohibited Medications and Non-Drug Therapies
The following asthma medications are prohibited during the conduct of the study or 
within the specified time frame:
Within 12 weeks of Visit 1 and during the study:

Systemic (oral, parenteral or depot) corticosteroids

Anti-IgE (e.g. Xolair, Nucala™)
Within 2 weeks of Visit 1 and during the study:

Theophyllines

Oral long-acting beta2-agonists (LABA) (e.g., bambuterol)


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Within 1 week of Visit 1 and during the study:

Anti-leukotrienes including suppressors of leukotriene production and antagonists
1 Day Prior to Visit 1 and during the study:

Inhaled long-acting beta2-agonists

Anticholinergics 
Use of anticholinergics are not permitted except for the use of ipratropium for rescue 
(secondary to albuterol/salbutamol) at exercise challenges, if required. 

Ketotifen

Nedocromil sodium

Sodium cromoglycate
7.10.2.1.
Prohibited Non-Asthma Medications
A subject may not use any other prescription or non-prescription medication which may 
affect the course of asthma or interact with sympathomimetic amines beginning at the 
respective time points defined below and during the remainder of the study.

Immunosuppressive medications: A subject must not be using or require the use of 
immunosuppressive medications during the study.

Prior use of study medication/other investigational drugs: Subjects who have 
received an investigational drug within 30 days of entry into this study (Screening), 
or within 5 drug half- lives of the investigational drug, whichever is longer.
A subject’s treatment must not be changed merely for the purpose of enabling the 
subject’s participation in the study.
8.
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 Table 3.


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8.1.
Time and Events Table
Table 3
Time and Events Table
Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412, 14
512
6
712, 14
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
0
118
14 (-2/+2) 
days
28 (-2/+2) 
days
2918
42 (-2/+2) 
days
47 to 
51 
days
Written Informed Consent
X
Genetics Consent
X1
Subject Demography
X
Medical History (including CV)
X
Disease (Asthma) History 
X
Medication History
X
X
Smoking history/status
X
Inclusion/Exclusion Criteria
X
Evidence of EIB
X
Efficacy Assessments
Spirometry (full FEV1 and FVC)
X
X2
X2
X2
X
X2
X2
X
Exercise Challenge Testing 
(Treadmill)
X3, 17
X4
X5
X4
X5
Post-Challenge Serial FEV1 
Measurements
X3
X6
X6
X6
X6
Asthma Control Questionnaire-5
X
X
X
X
X
Dispense SenseWear15
accelerometer
X
Collect SenseWear accelerometer
X
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X7


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Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412, 14
512
6
712, 14
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
0
118
14 (-2/+2) 
days
28 (-2/+2) 
days
2918
42 (-2/+2) 
days
47 to 
51 
days
Physical Examination
X
Vital Signs
X
X8
X8
X8
X
X8
X8
X
12-lead ECG 
X
Adverse Event Assessment
X9
X9
X
X
X
X
X
X
X
X
Issue Medical Conditions Diary 
Card
X
X
X
X
Review Medical Conditions Diary 
Card
X10
X
X10
X10
X
X10
X
Laboratory Assessments
Genetics Saliva Sample
X1
Urine Pregnancy Test
X
X
X
X
X13
Investigational Product
Dispense Fluticasone Propionate
X
X
Collect Fluticasone Propionate
X
X
Dispense Rescue16
Albuterol/salbutamol
X
X
X
X
X
X
Collect Rescue 
Albuterol/salbutamol
X
X
X
X
Dispense IP
X11
X
Assess study drug  compliance
X
X
X
X
X
X
X
Collect IP
X
X
X


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1.
Genetics saliva sample collected at Visit 2 (following Randomization) or at any scheduled visit thereafter. Genetics consent MUST be obtained PRIOR to 
collection of the Genetics sample.  
2.
Pre-exercise spirometry (full FEV1 and forced vital capacity (FVC) testing), conducted immediately pre-exercise (and after vital signs), if applicable. Subject 
should have withheld albuterol/salbutamol within previous 6 hours. 
3.
Performed for determination of eligibility. Serial spirometry performed 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Subjects must demonstrate a 
decrease in FEV1 of 20% at one time point within 30 minutes of the end of a standardized exercise challenge.  
4.
Exercise challenge testing will be performed at 23 hours following the evening study treatment doses given at Visit 2 and Visit 5 
5.
Exercise challenge testing will be performed at 12 hours and 23 hours following the evening study treatment doses given at the beginning of Visits 4 and 7.
6.
Serial spirometry performed at time points 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Longer monitoring may be required for those subjects 
who do not return to 95% of baseline FEV1 values within 60 minutes.
7.
Concomitant medications collected for adverse events only between end of treatment and follow-up phone contact. 
8.
Vital signs will be collected before (prior to the pre-exercise spirometry) and after each exercise challenge test.
9.
Adverse Event and Serious Adverse Events to be collected from the start of study Drug (Visit 1) until the follow up contact. However, any SAE related to study 
participation will be     recorded from the time of Informed Consent 
10. Review medical conditions diary card, including an assessment of any potential change in exercise capacity
11. An unblinding card will be dispensed along with double blind IP.
12. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear accelerometer for the 7 days preceeding 
these visits.
13. Pregnancy test will be conducted via home test kit and results will be reported at the Follow-up phone contact.
14. Visit 4 and Visit 7 will begin between 5PM and 11PM and continue over a period of approximately 24 hours. Subjects will return to the clinic at 12 hours (±1 
hour) and 23 hours (±1 hour) (after the evening dose of study medication from the evening visit) for an exercise challenge procedure.
15. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear Armband accelerometer for the 7 days 
preceding these visits.
16.
Collect and re-dispense rescue as needed from Visit 1
17.   Subjects who achieve a decrease in FEV1 of 15% to <20% may continue taking their daily run-in medication and repeat the eligibility exercise challenge and 
associated procedures once within a week of the original procedure.
18.   Visit 3 must be performed on the day immediately following Visit 2.  Visit 6 must be performed on the day immediately following Visit 5.


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8.2.
Critical Baseline Assessments
During the pre-screening visit (Visit 0); each subject will have the following information
collected:
1.
Demographic history (including gender, ethnic origin and date of birth)
2.
Concomitant medication review
3.
Adverse event assessment
The following data will be captured at Visit 1:
1.
Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 6.1
2.
Smoking history 
3.
Asthma history (including duration of asthma)
4.
Evidence of EIB questions
5.
Asthma and non-asthma concurrent medications
6.
Concurrent medical conditions
7.
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed 
at screening.
8.
Reason for screen failure (if applicable)
9.
Screening lung function
10. Vital signs (including height and weight)
11. Serious Adverse Events related to study participation
8.3.
Efficacy
8.3.1.
Spirometry
Subjects should abstain from drinking beverages with high caffeine content such as tea or 
coffee for 4 hours prior to the spirometry procedure. 
FEV1 should be measured using spirometry equipment that meets or exceeds the minimal 
recommendations of the American Thoracic Society (ATS)/European Respiratory Society 
(ERS) [Miller, 2005]. All sites will use standardized spirometry equipment provided by 
an external vendor. Full FEV1 and FVC will be conducted at Visit 1, and pre-dose at Visit 
5, and prior to each exercise challenge at Visits 2, 3, 4, 6 and 7. 
For full FEV1 and FVC testing at Screening and at randomisation (Visit 2), at least two 
valid and two repeatable (with no more than 8) efforts should be obtained using 
ATS/ERS guidelines. For all other visits where full FEV1 and FVC testing is performed 
(prior to each exercise test at visits 3, 4, 6 and 7), at least two valid efforts should be 


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obtained.  At each time point, the largest FEV1 and FVC should be recorded, even if they 
do not come from the same effort. 
Serial FEV1 measurements only (not FVC) will be conducted serially as described in 
Time and Events Table Table 3 following each exercise challenge at Visits 2, 3, 4, 6 and 
7. 
Subjects must have a FEV1 of at least 70% of their predicted normal value to be eligible 
to take part in the study at Visit 1.
After Visit 1, subjects will always be required to withhold their albuterol/salbutamol for 
at least 6 hours before each clinic visit.
Subjects must not administer study drug prior to coming to the clinic on study visit days.
8.3.1.1.
Target FEV1 Calculations
Three target FEV1values will be calculated from the pre-exercise FEV1 to determine 
subject eligibility and for monitoring the safety of the subject prior to exercise challenge 
testing: 
1.
The FEV1 value that represents a ≥20% decrease in FEV1, which is the 
eligibility criterion. 
2.
The FEV1 value that represents a ≥40% decrease in FEV1, which will serve as 
an alert for severe bronchoconstriction and need for administering rescue 
treatment. 
3.
The FEV1 value that represents a ≥95% recovery of the FEV1 result.  
Subjects should be monitored until they reach a recovery level where their FEV1 value 
represents a 95% recovery of the pre-exercise FEV1 result.  Additional spirometry and 
rescue medication may be used as needed (See Section 8.3.2.1).
8.3.2.
Exercise Challenge Testing
The exercise challenge test is a stepped challenge on a treadmill at a speed and incline 
that will allow the subject’s heart rate to reach between 80% to 95% of their maximum 
heart rate. All exercise challenges will be performed on a treadmill. During the exercise 
challenge, subjects will breathe medical grade dry air at ambient temperature from a 
reservoir using a two-way non-rebreathing valve.
Subjects will exercise sufficiently to attain a heart rate between 80 to 95% of their 
predicted maximum within 4 minutes and maintain this heart rate with exercise for an 
additional 6 minutes for a total of 10 minutes of exercise. The challenge will be followed 
immediately by serial spirometry (FEV1 efforts only) at 6 time points over 60 minutes (5, 
10, 15, 30, 45 and 60 minutes post-exercise). The information gained from the eligibility 
challenge(s) regarding incline and speed will be used to obtain the target heart rate in the 
subsequent exercise challenges.


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Exercise challenges should not be performed within 24 hours of exercise in cold air. 
Subjects should abstain from drinking beverages with high caffeine content such as tea or 
coffee for 4 hours prior to the exercise challenge. 
Additional instructions on exercise challenge testing can be found in the SRM.
8.3.2.1.
Worsening of Asthma during Exercise Challenge
Exercise challenges may be stopped at any time during the assessment for worsening 
asthma. Guidelines for treatment are provided in the SRM. 
If a subject's FEV1 decreases to ≥40% from their pre-exercise FEV1 following exercise 
challenge, he/she must receive rescue therapy. If he/she requires rescue therapy with 
anything other than MDI or nebulized albuterol/salbutamol or ipratropium (secondarily) 
following the exercise challenge assessment, he/she is not allowed to continue in the 
study (see Section 6.4.1). 
The subject should not leave the clinic until FEV1 returns to within 95% of the baseline 
FEV1 target recovery value or the subject is judged medically stable by the investigator to 
leave the clinic.
8.3.3.
Key Study Assessments
Information regarding spirometry, exercise testing, and study medication dosing at Visits 
will be conducted as described below. All other assessments will also be conducted as 
shown in Time and Events Table Table 3.
8.3.3.1.
Visit 1 (Screening)
Spirometry will be performed at Visit 1 between 5:00 PM and 11:00 PM, ideally at the 
end of the subjects ICS dosing interval. Full FEV1 and FVC testing will be conducted. At 
least two valid and two repeatable spirometry efforts should be obtained. Subjects must 
have a best pre-bronchodilator FEV1 of ≥ 70% of their predicted normal value to be 
eligible to take part in the study.  
8.3.3.2.
Visit 2 (Randomization)
Treatment period 1 baseline FEV1: Visit 2 begins between 5 PM and 11 PM and 
should begin at approximately the same time as Visit 1 (±1 hour).  Spirometry will be 
performed at Visit 2 at approximately the same time as at Visit 1 (±1 hour). The FEV1
should be measured approximately 12 hours (±1 hour) after dosing with run-in 
medication (FP 250 mcg). At least two valid and two repeatable spirometry efforts should 
be obtained before the first exercise challenge.
From this spirometry testing, the target FEV1 values #2 and #3 (Section 8.3.1.1) should 
be determined based on the pre-exercise FEV1. 


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Eligibility Exercise Challenge: After the pre-exercise baseline FEV1 has been 
determined, an exercise challenge will be performed according to the method described 
in the SRM. 
Post-exercise Serial Spirometry: Following the eligibility exercise challenge, serial 
spirometry (FEV1) will be performed at 5, 10, 15, 30, 45 and 60 minutes post-exercise. 
To qualify for randomization, subjects must demonstrate a decrease in FEV1 of ≥20% 
when compared to the FEV1 obtained immediately pre-exercise for at least one of the 
post-exercise spirometry efforts obtained within 30 minutes post-challenge.  Subjects 
who achieve a decrease in FEV1 of 15% to <20% may continue taking their daily run-in 
medication and repeat the eligibility exercise challenge once within a week. In the event 
where a repeat visit is required for the exercise challenge, spirometry and vital signs 
measurements will be performed pre- and post- exercise challenge as detailed in Table 3. 
In addition, ACQ-5 and a review of concomitant medication and adverse events will be 
performed at the repeat visit. 
Dosing: Eligible subjects will administer their evening dose of double-blinded study 
medication following the eligibility exercise challenge/serial spirometry. Evening dosing 
should occur between 5 PM and 11PM.
8.3.3.3.
Visit 3 and Visit 6 (23 hours Post First Dose Exercise Challenge)
Visit 3 and Visit 6 begins between 5 PM and 11 PM and should begin at approximately 
the same time as Visit 1 (±1 hour).  These visits should begin prior to the subject’s 
evening dose on that visit day.
Pre-exercise FEV1: Spirometry will be performed at Visits 3 and 6 at approximately the 
same time as at Visit 1 (±1 hour). The FEV1 should be measured approximately 23 hours 
(±1 hour) after the first dose in each treatment period. At least two valid spirometry 
efforts should be obtained before the exercise challenge.
From this spirometry testing, the target FEV1 values #2 and #3 (Section 8.3.1.1) should 
be determined based on the pre-exercise FEV1. 
Exercise Challenge: After the pre-exercise FEV1 has been determined, an exercise 
challenge will be performed according to the method described in the SRM. 
Post-exercise Serial Spirometry: Following the eligibility exercise challenge at each 
visit, serial spirometry (FEV1) will be performed at 5, 10, 15, 30, 45 and 60 minutes post-
exercise.
Medication Dosing: At the end of Visits 3 and 6, the evening dose of study treatment 
medication should be administered following completion of the 23-hour post evening 
dose exercise challenge/serial spirometry, and prior to the subject’s leaving the clinic.


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8.3.3.4.
Visit 4 and Visit 7 (Blinded Treatment Exercise Challenges)
Visit 4 and Visit 7 begin between 5 PM and 11 PM and are conducted over 
approximately 24 hours. Subjects will be required to attend three clinic visits during each 
24-hour period for Visit 4 and Visit 7. The evening visit should begin at approximately 
the same time as Visit 1 (±1 hour).  
Dosing: At the beginning of Visit 4 and Visit 7, subjects will administer their evening 
doses of double-blinded study medication in the clinic and the time of dosing will be 
recorded. In addition to administering the evening dose, vital signs will be measured and 
a review of concomitant medication and AEs performed.
Subjects will return to the clinic 12 (±1) hours and 23 (±1) hours after evening 
dosing for exercise challenge testing.
Pre-exercise FEV1: At least two valid spirometry efforts with full FEV1 and FVC 
maneuvers should be obtained just prior to each exercise challenge.
From this spirometry testing, the target FEV1 values #2 and #3 (Section 8.3.1.1) should 
be determined based on the pre-exercise FEV1. 
Exercise challenge testing: Exercise challenge testing will occur at 12 (±1) hours and 23 
(±1) hours after administering the evening dose. (The 12-hour exercise challenge and 
spirometry measurements should occur prior to dosing of the study medication). 
Post-exercise Serial Spirometry: Following the eligibility exercise challenge at each 
visit, serial spirometry (FEV1) will be performed at 5, 10, 15, 30, 45 and 60 minutes post-
exercise.
Washout Medication Dosing: At the end of Visit 4, the washout medication should be 
dispensed and first evening dose administered following completion of the 23-hour post 
evening dose exercise challenge/serial spirometry, and prior to the subject’s leaving the 
clinic.
8.3.3.5.
Visit 5
Treatment period 2 baseline FEV1: Spirometry will be performed at Visit 5 at 
approximately the same time as at Visit 1 (±1 hour). The FEV1 should be measured 
approximately 12 hours (±1 hour) after dosing with the washout medication. At least two 
valid spirometry efforts should be obtained.
Dosing: Subjects will administer their evening doses of double-blinded study medication 
following the spirometry.
8.3.4.
Physical Activity Monitor
Subjects should refrain from significant changes in their exercise level (e.g., joining a
gym), except as instructed by the investigator, for the duration of the study.


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A clinically validated physical activity monitor (accelerometer) will be used to measure 
specific levels of physical activity. There will be 4 assessment periods, including an 
initial baseline assessment in order to provide a reliable estimate of habitual physical 
activity. The physical activity monitor will be worn by the study subjects during the 
weeks prior to Visit 2, Visit 4, Visit 5 and Visit 7. Further details will be provided in the 
SRM.
Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and 
reminded to wear the SenseWear Armband accelerometer for the 7 days preceding these 
visits.
Physical activity monitors will be shipped from each study site directly to GSK for 
analysis and interpretation or to an independent vendor, contracted by GSK, blinded to 
treatment assignment, who will be responsible for transmitting the data to GSK.
8.3.5.
Asthma Control Questionnaire-5 (ACQ-5)
The ACQ-5 will be completed at the beginning of all study visits where the form is 
completed. 
The ACQ-5 is a five-item questionnaire, which has been developed as a measure of 
subject’ asthma control that can be quickly and easily completed [Juniper, 2005]. The 
questions are designed to be self-completed by the subject. The five questions enquire 
about the frequency and/or severity of symptoms (nocturnal awakening on waking in the 
morning, activity limitation, and shortness of breathe, wheeze). The response options for 
all these questions consist of a zero (no impairment/limitation) to six (total impairment/ 
limitation) scale.
The subject should be given a quiet area in which to complete the questionnaire. The 
investigator should ask the subject to complete the questions as accurately as possible. If 
the subject requests help or clarification with any of the questions, he/she will be asked to 
re-read the instructions and give the answer that best reflects how he/she felt over the 
previous week. The subject should be reassured that there are no right or wrong 
answers. The investigator should not provide the subject with any answer or attempt to 
interpret any portion of a question.
It is recommended that the ACQ-5 be administered at the same time during each visit.
To avoid biasing responses, the subjects should not be told the results of diagnostic tests 
prior to completing the questionnaire and should be completed before any procedures are 
performed on the subject to avoid influencing the subject’s response. Adequate time 
should be allowed to complete all items on the ACQ-5.
8.4.
Safety
Safety will be assessed, as indicated in the Time and Events Table Table 3, by monitoring 
of AEs, a physical examination at screening, and vital signs (systolic and diastolic blood 
pressure and heart rate [pulse] at each visit. A screening 12-ECG will be conducted. 


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In cases of suspected pneumonia, a confirmatory chest x-ray should be conducted within 
48 hours.
Planned time points for all safety assessments are listed in the Time and Events Table 
(Time and Events Table 3). 
8.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
8.4.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment (the start of the 
run-in period) until the follow-up contact (see Section 8.4.1.3), at the time points 
specified in the Time and Events Table Table 3).

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 eCRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5.
8.4.1.2.
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?” 


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
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
8.4.1.3.
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 5.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 6.4). Further information on follow-up procedures is given in 
Appendix 5.
8.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 5 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF 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.
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.
8.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs 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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8.4.2.
Asthma Exacerbations
Severe asthma exacerbations should not be recorded as an AE unless they meet the 
definition of an SAE (Section 13.5.2).  For the purposes of this study, severe asthma 
exacerbations will be collected and recorded on the exacerbations log in the eCRF. The 
treatment details must also be recorded in the eCRF. 
The time period for collection of severe asthma exacerbations will begin from the time of 
randomization (first receipt of investigational product) and will end after the 7-day 
follow-up period has been completed.
8.4.3.
Pregnancy

Details of all pregnancies in female subjects will be collected from the time the 
informed consent is signed (Visit 1) and until the follow up contact.

Any pregnancy that occurs during study participation must be reported using a 
clinical trial pregnancy form.  

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 Section 
13.6.1.

Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator 
as possibly related to the study treatment, must be promptly reported to GSK.
8.4.4.
Physical Exams

A detailed physical examination including, but not limited to an evaluation of the 
lungs and cardiovascular system, will be conducted at Visit 1.  Investigators 
should pay special attention to clinical signs related to previous serious illnesses

Licensed practitioners who are listed on the Form 1572 are permitted to perform 
the physical examination. A licensed physician on the Form 1572 must sign off on 
the physical examinations completed by non-physicians. The results will be 
recorded in the subject’s clinic notes. Whenever possible, the same person should 
perform the examination. 

If during routine clinical examination of the subject there is evidence of oral 
candidiasis infection, a culture can be taken and appropriate therapy should be 
instituted at the discretion of the Investigator.
8.4.5.
Vital Signs

Vital signs including pulse rate and systolic and diastolic blood pressure will be 
obtained at each clinic visit, including any Early Withdrawal visit. 

Vital signs will be obtained after subjects have rested for approximately 5 minutes 
in a semi-supine position, except in the case of the post exercise test vital signs 
which will be performed immediately following the end of the exercise test.


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
At all time points where both vital signs and spirometry are performed, vital signs 
will be done before the spriometry measurement. 

At visits where the exercise challenge is performed, vitals will be measured before 
(prior to the pre-exercise spirometry) and after the exercise challenge.

Heart rate will be measured during each exercise challenge. 

If there are any clinically significant abnormalities noted, further examinations 
must be performed until the abnormality is resolved.  
8.4.6.
Electrocardiogram (ECG)

A 12-lead ECG will be performed and interpreted by the investigator or his/her 
suitably qualified designee at Visit 1. The ECG will be recorded after 5 minutes 
rest; after vital signs and prior to performing spirometry.

Investigators will use a site ECG machine and perform a manual reading of the 
ECG parameters to determine whether a subject meets the eligibility criteria for 
enrolment in the study at screening (Visit 1). 

The ECG interpretation including the paper trace will be maintained at the site 
within the source documentation.
8.5.
Genetics
Information regarding genetic research is included in Appendix 4.
9.
DATA MANAGEMENT

For this study, subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
and full date of birth will not be collected or transmitted to GSK according to 
GSK policy.

For this study subject data will be collected using GSK defined case report forms 
and combined with data provided from other sources in a validated data system.


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
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.  

Original CRFs will be retained by GSK, while the investigator will retain a copy.  
Subject initials will not be collected or transmitted to GSK according to GSK 
policy.
10.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
10.1.
Hypotheses
The primary endpoint is the maximal percent decrease in FEV1 following exercise 
challenge at 12-hours post-dose at the end of the 2-week treatment period.  
The treatment comparison is the FF/VI combination versus FP.  Demonstration of 
efficacy for this treatment comparison will be based on a hypothesis testing approach 
whereby the null hypothesis is that there is no difference between treatment groups and 
the alternative hypothesis is that there is a difference between treatment groups.  
A 2-sided 5% probability associated with incorrectly rejecting the null hypothesis 
(significance level) is considered acceptable for this study. In order to account for 
multiplicity, this primary hypothesis test on the primary endpoint for the ITT (Intent-to-
Treat) population will act as a gatekeeper for all other hypothesis tests using the 
secondary endpoints, where these tests will proceed in a pre-defined order.
If the primary hypothesis on the primary endpoint for the ITT population is rejected then 
the following hierarchy of tests will be performed using the ITT population; 
1.
Test at the 5% level the null hypothesis that the true odds ratio between the two treatment 
groups of recovering to within 5% of pre-exercise FEV1 at the 30 minute post-exercise 
time point following the exercise challenge at 12 hours post evening dose is equal to one.
2.
Test at the 5% level the null hypothesis that the true population difference 
between the treatment group means in maximal percent decrease in FEV1 from 
pre-exercise at 23 hrs post-dose at the end of the 2-week treatment period is zero.
3.
Test at the 5% level the null hypothesis that the true odds ratio between the two treatment 
groups of recovering to within 5% of pre-exercise FEV1 at the 30 minute post-exercise 
time point following the exercise challenge at 23 hours post evening dose is equal to one.
4.
If 3 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in weighted mean 0-60 


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minutes for percentage decrease in FEV1 from pre-exercise FEV1 at 12 hrs post-
dose at the end of the 2-week treatment period is zero.
5.
If 4 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in weighted mean 0-60 
minutes for percentage decrease in FEV1 from pre-exercise FEV1 at 23 hrs post-
dose at the end of the 2-week treatment period is zero.
If either the primary null hypothesis or any of the above null hypotheses are not rejected, 
then although all of the subsequent hypothesis tests will be performed, each test result, 
and the associated p-value will be used for descriptive purposes only.
10.2.
Study Design Considerations
10.2.1.
Sample Size Assumptions
For the primary efficacy endpoint of maximal percent decrease in FEV1 following 
exercise challenge at 12 hours post-dose at the end of the 2-week treatment period, given 
an assumed 20% screen failure rate, a 70% run-in failure rate, and a 15% withdrawal rate 
post-randomisation, a total of approximately 275 subjects will be screened. Given these 
assumed failure and withdrawal rates we expect 220 subjects will enter the run-in period, 
of which 66 subjects will be randomized, of which 56 subjects will be evaluable, that is 
completing the exercise challenges and the FEV1 evaluations at the end of both treatment 
periods. With 56 evaluable subjects this study has approximately 90% power assuming a 
true population difference of 5% in maximal percent decrease in FEV1 between the two 
treatment groups.  This assumes a within-subject standard deviation (SD) of 8% where 
significance is declared at the two-sided 5% significance level. 
Subjects will be centrally randomized to one of the two treatment sequences shown 
below in Table 4 in a 1:1 ratio:
Table 4
Treatment Sequencing
Allocation 
ratio
Sequence
Period 1
Period 2
1
1
FF/VI 100/25 mcg QD via 
Ellipta + Placebo BD via 
Diskus
FP 250 mcg BD via Diskus + 
Placebo QD via Ellipta
1
2
FP 250 mcg BD via Diskus + 
Placebo QD via Ellipta
FF/VI 100/25 mcg QD via 
Ellipta + Placebo BD via 
Diskus


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10.2.2.
Sample Size Sensitivity
To demonstrate the sensitivity of the sample size calculation for this study, Table 5 shows 
the effect that different within-subject standard deviations would have on the power of 
the study.  
Table 5
Power as a function of within-subject SD
Within-subject 
Standard Deviation 
(%)
Power for the 
primary endpoint 
(%)
5
>99.9
6
99.1
7
96.0
8
90.1
9
82.3
10
73.9
11
65.7
Table 6
Sample size as a function of within-subject SD
Within-subject 
Standard Deviation 
(%)
Number of 
evaluable subjects 
5
24
6
33
7
44
8
56
9
71
10
87
11
104
Both Table 5 and Table 6 assume a true population difference of 5% between the two 
treatment groups.
10.2.3.
Sample Size Re-estimation
Blinded sample size re-estimation will be conducted when approximately 50% of the 
subjects have completed their second exercise challenge. In order to assess the accuracy 
of the sample size assumption for the within-subject SD, the linear mixed model for the 
primary analysis will be fitted to this blinded interim data, but with a dummy variable to 
denote treatment group membership. If this suggests the original assumptions behind the 
sample size were incorrect, an adjustment may be made to the planned number of 
subjects to be recruited.


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10.3.
Data Analysis Considerations
10.3.1.
Analysis Populations
Three subject populations will be identified.
Total Population: This population will comprise of all subjects screened and for whom a 
record exists on the study database and will be used for the tabulation and listing of 
reasons for withdrawal before randomization.
Intent-to-Treat (ITT) Population: The ITT Population will comprise all subjects 
randomized to treatment and who received at least one dose of trial medication.  
Randomized subjects will be assumed to have received trial medication unless definitive 
evidence to the contrary exists.  This will constitute the primary population for all 
analyses of efficacy measures and safety measures. Outcomes will be reported according 
to the randomized treatment allocation.
Per Protocol (PP) Population: The PP Population will consist of all subjects in the ITT
Population who do not have full protocol deviations.  Protocol deviations can either be 
full or partial.  Subjects with only partial deviations will be considered part of the PP 
population but their data will be excluded from the date of their deviation until either the 
end of the study or the end of the treatment period in which the deviation occurred.  The 
decision to exclude a subject, or part of their data, from the PP Population will be made 
prior to breaking the blind.  Protocol deviations that will lead to full or partial exclusion 
from the PP population will be detailed in the Reporting and Analysis Plan (RAP).  This 
population will be used for confirmatory analyses of the primary efficacy endpoint only.
10.3.2.
Analysis Data Sets
Details of the derived data in analysis datasets to be created will be given in the RAP.
10.3.3.
Treatment Comparisons
10.3.3.1.
Primary Comparisons of Interest
The primary treatment comparison is the comparison of group means for the FF/VI 
combination and FP for the primary endpoint of maximal percent decrease in FEV1 from 
pre-exercise at 12 hrs post-evening dose at the end of the 2-week treatment period. This 
comparison is to be performed using the ITT Population.
10.3.3.2.
Other Comparisons of Interest
The primary treatment comparison of FF/VI combination versus FP for the primary 
endpoint will also be performed for the PP population.
In addition FF/VI combination will be compared to FP for the secondary and other 
efficacy endpoints.


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10.3.4.
Interim Analysis
No interim analysis is planned.  
10.4.
Key Elements of Analysis Plan
Where possible, data from subjects who withdraw prematurely from the study will be 
included in any analyses. Specific details for inclusion will be detailed in the RAP but, in 
general, if a subject has completed a treatment period, including both exercise challenges 
and FEV1 evaluations, then the data for that period will be included in the analysis. 
Specifically if a subject has completed the first exercise challenge at 12 hours post-dose, 
as well as the FEV1 evaluations after this challenge, but has not completed the second 
exercise challenge at 23 hours post-dose, then the data for the 12 hour post-dose time 
point will be included, but will not be carried forward to replace the missing 23 hour time 
point.
Any tests for interactions will be 2-sided at the 10% level of significance.  In all cases, if 
any assumptions of the proposed methods of analyses are not met, alternative methods of 
analyses will be used.
The baseline FEV1 for all endpoints will be the pre-treatment FEV1 value obtained at the 
start of each Treatment Period (Visit 2 or Visit 5).
10.4.1.
Efficacy Analyses
All efficacy data will be summarized using means, standard deviations, medians and 
ranges for continuous variables and frequencies and percentages for categorical variables.
10.4.1.1.
Primary Analysis
The primary efficacy end point is maximal percent decrease from pre-exercise FEV1
following exercise challenge at 12 hours post-dose following two weeks of treatment. 
Maximal percent decrease will be defined as the percent change from pre-exercise FEV1
to the minimum FEV1 collected within one hour following exercise challenge at 12 hours 
post-dose.  Pre-exercise FEV1 will be defined as the FEV1 value collected prior to the 
exercise challenge test at 12 hours post-dose.  
The primary analysis is a comparison of the estimated means of the two treatment groups 
in maximal percent decrease in FEV1 from pre-exercise at 12 hrs post-dose using a LMM 
to adjust for covariate effects. The LMM will include the following covariates: treatment, 
subject-level mean of the pre-treatment FEV1 period baselines (mean of the 2 period 
baselines per subject), centered period-level baseline FEV1 (period baselines centered 
using subject-level mean of the pre-treatment FEV1 period baselines), gender, age, 
treatment period and smoking history as fixed effects, and a random intercept for each 
subject.  


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Details will be provided in the RAP of alternative analyses methods to be used in the 
event that distributional assumptions do not hold (e.g. if the distribution appears to be 
heavily skewed).
Mean post-exercise minimum FEV1 measurements and mean maximal percent decrease 
from pre-exercise FEV1 will be summarized with descriptive statistics by treatment 
group. Summaries and analyses for the primary endpoint will be provided for both the 
ITT and PP populations.  
10.4.1.2.
Secondary Analyses
Summaries and analyses for secondary endpoints will be provided for the ITT population.  
Maximal percent decrease from pre-exercise FEV1 following exercise challenge (at 23 
hours post-dose at the end of the 2-week treatment period):
This endpoint will be summarized and analyzed as for the primary endpoint of maximal 
percent decrease from pre-exercise FEV1 following exercise challenge at 12 hours post-
dose.  
Proportion of subjects with a 30 minute post-challenge FEV1 that was no more than 
5% lower than their pre-exercise FEV1 following the exercise challenge at 12 hours 
and 23 hours post evening dose at the end of the 2-week treatment period
This endpoint will be analysed using a logistic regression model separately for the 12 and 
23 hour challenges using the covariates baseline FEV1, treatment group, gender, age, and 
smoking history.
Weighted mean 0-60 minutes for percentage decrease from pre-exercise FEV1 after 
exercise (at 12 hours and 23 hours post-dose at the end of the 2-week treatment 
period):
A comparison will be made of the estimated means of the two treatment groups in for 
weighted mean 0-60 minutes of the percentage decrease in FEV1 from pre-exercise at 12 
and 23 hrs post-dose using a LMM to adjust for covariate effects. The LMM will include 
the following covariates: treatment, subject-level mean of the pre-treatment FEV1 period 
baselines (mean of the 2 period baselines per subject), centered period-level baseline 
FEV1 (period baselines centered using subject-level mean of the pre-treatment FEV1
period baselines),  gender, age, treatment period and smoking history as fixed effects, and 
a random intercept for each subject.  
10.4.1.2.1. Other Efficacy Analyses
Other measures of efficacy include the evaluation of a categorical treatment response 
evaluating the percentage of subjects who demonstrate a decrease from pre-exercise 
challenge FEV1<10%, a decrease 10% to <20%, or a decrease 20%, and an evaluation 
of maximal percent decrease from  treatment period baseline in FEV1 (period baseline) 
following exercise challenge (at 12 hours and 23 hours post-dose).  Additional endpoints 


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include evaluation of physical activity monitoring the ACQ-5 score, and the proportion of 
subjects with a 5 minute post-challenge FEV1 that was no more than 5% lower than their 
pre-exercise FEV1 following the exercise challenge at 12 hours and 23 hours post 
evening dose at the end of the 2-week treatment period (repeat for the 10, 15, 45 and 60 
minute time points).   
10.4.2.
Safety Analyses
Safety will be assessed with clinical adverse events and asthma exacerbations.  
10.4.2.1.
Extent of Exposure
The extent of exposure to study drug will be summarized by treatment group.
10.4.2.2.
Adverse Events (AEs)
Frequency of adverse events will be tabulated by treatment group as the number of 
subjects with events occurring during the treatment period.  Drug-related adverse events 
will be tabulated in the same manner.  Subject listings will include all reported adverse 
events, all adverse events rated as serious and all adverse events leading to study 
discontinuation.
10.4.2.3.
Exacerbations
The frequency of subjects experiencing an asthma exacerbation during the treatment 
period will be tabulated by treatment group.  A subject listing will include all reported 
exacerbations.
10.4.3.
Pharmacogenetic Analyses
See Appendix 4 for details about the PGx Analysis Plan.
11.
STUDY GOVERNANCE CONSIDERATIONS
11.1.
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.
11.2.
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.


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The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
11.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which CRF will 
serve as the source document.
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.


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The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
11.4.
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.
11.5.
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.
11.6.
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.  


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
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.
11.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.


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12.
REFERENCES
European Medicines Agency (EMA). Note for guidance on clinical investigation of 
medicinal products for treatment of asthma. 27Jun2013. CHMP/EWP/2922/01 Rev.1.
FDA Guidance for Industry: Exercise Induced Bronchospasm (EIB)—Development of 
Drugs to Prevent EIB, February 2002.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention. GINA, www.ginasthma.org; 2015.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007: 24. Table 3-2.
ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical 
trials and marketing authorisation for pharmaceuticals, 2009; EMA/CPMP/ICH/286/1995
Jones A, Fay JK, Burr ML, Stone M, Hood K, Roberts G. Inhaled Corticosteroids Effects 
on Bone Metabolism in Asthma and Mild Chronic Obstructive Pulmonary Disease. 
Cochrane Database of Systemic Reviews. 2002;1:1-21. 
Juniper EF, Svensson K, Mörk AC, Ståhl E. Modification of the Asthma Quality of Life 
Questionnaire (standardised) in patients 12 years and older. Health and Quality of Life 
Outcomes. 2005; 3:58.
König P, Hillmana L, Cervantesa C, Levine C, Maloney C, Douglass B, et al. Bone 
Metabolism in Children with Asthma Treated with Inhaled Beclomethasone 
Dipropionate. The Journal of Paediatrics. 1993;122:219-226. 
McFadden ER, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994;330:1362-1367.
McMahon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age and risks 
of FDA-approved long-acting 2-adrenergic receptor agonists. Pediatrics. 
2011;Nov;128(5):e1147-54. 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi F, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-338. 
Mitchell KE, Johnson-Warrington V, Apps LD, Bankart LS, Williams JE, Rees K,et al. . 
A Self-Management Programme for COPD: a Randomised Controlled Trial. Eur Respir 
J. 2014;44:1538-1547. 
Murray JJ, Waitkus-Edwards KR, Yancey SW. Evaluation of Fluticasone Propionate and 
Fluticasone Propionate/Salmeterol Combination on Exercise in Pediatric and Adolescent 
Patients with Asthma. Open Resp Med J, 2011, 5, 11-18.
National Institutes of Health (NIH). Guidelines for the Diagnosis and Management of 
Asthma - Expert Panel Report 3 2007. U.S. Department of Health and Human Services, 
Bethesda, MD; 2007. NIH Publication No. 07-4051.


2015N231308_03
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Parsons JP, Hallstrand TS, Mastronarde JG, Kaminsky DA, Rundell KW, Hull JH, et al. 
An Official American Thoracic Society Clinical Practice Guideline: Exercise-induced 
Bronchoconstriction. Am J Respir Crit Care Med 2013;187:1016–1027.
Pearlman D, Qaqundah P, Matz J, Yancey SJ, Stempel DA, Ortega HG. Fluticasone 
Propionate/Salmeterol and Exercise-Induced Asthma in Children With Persistent 
Asthma. Pediatric Pulm 2009;44:429–435.
Poppius H, Muittari A, Kreus KE, Korhonen O, Vilhanen A. Exercise Asthma and 
Disodium Cromoglycate. Br Med J 1970;4:337-339.
Quanjer P, Stanojevic S, Cole T, Baur X., Hall G, Enright P, et al. on behalf of the ERS 
Global Lung Function Initiative.  Multi-ethnic reference values for spirometry for the 3-
95 year age range: the global lung function 2012 equations. Eur Respir J, 2012; 40: 
1324–1343.
Turpeinen M, Pelkonen AS, Nikander K, Sorva R, Selroos O, Juntunen-Backman K,et al. 
. Bone mineral density in children treated with daily or periodical inhaled budesonide: the 
Helsinki Early Intervention Childhood Asthma study. Paediatric Research. 
2010;68(2):169-173. 
Weiler J, Anderson SD, Randolph C, Bonini S, Craig TJ, Pearlman DS, et al. 
Pathogenesis, prevalence, diagnosis, and management of exercise-induced 
bronchoconstriction: a practice parameter. Ann Allerg Asthma Immunol 2010;105 (6 
Supp): S1-S47. 
Weiler J, Nathan RA, Rupp NT, Kalberg CJ; Emmett A, Dorinsky PM. Effect of 
fluticasone/salmeterol administered via a single device on exercise-induced 
bronchospasm in patients with persistent asthma. Ann. Allergy Asthma Immunol. 
2005;94:65-72.


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13.
APPENDICES
13.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ACQ
Asthma Control Questionnaire-5
AE
Adverse Event
COPD
chronic obstructive pulmonary disorder
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
EIB
Exercise-induced bronchoconstriction
EMA
European Medicines Agency
ERS
European Respiratory Society
eCRF
Electronic Case Report Form
FEV1
Forced Expiratory Volume in One Second
FF
Fluticasone furoate
FP
Fluticasone propionate
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
HPA
Hypothalamic-pituitaryadrenal axis
IB
Investigator Brochure
ICF
Informed Consent Form
ICS
Inhaled Corticosteroid
IEC
Independent Ethics Committee
IP
Investigational product
INR
International normalized ratio
IRB
Independent Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
LABA
Long Acting Beta-Agonist
mcg
Microgram
MDI
Metered Dose Inhaler
mL
Milliliter
MET
Metabolic Equivalent of Tasks
MSDS
Material Safety Data Sheet
NHLBI
National Heart Lung and Blood Institute
PK
Pharmacokinetic
PP
Per Protocol
RAP
Reporting and Analysis Plan
RNA
Ribonucleic acid


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SABA
Short-acting beta-agonist
SAE
Serious Adverse Event
SAR
Symptomatic Allergic Rhinitis
SRM
Study Reference Manual
ULN
Upper Limit of Normal
VI
Vilanterol Trifenate (GW642444)
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ADVAIR
SenseWear Armband
DISKUS
ELLIPTA
NUCALA
RELVAR/BREO


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13.2.
Appendix 2: Liver Chemistry Stopping and Increased 
Monitoring Algorithm
Phase III-IV 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
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.


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Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.


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13.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2 
ALT 3xULN and International normalized ratio (INR)>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 72 hours after 
last dose6

Serum creatine phosphokinase (CPK) and 


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
Do not restart/rechallenge subject with 
study treatment. 

Permanently discontinue study treatment and 
may continue subject in the study for any 
protocol specified follow up assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, 
aspartate aminotransferase [AST], alkaline 
phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 


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studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
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 ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

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.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 


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13.4.
Appendix 4: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including FF/VI, FP 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.
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 2 ml saliva sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A saliva sample is collected at the randomisation 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 saliva 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 saliva 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 


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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 saliva being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 


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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.


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13.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
13.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition
of an AE or SAE.

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 


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Events NOT meeting definition of an AE include:
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.
13.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity


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


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13.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
13.5.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.


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
The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
13.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.


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
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
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.
13.5.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor 

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor 

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.


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13.6.
Appendix 6: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
(FRP) and Collection of Pregnancy Information
This list does not apply to FRP with same sex partners, when this is their preferred and
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis. 

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007] 

Injectable progestogen [Hatcher, 2007]

Contraceptive vaginal ring [Hatcher, 2007]

Percutaneous contraceptive patches [Hatcher, 2007]

Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2007].  

Male condom plus partner use of one of the contraceptive options below:
o
Contraceptive subdermal implant 
o
Intrauterine device or intrauterine system 
o
Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007]
Injectable progestogen [Hatcher, 2007]
o
Contraceptive vaginal ring [Hatcher, 2007]
o
Percutaneous contraceptive patches [Hatcher, 2007]
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2) 
2009].
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
13.6.1.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.


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
Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 5. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating

Will discontinue study medication and be withdrawn from the study.


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13.7.
Appendix 7 - Country Specific Requirements

No country-specific requirements exist.


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13.8.
Appendix 8 – Protocol Changes
13.8.1.
Protocol Amendment 01
This protocol amendment has been created to include an additional exercise challenge 
procedure at 23 hours after the first dose of double-blinded study medication in each 
Treatment Period. The purpose is to demonstrate that inhaled FF/VI 100/25 mcg provides 
improved bronchoprotection against EIB compared with FP 250 mcg after 23 hours of 
treatment with blinded medication. In addition, it will allow for an evaluation of the 
presence and extent of tachyphylaxis.
The study title has been revised to indicate the study is a randomised study with a 
crossover design.
Other minor corrections and edits have been made.
Method of Amendment
Original and amended texts are specified as follows:
Original text: as written in the original protocol
Revised text: as written in Amendment No. 01 with revisions in bold font.
Amendment Details
Protocol title 
Original title:
201832: A Double-Blind, Double-Dummy Comparison of Fluticasone Furoate/Vilanterol 
100/25 mcg Once Daily Versus Fluticasone Propionate 250 mcg Twice Daily in 
Adolescent and Adult Subjects with Asthma and Exercise-Induced Bronchoconstriction
Revised title:
201832: A Randomised, Double-Blind, Double-Dummy Crossover Comparison of 
Fluticasone Furoate/Vilanterol 100/25 mcg Once Daily Versus Fluticasone Propionate 
250 mcg Twice Daily in Adolescent and Adult Subjects with Asthma and Exercise-
Induced Bronchoconstriction
Protocol Synopsis: Overall Design
Original text:
This is a multicenter, randomized, double-blind, double-dummy, crossover study with 
two 2-week treatment periods separated by a 2-week wash-out period. Subjects will 
attend five evening visits over the course of the study. Standardized exercise challenge 
testing will be conducted at Visit 2 for eligibility determination, and at 12 and 23 hours 
post evening dose at Visits 3 and 5. Spirometry will be conducted at Screening (Visit 1), 


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and pre-dose at Visit 4, and prior to each exercise challenge at Visits 2, 3 and 5. Serial 
spirometry (6 time points over 60 minutes) as FEV1 only will be conducted after each 
exercise challenge test. Subjects should be monitored until they reach a recovery level 
where their FEV1 value represents a 95% recovery of the pre-exercise FEV1 result.  
Additional spirometry and rescue medication may be used as needed during recovery.
A Pre-Screening Visit (Visit 0) is included to obtain a signed Informed Consent and to 
review concomitant medications, and may be conducted on the same day as Visit 1, if 
appropriate. At Visit 1, subjects meeting eligibility criteria and will enter a 4 week single-
blinded run-in period on fluticasone propionate (FP) 250 mcg twice daily (BD). 
Albuterol/salbutamol will be issued for rescue use during the run-in, wash-out and 
treatment periods as needed.  Subjects will be instructed to contact the site if they develop 
worsening asthma.  
A screening electrocardiogram (ECG) and a complete physical examination will be 
conducted at Visit 1. Vital signs will be collected at each visit prior to spirometry and 
before and after each exercise challenge.
Physical activity levels will be monitored with the use of a physical activity monitor to 
assess activity outside the clinic worn for 7 days prior to Visit 2 (baseline), for 7 days 
during the last week of Treatment Period 1, for 7 days prior to Visit 4, and for 7 days 
during the last week of Treatment Period 2. Subjects unwilling or unable to participate in 
daily physical activity monitoring may still participate in the study, if appropriate.
Asthma control will be assessed using the Asthma Control Test at Visits 2 through 5. 
A follow up phone call will be conducted approximately 7 days after Visit 5.
Revised text:
This is a multicenter, randomized, double-blind, double-dummy, crossover study with 
two 2-week treatment periods separated by a 2-week wash-out period. Subjects will 
attend up to eight visits over the course of the study. Standardized exercise challenge 
testing will be conducted at Visit 2 for eligibility determination, Visit 3 and Visit 6 
(after 23 hours of the first treatment dose in each Treatment Period); and at 12 and 
23 hours post evening dose at Visits 4 and 7. Spirometry will be conducted at Screening 
(Visit 1), and pre-dose at Visit 5, and prior to each exercise challenge at Visits 2, 3, 4, 6
and 7. Serial spirometry (6 time points over 60 minutes) as FEV1 only will be conducted 
after each exercise challenge test. Subjects should be monitored until they reach a 
recovery level where their FEV1 value represents a 95% recovery of the pre-exercise 
FEV1 result.  Additional spirometry and rescue medication may be used as needed during 
recovery.
A Pre-Screening Visit (Visit 0) is included to obtain a signed Informed Consent and to 
review concomitant medications, and may be conducted on the same day as Visit 1, if 
appropriate. At Visit 1, subjects meeting eligibility criteria and will enter a 4 week single-
blinded run-in period on fluticasone propionate (FP) 250 mcg twice daily (BD). 


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Albuterol/salbutamol will be issued for rescue use during the run-in, wash-out and 
treatment periods as needed.  Subjects will be instructed to contact the site if they develop 
worsening asthma.  
A screening electrocardiogram (ECG) and a complete physical examination will be 
conducted at Visit 1. Vital signs will be collected at each visit prior to spirometry and 
before and after each exercise challenge.
Physical activity levels will be monitored with the use of a physical activity monitor to 
assess activity outside the clinic worn for 7 days prior to Visit 2 (baseline), for 7 days 
during the last week of Treatment Period 1, for 7 days prior to Visit 5, and for 7 days 
during the last week of Treatment Period 2. Subjects unwilling or unable to participate in 
daily physical activity monitoring may still participate in the study, if appropriate.
Asthma control will be assessed using the Asthma Control Test at Visits 2, 4, 5 and 7. 
A follow up phone call will be conducted approximately 7 days after Visit 7.
Protocol synopsis: Secondary and Other Endpoints
Original text:
Secondary Endpoints

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 
23 hours post evening dose at the end of the 2-week treatment period

Time required for recovery to within 5% of pre-exercise FEV1 from the time of the 
maximal percentage decrease from pre-exercise FEV1 following the exercise 
challenge at 12 hours and 23 hours post evening dose

Area under the curve for percentage decrease from pre-exercise FEV1 following 
exercise challenge at 12-hours and 23 hours  post evening dose (AUC 0-60 min)
Other Endpoints

Categorical treatment response evaluation of the percentage of subjects who
demonstrate a decrease from pre-exercise challenge FEV1 (at 12 hours and 23 hours 
post evening dose) of:
o
<10%, 
o
≥10% to <20%, 
o
≥20% 

Maximal percent decrease from pre-exercise baseline FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week 
treatment period  

Mean change from baseline in ACT score at the end of the treatment period

Percentage of subjects controlled defined as an Asthma Control Test (ACT) score ≥20 
at the end of the treatment period


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
Change in physical activity measures as assessed by a biosensor (SenseWear 
Armband) in terms of physical activity endpoints (e.g. daily step count, METs, sleep 
duration)
Revised text:
Secondary Endpoints

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 
23 hours post evening dose at the end of the 2-week treatment period

Time required for recovery to within 5% of pre-exercise FEV1 from the time of the 
maximal percentage decrease from pre-exercise FEV1 following the exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week 
treatment period

Area under the curve for percentage decrease from pre-exercise FEV1 following 
exercise challenge at 12-hours and 23 hours  post evening dose (AUC 0-60 min) at 
the end of the 2-week treatment period
Other Endpoints

Categorical treatment response evaluation of the percentage of subjects who
demonstrate a decrease from pre-exercise challenge FEV1 (at 12 hours and 23 hours 
post evening dose at the end of the 2-week treatment period) of:
o
<10%, 
o
≥10% to <20%, 
o
≥20% 

Maximal percent decrease from pre-exercise baseline FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week
treatment period  

Mean change from baseline in ACT score at the end of the 2-week treatment period

Percentage of subjects controlled defined as an Asthma Control Test (ACT) score ≥20 
at the end of the 2-week treatment period

Change in physical activity measures as assessed by a biosensor (SenseWear 
Armband) in terms of physical activity endpoints (e.g. daily step count, METs, sleep 
duration)


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Section 4.2: Secondary Endpoints
Original text:

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 
23 hours post evening dose at the end of the 2-week treatment period

Time required for recovery to within 5% of pre-exercise FEV1 from the time of the 
maximal percentage decrease from pre-exercise FEV1  following the exercise 
challenge at 12 hours and 23 hours post evening dose

Area under the curve for percentage decrease from pre-exercise FEV1 following 
exercise challenge at 12 hours and 23 hours post evening dose (AUC 0-60 min)
Revised text:

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 
23 hours post evening dose at the end of the 2-week treatment period

Time required for recovery to within 5% of pre-exercise FEV1 from the time of the 
maximal percentage decrease from pre-exercise FEV1 following the exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week
treatment period.

Area under the curve for percentage decrease from pre-exercise FEV1 following 
exercise challenge at 12 hours and 23 hours post evening dose (AUC 0-60 min) at 
the end of the 2-week treatment period.
Section 4.3: Other Endpoints
Original text:

Categorical treatment response evaluation of the percentage of subjects who
demonstrate a decrease from pre-exercise challenge FEV1 (at 12 hours and 23 hours 
post evening dose) of:
o
<10%, 
o
≥10% to <20%, 
o
≥20% 

Maximal percent decrease from pre-exercise baseline FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week 
treatment period

Mean change from baseline in ACT score at the end of the treatment period

Percentage of subjects controlled defined as an Asthma Control Test (ACT) score ≥20 
at the end of the treatment period

Change in physical activity measures as assessed by a biosensor (SenseWear 
Armband) in terms of physical activity endpoints (e.g. daily step count, METs, sleep 
duration)


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Revised text:

Categorical treatment response evaluation of the percentage of subjects who
demonstrate a decrease from pre-exercise challenge FEV1 (at 12 hours and 23 hours 
post evening dose at the end of the 2-week treatment period) of:
o
<10%, 
o
≥10% to <20%, 
o
≥20% 

Maximal percent decrease from pre-exercise baseline FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week 
treatment period

Mean change from baseline in ACT score at the end of the 2-week treatment period

Percentage of subjects controlled defined as an Asthma Control Test (ACT) score ≥20 
at the end of the 2-week treatment period

Change in physical activity measures as assessed by a biosensor (SenseWear 
Armband) in terms of physical activity endpoints (e.g. daily step count, METs, sleep 
duration)
Section 5.1: Overall Design
Original text:
This is a multicenter, randomized, double-blind, double-dummy, crossover study with 
two 2-week treatment periods separated by a 2-week wash-out period. Subjects will 
attend five evening visits over the course of the study. Standardized exercise challenge 
testing will be conducted at Visit 2 for eligibility determination, and at 12 and 23 hours 
post evening dose at Visits 3 and 5. Spirometry will be conducted at Screening (Visit 1), 
and pre-dose at Visit 4, and prior to each exercise challenge at Visits 2, 3 and 5. Serial 
spirometry (6 time points over 60 minutes) as FEV1 only will be conducted after each 
exercise challenge test. Subjects should be monitored until they reach a recovery level 
where their FEV1 value represents a 95% recovery of the pre-exercise FEV1 result.  
Additional spirometry and rescue medication may be used as needed during recovery.


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A Pre-Screening Visit (Visit 0) is included to obtain a signed Informed Consent (ICF) 
and to review concomitant medications, and may be conducted on the same day as Visit 
1, if appropriate. At Visit 1, subjects meeting eligibility criteria will enter a 4-week 
single-blinded run-in period on fluticasone propionate (FP) 250 mcg twice daily (BD). 
Albuterol will be issued for rescue use during the run-in, wash-out and treatment periods 
as needed.  Subjects will be instructed to contact the site if they develop worsening 
asthma.  
All subjects will be given a paper diary during the run-in, washout and treatment periods 
to record any medical problems experienced during the study, any medications taken, and 
rescue medication usage.
A screening electrocardiogram (ECG) and a complete physical examination will be 
conducted at Visit 1. Vital signs will be collected at each visit prior to spirometry, and 
before and after exercise challenge testing.  
Asthma control will be assessed using the Asthma Control Test (ACT) at Visits 2 through 
5.
Physical activity levels will be monitored to assess activity outside the clinic [Mitchell, 
2014] using a physical activity monitor (SenseWear Armband accelerometer) worn for 7 
days prior to Visit 2 (baseline), for 7 days prior to Visit 3 (during the last week of 
Treatment Period 1), for 7 days prior to Visit 4, and for 7 days prior to Visit 5 (during the 
last week of Treatment Period 2). Subjects unwilling or unable to participate in daily 
physical activity monitoring may still participate in the study, if appropriate. See Study 
Reference Manual (SRM) for additional details.
A follow up phone call will be conducted approximately 7 days after Visit 5.


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Revised text:
This is a multicenter, randomized, double-blind, double-dummy, crossover study with 
two 2-week treatment periods separated by a 2-week wash-out period. Subjects will 
attend up to eight visits over the course of the study. Standardized exercise challenge 
testing will be conducted at Visit 2 for eligibility determination, Visit 3 and Visit 6 
(after 23 hours of the first dose in each Treatment Period); and at 12 and 23 hours 
post evening dose at Visits 4 and 7. Spirometry will be conducted at Screening (Visit 1), 
and pre-dose at Visit 5 and prior to each exercise challenge at Visits 2, 3, 4, 6 and 7. 
Serial spirometry (6 time points over 60 minutes) as FEV1 only will be conducted after 
each exercise challenge test. Subjects should be monitored until they reach a recovery 
level where their FEV1 value represents a 95% recovery of the pre-exercise FEV1 result.  
Additional spirometry and rescue medication may be used as needed during recovery.
A Pre-Screening Visit (Visit 0) is included to obtain a signed Informed Consent (ICF) 
and to review concomitant medications, and may be conducted on the same day as Visit 
1, if appropriate. At Visit 1, subjects meeting eligibility criteria will enter a 4-week 
single-blinded run-in period on fluticasone propionate (FP) 250 mcg twice daily (BD). 
Albuterol will be issued for rescue use during the run-in, wash-out and treatment periods 
as needed.  Subjects will be instructed to contact the site if they develop worsening 
asthma.  
All subjects will be given a paper diary during the run-in, washout and treatment periods 
to record any medical problems experienced during the study, any medications taken, and 
rescue medication usage.


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A screening electrocardiogram (ECG) and a complete physical examination will be 
conducted at Visit 1. Vital signs will be collected at each visit prior to spirometry, and 
before and after exercise challenge testing.  
Asthma control will be assessed using the Asthma Control Test (ACT) at Visits 2, 4, 5 
and 7.
Physical activity levels will be monitored to assess activity outside the clinic [Mitchell, 
2014] using a physical activity monitor (SenseWear Armband accelerometer) worn for 7 
days prior to Visit 2 (baseline), for 7 days prior to Visit 4 (during the last week of 
Treatment Period 1), for 7 days prior to Visit 5, and for 7 days prior to Visit 7 (during the 
last week of Treatment Period 2). Subjects unwilling or unable to participate in daily 
physical activity monitoring may still participate in the study, if appropriate. See Study 
Reference Manual (SRM) for additional details.
A follow up phone call will be conducted approximately 7 days after Visit 7.
Section 7.8: Treatment after the End of the Study
Original text:
Subjects will not receive any additional treatment from GSK after completion of the 
study as other treatment options are available for persistent asthma. 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. At the end of Visit 5, investigators should prescribe asthma medication 
appropriate to the severity of the subject’s asthma in accordance with asthma guidelines 
[GINA, 2015; NIH, 2007]. Do not record asthma medications started on or after the final 
clinic visit in the eCRF.
Revised text:
Subjects will not receive any additional treatment from GSK after completion of the 
study as other treatment options are available for persistent asthma. 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. At the end of Visit 7, investigators should prescribe asthma medication 
appropriate to the severity of the subject’s asthma in accordance with asthma guidelines 
[GINA, 2015; NIH, 2007]. Do not record asthma medications started on or after the final 
clinic visit in the eCRF.


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Section 8: Study Assessments and Procedures – Table 3 Time and Events Table
Original table:
Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
211
Randomization
311
411
511
Week
-4
0
2
4
6
7
Treatment Day
-26 to -30 
days
1
14 (-2/+2) 
days
28 (-2/+2) 
days
42 (-2/+2) 
days
47 to 51 
days
Written Informed Consent
X
Genetics Consent
X1
Subject Demography
X
Medical History (including CV)
X
Disease (Asthma) History 
X
Medication History
X
X
Inclusion/Exclusion Criteria
X
Efficacy Assessments
Spirometry (full FEV1 and FVC)
X
X2
X2
X2
X2
X
Exercise Challenge Testing (Treadmill)
X3
X4
X4
Post-Challenge Serial FEV1 
Measurements
X3
X5
X5
Asthma Control Test
X
X
X
X
X
Dispense SenseWear accelerometer
X
Collect SenseWear accelerometer
X
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X6
Physical Examination
X
Vital Signs
X
X7
X7
X
X7
X
12-lead ECG 
X
Adverse Event Assessment
X8
X8
X
X
X
X
X
X


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Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
211
Randomization
311
411
511
Week
-4
0
2
4
6
7
Treatment Day
-26 to -30 
days
1
14 (-2/+2) 
days
28 (-2/+2) 
days
42 (-2/+2) 
days
47 to 51 
days
Issue Medical Conditions Diary Card
X
X
X
X
Review Medical Conditions Diary Card
X9
X9
X9
X9
X
Laboratory Assessments
Genetics Saliva Sample
X1
Urine Pregnancy Test
X
X
X
X
X12
Investigational Product
Dispense Fluticasone Propionate
X
X
Collect Fluticasone Propionate
X
X
Dispense Rescue Albuterol
X
X
X
X
X
Collect Rescue Albuterol
X
X
X
X
Dispense IP
X10
X
X
Assess study drug  compliance
X
X
X
X
X
Collect IP
X
X
X
X


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1.
Genetics saliva sample collected at Visit 2 (following Randomization) or at any scheduled visit thereafter. Genetics consent MUST be obtained PRIOR to collection of the Genetics 
sample.  
2.
Pre-exercise spirometry (full FEV1 and FVC testing), conducted immediately pre-exercise, if applicable. Subject should have withheld albuterol within previous 6 hours. 
3.
Performed for determination of eligibility. Serial spirometry performed 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges.  .  
4.
Exercise challenge testing will be performed at 12 hours and 23 hours following the evening study treatment doses given at the beginning of Visits 3 and 5.
5.
Serial spirometry performed at time points 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Longer monitoring may be required for those subjects who do not return to 
5% of baseline FEV1 values within 60 minutes.
6.
Concomitant medications collected for adverse events only between end of treatment and follow-up phone contact. 
7.
Vital signs will be collected before and after each exercise challenge test.
8.
Adverse Event and Serious Adverse Events to be collected from the start of study Drug (Visit 1) until the follow up contact. However, any SAE related to study participation will be     
recorded from the time of Informed Consent 
9.
Review medical conditions diary card, including an assessment of any potential change in exercise capacity
10. An unblinding card will be dispensed along with double blind IP.
11. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 3, 4 and 5 and reminded to wear the SenseWear accelerometer for the 7 days preceeding these visits.
12. Pregnancy test will be conducted via home test kit and results will be reported at the Follow-up phone contact.


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Revised table:
Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412
512
6
712
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
1
2
14 (-2/+2) 
days
28 (-2/+2) 
days
29 (-2/+2)
42 (-2/+2) 
days
47 to 
51 
days
Written Informed Consent
X
Genetics Consent
X1
Subject Demography
X
Medical History (including CV)
X
Disease (Asthma) History 
X
Medication History
X
X
Inclusion/Exclusion Criteria
X
Evidence of EIB
X
Efficacy Assessments
Spirometry (full FEV1 and FVC)
X
X2
X2
X2
X2
X2
X2
X
Exercise Challenge Testing 
(Treadmill)
X3
X4
X5
X4
X5
Post-Challenge Serial FEV1 
Measurements
X3
X
X6
X6
X6
Asthma Control Test
X
X
X
X
X
Dispense SenseWear 
accelerometer
X
Collect SenseWear accelerometer
X
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X7
Physical Examination
X
Vital Signs
X
X8
X8
X8
X
X8
X8
X


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Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412
512
6
712
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
1
2
14 (-2/+2) 
days
28 (-2/+2) 
days
29 (-2/+2)
42 (-2/+2) 
days
47 to 
51 
days
12-lead ECG 
X
Adverse Event Assessment
X9
X9
X
X
X
X
X
X
X
X
Issue Medical Conditions Diary 
Card
X
X
X
X
Review Medical Conditions Diary 
Card
X10
X10
X10
X10
X
Laboratory Assessments
Genetics Saliva Sample
X1
Urine Pregnancy Test
X
X
X
X
X13
Investigational Product
Dispense Fluticasone Propionate
X
X
Collect Fluticasone Propionate
X
X
Dispense Rescue Albuterol
X
X
X
X
X
Collect Rescue Albuterol
X
X
X
X
Dispense IP
X11
X
Assess study drug  compliance
X
X
X
X
X
Collect IP
X
X
X
X


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1.
Genetics saliva sample collected at Visit 2 (following Randomization) or at any scheduled visit thereafter. Genetics consent MUST be obtained PRIOR to 
collection of the Genetics sample.  
2.
Pre-exercise spirometry (full FEV1 and forced vital capacity (FVC) testing), conducted immediately pre-exercise, if applicable. Subject should have withheld 
albuterol within previous 6 hours. 
3.
Performed for determination of eligibility. Serial spirometry performed 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges.  Subjects must 
demonstrate a decrease in FEV1 of 20% at one time point within 30 minutes of the end of a standardized exercise challenge.  
4.
Exercise challenge testing will be performed at 23 hours following the evening study treatment doses given at Visit 2 and Visit 5 
5.
Exercise challenge testing will be performed at 12 hours and 23 hours following the evening study treatment doses given at the beginning of Visits 4 and 7.
6.
Serial spirometry performed at time points 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Longer monitoring may be required for those subjects 
who do not return to 5% of baseline FEV1 values within 60 minutes.
7.
Concomitant medications collected for adverse events only between end of treatment and follow-up phone contact. 
8.
Vital signs will be collected before and after each exercise challenge test.
9.
Adverse Event and Serious Adverse Events to be collected from the start of study Drug (Visit 1) until the follow up contact. However, any SAE related to study 
participation will be     recorded from the time of Informed Consent 
10. Review medical conditions diary card, including an assessment of any potential change in exercise capacity
11. An unblinding card will be dispensed along with double blind IP.
12. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear accelerometer for the 7 days preceeding 
these visits.
13. Pregnancy test will be conducted via home test kit and results will be reported at the Follow-up phone contact.


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Section 8.2.1: Spriometry
Original text:
FEV1 and FVC will be conducted at Visit 1, and pre-dose at Visit 4, and prior to each 
exercise challenge at Visits 2, 3 and 5. For full FEV1/FVC testing, at least 3 valid and 2 
repeatable (with no more than 8) efforts should be obtained using ATS/ERS guidelines. 
At each time point, the largest FEV1 and FVC should be recorded, even if they do not 
come from the same effort. 
Serial FEV1 measurements only (not FVC) will be conducted serially as described in 
Table 3 following each exercise challenge at Visits 2, 3 and 5. For serial FEV1 testing, 
two FEV1 efforts will be obtained at each time point. At each time point, the largest FEV1
will be selected.
Revised text:
FEV1 and FVC will be conducted at Visit 1, and pre-dose at Visit 5, and prior to each 
exercise challenge at Visits 2, 3, 4, 6 and 7. For full FEV1/FVC testing, at least 3 valid 
and 2 repeatable (with no more than 8) efforts should be obtained using ATS/ERS 
guidelines. At each time point, the largest FEV1 and FVC should be recorded, even if 
they do not come from the same effort. 
Serial FEV1 measurements only (not FVC) will be conducted serially as described in 
Table 3 following each exercise challenge at Visits 2, 3, 4, 6 and 7. For serial FEV1
testing, two FEV1 efforts will be obtained at each time point. At each time point, the 
largest FEV1 will be selected.
Section 8.2.3.3: Visit 3 and Visit 6 (23 hours Post First Dose Exercise 
Challenge)
New text:
Visit 3 and Visit 6 begin between 5 PM and 11 PM and should begin at 
approximately the same time as Visit 1 (±1 hour).  These visits should begin prior to 
the subject’s evening dose on that visit day.
Pre-exercise FEV1: Spirometry will be performed at Visits 3 and 6 at approximately 
the same time as at Visit 1 (±1 hour). The FEV1 should be measured approximately 
23 hours after the first dose in each treatment period. At least two adequate and 
repeatable spirometry efforts with full FEV1 and FVC maneuvers should be 
obtained before the exercise challenge.
Exercise Challenge: After the pre-exercise FEV1 has been determined, an exercise 
challenge will be performed according to the method described in the SRM. 


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Post-exercise Serial Spirometry: Following the exercise challenge, serial spirometry 
measurements will be performed at time points at 5, 10, 15, 30, 45 and 60 minutes 
post-challenge. Two FEV1 efforts (not full FVC maneuvers) will be performed at 
each time point.
Medication Dosing: At the end of Visits 3 and 6, the evening dose should be 
administered following completion of the 23-hour post evening dose exercise 
challenge/serial spirometry, and prior to the subject’s leaving the clinic.
Section 8.2.3.4: Visit 3 and Visit 5 (Blinded Treatment Exercise 
Challenge)
Original text:
Visit 3 and Visit 5 begin between 5 PM and 11 PM and are conducted over 
approximately 24 hours. These visits should begin at approximately the same time as 
Visit 1 (±1 hour) and approximately at the end of the dosing period for each IP.  
Dosing: At the beginning of Visit 3 and Visit 5, subjects will administer their evening 
doses of double-blinded study medication in the clinic and the time of dosing will be 
recorded. Subjects will return to the clinic 12 (±1) hours and 23 (±1) hours after dosing 
for exercise challenge testing.
Pre-exercise FEV1: At least two adequate and repeatable spirometry efforts with full 
FEV1 and FVC maneuvers should be obtained just prior to EACH exercise challenge.
From this spirometry testing, the target FEV1 values #2 and #3 (Section 8.2.1.1) should 
be determined based on the pre-exercise FEV1. 
Exercise challenge testing: Exercise challenge testing will occur at 12 (±1) hours and 23 
(±1) hours after administering the evening dose. (The 12-hour exercise challenge and 
spirometry measurements should occur prior to dosing of the study Diskus medication.) 
Following each challenge, serial spirometry measurements will be performed at time 
points at 5, 10, 15, 30, 45 and 60 minutes post-challenge. Two FEV1 efforts (not full FVC 
maneuvers) will be performed at each time point. 
Washout Medication Dosing: At the end of Visit 3, the washout medication should be 
dispensed and first evening dose administered following completion of the 23-hour post 
evening dose exercise challenge/serial spirometry, and prior to the subject’s leaving the 
clinic.


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Revised text:
Section 8.2.3.4: Visit 4 and Visit 7 (Blinded Treatment Exercise 
Challenge)
Visit 4 and Visit 7 begin between 5 PM and 11 PM and are conducted over 
approximately 24 hours. These visits should begin at approximately the same time as 
Visit 1 (±1 hour) and approximately at the end of the dosing period for each IP.  
Dosing: At the beginning of Visit 4 and Visit 7, subjects will administer their evening 
doses of double-blinded study medication in the clinic and the time of dosing will be 
recorded. Subjects will return to the clinic 12 (±1) hours and 23 (±1) hours after dosing 
for exercise challenge testing.
Pre-exercise FEV1: At least two adequate and repeatable spirometry efforts with full 
FEV1 and FVC maneuvers should be obtained just prior to EACH exercise challenge.
From this spirometry testing, the target FEV1 values #2 and #3 (Section 8.2.1.1) should 
be determined based on the pre-exercise FEV1. 
Exercise challenge testing: Exercise challenge testing will occur at 12 (±1) hours and 23 
(±1) hours after administering the evening dose. (The 12-hour exercise challenge and 
spirometry measurements should occur prior to dosing of the study Diskus medication.) 
Following each challenge, serial spirometry measurements will be performed at time 
points at 5, 10, 15, 30, 45 and 60 minutes post-challenge. Two FEV1 efforts (not full FVC 
maneuvers) will be performed at each time point. 
Washout Medication Dosing: At the end of Visit 4, the washout medication should be 
dispensed and first evening dose administered following completion of the 23-hour post 
evening dose exercise challenge/serial spirometry, and prior to the subject’s leaving the 
clinic.
Section 8.2.3.5: Visit 5 
Original text:
Period 2 pre-exercise baseline FEV1: Spirometry will be performed at Visit 4 at 
approximately the same time as at Visit 1 (±1 hour). The FEV1 should be measured 
approximately 12 hours after dosing with the washout medication. At least two adequate 
and repeatable spirometry efforts with full FEV1 and FVC maneuvers should be obtained.
Dosing: Subjects will administer their evening doses of double-blinded study medication 
following the spirometry.


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Revised text:
Period 2 pre-exercise baseline FEV1: Spirometry will be performed at Visit 5 at 
approximately the same time as at Visit 1 (±1 hour). The FEV1 should be measured 
approximately 12 hours after dosing with the washout medication. At least two adequate 
and repeatable spirometry efforts with full FEV1 and FVC maneuvers should be obtained.
Dosing: Subjects will administer their evening doses of double-blinded study medication 
following the spirometry.
Section 8.2.4 Physical Activity Monitor
Original text:
Subjects should refrain from significant changes in their exercise level (e.g., joining a 
gym), except as instructed by the investigator, for the duration of the study.
A clinically validated physical activity monitor (accelerometer) will be used to measure 
specific levels of physical activity. There will be 4 assessment periods, including an 
initial baseline assessment in order to provide a reliable estimate of habitual physical 
activity. The physical activity monitor will be worn by the study subjects during the 
weeks prior to Visit 2, Visit 3, Visit 4 and Visit 5. Further details will be provided in the 
SRM.
Subjects will be contacted by telephone 8-9 days prior to Visits 2, 3, 4 and 5 and 
reminded to wear the SenseWear Armband accelerometer for the 7 days preceeding these 
visits.
Revised text:
Subjects should refrain from significant changes in their exercise level (e.g., joining a 
gym), except as instructed by the investigator, for the duration of the study.
A clinically validated physical activity monitor (accelerometer) will be used to measure 
specific levels of physical activity. There will be 4 assessment periods, including an 
initial baseline assessment in order to provide a reliable estimate of habitual physical 
activity. The physical activity monitor will be worn by the study subjects during the 
weeks prior to Visit 2, Visit 4, Visit 5 and Visit 7. Further details will be provided in the 
SRM.
Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and 
reminded to wear the SenseWear Armband accelerometer for the 7 days preceeding these 
visits.
Section 10.1 Hypotheses
Original text:
If the primary hypothesis on the primary endpoint for the ITT population is rejected then 
the following hierarchy of tests will be performed using the ITT population; 


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1.
Test at the 5% level the null hypothesis that the true population difference 
between the treatment group means in maximal percent decrease in FEV1 from 
pre-exercise at 23 hrs post-dose is zero.
2.
If 1 is significant then test at the 5% level the null hypothesis that the true 
probability distributions for the treatment groups for not recovering to within 5% 
of pre-exercise FEV1 at 12 hrs post-dose (i.e. the “survival” distributions for the 
endpoint time to recovery to within 5% of pre-exercise FEV1 at 12 hrs post-dose) 
are equal.
3.
If 2 is significant then test at the 5% level the null hypothesis that the true 
population probability distributions for the treatment groups for not recovering to 
within 5% of pre-exercise FEV1 at 23 hrs post-dose (i.e. the “survival” 
distributions for the endpoint time to recovery to within 5% of pre-exercise FEV1
at 23 hrs post-dose) are equal.
4.
If 3 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in AUC for percentage 
decrease in FEV1 from pre-exercise FEV1 at 12 hrs post-dose is zero.
5.
If 4 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in AUC for percentage 
decrease in FEV1 from pre-exercise FEV1 at 23 hrs post-dose is zero.
Revised text:
If the primary hypothesis on the primary endpoint for the ITT population is rejected then 
the following hierarchy of tests will be performed using the ITT population; 
1.
Test at the 5% level the null hypothesis that the true population difference 
between the treatment group means in maximal percent decrease in FEV1 from 
pre-exercise at 23 hrs post-dose at the end of the 2-week treatment period is 
zero.
2.
If 1 is significant then test at the 5% level the null hypothesis that the true 
probability distributions for the treatment groups for not recovering to within 5% 
of pre-exercise FEV1 at 12 hrs post-dose at the end of the 2-week treatment 
period (i.e. the “survival” distributions for the endpoint time to recovery to within 
5% of pre-exercise FEV1 at 12 hrs post-dose) are equal.
3.
If 2 is significant then test at the 5% level the null hypothesis that the true 
population probability distributions for the treatment groups for not recovering to 
within 5% of pre-exercise FEV1 at 23 hrs post-dose at the end of the 2-week 
treatment period (i.e. the “survival” distributions for the endpoint time to 
recovery to within 5% of pre-exercise FEV1 at 23 hrs post-dose) are equal.


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4.
If 3 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in AUC for percentage 
decrease in FEV1 from pre-exercise FEV1 at 12 hrs post-dose at the end of the 2-
week treatment period is zero.
5.
If 4 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in AUC for percentage 
decrease in FEV1 from pre-exercise FEV1 at 23 hrs post-dose at the end of the 2-
week treatment period is zero.
Section 10.2.1: Sample Size Assumptions
Original text:
For the primary efficacy endpoint of maximal percent decrease in FEV1 following 
exercise challenge at 12 hours post-dose, given an assumed 10% screen failure rate, a 
55% run-in failure rate, and a 15% withdrawal rate post-randomisation, a total of 
approximately 165 subjects will be screened. Given these assumed failure and withdrawal 
rates we expect 148 subjects will enter the run-in period, of which 66 subjects will be 
randomized, of which 56 subjects will be evaluable, that is completing the exercise 
challenges and the FEV1 evaluations at the end of both treatment periods. With 56 
evaluable subjects this study has approximately 90% power assuming a true population 
difference of 5% in maximal percent decrease in FEV1 between the two treatment groups.  
This assumes a within-subject standard deviation (SD) of 8% where significance is 
declared at the two-sided 5% significance level. 
Revised text:
For the primary efficacy endpoint of maximal percent decrease in FEV1 following 
exercise challenge at 12 hours post-dose at the end of the 2-week treatment period, 
given an assumed 10% screen failure rate, a 55% run-in failure rate, and a 15% 
withdrawal rate post-randomisation, a total of approximately 165 subjects will be 
screened. Given these assumed failure and withdrawal rates we expect 148 subjects will 
enter the run-in period, of which 66 subjects will be randomized, of which 56 subjects 
will be evaluable, that is completing the exercise challenges and the FEV1 evaluations at 
the end of both treatment periods. With 56 evaluable subjects this study has 
approximately 90% power assuming a true population difference of 5% in maximal 
percent decrease in FEV1 between the two treatment groups.  This assumes a within-
subject standard deviation (SD) of 8% where significance is declared at the two-sided 5% 
significance level. 


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Section 10.3.3.1: Primary Comparisons of Interest
Original text:
The primary treatment comparison is the comparison of group means for the FF/VI 
combination and FP for the primary endpoint of maximal percent decrease in FEV1 from 
pre-exercise at 12 hrs post-evening dose. This comparison is to be performed using the 
ITT Population.
Revised text:
The primary treatment comparison is the comparison of group means for the FF/VI 
combination and FP for the primary endpoint of maximal percent decrease in FEV1 from 
pre-exercise at 12 hrs post-evening dose at the end of the 2-week treatment period. 
This comparison is to be performed using the ITT Population.
Section 10.3.5: Key Elements of Analysis Plan
Original text:
Any tests for interactions will be 2-sided at the 10% level of significance.  In all cases, if 
any assumptions of the proposed methods of analyses are not met, alternative methods of 
analyses will be used.
The baseline FEV1 for all endpoints will be the pre-treatment FEV1 value obtained at the 
start of each Treatment Period (Visit 2 or Visit 4).
Revised text:
Any tests for interactions will be 2-sided at the 10% level of significance.  In all cases, if 
any assumptions of the proposed methods of analyses are not met, alternative methods of 
analyses will be used.
The baseline FEV1 for all endpoints will be the pre-treatment FEV1 value obtained at the 
start of each Treatment Period (Visit 2 or Visit 5).
Section 10.3.5.1.2: Secondary Analyses
Original text:
Summaries and analyses for secondary endpoints will be provided for the ITT population.  
Maximal percent decrease from pre-exercise FEV1 following exercise challenge (at 23 
hours post-dose):


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This endpoint will be summarized and analyzed as for the primary endpoint of maximal 
percent decrease from pre-exercise FEV1 following exercise challenge at 12 hours post-
dose. 
Time required for recovery to within 5% of the pre-exercise FEV1 from the time of the 
maximal percentage decrease from pre-exercise FEV1 following the challenge (at 12 
hours and 23 hours post-dose):
The time required for recovery to within 5% of the pre-exercise FEV1 from the time of 
the maximal percentage decrease from pre-exercise FEV1 following exercise challenge at 
12 hours and 23 hours post-dose for both treatment groups will be compared using a log-
rank test. The log rank test will test the null hypotheses that the survival distributions of 
the two treatment groups are equal. In addition the estimated hazard ratio, confidence 
interval and p-value will be presented. Kaplan-Meier plots showing the cumulative 
incidence curves for each treatment group will be produced. 
AUC (0-60 min) for percentage decrease from pre-exercise FEV1 after exercise (at 12 
hours and 23 hours post-dose):
A comparison will be made of the estimated means of the two treatment groups in AUC 
of the percentage decrease in FEV1 from pre-exercise at 12 and 23 hrs post-dose using a 
LMM to adjust for covariate effects. The LMM will include the following covariates: 
treatment, subject-level mean of the pre-treatment FEV1 period baselines (mean of the 2 
period baselines per subject), centered period-level baseline FEV1 (period baselines 
centered using subject-level mean of the pre-treatment FEV1 period baselines),  gender, 
age, treatment period and smoking history as fixed effects, and a random intercept for 
each subject.  
Revised text:
Summaries and analyses for secondary endpoints will be provided for the ITT population.  
Maximal percent decrease from pre-exercise FEV1 following exercise challenge (at 23 
hours post-dose at the end of the 2-week treatment period):
This endpoint will be summarized and analyzed as for the primary endpoint of maximal 
percent decrease from pre-exercise FEV1 following exercise challenge at 12 hours post-
dose.  
Time required for recovery to within 5% of the pre-exercise FEV1 from the time of the 
maximal percentage decrease from pre-exercise FEV1 following the challenge (at 12 
hours and 23 hours post-dose at the end of the 2-week treatment period):
The time required for recovery to within 5% of the pre-exercise FEV1 from the time of 
the maximal percentage decrease from pre-exercise FEV1 following exercise challenge at 
12 hours and 23 hours post-dose for both treatment groups will be compared using a log-
rank test. The log rank test will test the null hypotheses that the survival distributions of 
the two treatment groups are equal. In addition the estimated hazard ratio, confidence 


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interval and p-value will be presented. Kaplan-Meier plots showing the cumulative 
incidence curves for each treatment group will be produced. 
AUC (0-60 min) for percentage decrease from pre-exercise FEV1 after exercise (at 12 hours 
and 23 hours post-dose at the end of the 2-week treatment period):
A comparison will be made of the estimated means of the two treatment groups in AUC 
of the percentage decrease in FEV1 from pre-exercise at 12 and 23 hrs post-dose using a 
LMM to adjust for covariate effects. The LMM will include the following covariates: 
treatment, subject-level mean of the pre-treatment FEV1 period baselines (mean of the 2 
period baselines per subject), centered period-level baseline FEV1 (period baselines 
centered using subject-level mean of the pre-treatment FEV1 period baselines),  gender, 
age, treatment period and smoking history as fixed effects, and a random intercept for 
each subject.  
13.8.2.
Protocol Amendment 02
This amendment applies to all trial centres participating in study 201832.
This protocol is being amended to make the following changes:

Increase the screen failure rate to 20% (from 10%) and the run-in failure rate to 70% 
(from 55%). This takes into consideration the challenge of enrolling EIB subjects 
with symptomatic allergic rhinitis (SAR) at screening and also the challenge for 
subjects to demonstrate a decrease in FEV1 of ≥20% at one time point within 30 
minutes of the end of the exercise challenge at Visit 2; after taking fluticasone 
propionate for approximately four weeks during the run-in period. 

Allow subjects with symptomatic allergic rhinitis at screening to be treated for up to 
four weeks with intranasal corticosteroids followed by a repeat screening visit to 
determine eligibility prior to entry into the study. Subjects that continue to be 
symptomatic after up to four weeks of treatment will be excluded. Eligible subjects 
will enter the run-in phase for 4 weeks on FP before the first exercise challenge at
Visit 2.

Allow subjects who are asymptomatic at screening, who become symptomatic during 
the study to remain in the study and be treated with intranasal corticosteroids at a 
constant dose for the duration of the study. Therefore, the randomisation exclusion 
criterion 6 (symptomatic allergic rhinitis) has been deleted. 

Include tobacco/marijuana use and pregnancy (which were omitted in error in the 
original protocol) as exclusion criteria.

Clarify the expectations for subjects for Visits 4 and 7 with regards to the number of 
anticipated clinic visits (and procedures) over the 24-hour period for both visits.

Extend the time window for the repeat exercise challenge from 24-48 hours to up to 
one week; taking into consideration the challenge for subjects to return within 48 
hours for a repeat procedure.

Replace the ACT questionnaire with the ACQ-5 questionnaire, given the mismatch 
between treatment periods of two weeks and the recall period of 4 weeks for the 


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ACT.  ACT will not clearly represent asthma control for the specific treatment 
periods.

Increase the restriction period for caffeinated beverages to 4 hours prior to 
spirometry and the exercise challenge procedure (previously 2 hours prior to 
spirometry) due to the possibility of inducing refractoriness. 

The time to recovery endpoint (time to recovery to within 5% of pre-exercise FEV1
as measured from the time of maximal decline in post-exercise FEV1) has been 
changed to a binary endpoint defining recovery as those subjects who have a 30 
minute post-exercise FEV1 measurement that is no more than 5% lower than their 
pre-exercise FEV1. This binary endpoint has also been included in the “other 
endpoints” at all the remaining post-exercise spirometry time points.

The statistical testing hierarchy has been changed to prioritise the maximal 
percentage FEV1 reduction (primary endpoint) and binary recovery endpoints 
following the 12 hour post-dose exercise challenge.

Other edits and minor corrections have been made.
Method of Amendment
Original and amended texts are specified as follows:
Original text: as written in the Protocol Amendment No. 01
Revised text: as written in Amendment No. 02 with revisions in bold font.
Amendment Details
Protocol Synopsis and Section 4.2: Secondary Endpoints
Original text:

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 
23 hours post evening dose at the end of the 2-week treatment period

Time required for recovery to within 5% of pre-exercise FEV1 from the time of the 
maximal percentage decrease from pre-exercise FEV1  following the exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week 
treatment period.

Area under the curve for percentage decrease from pre-exercise FEV1 following 
exercise challenge at 12 hours and 23 hours post evening dose (AUC 0-60 min) at 
the end of the 2-week treatment period.
Revised text:

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 
23 hours post evening dose at the end of the 2-week treatment period


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
Proportion of subjects with a 30 minute post-challenge FEV1 that was no more 
than 5% lower than their pre-exercise FEV1 following the exercise challenge at 
12 hours and 23 hours post evening dose at the end of the 2-week treatment 
period 

Weighted mean for percentage decrease from pre-exercise FEV1 following exercise 
challenge at 12-hours and 23 hours  post evening dose (weighted mean 0-60 min) at 
the end of the 2-week treatment period
Protocol Synopsis and Section 4.3: Other Endpoints
Original text:

Categorical treatment response evaluation of the percentage of subjects who 
demonstrate a decrease from pre-exercise challenge FEV1 (at 12 hours and 23 hours 
post evening dose at the end of the 2-week treatment period) of:
o <10%, 
o ≥10% to <20%,
o ≥20%

Maximal percent decrease from pre-exercise baseline FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week 
treatment period  

Mean change from baseline in ACT score at the end of the 2-week treatment period

Percentage of subjects controlled defined as an Asthma Control Test (ACT) score ≥20 
at the end of the 2-week treatment period

Change in physical activity measures as assessed by a biosensor (SenseWear 
Armband) in terms of physical activity endpoints (e.g. daily step count, METs, sleep 
duration)
Revised text:

Categorical treatment response evaluation of the percentage of subjects who
demonstrate a decrease from pre-exercise challenge FEV1 (at 12 hours and 23 hours 
post evening dose at the end of the 2-week treatment period) of:
o <10%, 
o ≥10% to <20%,
o ≥20%

Maximal percent decrease from treatment period baseline FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week 
treatment period.

Mean change from baseline in Asthma Control Questionnaire -5 (ACQ-5) score 
at the end of the 2-week treatment period. 


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
Percentage of subjects controlled, defined as an ACQ-5 score ≤0.75, at the end 
of the 2-week treatment period. 

Percentage of subjects achieving an improvement of ≥0.5 or greater in ACQ-5 
score at the end of the 2-week treatment. 

Change in physical activity measures as assessed by a biosensor (SenseWear 
Armband) in terms of physical activity endpoints (e.g. daily step count, Metabolic 
Equivalent of Tasks (METs), sleep duration).

Proportion of subjects with a 5 minute post-challenge FEV1 that was no more 
than 5% lower than their pre-exercise FEV1 following the exercise challenge at 
12 hours and 23 hours post evening dose at the end of the 2-week treatment 
period. Repeat for the 10, 15, 45 and 60 minute time points. 
Protocol Synopsis: Overall Design
Original text:
This is a multicenter, randomized, double-blind, double-dummy, crossover study with 
two 2-week treatment periods separated by a 2-week wash-out period. Subjects will 
attend up to eight visits over the course of the study. Standardized exercise challenge 
testing will be conducted at Visit 2 for eligibility determination, Visit 3 and Visit 6 (after 
23 hours of the first treatment dose in each Treatment Period); and at 12 and 23 hours 
post evening dose at Visits 4 and 7. Spirometry will be conducted at Screening (Visit 1), 
and pre-dose at Visit 5, and prior to each exercise challenge at Visits 2, 3, 4, 6 and 7. 
Serial spirometry (6 time points over 60 minutes) as FEV1 only will be conducted after 
each exercise challenge test. Subjects should be monitored until they reach a recovery 
level where their FEV1 value represents a 95% recovery of the pre-exercise FEV1 result.  
Additional spirometry and rescue medication may be used as needed during recovery.
A Pre-Screening Visit (Visit 0) is included to obtain a signed Informed Consent and to 
review concomitant medications, and may be conducted on the same day as Visit 1, if 
appropriate. At Visit 1, subjects meeting eligibility criteria and will enter a 4 week single-
blinded run-in period on fluticasone propionate (FP) 250 mcg twice daily (BD). 
Albuterol will be issued for rescue use during the run-in, wash-out and treatment periods 
as needed.  Subjects will be instructed to contact the site if they develop worsening 
asthma.  
A screening electrocardiogram (ECG) and a complete physical examination will be 
conducted at Visit 1. Vital signs will be collected at each visit prior to spirometry and 
before and after each exercise challenge.
Physical activity levels will be monitored with the use of a physical activity monitor to 
assess activity outside the clinic worn for 7 days prior to Visit 2 (baseline), for 7 days 
during the last week of Treatment Period 1, for 7 days prior to Visit 5, and for 7 days 
during the last week of Treatment Period 2. Subjects unwilling or unable to participate in 
daily physical activity monitoring may still participate in the study, if appropriate.


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Asthma control will be assessed using the Asthma Control Test at Visits 2, 4, 5 and 7. 
A follow up phone call will be conducted approximately 7 days after Visit 7.
Revised text:
This is a multicenter, randomized, double-blind, double-dummy, crossover study with 
two 2-week treatment periods separated by a 2-week wash-out period. Subjects will
participate in up to eight study visits (Visit 0 to Visit 7) over the course of the study 
and a follow up phone call approximately a week after Visit 7. Visits 1, 2, 3, 5 and 6 
are evening visits that will be conducted between 5PM and 11PM. Visit 4 and Visit 7 
are also evening visits that will begin between 5PM and 11PM and continue over a 
period of approximately 24 hours. Subjects will be required to attend three clinic 
visits during this 24-hour period.
Standardized exercise challenge testing (using a treadmill) will be conducted at Visit 2 
for eligibility determination, Visit 3 and Visit 6 (after 23 hours of the first treatment dose 
in each Treatment Period); and at 12 and 23 hours post evening dose at Visits 4 and 7. 
Spirometry will be conducted at Screening (Visit 1), and pre-dose at Visit 5, and prior to 
each exercise challenge at Visits 2, 3, 4, 6 and 7. Serial spirometry (6 time points over 60 
minutes) as FEV1 only will be conducted after each exercise challenge test. At Visit 2, 
subjects must demonstrate a decrease in FEV1 of ≥20% when compared to the FEV1
obtained immediately pre-exercise for at least one of the post-exercise spirometry 
efforts obtained within 30 minutes post-challenge.  Subjects who achieve a decrease 
in FEV1 of 15% to <20% may continue taking their daily run-in medication and 
repeat the eligibility exercise challenge and associated procedures once within a 
week of the original procedure. Subjects should be monitored until they reach a 
recovery level where their FEV1 value represents a 95% recovery of the pre-exercise 
FEV1 result.  Additional spirometry and rescue medication may be used as needed during 
recovery.
A Pre-Screening Visit (Visit 0) is included to obtain a signed Informed Consent, 
demography and to review concomitant medications, and may be conducted on the same 
day as Visit 1, if appropriate. 
At Visit 1, subjects meeting eligibility criteria and will enter a 4 week single-blinded run-
in period on fluticasone propionate (FP) 250 mcg twice daily (BD). Subjects with 
symptomatic allergic rhinitis at Visit 1 (screening) may be treated for up to four 
weeks with intranasal corticosteroids followed by a repeat screening visit to 
determine eligibility prior to entry into the study. Only one repeat screening visit 
will be performed following treatment with intranasal corticosteroids. Subjects that 
continue to be symptomatic after up to four weeks of treatment will be excluded. 
Eligible subjects will enter the run-in period. Subjects who are asymptomatic at 
screening, who become symptomatic during the study will remain in the study and 
may be treated with intranasal corticosteroids at a constant dose for the duration of 
the study.


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Albuterol/salbutamol will be issued for rescue use during the run-in, wash-out and 
treatment periods as needed.  Subjects will be instructed to contact the site if they develop 
worsening asthma.  
All subjects will be given a paper diary during the run-in, washout and treatment 
periods to record any medical problems experienced during the study, any 
medications taken, and rescue medication usage.
A screening electrocardiogram (ECG) and a complete physical examination will be 
conducted at Visit 1. Vital signs including pulse rate and systolic and diastolic blood 
pressure will be obtained at each clinic visit, including any Early Withdrawal visit. 
At all time points where both vital signs and spirometry are performed, vital signs 
will be done before the spriometry measurement. At visits where the exercise 
challenge is performed, vitals will be measured before (prior to the pre-exercise 
spirometry) and after the exercise challenge.
Asthma control will be assessed using the ACQ-5 at Visits 2, 4, 5 and 7. 
Physical activity levels will be monitored to assess activity outside the clinic with the 
use of a physical activity monitor (SenseWear Armband accelerometer) worn for 7 
days prior to Visit 2 (baseline), for 7 days prior to Visit 4 (during the last week of 
Treatment Period 1), for 7 days prior to Visit 5, and for 7 days prior to Visit 7 (during 
the last week of Treatment Period 2). Subjects unwilling or unable to participate in daily 
physical activity monitoring may still participate in the study, if appropriate.
A follow up phone call will be conducted approximately 7 days after Visit 7.
Section 2.2: Study rationale
Original text:
In patients with persistent asthma, improvements in protection from exercise-induced 
bronchoconstriction (EIB) with ICS/LABA combination product FP/salmeterol 
(Advair®) have been demonstrated [Murray, 2011; Pearlman, 2009; Weiler, 2005]. 
However, differences between FP/salmeterol and FP monotherapy have not consistently 
been observed [Murray, 2011; Weiler, 2005]. In a study that evaluated the effect of 
FP/salmeterol compared to FP over the 12 hour dosing interval [Weiler, 2005], a large 
percentage of subjects in both the FP/salmeterol (18%) and FP (36% and 33% at Day 1 
and Week 4, respectively) treatment arms failed to complete the second exercise 
challenge test 8.5 hours after dosing, suggesting loss of protection against EIB towards
the end of the 12 hour dosing interval
Revised text:
In patients with persistent asthma, improvements in protection from exercise-induced 
bronchoconstriction (EIB) with ICS/LABA combination product Fluticasone propionate
(FP)/salmeterol (Advair®) have been demonstrated [Murray, 2011; Pearlman, 2009; 
Weiler, 2005]. However, differences between FP/salmeterol and FP monotherapy have 


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not consistently been observed [Murray, 2011; Weiler, 2005]. In a study that evaluated 
the effect of FP/salmeterol compared to FP over the 12 hour dosing interval [Weiler, 
2005], a large percentage of subjects in both the FP/salmeterol (18%) and FP (36% and 
33% at Day 1 and Week 4, respectively) treatment arms failed to complete the second 
exercise challenge test 8.5 hours after dosing, suggesting loss of protection against EIB 
towards the end of the 12 hour dosing interval.
Protocol Synopsis and Section 5.2: Treatment Arms and Duration
Original text:
Two treatment arms will be employed for the study: 

FF/VI 100/25 mcg QD via ELLIPTA + Placebo BD via Diskus

FP 250 mcg BD via Diskus + Placebo QD via ELLIPTA
As this is a 2-period cross-over study, all randomized subjects will receive both 
treatments in the study, either in Treatment Period 1 or Treatment Period 2. Also, each 
subject will receive a Diskus and ELLIPTA inhaler in Treatment Period 1 and Treatment 
Period 2.
Subjects will complete a 4-week run-in on FP 250 mcg, followed by 2-week Treatment 
Period 1 on randomized treatment, a 2-week washout period on FP 250 mcg, 2-week 
Treatment Period 2 receiving the alternative treatment, and follow-up contact 
approximately 7-days after completing Treatment Period 2. The total duration of study 
participation is approximately 11 weeks.
Revised text:
Two treatment arms will be employed for the study: 

FF/VI 100/25 mcg QD via ELLIPTA + Placebo BD via Diskus

FP 250 mcg BD via Diskus + Placebo QD via ELLIPTA
As this is a 2-period cross-over study, all randomized subjects will receive both 
treatments in the study, either in Treatment Period 1 or Treatment Period 2. Also, each 
subject will receive a Diskus and ELLIPTA inhaler in Treatment Period 1 and Treatment 
Period 2.
Subjects will complete a 4-week single-blind run-in on FP 250 mcg BID, followed by 2-
week double-blind Treatment Period 1 on randomized treatment, a 2-week single-blind
washout period on FP 250 mcg BID, 2-week double-blind Treatment Period 2 receiving 
the alternative treatment, and follow-up contact approximately 7-days after completing 
Treatment Period 2. The total duration of study participation is approximately 11 weeks; 
and up to 15 weeks for subjects with SAR at screening who may need to be treated 
with intranasal corticosteroids followed by repeat screening visit.


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Protocol Synopsis and Section 5.3: Type and Number of Subjects
Original text:
Approximately 165 subjects with persistent asthma with evidence of EIB and current use 
of a low- to moderate-dose inhaled corticosteroid (ICS) will be screened in order to 
randomize 66 subjects, assuming a 10% screen failure rate and 55% run-in failure rate. 
This is to achieve 56 evaluable subjects completing the exercise challenges and the FEV1
evaluations at the end of both treatment periods. This calculation assumes a 15% 
withdrawal rate during the study.  
Revised text:
Approximately 275 subjects with persistent asthma with evidence of EIB and current use 
of a low- to moderate-dose inhaled corticosteroid (ICS) will be screened in order to 
randomize 66 subjects, assuming a 20% screen failure rate and 70% run-in failure rate. 
This is to achieve 56 evaluable subjects completing the exercise challenges and the FEV1
evaluations at the end of both treatment periods. This calculation assumes a 15% 
withdrawal rate during the study.  
Protocol Synopsis: Analysis
Original text:
The primary treatment comparison will be between the FF/VI combination and FP and 
will be performed using the ITT Population. Demonstration of efficacy for the treatments 
will be based on a hypothesis testing approach whereby the null hypothesis is that there is 
no difference between the population treatment groups and the alternative hypothesis is 
that there is a difference between the population treatment groups.  
Revised text:
The primary treatment comparison will be between the FF/VI combination and FP and 
will be performed using the intent-to-treat (ITT) Population. Demonstration of efficacy 
for the treatments will be based on a hypothesis testing approach whereby the null 
hypothesis is that there is no difference between the population treatment groups and the 
alternative hypothesis is that there is a difference between the population treatment 
groups
Section 5.1: Overall Design
Original text:
This is a multicenter, randomized, double-blind, double-dummy, crossover study with 
two 2-week treatment periods separated by a 2-week wash-out period. Subjects will 


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attend up to eight visits over the course of the study. Standardized exercise challenge 
testing will be conducted at Visit 2 for eligibility determination, Visit 3 and Visit 6 (after 
23 hours of the first dose in each Treatment Period); and at 12 and 23 hours post evening 
dose at Visits 4 and 7. Spirometry will be conducted at Screening (Visit 1), and pre-dose 
at Visit 5 and prior to each exercise challenge at Visits 2, 3, 4, 6 and 7. Serial spirometry 
(6 time points over 60 minutes) as FEV1 only will be conducted after each exercise 
challenge test. Subjects should be monitored until they reach a recovery level where their 
FEV1 value represents a 95% recovery of the pre-exercise FEV1 result.  Additional 
spirometry and rescue medication may be used as needed during recovery.
A Pre-Screening Visit (Visit 0) is included to obtain a signed Informed Consent (ICF) 
and to review concomitant medications, and may be conducted on the same day as Visit 
1, if appropriate. At Visit 1, subjects meeting eligibility criteria will enter a 4-week 
single-blinded run-in period on fluticasone propionate (FP) 250 mcg twice daily (BD). 
Albuterol will be issued for rescue use during the run-in, wash-out and treatment periods 
as needed.  Subjects will be instructed to contact the site if they develop worsening 
asthma.  
All subjects will be given a paper diary during the run-in, washout and treatment periods 
to record any medical problems experienced during the study, any medications taken, and 
rescue medication usage.
A screening electrocardiogram (ECG) and a complete physical examination will be 
conducted at Visit 1. Vital signs will be collected at each visit prior to spirometry, and 
before and after exercise challenge testing.  


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Asthma control will be assessed using the Asthma Control Test (ACT) at Visits 2, 4, 5 
and 7.
Physical activity levels will be monitored to assess activity outside the clinic [Mitchell, 
2014] using a physical activity monitor (SenseWear Armband accelerometer) worn for 7 
days prior to Visit 2 (baseline), for 7 days prior to Visit 4 (during the last week of 
Treatment Period 1), for 7 days prior to Visit 5, and for 7 days prior to Visit 7 (during the 
last week of Treatment Period 2). Subjects unwilling or unable to participate in daily 
physical activity monitoring may still participate in the study, if appropriate. See Study 
Reference Manual (SRM) for additional details.
A follow up phone call will be conducted approximately 7 days after Visit 7.
For determination of subject disposition, subjects will be considered to have completed 
the study upon completion of Visit 7. For entry into the electronic case report form 
(eCRF), study completion will be defined as completion of the follow up contact.
There are no plans to routinely provide any of the study treatments for compassionate use 
following study completion, as asthma treatments including ICS/LABA combination 
products are available worldwide.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the SRM. The SRM will provide the site personnel with administrative and 
detailed technical information that does not impact subject safety.
Revised text:
This is a multicenter, randomized, double-blind, double-dummy, crossover study with 
two 2-week treatment periods separated by a 2-week wash-out period. Subjects will
participate in up to eight study visits (Visit 0 to Visit 7) over the course of the study
and a follow up phone call approximately a week after Visit 7. Visits 1, 2, 3, 5 and 6 
are evening visits that will be conducted between 5PM and 11PM. Visit 4 and Visit 7 
are also evening visits that will begin between 5PM and 11PM and continue over a 
period of approximately 24 hours. Subjects will be required to attend three clinic 
visits during this 24-hour period.
Standardized exercise challenge testing (using a treadmill) will be conducted at Visit 2 
for eligibility determination, Visit 3 and Visit 6 (after 23 hours of the first dose in each 
Treatment Period); and at 12 and 23 hours post evening dose at Visits 4 and 7. 
Spirometry will be conducted at Screening (Visit 1), and pre-dose at Visit 5 and prior to 
each exercise challenge at Visits 2, 3, 4, 6 and 7. Serial spirometry (6 time points over 60 
minutes) as FEV1 only will be conducted after each exercise challenge test. At Visit 2, 
subjects must demonstrate a decrease in FEV1 of ≥20% when compared to the FEV1
obtained immediately pre-exercise for at least one of the post-exercise spirometry 
efforts obtained within 30 minutes post-challenge.  Subjects who achieve a decrease 
in FEV1 of 15% to <20% may continue taking their daily run-in medication and 


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repeat the eligibility exercise challenge and associated procedures once within a 
week of the original procedure. Subjects should be monitored until they reach a 
recovery level where their FEV1 value represents a 95% recovery of the pre-exercise 
FEV1 result.  Additional spirometry and rescue medication may be used as needed during 
recovery. 
A Pre-Screening Visit (Visit 0) is included to obtain a signed Informed Consent (ICF), 
demography and to review concomitant medications, and may be conducted on the same 
day as Visit 1, if appropriate. 
At Visit 1, subjects meeting eligibility criteria will enter a 4-week single-blinded run-in 
period on fluticasone propionate (FP) 250 mcg twice daily (BD). Subjects with 
symptomatic allergic rhinitis at Visit 1 (screening) may be treated for up to four 
weeks with intranasal corticosteroids followed by a repeat screening visit to 
determine eligibility prior to entry into the study. Only one repeat screening visit 
will be performed following treatment with intranasal corticosteroids. Subjects that 
continue to be symptomatic after up to four weeks of treatment will be excluded. 
Eligible subjects will enter the run-in period. Subjects who are asymptomatic at 
screening, who become symptomatic during the study will remain in the study and 
may be treated with intranasal corticosteroids at a constant dose for the duration of 
the study.
Albuterol/salbutamol will be issued for rescue use during the run-in, wash-out and 
treatment periods as needed.  Subjects will be instructed to contact the site if they develop 
worsening asthma.  


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All subjects will be given a paper diary during the run-in, washout and treatment periods 
to record any medical problems experienced during the study, any medications taken, and 
rescue medication usage.
A screening electrocardiogram (ECG) and a complete physical examination will be 
conducted at Visit 1. Vital signs including pulse rate and systolic and diastolic blood 
pressure will be obtained at each clinic visit, including any Early Withdrawal visit. 
At all time points where both vital signs and spirometry are performed, vital signs 
will be done before the spriometry measurement. At visits where the exercise 
challenge is performed, vitals will be measured before (prior to the pre-exercise 
spirometry) and after the exercise challenge.
Asthma control will be assessed using the ACQ-5 at Visits 2, 4, 5 and 7.
Physical activity levels will be monitored to assess activity outside the clinic [Mitchell, 
2014] using a physical activity monitor (SenseWear Armband accelerometer) worn for 7 
days prior to Visit 2 (baseline), for 7 days prior to Visit 4 (during the last week of 
Treatment Period 1), for 7 days prior to Visit 5, and for 7 days prior to Visit 7 (during the 
last week of Treatment Period 2). Subjects unwilling or unable to participate in daily 
physical activity monitoring may still participate in the study, if appropriate. See Study 
Reference Manual (SRM) for additional details.
A follow up phone call will be conducted approximately 7 days after Visit 7.
Re-screening of subjects is not allowed in this study with the exception of subjects 
with symptomatic allergic rhinitis at screening who may have a repeat screening 
visit after treatment with intranasal corticosteroids.
There are no plans to routinely provide any of the study treatments for compassionate use 
following study completion, as asthma treatments including ICS/LABA combination 
products are available worldwide.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the SRM. The SRM will provide the site personnel with administrative and 
detailed technical information that does not impact subject safety.
Section 6.1.2: Exclusion Criteria #4
Original text:
Symptomatic Allergic Rhinitis:  Subjects with symptomatic allergic rhinitis within the 
past two weeks are excluded from the study.  
Revised text:
Symptomatic Allergic Rhinitis:  Subjects with symptomatic allergic rhinitis at Visit 1 
may be treated for up to four weeks with intranasal corticosteroids followed by a 


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repeat screening visit to determine eligibility prior to entry into the study. Subjects 
that continue to be symptomatic after up to four weeks of treatment will be 
excluded.
Section 6.1.2: Screening Exclusion Criteria #5
Original text:
12-Lead Electrocardiogram (ECG):  A subject is not eligible if he/she has an abnormal, 
clinically significant ECG at the Screening Visit. 
Revised text:
12-Lead Electrocardiogram (ECG):  A subject is not eligible if he/she has an abnormal, 
clinically significant ECG as determined by the investigator at the Screening Visit. 
Section 6.1.2: New Screening Exclusion Criterion 
Pregnancy: Women who are pregnant or lactating or are planning on becoming 
pregnant during the study.
Section 6.1.2: Screening Exclusion Criteria #10
Original text:
Allergies:
a) Drug Allergy:  Any adverse reaction including immediate or delayed 
hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, 
inhaled, or systemic corticosteroid therapy, or excipients used with  FF/VI 100/25 or 
FP 250 (i.e., drug, lactose or magnesium stearate).
b) Milk Protein Allergy: History of severe milk protein allergy.
Revised text:
a) Drug Allergy:  Any adverse reaction including immediate or delayed 
hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, 
inhaled, or systemic corticosteroid therapy, or excipients used with  FF/VI 100/25 or 
FP 250 (i.e., drug, lactose or magnesium stearate).
b) Milk Protein Allergy: History of severe milk protein allergy.
c) Latex Allergy: History of allergy or sensitivity to latex that in the opinion of the 
investigator contraindicates the subject’s participation in the study.


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Section 6.1.2: New Screening Exclusion Criterion 
Tobacco/Marijuana Use: Current tobacco smoker or has a smoking history of ≥10 
pack-years (20 cigarettes/day for 10 years). A subject may not have used inhaled 
tobacco products or inhaled marijuana within the past 3 months (e.g., cigarettes, 
cigars, electronic cigarettes, or pipe tobacco)
Section 6.2.1: Randomisation Inclusion Criteria #2
Original text:
FEV1 Target: Subjects must demonstrate a decrease in FEV1 of 20% at one time point 
within 30 minutes of the end of a standardized exercise challenge.  Subjects who achieve 
a decrease in FEV1 of 15% to <20% may continue taking their daily run-in medication 
and repeat the eligibility exercise challenge once within 24 to 48 hours.   
Revised text:
FEV1 Target: Subjects must demonstrate a decrease in FEV1 of 20% at one time point 
within 30 minutes of the end of a standardized exercise challenge.  Subjects who achieve 
a decrease in FEV1 of 15% to <20% may continue taking their daily run-in medication 
and repeat the eligibility exercise challenge and associated procedures once within a 
week of the original procedure.   
Section 6.2.2: Randomisation Exclusion Criteria 
Original text:
1.
Pregnancy: Positive urine pregnancy test at Visit 2.
2.
Asthma Medication Changes:  Changes in asthma medication after Visit 1 
(excluding albuterol inhalation aerosol provided at Visit 1) are not permitted.
3.
Prohibited Medication:  No use of any prohibited medications (Section 7.10.2) 
during the run-in period or at Visit 2.
4.
Respiratory Infections:  Occurrence of a culture-documented or suspected bacterial 
or viral infection of the upper or lower respiratory tract, sinus or middle ear during 
the run-in period that led to a change in asthma management or, in the opinion of the 
investigator, is expected to affect the subject’s asthma status or the subject’s ability 
to participate in the study.
5.
Asthma Exacerbation:  Evidence of a severe exacerbation, defined as deterioration 
of asthma requiring the use of systemic corticosteroids (tablets, suspension, or 
injection) for at least 3 days or an in-patient hospitalization or emergency department 
(ED) visit due to asthma that required systemic corticosteroids between Visits 1 and 
2.


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6.
Symptomatic Allergic Rhinitis: Subjects with symptoms of allergic rhinitis within 
the 2 weeks prior to the randomization visit (Visit 2). 
Revised text:
1. Pregnancy: Positive urine pregnancy test at Visit 2.
2. Asthma Medication Changes:  Changes in asthma medication after Visit 1 
(excluding albuterol/salbutamol inhalation aerosol provided at Visit 1) are not 
permitted.
3. Prohibited Medication:  Use of any prohibited medications (Section 7.9.2) 
during the run-in period or at Visit 2.
4. Respiratory Infections:  Occurrence of a culture-documented or suspected 
bacterial or viral infection of the upper or lower respiratory tract, sinus or middle 
ear during the run-in period that led to a change in asthma management or, in the 
opinion of the investigator, is expected to affect the subject’s asthma status or the 
subject’s ability to participate in the study.
5. Asthma Exacerbation:  Evidence of a severe exacerbation, defined as 
deterioration of asthma requiring the use of systemic corticosteroids (tablets, 
suspension, or injection) for at least 3 days or an in-patient hospitalization or 
emergency department (ED) visit due to asthma that required systemic 
corticosteroids between Visits 1 and 2.
Section 6.3: Screening/Baseline/Run-in Failures
Original text:
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 reason 
details, Eligibility Criteria, and any Serious Adverse Events.
A subject who is assigned a subject number, has signed the informed consent, and has 
completed at least one study procedure, but does not enter the run-in period of the study 
is considered a ‘screen failure’.  
A subject who completes the screening visit and is dispensed FP 250 mcg, albuterol for 
rescue use, and a medical conditions card is considered to have entered the run-in period.  
A subject who has entered the run-in period, but is not randomized to study treatment 
medication, is classified as a ‘run-in failure’.  
At a minimum, the following information will be collected for subjects who fail 
screening or run-in:


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1.
Demographic information for race, age and gender
2.
Reason for screen/run-in failure (screen/run-in failure eCRF page, 
inclusion/exclusion criteria eCRF page, and randomization criteria eCRF page 
[if applicable])
3.
SAE information
4.
Investigator signature page
Revised text: 
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 reason details, Eligibility Criteria, and
any Serious Adverse Events.
A subject who is assigned a subject number, has signed the informed consent, and has 
completed at least one study procedure, but does not enter the run-in period of the study 
is considered a ‘screen failure’.  
A subject who completes the screening visit and is dispensed FP 250 mcg, 
albuterol/salbutamol for rescue use, and a medical conditions diary card is considered to 
have entered the run-in period.  A subject who has entered the run-in period, but is not 
randomized to study treatment medication, is classified as a ‘run-in failure’.  
At a minimum, the following information will be collected for subjects who fail 
screening or run-in:
1.
Demographic information for race, age and gender
2.
Reason for screen/run-in failure (screen/run-in failure eCRF page, 
inclusion/exclusion criteria eCRF page, and randomization criteria eCRF page 
[if applicable])
3.
SAE information
4.
Investigator signature page
Re-screening of subjects is not allowed in this study with the exception of subjects 
with symptomatic allergic rhinitis at screening who may have a repeat screening 
visit after treatment with intranasal corticosteroids.


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Section 6.4.2: Reasons for Study Withdrawal
Original text:
The primary reason for Study Withdrawal will be recorded in the eCRF and any data 
collected up until the point of withdrawal will be used in the data analyses.
General reasons for withdrawal may include: 
1. Adverse event 
2. Withdrew consent
3. Lost to follow-up 
4. Protocol violation impacting safety
5. Lack of efficacy
6. Subject reached protocol-defined withdrawal criteria

Liver function

Asthma Exacerbation

Asthma Worsening

Pregnancy

ECG
7. Non-compliance 
8. Injury during the exercise challenge
9. Study closed/terminated
Revised text:
The primary reason for Study Withdrawal will be recorded in the eCRF and any data 
collected up until the point of withdrawal will be used in the data analyses.
General reasons for withdrawal may include: 
1. Adverse event 
2. Withdrew consent
3. Lost to follow-up 
4. Protocol deviation impacting safety
5. Lack of efficacy
6. Subject reached protocol-defined withdrawal criteria

Liver function


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
Asthma Exacerbation

Asthma Worsening

Pregnancy

ECG
7. Non-compliance 
8. Injury during the exercise challenge
9. Study closed/terminated
Section 7: Study Treatment
Original text:
Albuterol will be given to all subjects to use throughout the study to treat acute asthma 
symptoms as needed per product label. Only study-supplied albuterol should be used for 
rescue during the study. Rescue usage will be recorded twice daily in the subject’s paper 
diary. Do not record albuterol use in the eCRF.
Revised text:
Albuterol/salbutamol will be given to all subjects to use throughout the study to treat 
acute asthma symptoms as needed per product label. Only study-supplied 
albuterol/salbutamol should be used for rescue during the study. Rescue usage will be 
recorded once daily in the subject’s paper diary. Do not record albuterol/salbutamol 
use in the eCRF.
Section 7.1: New sub-title included
Section 7.1: Investigational product and other study treatment
Section 7.2.1: Assignment of Subject Number
Original text:
At Visit 1, a unique Subject Number (CRF number) will be assigned to any subject who 
has at least one Visit 1 procedure performed, other than informed consent. The unique 
Subject Number will be used to identify individual subjects during the course of the 
study. 
Revised text:
At Visit 1, a unique Subject Number (CRF number) will be assigned to any subject who 
has at least one Visit 1 procedure performed, other than informed consent. The unique 


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Subject Number will be used to identify individual subjects during the course of the 
study. 
All subjects that have a repeat screening visit following treatment for symptomatic 
allergic rhinitis will continue to use the same subject number assigned at the 
original screening visit.
Section 7.9.1.2: Permitted Non-Asthma Medications
Original text:
The following non-asthma medications are permitted. This list is not all inclusive. For 
any questions contact the Medical Monitor.

Cardioselective beta-blockers (stable dose) and ophthalmic beta-blockers: 
Administer with caution as they may block bronchodilatory effects of beta-agonists 
and produce severe bronchospasm.

Strong cytochrome P450 3A4 inhibitors (e.g. ketoconazole, ritonavir, 
clarithromycin): Use with caution. May cause systemic corticosteroid and 
cardiovascular effects.

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs):
Administer with extreme caution as they may potentiate the effects of beta-
agonists on the vascular system.

Diuretics: Caution is advised in the co-administration of beta-agonists with non 
potassium–sparing diuretics.

Decongestants: Subjects may take decongestants during the study except during the 
24 hours prior to ECG measurements.

Antihistamines: Short-acting and long-acting antihistamines are allowed to control 
symptoms of allergic disorders, however are not permitted the week prior to 
exercise testing. In addition, antihistamine eye drops are allowed during the study. 

Intranasal corticosteroids: Subjects may take intranasal corticosteroids to control 
symptoms of allergic disorders as long as the dose remains constant for the duration 
of the study.

Topical corticosteroids: Subjects may use topical corticosteroids (≤ 1% 
hydrocortisone) for dermatological diseases.
Revised text:
The following non-asthma medications are permitted. This list is not all inclusive. For 
any questions contact the Medical Monitor.


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
Cardioselective beta-blockers (stable dose) and ophthalmic beta-blockers: 
Administer with caution as they may block bronchodilatory effects of beta-agonists 
and produce severe bronchospasm.

Strong cytochrome P450 3A4 inhibitors (e.g. ketoconazole, ritonavir, 
clarithromycin): Use with caution. May cause systemic corticosteroid and 
cardiovascular effects.

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs):
Administer with extreme caution as they may potentiate the effects of beta-
agonists on the vascular system.

Diuretics: Caution is advised in the co-administration of beta-agonists with non 
potassium–sparing diuretics.

Decongestants: Subjects may take decongestants during the study except during the 
24 hours prior to ECG measurements.

Antihistamines: Short-acting and long-acting antihistamines are allowed to control 
symptoms of allergic disorders, however are not permitted the week prior to 
exercise testing. In addition, antihistamine eye drops are allowed during the study. 
Subjects should be reminded to avoid taking any antihistamines a week before 
each exercise challenge procedure.

Intranasal corticosteroids: Subjects may take intranasal corticosteroids to control 
symptoms of allergic disorders as long as the dose remains constant for the duration 
of the study.

Topical corticosteroids: Subjects may use topical corticosteroids (≤ 1% 
hydrocortisone) for dermatological diseases.

Influenza and/or pneumonia vaccination.

All medications for other disorders as long as the dose remains constant 
wherever possible and their use is not expected to affect the subjects’ lung 
function or safety assessments.


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Section 8: Assessments and Procedures – Table 3 Time and Events Table
Original table:
Table 7
Time and Events Table
Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412
512
6
712
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
1
2
14 (-2/+2) 
days
28 (-2/+2) 
days
29 (-2/+2)
42 (-2/+2) 
days
47 to 
51 
days
Written Informed Consent
X
Genetics Consent
X1
Subject Demography
X
Medical History (including CV)
X
Disease (Asthma) History 
X
Medication History
X
X
Inclusion/Exclusion Criteria
X
Evidence of EIB
X
Efficacy Assessments
Spirometry (full FEV1 and FVC)
X
X2
X2
X2
X
X2
X2
X
Exercise Challenge Testing 
(Treadmill)
X3
X4
X5
X4
X5
Post-Challenge Serial FEV1 
Measurements
X3
X6
X6
X6
X6
Asthma Control Test
X
X
X
X
X
Dispense SenseWear 
accelerometer
X
Collect SenseWear accelerometer
X
X


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Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412
512
6
712
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
1
2
14 (-2/+2) 
days
28 (-2/+2) 
days
29 (-2/+2)
42 (-2/+2) 
days
47 to 
51 
days
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X7
Physical Examination
X
Vital Signs
X
X8
X8
X8
X
X8
X8
X
12-lead ECG 
X
Adverse Event Assessment
X9
X9
X
X
X
X
X
X
X
X
Issue Medical Conditions Diary 
Card
X
X
X
X
Review Medical Conditions Diary 
Card
X10
X10
X10
X10
X
Laboratory Assessments
Genetics Saliva Sample
X1
Urine Pregnancy Test
X
X
X
X
X13
Investigational Product
Dispense Fluticasone Propionate
X
X
Collect Fluticasone Propionate
X
X
Dispense Rescue Albuterol
X
X
X
X
X
Collect Rescue Albuterol
X
X
X
X
Dispense IP
X11
X
Assess study drug  compliance
X
X
X
X
X
Collect IP
X
X
X
X


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1.
Genetics saliva sample collected at Visit 2 (following Randomization) or at any scheduled visit thereafter. Genetics consent MUST be obtained PRIOR to 
collection of the Genetics sample.  
2.
Pre-exercise spirometry (full FEV1 and FVC testing), conducted immediately pre-exercise, if applicable. Subject should have withheld albuterol within previous 6 
hours. 
3.
Performed for determination of eligibility. Serial spirometry performed 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Subjects must demonstrate a 
decrease in FEV1 of 20% at one time point within 30 minutes of the end of a standardized exercise challenge.  
4.
Exercise challenge testing will be performed at 23 hours following the evening study treatment doses given at Visit 2 and Visit 5 
5.
Exercise challenge testing will be performed at 12 hours and 23 hours following the evening study treatment doses given at the beginning of Visits 4 and 7.
6.
Serial spirometry performed at time points 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Longer monitoring may be required for those subjects 
who do not return to 5% of baseline FEV1 values within 60 minutes.
7.
Concomitant medications collected for adverse events only between end of treatment and follow-up phone contact. 
8.
Vital signs will be collected before and after each exercise challenge test.
9.
Adverse Event and Serious Adverse Events to be collected from the start of study Drug (Visit 1) until the follow up contact. However, any SAE related to study 
participation will be     recorded from the time of Informed Consent 
10. Review medical conditions diary card, including an assessment of any potential change in exercise capacity
11. An unblinding card will be dispensed along with double blind IP.
12. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear accelerometer for the 7 days preceeding 
these visits.
13. Pregnancy test will be conducted via home test kit and results will be reported at the Follow-up phone contact.


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Revised table:
Section 8.1: Time and Events Table
Table 8
Time and Events Table
Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412; 14
512
6
712; 14
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
1
2
14 (-2/+2) 
days
28 (-2/+2) 
days
29 (-2/+2)
42 (-2/+2) 
days
47 to 
51 
days
Written Informed Consent
X
Genetics Consent
X1
Subject Demography
X
Medical History (including CV)
X
Disease (Asthma) History 
X
Medication History
X
X
Smoking history/status
X
Inclusion/Exclusion Criteria
X
Evidence of EIB
X
Efficacy Assessments
Spirometry (full FEV1 and FVC)
X
X2
X2
X2
X
X2
X2
X
Exercise Challenge Testing 
(Treadmill)
X3, 17
X4
X5
X4
X5
Post-Challenge Serial FEV1 
Measurements
X3
X6
X6
X6
X6
Asthma Control Questionnaire-5
X
X
X
X
X


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Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412; 14
512
6
712; 14
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
1
2
14 (-2/+2) 
days
28 (-2/+2) 
days
29 (-2/+2)
42 (-2/+2) 
days
47 to 
51 
days
Dispense SenseWear15
accelerometer
X
Collect SenseWear accelerometer
X
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X7
Physical Examination
X
Vital Signs
X
X8
X8
X8
X
X8
X8
X
12-lead ECG 
X
Adverse Event Assessment
X9
X9
X
X
X
X
X
X
X
X
Issue Medical Conditions Diary 
Card
X
X
X
X
Review Medical Conditions Diary 
Card
X10
X
X10
X10
X
X10
X
Laboratory Assessments
Genetics Saliva Sample
X1
Urine Pregnancy Test
X
X
X
X
X13
Investigational Product
Dispense Fluticasone Propionate
X
X
Collect Fluticasone Propionate
X
X
Dispense Rescue16
Albuterol/salbutamol
X
X
X
X
X
X
Collect Rescue 
Albuterol/salbutamol
X
X
X
X
Dispense IP
X11
X
Assess study drug  compliance
X
X
X
X
X
X
X
Collect IP
X
X
X


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1.
Genetics saliva sample collected at Visit 2 (following Randomization) or at any scheduled visit thereafter. Genetics consent MUST be obtained PRIOR to 
collection of the Genetics sample.  
2.
Pre-exercise spirometry (full FEV1 and FVC testing), conducted immediately pre-exercise (and after vital signs), if applicable. Subject should have withheld 
albuterol/salbutamol within previous 6 hours. 
3.
Performed for determination of eligibility. Serial spirometry performed 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Subjects must demonstrate a 
decrease in FEV1 of 20% at one time point within 30 minutes of the end of a standardized exercise challenge.  
4.
Exercise challenge testing will be performed at 23 hours following the evening study treatment doses given at Visit 2 and Visit 5 
5.
Exercise challenge testing will be performed at 12 hours and 23 hours following the evening study treatment doses given at the beginning of Visits 4 and 7.
6.
Serial spirometry performed at time points 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Longer monitoring may be required for those subjects 
who do not return to 5% of baseline FEV1 values within 60 minutes.
7.
Concomitant medications collected for adverse events only between end of treatment and follow-up phone contact. 
8.
Vital signs will be collected before (prior to the pre-exercise spirometry) and after each exercise challenge test.
9.
Adverse Event and Serious Adverse Events to be collected from the start of study Drug (Visit 1) until the follow up contact. However, any SAE related to study 
participation will be     recorded from the time of Informed Consent 
10. Review medical conditions diary card, including an assessment of any potential change in exercise capacity
11. An unblinding card will be dispensed along with double blind IP.
12. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear accelerometer for the 7 days preceeding 
these visits.
13. Pregnancy test will be conducted via home test kit and results will be reported at the Follow-up phone contact.
14. Visit 4 and Visit 7 will begin between 5PM and 11PM and continue over a period of approximately 24 hours. After the evening visit, subjects will 
return to the clinic at 12 hours and 23 hours (after the evening dose of study medication) for an exercise challenge procedure.
15. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear Armband accelerometer for the 7 
days preceding these visits.
16.
Collect and re-dispense rescue as needed from Visit 1
17.   Subjects who achieve a decrease in FEV1 of 15% to <20% may continue taking their daily run-in medication and repeat the eligibility exercise 
challenge and associated procedures once within a week of the original procedure.


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Section 8.2: Screening and Critical Baseline Assessments
Original text:
The following data will be captured at Visit 1:
1.
Demographic parameters for year of birth, sex, race and ethnicity 
2.
Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 6.1. 
3.
Asthma history (including duration of asthma)
4.
Evidence of EIB questions
5.
Asthma and non-asthma concurrent medications
6.
Concurrent medical conditions
7.
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed 
at screening.
8.
Reason for screen failure (if applicable)
9.
Screening lung function
10. Vital signs (including height and weight)
11. Serious Adverse Events related to study participation
Revised text:
Critical Baseline Assessments
During the pre-screening visit (Visit 0); each subject will have the following 
information collected:
1. Demographic history (including gender, ethnic origin and date of birth)
2. Concomitant medication review
3. Adverse event assessment
The following data will be captured at Visit 1:
1.
Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 6.1. 
2.
Smoking history 
3.
Asthma history (including duration of asthma)
4.
Evidence of EIB questions
5.
Asthma and non-asthma concurrent medications


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6.
Concurrent medical conditions
7.
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed 
at screening.
8.
Reason for screen failure (if applicable)
9.
Screening lung function
10. Vital signs (including height and weight)
11. Serious Adverse Events related to study participation
Section 8.3.1: Spirometry
Original text:
Subjects will be required to withhold their rescue medication (albuterol) for at least 6 
hours before each visit. 
Exercise challenges should not be performed within 24 hours of exercise in cold air. 
Subjects should abstain from smoking or drinking beverages with high caffeine content 
such as tea or coffee for 2 hours prior to pulmonary function testing. 
The FEV1 should be measured using spirometry equipment that meets or exceeds the 
minimal recommendations of the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) [Miller, 2005]. All sites will use standardized spirometry 
equipment provided by an external vendor. 
FEV1 and FVC will be conducted at Visit 1, and pre-dose at Visit 5, and prior to each 
exercise challenge at Visits 2, 3, 4, 6 and 7. For full FEV1/FVC testing, at least 3 valid 
and 2 repeatable (with no more than 8) efforts should be obtained using ATS/ERS 
guidelines. At each time point, the largest FEV1 and FVC should be recorded, even if 
they do not come from the same effort. 
Serial FEV1 measurements only (not FVC) will be conducted serially as described in 
Table 3 following each exercise challenge at Visits 2, 3, 4, 6 and 7. For serial FEV1
testing, two FEV1 efforts will be obtained at each time point. At each time point, the 
largest FEV1 will be selected.
Revised text:
Subjects should abstain from drinking beverages with high caffeine content such as 
tea or coffee for 4 hours prior to the spirometry procedure. 
FEV1 should be measured using spirometry equipment that meets or exceeds the minimal 
recommendations of the American Thoracic Society (ATS)/European Respiratory Society 
(ERS) [Miller, 2005]. All sites will use standardized spirometry equipment provided by 
an external vendor. Full FEV1 and FVC will be conducted at Visit 1, and pre-dose at Visit 
5, and prior to each exercise challenge at Visits 2, 3, 4, 6 and 7. 


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For full FEV1 and FVC testing at Screening and at randomisation (Visit 2), at least two
valid and two repeatable (with no more than 8) efforts should be obtained using 
ATS/ERS guidelines. For all other visits where full FEV1 and FVC testing is performed 
(prior to each exercise test at visits 3, 4, 6 and 7), at least two valid efforts should be 
obtained.  At each time point, the largest FEV1 and FVC should be recorded, even if they 
do not come from the same effort. 
Serial FEV1 measurements only (not FVC) will be conducted serially as described in 
Table 3 following each exercise challenge at Visits 2, 3, 4, 6 and 7. 
Subjects must have a FEV1 of at least 70% of their predicted normal value to be 
eligible to take part in the study at Visit 1.
After Visit 1, subjects will always be required to withhold their albuterol/salbutamol 
for at least 6 hours before each clinic visit.
Subjects must not administer study drug prior to coming to the clinic on study visit 
days.
Section 8.3.2: Exercise Challenge Testing
Original text:
The exercise challenge test is a stepped challenge on a treadmill at a speed and incline 
that will allow the subject’s heart rate to reach between 80% to 95% of their maximum 
heart rate. All exercise challenges will be performed on a treadmill. During the exercise 
challenge, subjects will breathe medical grade dry air at ambient temperature from a 
reservoir using a two-way non-rebreathing valve.
Subjects will exercise sufficiently to attain a heart rate between 80 to 95% of their 
predicted maximum within 4 minutes and maintain this heart rate with exercise for an 
additional 6 minutes for a total of 10 minutes of exercise. The challenge will be followed 
immediately by serial spirometry (FEV1 efforts only) at 6 time points over 60 minutes (5, 
10, 15, 30, 45 and 60 minutes post-exercise). The information gained from the eligibility 
challenge(s) regarding incline and speed will be used to obtain the target heart rate in the 
subsequent exercise challenges.
Additional instructions on exercise challenge testing can be found in the SRM.
Revised text:
The exercise challenge test is a stepped challenge on a treadmill at a speed and incline 
that will allow the subject’s heart rate to reach between 80% to 95% of their maximum 
heart rate. All exercise challenges will be performed on a treadmill. During the exercise 
challenge, subjects will breathe medical grade dry air at ambient temperature from a 
reservoir using a two-way non-rebreathing valve.


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Subjects will exercise sufficiently to attain a heart rate between 80 to 95% of their 
predicted maximum within 4 minutes and maintain this heart rate with exercise for an 
additional 6 minutes for a total of 10 minutes of exercise. The challenge will be followed 
immediately by serial spirometry (FEV1 efforts only) at 6 time points over 60 minutes (5, 
10, 15, 30, 45 and 60 minutes post-exercise). The information gained from the eligibility 
challenge(s) regarding incline and speed will be used to obtain the target heart rate in the 
subsequent exercise challenges.
Exercise challenges should not be performed within 24 hours of exercise in cold air. 
Subjects should abstain from drinking beverages with high caffeine content such as 
tea or coffee for 4 hours prior to the exercise challenge. 
Additional instructions on exercise challenge testing can be found in the SRM.
Section 8.3.3.1: Visit 1 (Screening)
Original text:
Spirometry will be performed at Visit 1 between 5:00 PM and 11:00 PM, ideally at the 
end of the subjects ICS dosing interval. Full FEV1 and FVC testing will be conducted. 
Subjects must have a best pre-bronchodilator FEV1 of ≥ 70% of their predicted normal 
value to be eligible to take part in the study.  
Revised text:
Spirometry will be performed at Visit 1 between 5:00 PM and 11:00 PM, ideally at the 
end of the subjects ICS dosing interval. Full FEV1 and FVC testing will be conducted. At 
least two valid and two repeatable spirometry efforts should be obtained. Subjects 
must have a best pre-bronchodilator FEV1 of ≥70% of their predicted normal value to be 
eligible to take part in the study.  
Section 8.3.3.2: Visit 2 (Randomization)
Original text:
Pre-exercise baseline (Period 1 baseline) FEV1: Spirometry will be performed at Visit 
2 at approximately the same time as at Visit 1 (±1 hour). The FEV1 should be measured 
approximately 12 hours after dosing with run-in medication (FP 250 mcg). At least two 
adequate and repeatable spirometry efforts with full FEV1 and FVC maneuvers should be 
obtained before the first exercise challenge.
From this spirometry testing, the target FEV1 values (Section 8.3.1.1) should be 
determined based on the pre-exercise FEV1. 
Eligibility Exercise Challenge: After the pre-exercise baseline FEV1 has been 
determined, an exercise challenge will be performed according to the method described 
in the SRM. 


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Post-exercise Serial Spirometry: Following the eligibility exercise challenge, two FEV1
efforts (not full FVC maneuvers) will be performed at 5, 10, 15, 30, 45 and 60 minutes 
post-exercise. 
To qualify for randomization, subjects must demonstrate a decrease in FEV1 of ≥20% 
when compared to the FEV1 obtained immediately pre-exercise for at least one of the 
post-exercise spirometry efforts obtained within 30 minutes post-challenge.  Subjects 
who achieve a decrease in FEV1 of 15% to <20% may continue taking their daily run-in 
medication and repeat the eligibility exercise challenge once within 24 to 48 hours. 
Dosing: Eligible subjects will administer their evening doses of double-blinded study 
medication following the eligibility exercise challenge/serial spirometry. Evening dosing 
should occur between 5 PM and 11PM.
Revised text:
Treatment period 1 baseline FEV1: Spirometry will be performed at Visit 2 at 
approximately the same time as at Visit 1 (±1 hour). The FEV1 should be measured 
approximately 12 hours after dosing with run-in medication (FP 250 mcg). At least two 
valid and two repeatable spirometry efforts should be obtained before the first exercise 
challenge.
From this spirometry testing, the target FEV1 values #2 and #3 (Section 8.3.1.1) should 
be determined based on the pre-exercise FEV1. 
Eligibility Exercise Challenge: After the pre-exercise baseline FEV1 has been 
determined, an exercise challenge will be performed according to the method described 
in the SRM. 
Post-exercise Serial Spirometry: Following the eligibility exercise challenge, serial 
spirometry (FEV1) will be performed at 5, 10, 15, 30, 45 and 60 minutes post-exercise. 
To qualify for randomization, subjects must demonstrate a decrease in FEV1 of ≥20% 
when compared to the FEV1 obtained immediately pre-exercise for at least one of the 
post-exercise spirometry efforts obtained within 30 minutes post-challenge.  Subjects 
who achieve a decrease in FEV1 of 15% to <20% may continue taking their daily run-in 
medication and repeat the eligibility exercise challenge once within a week. In the event 
where a repeat visit is required for the exercise challenge, spirometry and vital signs 
measurements will be performed pre- and post- exercise challenge as detailed in 
Table 3. In addition, ACQ-5 and a review of concomitant medication and adverse 
events will be performed at the repeat visit. 
Dosing: Eligible subjects will administer their evening dose of double-blinded study 
medication following the eligibility exercise challenge/serial spirometry. Evening dosing
should occur between 5 PM and 11PM.


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Section 8.3.3.3: Visit 3 and Visit 6 (23 hours Post First Dose Exercise 
Challenge)
Original text:
Visit 3 and Visit 6 begin between 5 PM and 11 PM and should begin at approximately 
the same time as Visit 1 (±1 hour). These visits should begin prior to the subject’s 
evening dose on that visit day.
Pre-exercise FEV1: Spirometry will be performed at Visits 3 and 6 at approximately the 
same time as at Visit 1 (±1 hour). The FEV1 should be measured approximately 23 hours 
after the first dose in each treatment period. At least two adequate and repeatable 
spirometry efforts with full FEV1 and FVC maneuvers should be obtained before the 
exercise challenge.
Exercise Challenge: After the pre-exercise FEV1 has been determined, an exercise 
challenge will be performed according to the method described in the SRM. 
Post-exercise Serial Spirometry: Following the exercise challenge, serial spirometry 
measurements will be performed at time points at 5, 10, 15, 30, 45 and 60 minutes post-
challenge. Two FEV1 efforts (not full FVC maneuvers) will be performed at each time 
point.
Medication Dosing: At the end of Visits 3 and 6, the evening dose should be 
administered following completion of the 23-hour post evening dose exercise 
challenge/serial spirometry, and prior to the subject’s leaving the clinic.
Revised text:
Visit 3 and Visit 6 begin between 5 PM and 11 PM and should begin at approximately 
the same time as Visit 1 (±1 hour).  These visits should begin prior to the subject’s 
evening dose on that visit day.
Pre-exercise FEV1: Spirometry will be performed at Visits 3 and 6 at approximately the 
same time as at Visit 1 (±1 hour). The FEV1 should be measured approximately 23 hours 
after the first dose in each treatment period. At least two valid spirometry efforts should 
be obtained before the exercise challenge.
From this spirometry testing, the target FEV1 values #2 and #3 (Section 8.3.1.1) 
should be determined based on the pre-exercise FEV1. 
Exercise Challenge: After the pre-exercise FEV1 has been determined, an exercise 
challenge will be performed according to the method described in the SRM. 
Post-exercise Serial Spirometry: Following the eligibility exercise challenge at each
visit, serial spirometry (FEV1) will be performed at 5, 10, 15, 30, 45 and 60 minutes post-
exercise.


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Medication Dosing: At the end of Visits 3 and 6, the evening dose of study treatment
medication should be administered following completion of the 23-hour post evening 
dose exercise challenge/serial spirometry, and prior to the subject’s leaving the clinic.
Section 8.3.3.4: Visit 4 and Visit 7 (Blinded Treatment Exercise 
Challenges)
Original text:
Visit 4 and Visit 7 begin between 5 PM and 11 PM and are conducted over 
approximately 24 hours. These visits should begin at approximately the same time as 
Visit 1 (±1 hour) and approximately at the end of the dosing period for each IP.  
Dosing: At the beginning of Visit 4 and Visit 7, subjects will administer their evening 
doses of double-blinded study medication in the clinic and the time of dosing will be 
recorded. Subjects will return to the clinic 12 (±1) hours and 23 (±1) hours after dosing 
for exercise challenge testing.
Pre-exercise FEV1: At least two adequate and repeatable spirometry efforts with full 
FEV1 and FVC maneuvers should be obtained just prior to EACH exercise challenge.
From this spirometry testing, the target FEV1 values #2 and #3 (Section 8.3.1.1) should 
be determined based on the pre-exercise FEV1. 
Exercise challenge testing: Exercise challenge testing will occur at 12 (±1) hours and 23 
(±1) hours after administering the evening dose. (The 12-hour exercise challenge and 
spirometry measurements should occur prior to dosing of the study Diskus medication.) 
Following each challenge, serial spirometry measurements will be performed at time 
points at 5, 10, 15, 30, 45 and 60 minutes post-challenge. Two FEV1 efforts (not full FVC 
maneuvers) will be performed at each time point. 
Washout Medication Dosing: At the end of Visit 4, the washout medication should be 
dispensed and first evening dose administered following completion of the 23-hour post 
evening dose exercise challenge/serial spirometry, and prior to the subject’s leaving the 
clinic.
Revised text:
Visit 4 and Visit 7 begin between 5 PM and 11 PM and are conducted over 
approximately 24 hours. Subjects will be required to attend three clinic visits during 
each 24-hour period for Visit 4 and Visit 7. The evening visit should begin at 
approximately the same time as Visit 1 (±1 hour).  
Dosing: At the beginning of Visit 4 and Visit 7, subjects will administer their evening 
doses of double-blinded study medication in the clinic and the time of dosing will be 
recorded. In addition to administering the evening dose, vital signs will be measured 
and a review of concomitant medication and AEs performed.


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Subjects will return to the clinic 12 (±1) hours and 23 (±1) hours after evening 
dosing for exercise challenge testing.
Pre-exercise FEV1: At least two valid spirometry efforts with full FEV1 and FVC 
maneuvers should be obtained just prior to each exercise challenge.
From this spirometry testing, the target FEV1 values #2 and #3 (Section 8.3.1.1) should 
be determined based on the pre-exercise FEV1. 
Exercise challenge testing: Exercise challenge testing will occur at 12 (±1) hours and 23 
(±1) hours after administering the evening dose. (The 12-hour exercise challenge and 
spirometry measurements should occur prior to dosing of the study medication). 
Post-exercise Serial Spirometry: Following the eligibility exercise challenge at each 
visit, serial spirometry (FEV1) will be performed at 5, 10, 15, 30, 45 and 60 minutes post-
exercise.
Washout Medication Dosing: At the end of Visit 4, the washout medication should be 
dispensed and first evening dose administered following completion of the 23-hour post 
evening dose exercise challenge/serial spirometry, and prior to the subject’s leaving the 
clinic.
Section 8.3.3.5: Visit 5 
Original text:
Period 2 pre-exercise baseline FEV1: Spirometry will be performed at Visit 5 at 
approximately the same time as at Visit 1 (±1 hour). The FEV1 should be measured 
approximately 12 hours after dosing with the washout medication. At least two adequate 
and repeatable spirometry efforts with full FEV1 and FVC maneuvers should be obtained.
Dosing: Subjects will administer their evening doses of double-blinded study medication 
following the spirometry.
Revised text:
Treatment period 2 baseline FEV1: Spirometry will be performed at Visit 5 at 
approximately the same time as at Visit 1 (±1 hour). The FEV1 should be measured 
approximately 12 hours after dosing with the washout medication. At least two valid 
spirometry efforts should be obtained.
Dosing: Subjects will administer their evening doses of double-blinded study medication 
following the spirometry.


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Section 8.3.5: Asthma Control Test (ACT) 
Original text:
The ACT is a five-item questionnaire developed as a measure of subjects’ asthma control 
that can be quickly and easily completed in clinical practice. The questions are designed 
to be self-completed by the subject. It is recommended that the ACT be administered at 
the same time during each visit. To avoid biasing responses, the subjects should not be 
told the results of diagnostic tests prior to completing the questionnaire and should be 
completed before any procedures are performed on the subject to avoid influencing the 
subject’s response. Adequate time should be allowed to complete all items on the ACT.
The subject should be given a quiet area in which to complete the questionnaire.
The investigator should ask the subject to complete the questions as accurately as 
possible. If the subject requests help or clarification with any of the questions, he/she will 
be asked to re-read the instructions and give the answer that best reflects how he/she felt 
over the previous 4 weeks. The subject should be reassured that there are no right or 
wrong answers. The investigator should not provide the subject with any answer or 
attempt to interpret any portion of a question.
Revised text:
Asthma Control Questionnaire-5 (ACQ-5) (New text)
The ACQ-5 will be completed at the beginning of all study visits where the form is 
completed. 
The ACQ-5 is a five-item questionnaire, which has been developed as a measure of 
subject’ asthma control that can be quickly and easily completed [Juniper, 2005].
The questions are designed to be self-completed by the subject. The five questions 
enquire about the frequency and/or severity of symptoms (nocturnal awakening on 
waking in the morning, activity limitation, and shortness of breath, wheeze). The 
response options for all these questions consist of a zero (no impairment/limitation) 
to six (total impairment/ limitation) scale.
The subject should be given a quiet area in which to complete the questionnaire. 
The investigator should ask the subject to complete the questions as accurately as 
possible. If the subject requests help or clarification with any of the questions, 
he/she will be asked to re-read the instructions and give the answer that best reflects 
how he/she felt over the previous week. The subject should be reassured that there 
are no right or wrong answers. The investigator should not provide the subject with 
any answer or attempt to interpret any portion of a question.
It is recommended that the ACQ-5 be administered at the same time during each 
visit. To avoid biasing responses, the subjects should not be told the results of 
diagnostic tests prior to completing the questionnaire and should be completed 


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before any procedures are performed on the subject to avoid influencing the 
subject’s response. Adequate time should be allowed to complete all items on the 
ACQ-5.
Section 8.4: Safety 
Original text:
Safety will be assessed, as indicated in the Time and Events Time and Events Table 
Table 3, by monitoring of AEs, a physical examination at screening, and vital signs 
(systolic and diastolic blood pressure and heart rate [pulse] at each visit. A screening 12-
ECG will be conducted.
Planned time points for all safety assessments are listed in the Time and Events Table 
(Time and Events Table Table 3). 
Revised text:
Safety will be assessed, as indicated in the Time and Events Time and Events Table 
Table 3, by monitoring of AEs, a physical examination at screening, and vital signs 
(systolic and diastolic blood pressure and heart rate [pulse] at each visit. A screening 12-
ECG will be conducted. 
In cases of suspected pneumonia, a confirmatory chest x-ray should be conducted 
within 48 hours.
Planned time points for all safety assessments are listed in the Time and Events Table 
(Time and Events Table Table 3).
Section 8.4.5: Vital Signs
Original text:

Vital signs will be measured in semi-supine position after 5 minutes rest prior to 
spirometry and will include temperature, systolic and diastolic blood pressure and 
pulse rate. 

Vital signs (systolic and diastolic blood pressure and pulse rate) will be measured 
again before and after each exercise challenge and recorded in the eCRF. Heart 
rate and oxygen saturation will be measured during each exercise challenge.

If there are any clinically significant abnormalities noted, further examinations 
must be performed until the abnormality is resolved.  


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Revised text:

Vital signs including pulse rate and systolic and diastolic blood pressure will be 
obtained at each clinic visit, including any Early Withdrawal visit. 

Vital signs will be obtained after subjects have rested for approximately 5 
minutes in a semi-supine position.

At all time points where vital signs and spirometry are performed, vital signs 
will be done before the spriometry measurement. . 

Heart rate will be measured during each exercise challenge. 

If there are any clinically significant abnormalities noted, further examinations 
must be performed until the abnormality is resolved.  
Section 8.4.6: Electrocardiogram (ECG)
Original text:

A pre-dose, 12-lead ECG will be performed and interpreted by the investigator or 
his/her suitably qualified designee at Visit 1. The ECG will be recorded after 5 
minutes rest prior to performing spirometry.

Investigators will use a site ECG machine and perform a manual reading of the 
ECG parameters to determine whether a subject meets the eligibility criteria for 
enrolment in the study at screening (Visit 1). 

The ECG interpretation including the paper trace will be maintained at the site 
within the source documentation.
Revised text:

A 12-lead ECG will be performed and interpreted by the investigator or his/her 
suitably qualified designee at Visit 1. The ECG will be recorded after 5 minutes 
rest after vital signs and prior to performing spirometry.

Investigators will use a site ECG machine and perform a manual reading of the 
ECG parameters to determine whether a subject meets the eligibility criteria for 
enrolment in the study at screening (Visit 1). 

The ECG interpretation including the paper trace will be maintained at the site 
within the source documentation.


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Section 10.1: Hypotheses
Original text:
The primary endpoint is the maximal percent decrease in FEV1 following exercise 
challenge at 12-hours post-dose at the end of the 2-week treatment period.  
The treatment comparison is the FF/VI combination versus FP.  Demonstration of 
efficacy for this treatment comparison will be based on a hypothesis testing approach 
whereby the null hypothesis is that there is no difference between treatment groups and 
the alternative hypothesis is that there is a difference between treatment groups.  
A 2-sided 5% probability associated with incorrectly rejecting the null hypothesis 
(significance level) is considered acceptable for this study. In order to account for 
multiplicity, this primary hypothesis test on the primary endpoint for the ITT (Intent-to-
Treat) population will act as a gatekeeper for all other hypothesis tests using the 
secondary endpoints, where these tests will proceed in a pre-defined order.
If the primary hypothesis on the primary endpoint for the ITT population is rejected then 
the following hierarchy of tests will be performed using the ITT population; 
1.
Test at the 5% level the null hypothesis that the true population difference 
between the treatment group means in maximal percent decrease in FEV1 from 
pre-exercise at 23 hrs post-dose at the end of the 2-week treatment period is zero.
2.
If 1 is significant then test at the 5% level the null hypothesis that the true 
probability distributions for the treatment groups for not recovering to within 5% 
of pre-exercise FEV1 at 12 hrs post-dose at the end of the 2-week treatment 
period (i.e. the “survival” distributions for the endpoint time to recovery to within 
5% of pre-exercise FEV1 at 12 hrs post-dose) are equal.
3.
If 2 is significant then test at the 5% level the null hypothesis that the true 
population probability distributions for the treatment groups for not recovering to 
within 5% of pre-exercise FEV1 at 23 hrs post-dose at the end of the 2-week 
treatment period (i.e. the “survival” distributions for the endpoint time to recovery 
to within 5% of pre-exercise FEV1 at 23 hrs post-dose) are equal.
4.
If 3 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in AUC for percentage 
decrease in FEV1 from pre-exercise FEV1 at 12 hrs post-dose at the end of the 2-
week treatment period is zero.
5.
If 4 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in AUC for percentage 
decrease in FEV1 from pre-exercise FEV1 at 23 hrs post-dose at the end of the 2-
week treatment period is zero.


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Revised text:
The primary endpoint is the maximal percent decrease in FEV1 following exercise 
challenge at 12-hours post-dose at the end of the 2-week treatment period.  
The treatment comparison is the FF/VI combination versus FP.  Demonstration of 
efficacy for this treatment comparison will be based on a hypothesis testing approach 
whereby the null hypothesis is that there is no difference between treatment groups and 
the alternative hypothesis is that there is a difference between treatment groups.  
A 2-sided 5% probability associated with incorrectly rejecting the null hypothesis 
(significance level) is considered acceptable for this study. In order to account for 
multiplicity, this primary hypothesis test on the primary endpoint for the ITT (Intent-to-
Treat) population will act as a gatekeeper for all other hypothesis tests using the 
secondary endpoints, where these tests will proceed in a pre-defined order.
If the primary hypothesis on the primary endpoint for the ITT population is rejected then 
the following hierarchy of tests will be performed using the ITT population; 
1.
Test at the 5% level the null hypothesis that the true odds ratio between the 
two treatment groups of recovering to within 5% of pre-exercise FEV1 at the 
30 minute post-exercise time point following the exercise challenge at 12 
hours post evening dose is equal to one.
2.
Test at the 5% level the null hypothesis that the true population difference 
between the treatment group means in maximal percent decrease in FEV1
from pre-exercise at 23 hrs post-dose at the end of the 2-week treatment 
period is zero.
3.
Test at the 5% level the null hypothesis that the true odds ratio between the 
two treatment groups of recovering to within 5% of pre-exercise FEV1 at the 
30 minute post-exercise time point following the exercise challenge at 23 
hours post evening dose is equal to one.
4.
If 3 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in weighted mean 
0-60 minutes for percentage decrease in FEV1 from pre-exercise FEV1 at 12 
hrs post-dose at the end of the 2-week treatment period is zero.
5.
If 4 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in weighted mean 
0-60 minutes for percentage decrease in FEV1 from pre-exercise FEV1 at 23 
hrs post-dose at the end of the 2-week treatment period is zero.


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Section 10.2.1: Sample Size Assumptions
Original text:
For the primary efficacy endpoint of maximal percent decrease in FEV1 following 
exercise challenge at 12 hours post-dose at the end of the 2-week treatment period, given 
an assumed 10% screen failure rate, a 55% run-in failure rate, and a 15% withdrawal rate 
post-randomisation, a total of approximately 165 subjects will be screened. Given these 
assumed failure and withdrawal rates we expect 148 subjects will enter the run-in period, 
of which 66 subjects will be randomized, of which 56 subjects will be evaluable, that is 
completing the exercise challenges and the FEV1 evaluations at the end of both treatment 
periods. With 56 evaluable subjects this study has approximately 90% power assuming a 
true population difference of 5% in maximal percent decrease in FEV1 between the two 
treatment groups.  This assumes a within-subject standard deviation (SD) of 8% where 
significance is declared at the two-sided 5% significance level. 
Subjects will be centrally randomized to one of the two treatment sequences shown 
below in Table 4 in a 1:1 ratio:
Revised text:
For the primary efficacy endpoint of maximal percent decrease in FEV1 following 
exercise challenge at 12 hours post-dose at the end of the 2-week treatment period, given 
an assumed 20% screen failure rate, a 70% run-in failure rate, and a 15% withdrawal rate 
post-randomisation, a total of approximately 275 subjects will be screened. Given these 
assumed failure and withdrawal rates we expect 220 subjects will enter the run-in period, 
of which 66 subjects will be randomized, of which 56 subjects will be evaluable, that is 
completing the exercise challenges and the FEV1 evaluations at the end of both treatment 
periods. With 56 evaluable subjects this study has approximately 90% power assuming a 
true population difference of 5% in maximal percent decrease in FEV1 between the two 
treatment groups.  This assumes a within-subject standard deviation (SD) of 8% where 
significance is declared at the two-sided 5% significance level. 
Subjects will be centrally randomized to one of the two treatment sequences shown 
below in Table 4 in a 1:1 ratio:
Other measures of efficacy include the evaluation of a categorical treatment response 
evaluating the percentage of subjects who demonstrate a decrease from pre-exercise 
challenge FEV1<10%, a decrease 10% to <20%, or a decrease 20%, and an evaluation 
of maximal percent decrease from pre-treatment baseline in FEV1 (period baseline) 
following exercise challenge (at 12 hours and 23 hours post-dose).  Additional endpoints 
include evaluation of physical activity monitoring and Asthma Control Test.  All 
endpoints will be described further in the RAP.  


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Section 10.4.1.2: Secondary Analyses
Original text:
Summaries and analyses for secondary endpoints will be provided for the ITT population.  
Maximal percent decrease from pre-exercise FEV1 following exercise challenge (at 23 
hours post-dose at the end of the 2-week treatment period):
This endpoint will be summarized and analyzed as for the primary endpoint of maximal 
percent decrease from pre-exercise FEV1 following exercise challenge at 12 hours post-
dose.  
Time required for recovery to within 5% of the pre-exercise FEV1 from the time of the 
maximal percentage decrease from pre-exercise FEV1 following the challenge (at 12 
hours and 23 hours post-dose at the end of the 2-week treatment period):
The time required for recovery to within 5% of the pre-exercise FEV1 from the time of 
the maximal percentage decrease from pre-exercise FEV1 following exercise challenge at 
12 hours and 23 hours post-dose for both treatment groups will be compared using a log-
rank test. The log rank test will test the null hypotheses that the survival distributions of 
the two treatment groups are equal. In addition the estimated hazard ratio, confidence 
interval and p-value will be presented. Kaplan-Meier plots showing the cumulative 
incidence curves for each treatment group will be produced. 
AUC (0-60 min) for percentage decrease from pre-exercise FEV1 after exercise (at 12 
hours and 23 hours post-dose at the end of the 2-week treatment period):
A comparison will be made of the estimated means of the two treatment groups in AUC 
of the percentage decrease in FEV1 from pre-exercise at 12 and 23 hrs post-dose using a 
LMM to adjust for covariate effects. The LMM will include the following covariates: 
treatment, subject-level mean of the pre-treatment FEV1 period baselines (mean of the 2 
period baselines per subject), centered period-level baseline FEV1 (period baselines 
centered using subject-level mean of the pre-treatment FEV1 period baselines),  gender, 
age, treatment period and smoking history as fixed effects, and a random intercept for 
each subject.  
Revised text:
Summaries and analyses for secondary endpoints will be provided for the ITT population.  
Maximal percent decrease from pre-exercise FEV1 following exercise challenge (at 23 
hours post-dose at the end of the 2-week treatment period):
This endpoint will be summarized and analyzed as for the primary endpoint of maximal 
percent decrease from pre-exercise FEV1 following exercise challenge at 12 hours post-
dose.  


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Proportion of subjects with a 30 minute post-challenge FEV1 that was no more than 
5% lower than their pre-exercise FEV1 following the exercise challenge at 12 hours 
and 23 hours post evening dose at the end of the 2-week treatment period
This endpoint will be analysed using a logistic regression model separately for the 12 and 
23 hour challenges using the covariates baseline FEV1, treatment group, gender, age, and 
smoking history.
Weighted mean 0-60 minutes for percentage decrease from pre-exercise FEV1 after 
exercise (at 12 hours and 23 hours post-dose at the end of the 2-week treatment 
period):
A comparison will be made of the estimated means of the two treatment groups in for 
weighted mean 0-60 minutes of the percentage decrease in FEV1 from pre-exercise at 
12 and 23 hrs post-dose using a LMM to adjust for covariate effects. The LMM will 
include the following covariates: treatment, subject-level mean of the pre-treatment FEV1 
period baselines (mean of the 2 period baselines per subject), centered period-level 
baseline FEV1 (period baselines centered using subject-level mean of the pre-treatment 
FEV1 period baselines),  gender, age, treatment period and smoking history as fixed 
effects, and a random intercept for each subject.  
Section 10.4.1.2.1: Other Efficacy Analyses
Original text:
Other measures of efficacy include the evaluation of a categorical treatment response 
evaluating the percentage of subjects who demonstrate a decrease from pre-exercise 
challenge FEV1<10%, a decrease 10% to <20%, or a decrease 20%, and an evaluation 
of maximal percent decrease from pre-treatment baseline in FEV1 (period baseline) 
following exercise challenge (at 12 hours and 23 hours post-dose).  Additional endpoints 
include evaluation of physical activity monitoring and Asthma Control Test.  All 
endpoints will be described further in the RAP.  
Revised text:
Other measures of efficacy include the evaluation of a categorical treatment response 
evaluating the percentage of subjects who demonstrate a decrease from pre-exercise 
challenge FEV1<10%, a decrease 10% to <20%, or a decrease 20%, and an evaluation 
of maximal percent decrease from treatment period baseline in FEV1 (period baseline) 
following exercise challenge (at 12 hours and 23 hours post-dose).  Additional 
endpoints include evaluation of physical activity monitoring the ACQ-5 score, and 
the proportion of subjects with a 5 minute post-challenge FEV1 that was no more 
than 5% lower than their pre-exercise FEV1 following the exercise challenge at 12 
hours and 23 hours post evening dose at the end of the 2-week treatment period 
(repeat for the 10, 15, 45 and 60 minute time points).


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Section 12: References
Original text:
European Medicines Agency (EMA). Note for guidance on clinical investigation of 
medicinal products for treatment of asthma. 27Jun2013. CHMP/EWP/2922/01 Rev.1.
FDA Guidance for Industry: Exercise Induced Bronchospasm (EIB)—Development of 
Drugs to Prevent EIB, February 2002.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention. GINA, www.ginasthma.org; 2015.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical 
trials and marketing authorisation for pharmaceuticals, 2009; EMA/CPMP/ICH/286/1995
Jones A, Fay JK, Burr ML, Stone M, Hood K, Roberts G. Inhaled Corticosteroids Effects 
on Bone Metabolism in Asthma and Mild Chronic Obstructive Pulmonary Disease. 
Cochrane Database of Systemic Reviews. 2002;1:1-21. 
König P, Hillmana L, Cervantesa C, Levinea C, et al. Bone Metabolism in Children with 
Asthma Treated with Inhaled Beclomethasone Dipropionate. The Journal of Paediatrics. 
1993;122:219-226. 
McFadden ER, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994;330:1362-1367.
McMahon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age and risks 
of FDA-approved long-acting 2-adrenergic receptor agonists. Pediatrics. 
2011;Nov;128(5):e1147-54. 
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 
2005;26:319-338. 
Mitchell KE, Johnson-Warrington V, Apps LD, Bankart LS, Williams JE, Rees K, Jolly 
K, Steiner M, Morgan M, Singh SJ. A Self-Management Programme for COPD: a 
Randomised Controlled Trial. Eur Respir J. 2014;44:1538-1547. 
Murray JJ, Waitkus-Edwards KR, Yancey SW. Evaluation of Fluticasone Propionate and 
Fluticasone Propionate/Salmeterol Combination on Exercise in Pediatric and Adolescent 
Patients with Asthma. Open Resp Med J, 2011, 5, 11-18.
National Institutes of Health (NIH). Guidelines for the Diagnosis and Management of 
Asthma - Expert Panel Report 3 2007. U.S. Department of Health and Human Services, 
Bethesda, MD; 2007. NIH Publication No. 07-4051.


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Parsons JP, Hallstrand TS, Mastronarde JG, Kaminsky DA, Rundell KW, et al. An 
Official American Thoracic Society Clinical Practice Guideline: Exercise-induced 
Bronchoconstriction. Am J Respir Crit Care Med 2013;187:1016–1027.
Pearlman D, Qaqundah P, Matz J, Yancey SJ, Stempel DA, Ortega HG. Fluticasone 
Propionate/Salmeterol and Exercise-Induced Asthma in Children With Persistent 
Asthma. Pediatric Pulm 2009;44:429–435.
Poppius H, Muittari A, Kreus KE, Korhonen O, Vilhanen A. Exercise Asthma and 
Disodium Cromoglycate. Br Med J 1970;4:337-339.
Quanjer P, Stanojevic S, Cole T, Baur X., Hall G, Enright P, et al. on behalf of the ERS 
Global Lung Function Initiative.  Multi-ethnic reference values for spirometry for the 3-
95 year age range: the global lung function 2012 equations. Eur Respir J, 2012; 40: 
1324–1343.
Turpeinen M, Pelkonen AS, Nikander K, Sorva R, Selroos O, Juntunen-Backman K, 
Haahtela T. Bone mineral density in children treated with daily or periodical inhaled 
budesonide: the Helsinki Early Intervention Childhood Asthma study. Paediatric 
Research. 2010;68(2):169-173. 
Weiler J, et al. Pathogenesis, prevalence, diagnosis, and management of exercise-induced 
bronchoconstriction: a practice parameter. Ann Allerg Asthma Immunol 2010;105 (6 
Supp): S1-S47. 
Weiler J, Nathan RA, Rupp NT, Kalberg CJ; Emmett A, Dorinsky PM. Effect of 
fluticasone/salmeterol administered via a single device on exercise-induced 
bronchospasm in patients with persistent asthma. Ann. Allergy Asthma Immunol. 
2005;94:65-72.
Revised text:
European Medicines Agency (EMA). Note for guidance on clinical investigation of 
medicinal products for treatment of asthma. 27Jun2013. CHMP/EWP/2922/01 Rev.1.
FDA Guidance for Industry: Exercise Induced Bronchospasm (EIB)—Development of 
Drugs to Prevent EIB, February 2002.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention. GINA, www.ginasthma.org; 2015.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical 
trials and marketing authorisation for pharmaceuticals, 2009; EMA/CPMP/ICH/286/1995


2015N231308_03
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Jones A, Fay JK, Burr ML, Stone M, Hood K, Roberts G. Inhaled Corticosteroids Effects 
on Bone Metabolism in Asthma and Mild Chronic Obstructive Pulmonary Disease. 
Cochrane Database of Systemic Reviews. 2002;1:1-21. 
Juniper EF, Svensson K, Mörk AC, Ståhl E. Modification of the Asthma Quality of 
Life Questionnaire (standardised) in patients 12 years and older. Health and Quality 
of Life Outcomes. 2005; 3:58.
König P, Hillmana L, Cervantesa C, Levine C, Maloney C, Douglass B, et al. Bone 
Metabolism in Children with Asthma Treated with Inhaled Beclomethasone 
Dipropionate. The Journal of Paediatrics. 1993;122:219-226. 
McFadden ER, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994;330:1362-1367.
McMahon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age and risks 
of FDA-approved long-acting 2-adrenergic receptor agonists. Pediatrics. 
2011;Nov;128(5):e1147-54. 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi F, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-338. 
Mitchell KE, Johnson-Warrington V, Apps LD, Bankart LS, Williams JE, Rees K,et al. . 
A Self-Management Programme for COPD: a Randomised Controlled Trial. Eur Respir 
J. 2014;44:1538-1547. 
Murray JJ, Waitkus-Edwards KR, Yancey SW. Evaluation of Fluticasone Propionate and 
Fluticasone Propionate/Salmeterol Combination on Exercise in Pediatric and Adolescent 
Patients with Asthma. Open Resp Med J, 2011, 5, 11-18.
National Institutes of Health (NIH). Guidelines for the Diagnosis and Management of 
Asthma - Expert Panel Report 3 2007. U.S. Department of Health and Human Services, 
Bethesda, MD; 2007. NIH Publication No. 07-4051.
Parsons JP, Hallstrand TS, Mastronarde JG, Kaminsky DA, Rundell KW, Hull JH, et al. 
An Official American Thoracic Society Clinical Practice Guideline: Exercise-induced 
Bronchoconstriction. Am J Respir Crit Care Med 2013;187:1016–1027.
Pearlman D, Qaqundah P, Matz J, Yancey SJ, Stempel DA, Ortega HG. Fluticasone 
Propionate/Salmeterol and Exercise-Induced Asthma in Children With Persistent 
Asthma. Pediatric Pulm 2009;44:429–435.
Poppius H, Muittari A, Kreus KE, Korhonen O, Vilhanen A. Exercise Asthma and 
Disodium Cromoglycate. Br Med J 1970;4:337-339.
Quanjer P, Stanojevic S, Cole T, Baur X., Hall G, Enright P, et al. on behalf of the ERS 
Global Lung Function Initiative.  Multi-ethnic reference values for spirometry for the 3-
95 year age range: the global lung function 2012 equations. Eur Respir J, 2012; 40: 
1324–1343.


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Turpeinen M, Pelkonen AS, Nikander K, Sorva R, Selroos O, Juntunen-Backman K,et al. 
Bone mineral density in children treated with daily or periodical inhaled budesonide: the 
Helsinki Early Intervention Childhood Asthma study. Paediatric Research. 
2010;68(2):169-173. 
Weiler J, Anderson SD, Randolph C, Bonini S, Craig TJ, Pearlman DS, et al. 
Pathogenesis, prevalence, diagnosis, and management of exercise-induced
bronchoconstriction: a practice parameter. Ann Allerg Asthma Immunol 2010;105 (6 
Supp): S1-S47. 
Weiler J, Nathan RA, Rupp NT, Kalberg CJ; Emmett A, Dorinsky PM. Effect of 
fluticasone/salmeterol administered via a single device on exercise-induced 
bronchospasm in patients with persistent asthma. Ann. Allergy Asthma Immunol. 
2005;94:65-72.


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13.8.3.
Protocol Amendment 03 (25-MAY-2016) from Protocol 
Amendment 02 (16-DEC-2015)
Amendment 3 is applicable to all investigator sites in study 201832.
This amendment has been written to clarify text regarding timing of visits to ensure that 
the intention of the protocol is correctly reflected.  Other amendments were made where 
deemed necessary.
Method of Amendment
Original and revised texts are specified as follows:

Original text: as written in the Amendment No. 2

Revised text: as written in Amendment No. 03 with additional or revised text 
indicated by bold font, or bold underline (Time and Events Table).
Amendment Details
Section 5.1  Overall Design
Original text:


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Revised text:
Rationale:
Day 1 redefined as Day 0 to better reflect the intention of the protocol to ensure that the 
two treatment periods are 14 days in length.
Section 6.2 Randomisation Criteria
Original text:
At the end of the run-in period, a subject will be eligible for Randomization to double-
blinded study treatment if he/she meets all the following criteria at Visit 2. Visit 2 may be 
conducted over the course of 48 hours (within the designated window), if the eligibility 
exercise challenge is repeated.
Revised Text:
At the end of the run-in period, a subject will be eligible for Randomization to double-
blinded study treatment if he/she meets all the following criteria at Visit 2.
Rationale:
Visit 2 repeat timelines were updated in Amendment 2 but this text was not updated in 
error.
Section 7.1 Investigational Product and Other Study Treatment
Original text:
Albuterol/salbutamol inhalation aerosol will be supplied by GSK


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Revised Text:
Albuterol/salbutamol inhalation aerosol will be supplied as detailed in the SRM.
Rationale:
Change in strategy for rescue medication supply.
Section 7.2.1  Assignment of Subject Number
Original text:
At Visit1, a unique Subject Number (CRF number) will be assigned to any subject who 
has at least one Visit 1 procedure performed, other than informed consent. The unique 
Subject Number will be used to identify individual subjects during the course of the 
study.
Revised Text:
At the Pre-screen visit, a unique Subject Number (CRF number) will be assigned to 
any subject who has given informed consent. The unique Subject Number will be used to 
identify individual subjects during the course of the study.
Rationale:
Subject numbers must be assigned as soon as informed consent is given and the informed 
consent form signed, regardless of study procedures.
Section 7.10.2  Prohibited Medications and Non-Drug Therapies
Original text:
The following asthma medications are prohibited during the conduct of the study or 
within the specified time frame:
Within 12 weeks of Visit 1 and during the study:

Systemic (oral, parenteral or depot) corticosteroids

Anti-IgE (e.g. Xolair)
Revised Text:
The following asthma medications are prohibited during the conduct of the study or 
within the specified time frame:
Within 12 weeks of Visit 1 and during the study:

Systemic (oral, parenteral or depot) corticosteroids

Anti-IgE (e.g. Xolair, Nucala™)
Rationale:
Nucala has recently received a license for asthma and should be excluded.


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Table 3  Time and Events Table
Original text:
Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412, 14
512
6
712, 14
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
1
2
14 (-2/+2) 
days
28 (-2/+2) 
days
29 (-2/+2) 
42 (-2/+2) 
days
47 to 
51 
days
Written Informed Consent
X
Genetics Consent
X1
Subject Demography
X
Medical History (including CV)
X
Disease (Asthma) History 
X
Medication History
X
X
Smoking history/status
X
Inclusion/Exclusion Criteria
X
Evidence of EIB
X
Efficacy Assessments
Spirometry (full FEV1 and FVC)
X
X2
X2
X2
X
X2
X2
X
Exercise Challenge Testing 
(Treadmill)
X3, 17
X4
X5
X4
X5
Post-Challenge Serial FEV1 
Measurements
X3
X6
X6
X6
X6
Asthma Control Questionnaire-5
X
X
X
X
X
Dispense SenseWear15
accelerometer
X
Collect SenseWear accelerometer
X
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X7
Physical Examination
X


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Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412, 14
512
6
712, 14
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
1
2
14 (-2/+2) 
days
28 (-2/+2) 
days
29 (-2/+2) 
42 (-2/+2) 
days
47 to 
51 
days
Vital Signs
X
X8
X8
X8
X
X8
X8
X
12-lead ECG 
X
Adverse Event Assessment
X9
X9
X
X
X
X
X
X
X
X
Issue Medical Conditions Diary 
Card
X
X
X
X
Review Medical Conditions Diary 
Card
X10
X
X10
X10
X
X10
X
Laboratory Assessments
Genetics Saliva Sample
X1
Urine Pregnancy Test
X
X
X
X
X13
Investigational Product
Dispense Fluticasone Propionate
X
X
Collect Fluticasone Propionate
X
X
Dispense Rescue16
Albuterol/salbutamol
X
X
X
X
X
X
Collect Rescue 
Albuterol/salbutamol
X
X
X
X
Dispense IP
X11
X
Assess study drug  compliance
X
X
X
X
X
X
X
Collect IP
X
X
X


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1.
Genetics saliva sample collected at Visit 2 (following Randomization) or at any scheduled visit thereafter. Genetics consent MUST be obtained PRIOR to 
collection of the Genetics sample.  
2.
Pre-exercise spirometry (full FEV1 and forced vital capacity (FVC) testing), conducted immediately pre-exercise (and after vital signs), if applicable. Subject 
should have withheld albuterol/salbutamol within previous 6 hours. 
3.
Performed for determination of eligibility. Serial spirometry performed 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Subjects must demonstrate a 
decrease in FEV1 of 20% at one time point within 30 minutes of the end of a standardized exercise challenge.  
4.
Exercise challenge testing will be performed at 23 hours following the evening study treatment doses given at Visit 2 and Visit 5 
5.
Exercise challenge testing will be performed at 12 hours and 23 hours following the evening study treatment doses given at the beginning of Visits 4 and 7.
6.
Serial spirometry performed at time points 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Longer monitoring may be required for those subjects 
who do not return to 5% of baseline FEV1 values within 60 minutes.
7.
Concomitant medications collected for adverse events only between end of treatment and follow-up phone contact. 
8.
Vital signs will be collected before (prior to the pre-exercise spirometry) and after each exercise challenge test.
9.
Adverse Event and Serious Adverse Events to be collected from the start of study Drug (Visit 1) until the follow up contact. However, any SAE related to study 
participation will be     recorded from the time of Informed Consent 
10. Review medical conditions diary card, including an assessment of any potential change in exercise capacity
11. An unblinding card will be dispensed along with double blind IP.
12. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear accelerometer for the 7 days preceding 
these visits.
13. Pregnancy test will be conducted via home test kit and results will be reported at the Follow-up phone contact.
14. Visit 4 and Visit 7 will begin between 5PM and 11PM and continue over a period of approximately 24 hours. Subjects will return to the clinic at 12 hours and 23 
hours (after the evening dose of study medication from the evening visit) for an exercise challenge procedure.
15. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear Armband accelerometer for the 7 days 
preceding these visits.
16.
Collect and re-dispense rescue as needed from Visit 1
17.   Subjects who achieve a decrease in FEV1 of 15% to <20% may continue taking their daily run-in medication and repeat the eligibility exercise challenge and 
associated procedures once within a week of the original procedure.


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Revised Text:
Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412, 14
512
6
712, 14
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
0
118
14 (-2/+2) 
days
28 (-2/+2) 
days
29 18
42 (-2/+2) 
days
47 to 
51 
days
Written Informed Consent
X
Genetics Consent
X1
Subject Demography
X
Medical History (including CV)
X
Disease (Asthma) History 
X
Medication History
X
X
Smoking history/status
X
Inclusion/Exclusion Criteria
X
Evidence of EIB
X
Efficacy Assessments
Spirometry (full FEV1 and FVC)
X
X2
X2
X2
X
X2
X2
X
Exercise Challenge Testing 
(Treadmill)
X3, 17
X4
X5
X4
X5
Post-Challenge Serial FEV1 
Measurements
X3
X6
X6
X6
X6
Asthma Control Questionnaire-5
X
X
X
X
X
Dispense SenseWear15
accelerometer
X
Collect SenseWear accelerometer
X
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X7
Physical Examination
X
Vital Signs
X
X8
X8
X8
X
X8
X8
X


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Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412, 14
512
6
712, 14
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
0
118
14 (-2/+2) 
days
28 (-2/+2) 
days
29 18
42 (-2/+2) 
days
47 to 
51 
days
12-lead ECG 
X
Adverse Event Assessment
X9
X9
X
X
X
X
X
X
X
X
Issue Medical Conditions Diary 
Card
X
X
X
X
Review Medical Conditions Diary 
Card
X10
X
X10
X10
X
X10
X
Laboratory Assessments
Genetics Saliva Sample
X1
Urine Pregnancy Test
X
X
X
X
X13
Investigational Product
Dispense Fluticasone Propionate
X
X
Collect Fluticasone Propionate
X
X
Dispense Rescue16
Albuterol/salbutamol
X
X
X
X
X
X
Collect Rescue 
Albuterol/salbutamol
X
X
X
X
Dispense IP
X11
X
Assess study drug  compliance
X
X
X
X
X
X
X
Collect IP
X
X
X


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1.
Genetics saliva sample collected at Visit 2 (following Randomization) or at any scheduled visit thereafter. Genetics consent MUST be obtained PRIOR to 
collection of the Genetics sample.  
2.
Pre-exercise spirometry (full FEV1 and forced vital capacity (FVC) testing), conducted immediately pre-exercise (and after vital signs), if applicable. Subject 
should have withheld albuterol/salbutamol within previous 6 hours. 
3.
Performed for determination of eligibility. Serial spirometry performed 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Subjects must demonstrate a 
decrease in FEV1 of 20% at one time point within 30 minutes of the end of a standardized exercise challenge.  
4.
Exercise challenge testing will be performed at 23 hours following the evening study treatment doses given at Visit 2 and Visit 5 
5.
Exercise challenge testing will be performed at 12 hours and 23 hours following the evening study treatment doses given at the beginning of Visits 4 and 7.
6.
Serial spirometry performed at time points 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Longer monitoring may be required for those subjects 
who do not return to 95% of baseline FEV1 values within 60 minutes.
7.
Concomitant medications collected for adverse events only between end of treatment and follow-up phone contact. 
8.
Vital signs will be collected before (prior to the pre-exercise spirometry) and after each exercise challenge test.
9.
Adverse Event and Serious Adverse Events to be collected from the start of study Drug (Visit 1) until the follow up contact. However, any SAE related to study 
participation will be recorded from the time of Informed Consent 
10. Review medical conditions diary card, including an assessment of any potential change in exercise capacity
11. An unblinding card will be dispensed along with double blind IP.
12. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear accelerometer for the 7 days preceding 
these visits.
13. Pregnancy test will be conducted via home test kit and results will be reported at the Follow-up phone contact.
14. Visit 4 and Visit 7 will begin between 5PM and 11PM and continue over a period of approximately 24 hours. Subjects will return to the clinic at 12 hours (±1 
hour) and 23 hours (±1 hour) (after the evening dose of study medication from the evening visit) for an exercise challenge procedure.
15. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear Armband accelerometer for the 7 days 
preceding these visits.
16.
Collect and re-dispense rescue as needed from Visit 1
17.   Subjects who achieve a decrease in FEV1 of 15% to <20% may continue taking their daily run-in medication and repeat the eligibility exercise challenge and 
associated procedures once within a week of the original procedure.
18.   Visit 3 must be performed on the day immediately following Visit 2.  Visit 6 must be performed on the day immediately following Visit 5.
Rationale:
Corresponding Day for Visit 2 and Visit 3 updated to better reflect the intention of the protocol to ensure that the two treatment periods 
are 14 days in length.  Other minor adjustments made to clarify the timing of visits.


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Section 8.3.3.2  Visit 2 (Randomization)
Original text:
Treatment period 1 baseline FEV1: Spirometry will be performed at Visit 2 at 
approximately the same time as at Visit 1 (±1 hour). The FEV1 should be measured 
approximately 12 hours after dosing with run-in medication (FP 250 mcg). At least two 
valid and two repeatable spirometry efforts should be obtained before the first exercise 
challenge.
Revised Text:
Treatment period 1 baseline FEV1: Visit 2 begins between 5 PM and 11 PM and 
should begin at approximately the same time as Visit 1 (±1 hour).  Spirometry will be 
performed at Visit 2 at approximately the same time as at Visit 1 (±1 hour). The FEV1
should be measured approximately 12 hours (±1 hour) after dosing with run-in 
medication (FP 250 mcg). At least two valid and two repeatable spirometry efforts should 
be obtained before the first exercise challenge.
Rationale:
To ensure clarity of the timing of visit 2.
Section 8.3.3.3 - Visit 3 and Visit 6 (23 hours Post First Dose Exercise 
Challenge)
Original text:
Pre-exercise FEV1: Spirometry will be performed at Visits 3 and 6 at approximately the 
same time as at Visit 1 (±1 hour). The FEV1 should be measured approximately 23 hours 
after the first dose in each treatment period. At least two valid spirometry efforts should 
be obtained before the exercise challenge.
Revised Text:
Pre-exercise FEV1: Spirometry will be performed at Visits 3 and 6 at approximately the 
same time as at Visit 1 (±1 hour). The FEV1 should be measured approximately 23 hours 
(±1 hour) after the first dose in each treatment period. At least two valid spirometry 
efforts should be obtained before the exercise challenge.
Rationale:
To ensure clarity of the timing of Spirometry at visits 3 and 6.
Section 8.3.3.5 – Visit 5
Original text:
Treatment period 2 baseline FEV1: Spirometry will be performed at Visit 5 at 
approximately the same time as at Visit 1 (±1 hour). The FEV1 should be measured 
approximately 12 hours after dosing with the washout medication. At least two valid 
spirometry efforts should be obtained.


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Revised Text:
Treatment period 2 baseline FEV1: Spirometry will be performed at Visit 5 at 
approximately the same time as at Visit 1 (±1 hour). The FEV1 should be measured 
approximately 12 hours (±1 hour) after dosing with the washout medication. At least two 
valid spirometry efforts should be obtained.
Rationale:
To ensure clarity of the timing of Spirometry at visit 5.
Section 8.4.5 
Original Text:
Vital signs will be obtained after subjects have rested for approximately 5 minutes in a 
semi-supine position.
Revised Text:
Vital signs will be obtained after subjects have rested for approximately 5 minutes in a 
semi-supine position, except in the case of the post exercise test vital signs which will 
be performed immediately following the end of the exercise test.
Rationale
The post exercise vital signs will be performed immediately following the exercise test to 
ensure that the 5mins post exercise spirometry can be performed on time.
Section 13.1 – Appendix 1 – Abbreviations and Trademarks -
Original text:
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ADVAIR
SenseWear Armband
DISKUS
ELLIPTA
RELVAR/BREO


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Revised Text:
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ADVAIR
SenseWear Armband
DISKUS
ELLIPTA
RELVAR/BREO
NUCALA
Rationale:
Addition of Trademark to reflect addition of prohibited medication.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
201832
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 201832. A Randomised, 
Double-Blind, Double-Dummy, Crossover Comparison of 
Fluticasone Furoate/Vilanterol 100/25 mcg Once Daily 
Versus Fluticasone Propionate 250 mcg Twice Daily in 
Adolescent and Adult Subjects with Asthma and Exercise-
Induced Bronchoconstriction.
Compound Number 
:
GW685698+GW642444
Effective Date 
:
15-DEC-2016
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 201832.

This RAP is intended to describe the planned efficacy and safety analyses required 
for the study. 

This RAP will be provided to the study team members to convey the content of the 
final Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
15-DEC-2016
Manager, Statistics (Clinical Statistics)
Approved by: 
15-DEC-2016
Director, Statistics & Programming (Clinical Statistics)
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
201832
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 and Endpoints.....................................................................7
2.2.1.
Primary Objective ..........................................................................7
2.2.2.
Primary Efficacy Endpoint..............................................................7
2.2.3.
Secondary Efficacy Endpoint .........................................................7
2.2.4.
Other Efficacy Endpoints ...............................................................7
2.2.5.
Safety Endpoints............................................................................8
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses.................................................................................10
2.5.
Sample Size Assumptions ..........................................................................10
2.6.
Treatment Comparisons .............................................................................11
2.6.1.
Primary Comparisons of Interest..................................................11
2.6.2.
Other Comparisons of Interest.....................................................11
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Analyses ...................................................................14
6.2.
Supplementary Information for Study Population Tables and 
Listings .......................................................................................................15
6.2.1.
Concomitant Medications.............................................................15
7.
EFFICACY ANALYSES..........................................................................................16
7.1.
Primary Efficacy Analyses ..........................................................................16
7.1.1.
Overview of Planned Primary Efficacy Analyses..........................16
7.1.2.
Planned Primary Efficacy Statistical Analyses .............................17
7.2.
Secondary and Other Efficacy Analyses .....................................................18
7.2.1.
Overview of Planned Secondary and Other Efficacy 
Analyses......................................................................................18
7.2.2.
Planned Secondary and Other Efficacy Statistical 
Analyses......................................................................................19
7.2.2.1.
Maximal Percent Decrease from Pre-Exercise 
FEV1 Following Exercise Challenge at 23 
Hours Post Evening Dose at the End of the 2-
Week Treatment Period..............................................19
7.2.2.2.
Proportion of Subjects with a 5/10/15/30/45/60 
Minute Post-Challenge FEV1 that was no More 
Than 5% Lower Than Their Pre-exercise FEV1


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Following the Exercise Challenge at 12 Hours 
and 23 Hours Post Evening Dose at the End of 
the 2-Week Treatment Period.....................................19
7.2.2.3.
Weighted Mean 0-60 min for Percentage 
Decrease from Pre-Exercise FEV1 Following 
Exercise Challenge at 12 Hours and 23 Hours 
Post Evening Dose at the End of the 2-Week 
Treatment Period........................................................21
7.2.2.4.
Categorical Treatment Response Evaluation of 
the Percentage of Subjects who Demonstrate a
Decrease from Pre-Exercise Challenge FEV1 in 
3 Categories...............................................................21
7.2.2.5.
Maximal Percent Decrease from Treatment 
Period Baseline FEV1 Following Exercise 
Challenge at 12 Hours and 23 Hours Post 
Evening Dose at the End of the 2-Week 
Treatment Period........................................................23
7.2.2.6.
ACQ-5 Score at the End of the 2-Week 
Treatment Period........................................................23
7.2.2.7.
Change in Physical Activity Measures as 
Assessed by a Biosensor ...........................................24
7.3.
Supplementary Information for Efficacy Tables, Listings and Figures .........24
8.
SAFETY ANALYSES .............................................................................................25
8.1.
Safety Analyses..........................................................................................25
8.1.1.
Overview of Planned Safety Analyses .........................................25
8.2.
Supplementary Information for Safety Tables and Listings .........................26
8.2.1.
Adverse Events............................................................................26
8.2.1.1.
Adverse Events of Special Interest.............................26
9.
REFERENCES.......................................................................................................27
10. APPENDICES........................................................................................................28
10.1.
Appendix 1: Definitions for Per Protocol Population....................................29
10.1.1.
Protocol Deviations Impacting the Per Protocol Population..........29
10.2.
Appendix 2: Time & Events.........................................................................31
10.2.1.
Protocol Defined Time & Events ..................................................31
10.3.
Appendix 3: Assessment Windows .............................................................34
10.4.
Appendix 4: Treatment States.....................................................................35
10.4.1.
Treatment States .........................................................................35
10.4.1.1.
Treatment States for Concomitant Medications ..........35
10.4.1.2.
Treatment States for Adverse Events and 
Severe Asthma Exacerbations ...................................35
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................37
10.5.1.
Study Treatment & Sub-group Display Descriptors......................37
10.5.2.
Baseline Definition & Derivations .................................................37
10.5.2.1.
Baseline Definitions....................................................37
10.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................37
10.5.3.
Reporting Process & Standards...................................................38
10.6.
Appendix 6: Derived and Transformed Data ...............................................41
10.6.1.
General........................................................................................41


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10.6.2.
Study Population..........................................................................41
10.6.3.
Efficacy........................................................................................44
10.6.4.
Safety ..........................................................................................47
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............48
10.7.1.
Premature Withdrawals................................................................48
10.7.2.
Handling of Missing Data.............................................................48
10.7.2.1.
Handling of Missing/Partial Dates...............................49
10.8.
Appendix 8: Multicenter Studies..................................................................50
10.8.1.
Definition of Country ....................................................................50
10.9.
Appendix 9: Examination of Covariates, Subgroups & Other Strata............51
10.9.1.
Covariates ...................................................................................51
10.9.2.
Subgroups ...................................................................................51
10.10. Appendix 10: Multiple Comparisons & Multiplicity .......................................52
10.10.1. Handling of Multiple Comparisons & Multiplicity...........................52
10.11. Appendix 11: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................54
10.11.1. Model Checking...........................................................................54
10.12. Appendix 12: Abbreviations & Trade Marks ................................................55
10.12.1. Abbreviations...............................................................................55
10.12.2. Trademarks .................................................................................56
10.13. Appendix 13: List of Data Displays..............................................................57
10.13.1. Data Display Numbering..............................................................57
10.13.2. Study Population Tables..............................................................58
10.13.3. Efficacy Tables ............................................................................60
10.13.4. Efficacy Figures ...........................................................................62
10.13.5. Safety Tables...............................................................................63
10.13.6. ICH Listings .................................................................................65
10.13.7. Non-ICH Listings..........................................................................66
10.14. Appendix 14: Example Mock Shells for Data Displays ................................67


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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

This RAP details all of the planned analyses and output required for the final 
Clinical Study Report for study 201832.
Protocol

This RAP is based on the third amendment of the protocol (Dated: 25-May-
2016) of study 201832 [GlaxoSmithKline Document Number 2015N231308_03].
Primary 
Objective

To evaluate the protective effect of fluticasone furoate/vilanterol (FF/VI) 100/25 
mcg once-daily compared with fluticasone propionate (FP) 250 mcg twice-daily 
against exercise-induced bronchoconstriction in adolescent and adult subjects 
aged 12 to 50 with persistent asthma.
Primary 
Endpoint

Maximal percent decrease from pre-exercise FEV1 following exercise challenge 
at12 hours post evening dose at the end of the 2-week treatment period
Study 
Design

This is a multicenter, randomized, double-blind, double-dummy, crossover 
study with two 2-week treatment periods separated by a 2-week wash-out 
period. Subjects will participate in up to eight study visits (Visit 0 to Visit 7) over 
the course of the study and a follow up phone call approximately a week after 
Visit 7. Visits 1, 2, 3, 5 and 6 are evening visits that will be conducted between 
5PM and 11PM. Visit 4 and Visit 7 are also evening visits that will begin 
between 5PM and 11PM and continue over a period of approximately 24 hours. 
Subjects will be required to attend three clinic visits during this 24-hour period.
Planned 
Analyses

No interim analysis is planned for this study.

All planned analyses will be carried out once the clinical study database freeze 
(DBF) has taken place. Once this has been achieved, unblinding will occur and 
the analyses will be performed.
Primary 
Analysis 
Populations

The ITT Population will comprise all subjects randomized to treatment and who 
received at least one dose of trial medication. Randomized subjects will be 
assumed to have received trial medication unless definitive evidence to the 
contrary exists. This will constitute the primary population for all analyses of 
efficacy measures and safety measures. Outcomes will be reported according 
to the randomized treatment allocation.

The PP Population will consist of all subjects in the ITT Population who do not 
have any full protocol deviations and have at least one treatment period without 
a partial deviation. Protocol deviations can either be full or partial. Subjects with 
only partial deviations in 1 treatment period will be considered part of the PP 
population but their data from the treatment period affected by the deviations
will be excluded. The decision to exclude a subject, or part of their data, from 
the PP Population will be made prior to breaking the blind. This population will 
be used for confirmatory analyses of the primary efficacy endpoint only.


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Overview
Key Elements of the RAP
Hypothesis

Demonstration of efficacy will be based on a hypothesis testing approach, 
whereby the null hypothesis is that there is no difference between treatment 
groups for the endpoint of interest and the alternative hypothesis is that there is 
a difference between treatment groups
Primary 
Analyses

The primary efficacy endpoint will be analysed using a mixed model repeated 
measures (MMRM) model allowing for fixed covariate effects of treatment, 
period baseline FEV1, the mean of the two period baseline FEV1 values, sex, 
age, treatment period and smoking history (number of pack years) as fixed 
effects, and a random intercept for each subject. The covariate-adjusted means 
for the primary endpoint for each treatment group will be presented together 
with the estimated difference between the treatment groups, a 95% confidence 
interval and a 2-sided p-value allowing the null hypothesis to be tested.


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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 planned statistical analysis specified in the 
third amendment of the protocol (Dated: 25-MAY-2016) of study 201832
[GlaxoSmithKline Document Number 2015N231308_03].
2.2.
Study Objective and Endpoints
2.2.1.
Primary Objective
To evaluate the protective effect of fluticasone furoate/vilanterol (FF/VI) 100/25 mcg 
once-daily compared with fluticasone propionate (FP) 250 mcg twice-daily against 
exercise-induced bronchoconstriction in adolescent and adult subjects aged 12 to 50 with 
persistent asthma.
2.2.2.
Primary Efficacy Endpoint

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 12 
hours post evening dose at the end of the 2-week treatment period
2.2.3.
Secondary Efficacy Endpoint

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 
23 hours post evening dose at the end of the 2-week treatment period

Proportion of subjects with a 30 minute post-challenge FEV1 that was no more than 
5% lower than their pre-exercise FEV1 following the exercise challenge at 12 hours 
and 23 hours post evening dose at the end of the 2-week treatment period

Weighted mean for percentage decrease from pre-exercise FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose (weighted mean 0-60 min) at 
the end of the 2-week treatment period
2.2.4.
Other Efficacy Endpoints

Categorical treatment response evaluation of the percentage of subjects who 
demonstrate a decrease from pre-exercise challenge FEV1 (at 12 hours and 23 hours 
post evening dose at the end of the 2-week treatment period) of:
o
<10%,
o
≥10% to <20%,
o
≥20%

Maximal percent decrease from treatment period baseline FEV1 following exercise 
challenge at 12 hours and 23 hours post evening dose at the end of the 2-week 
treatment period

Change from baseline in Asthma Control Questionnaire -5 (ACQ-5) score at the end 
of the 2-week treatment period


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
Percentage of subjects controlled, defined as an ACQ-5 score ≤0.75, at the end of the 
2-week treatment period

Percentage of subjects achieving an improvement of ≥0.5 in ACQ-5 score at the end 
of the 2-week treatment

Change in physical activity measures as assessed by a biosensor (SenseWear 
Armband) in terms of physical activity endpoints (e.g. daily step count, Metabolic 
Equivalent of Tasks (METs), sleep duration)

Proportion of subjects with a 5 minute post-challenge FEV1 that was no more than 
5% lower than their pre-exercise FEV1 following the exercise challenge at 12 hours 
and 23 hours post evening dose at the end of the 2-week treatment period. Repeat for 
the 10, 15, 45 and 60 minute time points.
2.2.5.
Safety Endpoints

Adverse events


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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

This is a multicenter, randomized, double-blind, double-dummy, crossover 
study with two 2-week treatment periods separated by a 2-week wash-out 
period. Visits 1, 2, 3, 5 and 6 are evening visits that will be conducted between 
5PM and 11PM. Visit 4 and Visit 7 are also evening visits that will begin 
between 5PM and 11PM and continue over a period of approximately 24 
hours. Subjects will be required to attend three clinic visits during this 24-hour 
period. 

Subjects will complete a 4-week single blind run-in on FP 250 mcg twice daily, 
followed by 2-week double-blind Treatment Period 1 on randomized treatment, 
a 2-week single blind washout period on FP 250 mcg twice daily, 2-week 
double-blind Treatment Period 2 receiving the alternative treatment, and follow-
up contact approximately 7-days after completing Treatment Period 2. 

The total duration of study participation is approximately 11 weeks; and up to 
15 weeks for subjects with symptomatic allergic rhinitis at screening who may 
need to have a repeat screening visit performed.

Subjects with symptomatic allergic rhinitis at Visit 1 (screening) may be treated 
for up to four weeks with intranasal corticosteroids followed by a repeat 
screening visit to determine eligibility prior to entry into the study. Eligible 
subjects will enter the run-in period

At Visit 2 subjects will complete an exercise challenge. To be eligible for 
randomisation subjects must demonstrate a decrease in FEV1 of ≥20% when 
compared to the FEV1 obtained immediately pre-exercise for at least one of the 
post-exercise spirometry efforts obtained within 30 minutes post-challenge. 
Subjects who achieve a decrease in FEV1 of 15% to <20% may continue taking 
their daily run-in medication and repeat the eligibility exercise challenge once 
within a week. 


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Overview of Study Design and Key Features

Exercise challenges will be performed at Visits 2, 3, 4, 6 and 7.  Serial 
spirometry will be conducted at 5, 10, 15, 30, 45 and 60 mins after each 
exercise challenge. For Visits 3 and 6, the exercise challenge will be performed 
at 23 hours after evening dosing (first dose of each treatment period). For 
Visits 4 and 7, the exercise challenges will be performed at 12 and 23 hours 
after evening dosing.

In addition all subjects will be supplied with albuterol/salbutamol to use as 
needed throughout the study.

Only subjects completing both treatment periods and follow-up period will be 
considered to have completed the study.

Further details of the study design can be found in Section 5 (Study Design) of 
the 201832 protocol [GlaxoSmithKline Document Number 2015N231308_03].
Treatment 
Assignment

Subjects will be randomized in a 1:1 ratio to one of the 2 following treatment 
sequences:
o
FF/VI 100/25 OD followed by FP 250 BD 
o
FP 250 BD followed by FF/VI 100/25 OD

GSK RandAll NG will be used to generate the randomization schedule.

Centralized randomization will be used.

GSK RAMOS NG will be used for treatment allocation.
Interim 
Analysis

No interim analysis is planned for this study.
2.4.
Statistical Hypotheses
The primary endpoint is the maximal percent decrease in FEV1 following exercise 
challenge at 12-hours post-dose at the end of the 2-week treatment period. The primary 
treatment comparison is FF/VI 100/25 versus FP 250. Demonstration of efficacy will be 
based on a hypothesis testing approach, whereby the null hypothesis is that there is no 
difference between treatment groups for the endpoint of interest and the alternative 
hypothesis is that there is a difference between treatment groups. Specifically the null and 
alternative hypotheses for this comparison are:
H0: FF/VI = FP
H1: FF/VI ≠ FP
where FF/VI and FP represent the population mean maximal percent decrease in FEV1
following exercise challenge at 12-hours post-dose at the end of the 2-week treatment 
period for FF/VI and FP respectively.
2.5.
Sample Size Assumptions
A total of approximately 275 subjects will be screened in order to achieve 66 randomized 
subjects. Allowing for a 15% withdrawal rate, this will give 56 evaluable subjects who 
complete the exercise challenges and the FEV1 evaluations at the end of both treatment 
periods.


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The sample size calculations are based on the primary efficacy endpoint of maximal 
percent decrease in FEV1 following exercise challenge at 12 hours post-dose at the end of 
the 2-week treatment period. 
With 56 evaluable subjects this study has approximately 90% power assuming a true 
population difference of 5% in maximal percent decrease in FEV1 between the two 
treatment group means. This assumes a within-subject standard deviation (SD) of 8% 
where significance is declared at the two-sided 5% significance level.
A blinded sample size re-estimation will be conducted when approximately 50% of the 
subjects have completed their second exercise challenge. In order to assess the accuracy 
of the sample size assumption for the within-subject SD, the primary analysis will be run 
on this blinded interim data, but with a dummy variable to denote treatment group 
membership. If this suggests the original assumptions behind the sample size were 
incorrect, an adjustment may be made to the planned number of subjects to be recruited.
2.6.
Treatment Comparisons
2.6.1.
Primary Comparisons of Interest
The primary treatment comparison will be FF/VI 100/25 OD versus FP 250 BD for the 
primary efficacy endpoint of maximal percent decrease in FEV1 following exercise 
challenge at 12 hours post-dose at the end of the 2-week treatment period..
2.6.2.
Other Comparisons of Interest
FF/VI 100/25 OD will also be compared to FP 250 BD for the secondary and other 
efficacy endpoints.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned for this study.
3.2.
Final Analyses
All planned analyses will be carried out once the clinical study database freeze (DBF) has 
taken place. Once this has been achieved, unblinding will occur and the analyses will be 
performed.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Total

This population will comprise all subjects 
screened and for whom a record exists on the 
study database

The tabulations of 
reasons for withdrawal 
before randomization.
Intent-To-Treat
(ITT)

This population will comprise all subjects 
randomized to treatment and who received at 
least one dose of study medication. 

Randomized subjects will be assumed to have 
received study medication unless definitive 
evidence to the contrary exists. 

Outcomes will be reported according to the 
randomized treatment allocation.

Study population, 
efficacy and safety 
displays

This will constitute the 
primary population for 
all analyses of efficacy 
measures and safety 
measures.
Per-Protocol
(PP)

The PP Population will consist of all subjects in 
the ITT Population who do not have any full 
protocol deviations and have at least one 
treatment period without a partial deviation. 

Protocol deviations can be either full or partial. 
Subjects with only partial deviations in 1 
treatment period will be considered part of the 
PP population but their data from the treatment 
period affected by the deviations will be 
excluded.

Protocol deviations that would exclude 
subjects or part of their data from the PP 
population are defined in Appendix 1
(Definitions for Per-Protocol Population).

This population will be 
used for confirmatory 
analysis of the primary 
efficacy endpoint only.
ITT (12-17 
Years Old)

This will be a subset of the ITT population for 
subjects aged 12-17 years old.

This population will be 
used for adolescent 
displays.
ITT (15 Years 
or Older)

This will be a subset of the ITT population for 
subjects aged 15 years or older.

This population will be 
used for displays on 
the subset of subjects 
aged 15 years or 
older.
NOTES : 

Please refer to Appendix 13: List of Data Displays, which details the population to be used for each display being 
generated.


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4.1.
Protocol Deviations

Important protocol deviations recorded in the eCRF (including deviations related to 
study inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Protocol deviations impacting the Per Protocol population will also be summarised
and listed. (Please refer to Appendix 1: Definitions for Per Protocol Population).

Apart from any incorrect treatment deviations, all protocol deviations impacting the 
Per Protocol population (full and partial) will be agreed upon prior to unblinding the 
study. 

A separate summary and listing of inclusion/exclusion criteria deviations based on 
the data recorded on the inclusion/exclusion page of the eCRF will also be provided.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
10.1
Appendix 1: Definitions for Per Protocol Population
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Treatment States
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
10.8
Appendix 8: Multicenter Studies
10.9
Appendix 9: Examination of Covariates, Subgroups & Other Strata
10.10
Appendix 10: Multiple Comparisons & Multiplicity
10.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses.


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the Intent-To-Treat population, unless 
otherwise specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 13: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Populations
Y[1]
Screen Failures
Y[1]
Run-in Failures
Y[1]
Study Completion/Withdrawal
Y
Y
Treatment Completion/Withdrawal
Y
Clinic Visit Attendance
Y
Number of Subjects by Centre
Y[4]
Randomized and Actual Treatments
Y
Incorrect Medication
Y
Protocol Deviations
Inclusion/Exclusion Criteria Deviations Recorded in the 
eCRF
Y
Y
Subjects for Whom Treatment Blind was Broken
Y
Important Protocol Deviations Recorded in the eCRF
Y
Y
Protocol Deviations Impacting the Per Protocol Population
Y
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y[2]
Y
Race and Racial Combinations
Y
Race and Racial Combination Details
Y
Y
History of Tobacco Use at Screening
Y
Y
Duration of Asthma and Exacerbation History
Y[3]
Y
Current Medical Conditions
Y
Y
Past Medical Conditions
Y
Y
Family History of CV Risk Factors
Y
Y
Screening and Study Baseline Lung Function 
Y[3]
Y
Study Baseline Serial FEV1
Y
Y
Maximal Percent Decrease from Pre-Exercise FEV1 at 
Study Baseline
Y[5]
Study Baseline Lung Function by Completion Status
Y
Exposure and Treatment Compliance
Exposure
Y
Y
Treatment Compliance
Y
Y


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Display Type
Data Displays Generated
Table
Figure
Listing
Concomitant Medications
Pre-Treatment Asthma Concomitant Medications
Y
Y
During Treatment Asthma Concomitant Medications
Y
Y
Post Treatment Asthma Concomitant Medications
Y
Y
Pre-Treatment Non-Asthma Concomitant Medications
Y
Y
During Treatment Non-Asthma Concomitant Medications
Y
Y
Post Treatment Non-Asthma Concomitant Medications
Y
Y
Relationship Between ATC Level 1, Ingredient and 
Verbatim Text
Y
NOTES :

Y = Yes display generated.

[1]: Display will be based on Total population

[2]: Display will be based on the ITT population and repeated for the Per Protocol, Total, ITT (12-17 Years Old) 
and ITT (15 Years or Older) populations

[3]: Display will be based on the ITT population and repeated for both the ITT (12-17 Years Old) population and 
the ITT (15 Years or Older) population

[4]: Display will be based on the ITT population and repeated for Total population

[5]: Display will be based on the ITT population and repeated for the ITT (15 Years or Older) population
6.2.
Supplementary Information for Study Population Tables and 
Listings
6.2.1.
Concomitant Medications
Concomitant medications will be coded using the GSK Drug coding dictionary. A 
summary of the number and percentage of subjects with concomitant medications will be 
displayed by ingredient without regard to ATC classifications. This summary will present 
multi-ingredient medications according to the combination of the component ingredients, 
and will also include single-ingredient medications. Summaries will be split into asthma 
and non-asthma concomitant medications, as well as into those taken pre-, during, and 
post-treatment.


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7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Overview of Planned Primary Efficacy Analyses
The primary efficacy endpoint is the maximal percent decrease from pre-exercise FEV1
following exercise challenge at12 hours post evening dose at the end of the 2-week 
treatment period.
Table 3 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 3
Overview of Planned Primary Efficacy Analyses
Stats Analysis
Summary
Individual
T
F
T
F
L
Primary Analysis
Max % Decrease - ITT
Y
Y
Y
Sensitivity Analysis
Max % Decrease - PP
Y
Y
Y
Max % Decrease - ITT (15 Years or Older)
Y
Y
Supporting Analyses and Other Summaries
Max % Decrease - ITT (12-17 Years Old)
Y
Max (L) Decrease  - ITT
Y
Y
Y
Max (L) Decrease  - ITT (15 Years or Older)
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 Primary Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 12 hours 
post evening dose at the end of the 2-week treatment period
Populations

This analysis will be performed on both the Intent-to-Treat (ITT) and the Per Protocol (PP) 
populations.
Model Specification
The mixed model repeated measures (MMRM) model will include the following covariates (with 
example variable names): treatment (ptrtcd), sex (sex), age (age), treatment period (pernum), 
smoking history (supkyr: number of pack years), period baseline FEV1 (pbli) and the mean of the 
two period baseline FEV1 values (mpbli) as fixed effects, and a random intercept for each subject 
(subjid). A SAS procedure of the following structure will be used:
proc mixed data=start cl nobound ;    
    class subjid ptrtcd sex pernum ;
    model maxd = ptrtcd pernum pbli mpbli age sex supkyr 
                  / solution ddfm=kr ;
    random int / subject=subjid type=simple ;
    repeated pernum / subject=subjid type=simple ;
    lsmeans ptrtcd / diff cl e om=OMdset 
                     at (age mpbli)=(&agem. &mpblim.) ;
    
    ods output lsmeans=lsmeans ;
   ods output diffs=diffs ;
run ; 
Where OMdset is a dataset with a row for every period-subject combination that contains all of the 
covariates and mpblim and agem are macro variables containing the means for mpbli and age for 
the subjects used in the analysis. These are used to derive the adjusted means using coefficients 
which are based on the subjects used in the analysis.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The adjusted means for each treatment and the estimated treatment difference for the 
treatment comparison will be presented together with a 95% confidence interval for the 
difference and a p-value. The adjusted treatment difference and 95% confidence interval will 
be plotted.
Sensitivity and Supportive Statistical Analyses
Maximal Decrease (L) from Pre-Exercise FEV1 Analysis
This supporting analysis will be analysed using a model of the same structure as described for the 
primary analysis.


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7.2.
Secondary and Other Efficacy Analyses
7.2.1.
Overview of Planned Secondary and Other Efficacy Analyses
The secondary and other efficacy analyses will be based on the Intent-To-Treat
population, unless otherwise specified.
Table 4 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 13: List of Data Displays.
Table 4
Overview of Planned Secondary and Other Efficacy Analyses
Stats Analysis
Summary
Individual
T
F
T
F
L
Max % Decrease from Pre-Exercise FEV1 Following 23 Hr Challenge
Max % Decrease
Y[3]
Y[3]
Y[1]
Max (L) Decrease  
Y[3]
Y[3]
Y
Proportion of Subjects with a 5/10/15/30/45/60 min Post-Challenge FEV1 no More Than 5% Lower 
Than Pre-Exercise FEV1 Following Exercise Challenge
Proportion of Subjects
Y[3]
Y[3]
Y[2]
Weighted Mean 0-60 min for % Decrease from Pre-Exercise FEV1 Following Exercise Challenge
Weighted Mean 0-60 min
Y[3]
Y[3]
Y[1]
Percentage of Subjects With a Decrease from Pre-Exercise Challenge FEV1 in 3 Categories
Percentage of Subjects
Y
Y
Maximal % Decrease from Treatment Period Baseline FEV1 Following Exercise Challenge
Max % Decrease
Y
Y
Y
Max (L) Decrease  
Y
Y
Y
Change in Individual Serial Measurements (L)
Y[3]
Y[3]
Y
ACQ-5 Score
Change from period baseline in ACQ-5 score
Y
Y
Y
%  of subjects controlled (ACQ-5 score ≤0.75)
Y
Y
%  of subjects with an improvement of ≥0.5
Y
Y
Change in Physical Activity Measures as Assessed by a Biosensor
Step Count
Y
METs
Y
Sleep Duration
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.

[1]: Display will be based on the ITT population and repeated for the ITT (12-17 Years Old) population

[2]: Display will be based the ITT (12-17 Years Old) population

[3]: Display will be based on the ITT population and repeated for the ITT (15 Years or Older) population


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7.2.2.
Planned Secondary and Other Efficacy Statistical Analyses
7.2.2.1.
Maximal Percent Decrease from Pre-Exercise FEV1 Following Exercise 
Challenge at 23 Hours Post Evening Dose at the End of the 2-Week 
Treatment Period
Statistical Analyses
Endpoint(s)

Maximal percent decrease from pre-exercise FEV1 following exercise challenge at 23 hours 
post evening dose at the end of the 2-week treatment period
Populations

This analysis will be performed on the Intent-to-Treat (ITT) populations
Model Specification
This endpoint will be analysed using a model of the same structure as described for the primary 
endpoint in Section 7.1.2.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The adjusted means for each treatment and the estimated treatment difference for the 
treatment comparison will be presented together with a 95% confidence interval for the 
difference and a p-value. The adjusted treatment difference and 95% confidence interval will 
be plotted.

The analysis will also be performed for the maximal percent decrease from pre-exercise FEV1
following exercise challenge at 23 hours post evening dose on day 1 of the treatment period. 
7.2.2.2.
Proportion of Subjects with a 5/10/15/30/45/60 Minute Post-Challenge 
FEV1 that was no More Than 5% Lower Than Their Pre-exercise FEV1
Following the Exercise Challenge at 12 Hours and 23 Hours Post 
Evening Dose at the End of the 2-Week Treatment Period
Statistical Analyses
Endpoint(s)

Proportion of subjects with a 30 minute post-challenge FEV1 that was no more than 5% lower 
than their pre-exercise FEV1 following the exercise challenge at 12 hours and 23 hours post 
evening dose at the end of the 2-week treatment period

Proportion of subjects with a 5 minute post-challenge FEV1 that was no more than 5% lower 
than their pre-exercise FEV1 following the exercise challenge at 12 hours and 23 hours post 
evening dose at the end of the 2-week treatment period. Repeat for the 10, 15, 45 and 60 
minute time points.
Populations

These analyses will be performed on the Intent-to-Treat (ITT) populations
Model Specification
The repeated measures logistic regression model will include the following covariates (with 
example variable names): treatment (ptrtcd), period baseline FEV1 (pbli), sex (sex), age (age), 
treatment period (pernum) and smoking history (supkyr: number of pack years) as fixed effects. A 
SAS procedure of the following structure will be used:


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Statistical Analyses
proc genmod data=start descending ;
    class ptrtcd sex pernum subjid / param=ref ;
    model binv = ptrtcd pernum pbli age sex supkyr / dist=bin ;
    repeated subject=subjid / type=unstr corrw;
    estimate "logit FF/VI Vs FP" ptrtcd 1 / exp ;
    ods output Estimates=GEE_or_est ;
run ;
Where binv is the binary variable that takes the value 1 if at the given post-challenge time point a 
subject has an FEV1 measurement that is >= 95% of their pre-exercise FEV1 measurement and 0 
otherwise. 
The above code specifies a repeated measures logistic regression model where parameters are 
estimated using the Generalized Estimating Equation (GEE) method. GEE uses a “working” 
covariance matrix to model the within-subject dependences during estimation but calculates 
parameter estimator standard errors using an empirical estimate of the within-subject covariance 
matrix. 
The “estimate” statement estimates the odds ratio of FF/VI compared to FP with 95% confidence 
limits which are displayed in the SAS output in the “L’Beta Estimate” and “L’Beta Confidence 
Limits” columns using the “Exp(logit FF/VI Vs FP)” row - these can be found in the “GEE_or_est” 
dataset produced by the “ods output” statement in the “LBetaEstimate” and “LBetaLowerCL/ 
LBetaupperCL” columns using the entry in row 2. Note that the quantity displayed in the SAS 
output in the “Mean Estimate” column is the inverse logit of the FF/VI estimate which is not equal to 
the odds ratio of FF/VI relative to FP.  
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The estimated treatment difference will be displayed as an odds ratio together with the 95% CI 
and p-value for the treatment comparison along with the number and percentage of subjects in 
each category. The adjusted treatment ratio and 95% confidence interval will be plotted.

The analysis will also be performed for the proportion of subjects with a post-challenge FEV1
that was no more than 5% lower than their pre-exercise FEV1 following the exercise challenge 
at 23 hours post evening dose on day 1 of the treatment period.


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7.2.2.3.
Weighted Mean 0-60 min for Percentage Decrease from Pre-Exercise 
FEV1 Following Exercise Challenge at 12 Hours and 23 Hours Post 
Evening Dose at the End of the 2-Week Treatment Period
Statistical Analyses
Endpoint(s)

Weighted mean 0-60 min for percentage decrease from pre-exercise FEV1 following exercise 
challenge at 12 hours and 23 hours  post evening dose at the end of the 2-week treatment 
period
Populations

These analyses will be performed on the Intent-to-Treat (ITT) populations
Model Specification
This endpoint will be analysed using a model of the same structure as described for the primary 
endpoint in Section 7.1.2.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The adjusted means for each treatment and the estimated treatment difference for the 
treatment comparison will be presented together with a 95% confidence interval for the 
difference and a p-value. The adjusted treatment difference and 95% confidence interval will 
be plotted.

The analysis will also be performed for the weighted mean 0-60 min for percentage decrease 
from pre-exercise FEV1 following exercise challenge at 23 hours post evening dose on day 1 of 
the treatment period.
7.2.2.4.
Categorical Treatment Response Evaluation of the Percentage of 
Subjects who Demonstrate a Decrease from Pre-Exercise Challenge 
FEV1 in 3 Categories
Statistical Analyses
Endpoint(s)

Categorical treatment response evaluation of the percentage of subjects who demonstrate a 
decrease from pre-exercise challenge FEV1 (at 12 hours and 23 hours post evening dose at 
the end of the 2-week treatment period) of:
o
<10%, 
o
≥10% to <20%, 
o
≥20%
Populations

These analyses will be performed on the Intent-to-Treat (ITT) populations
Model Specification
The repeated measures ordinal multinomial regression model will include the following covariates 
(with example variable names): treatment (ptrtcd), period baseline FEV1 (pbli), sex (sex), age 
(age), treatment period (pernum) and smoking history (supkyr: number of pack years) as fixed 
effects. A SAS procedure of the following structure will be used:


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Statistical Analyses
proc genmod data=start descending ;
    class ptrtcd sex pernum subjid  / param=ref ;
    model catv = ptrtcd pernum pbli age sex supkyr 
            / dist=multinomial ;
    repeated subject=subjid / type=ind corrw ;
    estimate "logit FF/VI Vs FP" ptrtcd 1 / exp ;
    ods output Estimates=GEE_or_estm ;
run ;
Where catv is the multinomial variable that takes the value 1, 2 or 3 if a subject has a post-exercise 
minus pre-exercise FEV1 value, denoted by X, of -10<X, -20<X≤-10, or X≤-20 respectively. 
The above code specifies a repeated measures ordinal multinomial regression model where 
parameters are estimated using the Generalized Estimating Equation (GEE) method. GEE uses a 
“working” covariance matrix to model the within-subject dependences during estimation but 
calculates parameter estimator standard errors using an empirical estimate of the within-subject 
covariance matrix. The multinomial regression model assumes proportional odds, that is, the odds 
ratio of catv ≤1 for FF/VI compared to FP is the same as the odds ratio of catv ≤2 for FF/VI 
compared to FP. Thus it is assumed there is a single true odds ratio of catv being in an equal or 
lower category than j, for j=1, 2 (henceforth referred to simply as the odds ratio).
The “estimate” statement estimates the odds ratio of FF/VI compared to FP with 95% confidence 
limits which are displayed in the SAS output in the “L’Beta Estimate” and “L’Beta Confidence 
Limits” columns using the “Exp(logit FF/VI Vs FP)” row - these can be found in the “GEE_or_est” 
dataset produced by the “ods output” statement in the “LBetaEstimate” and “LBetaLowerCL/ 
LBetaupperCL” columns using the entry in row 2. Note that the quantity displayed in the SAS 
output in the “Mean Estimate” column is the inverse logit of the FF/VI estimate which is not equal to 
the odds ratio of FF/VI relative to FP.  
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The estimated treatment difference will be displayed as an odds ratio together with the 95% CI 
and p-value for the treatment comparison along with the number and percentage of subjects in 
each category. The adjusted treatment ratio and 95% confidence interval will be plotted.

The analysis will also be performed for the percentage of subjects who demonstrate a 
decrease from pre-exercise challenge FEV1 following the exercise challenge at 23 hours post 
evening dose on day 1 of the treatment period.


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7.2.2.5.
Maximal Percent Decrease from Treatment Period Baseline FEV1
Following Exercise Challenge at 12 Hours and 23 Hours Post Evening 
Dose at the End of the 2-Week Treatment Period
Statistical Analyses
Endpoint(s)

Maximal percent decrease from treatment period baseline FEV1 following exercise challenge at 
12 hours and 23 hours post evening dose at the end of the 2-week treatment period
Populations

These analyses will be performed on the Intent-to-Treat (ITT) populations
Model Specification
This endpoint will be analysed using a model of the same structure as described for the primary 
endpoint in Section 7.1.2.
An analysis of the change from period baseline in each of the individual serial FEV1 measurements 
will be performed separately (by their planned time). In each case the analysis will use a model of 
the same structure as described for the primary endpoint in Section 7.1.2.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

For the maximal percent decrease, the adjusted means for each treatment and the estimated 
treatment difference for the treatment comparison will be presented together with a 95% 
confidence interval for the difference and a p-value. The adjusted treatment difference and 
95% confidence interval will be plotted.

For the individual serial FEV1 measurements, the adjusted means for the measurements as 
well as the adjusted means for the changes from period baseline for each treatment will be 
presented. In addition the estimated treatment difference for the treatment comparison will be 
presented together with a 95% confidence interval for the difference and a p-value. The 
adjusted mean changes from period baseline will be plotted along with their 95% confidence 
intervals.

The analyses will also be performed using the data from day 1 of the treatment period.
7.2.2.6.
ACQ-5 Score at the End of the 2-Week Treatment Period
Statistical Analyses
Endpoint(s)

Change from baseline in Asthma Control Questionnaire-5 (ACQ-5) score at the end of the 2-
week treatment period

Percentage of subjects controlled, defined as an ACQ-5 score ≤0.75, at the end of the 2-week 
treatment period

Percentage of subjects achieving an improvement of ≥0.5 in ACQ-5 score at the end of the 2-
week treatment period
Populations

These analyses will be performed on the Intent-to-Treat (ITT) populations


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Statistical Analyses
Model Specification
For the change from period baseline analysis, a mixed model repeated measures (MMRM) model 
will include the following covariates (with example variable names): treatment (ptrtcd), sex (sex), 
age (age), treatment period (pernum), smoking history (supkyr: number of pack years), period 
baseline ACQ-5 score (pbli) and the mean of the two period baseline ACQ-5 scores (mpbli) as 
fixed effects, and a random intercept for each subject (subjid). A SAS procedure of a similar 
structure to that shown for the primary endpoint in Section 7.1.2 will be used.
For both of the binary endpoints, a repeated measures logistic regression model will include the 
following covariates (with example variable names): treatment (ptrtcd), sex (sex), age (age), 
treatment period (pernum), smoking history (supkyr: number of pack years), period baseline ACQ-5 
score (pbli) as fixed effects. A SAS procedure will be used that is of a similar structure to that 
shown in Section 7.2.2.2 for the secondary endpoint of the proportion of subjects with a 30 minute 
post-challenge FEV1 that was no more than 5% lower than their pre-exercise FEV1 following the 
exercise challenge at 12 hours and 23 hours post evening dose at the end of the 2-week treatment 
period.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

For the change from period baseline analysis, the adjusted means for each treatment and the 
estimated treatment difference for the treatment comparison will be presented together with a 
95% confidence interval for the difference and a p-value. The adjusted treatment difference 
and 95% confidence interval will be plotted.

For both of the binary endpoints, the estimated treatment difference will be displayed as an 
odds ratio together with the 95% CI and p-value for the treatment comparison along with the 
number and percentage of subjects in each category. The adjusted treatment ratio and 95% 
confidence interval will be plotted.
7.2.2.7.
Change in Physical Activity Measures as Assessed by a Biosensor
No statistical analysis is planned for this endpoint, but summary statistics will be 
produced for the following variables:

Daily Step Count

Daily Average Metabolic Equivalent of Tasks (METs)

Daily Sleep Duration
7.3.
Supplementary Information for Efficacy Tables, Listings and 
Figures
An overall forest plot will be produced showing the adjusted treatment differences/ratios 
and 95% confidence intervals for the primary and secondary efficacy endpoints. This will 
be produced for the ITT population and repeated for the ITT (15 Years or Older) 
population.


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8.
SAFETY ANALYSES
8.1.
Safety Analyses
8.1.1.
Overview of Planned Safety Analyses
The safety analyses will be based on the ITT population, unless otherwise specified.
Table 5 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 5
Overview of Planned Safety Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Adverse Events 
Overview
Y
AEs for Subjects not in ITT
Y[2]
Pre-Treatment AEs
Y
On-Treatment AEs
Y[3]
Y
Post-Treatment AEs
Y
Y
Most Frequent On-Treatment AEs (≥3% after rounding)
Y
Top Ten Most Common On-Treatment AEs
Y
Drug-Related AEs
Y
Drug-Related SAEs
Y
AEs Leading to Withdrawal
Y
Y
On-Treatment SAEs
Y
Y
Post-Treatment SAEs
Y
Y
Common On-Treatment Non-Serious AEs (≥3% without
rounding including event numbers and drug-related event 
numbers)
Y
On-Treatment SAEs (including event numbers and drug-
related event numbers)
Y
On-Treatment Fatal AEs (including event numbers and 
drug-related event numbers)
Y
Post-Treatment Fatal SAEs (including event numbers and 
drug-related event numbers)
Y
AEs of Special Interest
Y[1]
SAEs of Special Interest
Y
Relationship of AE System Organ Class, Preferred Term 
and Verbatim Text
Y
Record of all Preferred Term’s That Could Have Mapped to 
Special Interest Terms
Y
Pneumonia
On-Treatment Pneumonia
Y
Y
Post-Treatment Pneumonia
Y
Y
Chest X-ray
Y
Severe Asthma Exacerbations
Severe Asthma Exacerbations
Y[3]
Y


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Display Type
Data Displays Generated
Table
Figure
Listing
Other
Vital Signs
Y
Y
Change from Baseline in Vital Signs
Y
Family History of CV Risk Factors
Y
Y
IP Inhaler Malfunctions
Y
NOTES :

Y = Yes display generated.

[1]: Display will be based on the ITT population and repeated for the ITT (12-17 Years Old) population 

[2]: Display will be based on the inverse of the ITT population i.e. all subjects not in the ITT population

[3]: Display will be based on the ITT population and repeated for the ITT (12-17 Years Old) population and also for 
the ITT (15 Years or Older) population
8.2.
Supplementary Information for Safety Tables and Listings
8.2.1.
Adverse Events
The version of MedDRA used to report the study will be noted in a footnote of the AE 
overview table.
For the main on-treatment and post-treatment AE tables, the number and percentage of 
subjects with all adverse events (regardless of causality) will be summarized for each 
treatment by system organ class (SOC) and preferred term (PT). The ordering of the 
SOCs and the PTs within the SOCs will both be in descending order of total incidence. A 
SOC will not be presented when the overall incidence for any adverse event within the 
particular system is 0. If the total incidence for any two or more adverse events is equal, 
the events will be presented in alphabetical order. 
8.2.1.1.
Adverse Events of Special Interest
The number and percentage of subjects with adverse events of special interest to FF 
and/or VI will be summarized for each treatment by special interest term, subgroup and 
preferred term (PT). The ordering of the special interest terms, the subgroups and the PTs 
within them will all be in descending order of total incidence. If the total incidence for 
any two or more adverse events is equal, the events will be presented in alphabetical 
order. This summary will include both on-treatment and post-treatment AEs.


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9.
REFERENCES
GlaxoSmithKline Document Number 2015N231308_03. Study 201832: A Randomised, 
Double-Blind, Double-Dummy, Crossover Comparison of Fluticasone Furoate/Vilanterol 
100/25mcg Once Daily Versus Fluticasone Propionate 250 mcg Twice Daily in 
Adolescent and Adult Subjects with Asthma and Exercise-Induced Bronchoconstriction. 
Effective date: 25-MAY-2016.
Kenward MG, Roger, JH. Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood. Biometrics. 1997;53:983-997.


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10.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Definitions for Per Protocol Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time and Events
Section 10.3
Appendix 3: Assessment Windows
Section 10.4
Appendix 4: Treatment States
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.6
Appendix 6: Derived and Transformed Data

General, Study Population & Safety

Efficacy
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.8
Appendix 8: Multicentre Studies
Section 10.9
Appendix 9: Examination of Covariates and Subgroups
Section 10.10
Appendix 10: Multiple Comparisons and Multiplicity
Section 10.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.12
Appendix 12: Abbreviations & Trade Marks
Section 10.13
Appendix 13: List of Data Displays
Section 10.14
Appendix 14: Example Mock Shells for Data Displays


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10.1.
Appendix 1: Definitions for Per Protocol Population
10.1.1.
Protocol Deviations Impacting the Per Protocol Population
A protocol deviation which could affect all treatment periods will be considered a full 
deviation and will result in exclusion from the Per Protocol population. A protocol 
deviation which would only affect a specific treatment period will be considered a partial 
deviation and the data from the treatment period affected by the deviation will be 
excluded. If a subject has partial deviations in both treatment periods then the subject will 
be excluded from the Per Protocol population, however if a subject only has partial 
deviations in 1 treatment period, they will be considered part of the PP population but 
their data from the treatment period affected by the deviations will be excluded.
Reasons for protocol deviations that will impact the Per Protocol population include the 
following:
Number
Exclusion Description
Full or Partial?
1
Failure of inclusion criteria 3, 4, 5, 6 or 9; exclusion criteria 1, 3, 4, 
7, 8, 9, 12, 13 or 15; randomization inclusion criteria 1 or 2 or 
randomization exclusion criteria 2, 4 or 5 as described in Section 6 
of the protocol [GlaxoSmithKline Document Number 
2015N231308_03].
Full
2
Remaining in the study after meeting the following withdrawal 
criteria described in Section 6 of the protocol [GlaxoSmithKline
Document Number 2015N231308_03]:

Severe asthma exacerbation
Full if during 1st
treatment 
period. 
Otherwise 
partial.
3
Taking of prohibited medication as described in Section 7.10.2 of 
the protocol [GlaxoSmithKline Document Number 
2015N231308_03], where that medication could conceivably have 
an effect on a subject’s efficacy.
Full if it affects 
both periods. 
Otherwise 
partial.
4
Overall treatment compliance for either DISKUS or ELLIPTA of < 
80% or > 120%.  (The protocol required subjects to take their study 
medication each day. For reporting and analysis purposes, 
treatment compliance of 80% and 120% are defined here as lower 
and upper limits for subjects to remain in the Per Protocol 
population.) Only treatment periods affected will be excluded.
Partial
5
Taking the wrong treatment at any time during the study. Only 
treatment periods affected will be excluded.
Partial
6
The 12 hour exercise challenge on day 14 of a treatment period
(Visit 4/7) occurring on day 11 or earlier of the treatment period i.e. 
11 days or less after day 0 of the treatment period (Visit 2/5).
Partial
7
The pre-exercise FEV1 prior to the 12 hour challenge on day 14 of 
a treatment period (Visit 4/7) occurring <11 hours or >13 hours after 
the previous dose of study medication.
Partial


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Apart from any incorrect treatment deviations, all full and partial protocol deviations will 
be agreed upon prior to unblinding the study. 
In addition to the subject level protocol deviations mentioned above, a given FEV1
measurement must not be within 6 hours after the last use of rescue medication to be 
included in the Per Protocol analysis of the primary endpoint. Any FEV1 measurement
that was taken within 6 hours after the last use of rescue medication will be considered 
missing in the Per Protocol analysis of the primary endpoint.
Any FEV1 measurements that are labelled as ‘Unacceptable’ will be considered missing 
for both the Intent-to-Treat and the Per Protocol populations.


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10.2.
Appendix 2: Time & Events
10.2.1.
Protocol Defined Time & Events
Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412, 14
512
6
712, 14
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
0
118
14 (-2/+2) 
days
28 (-2/+2) 
days
2918
42 (-2/+2) 
days
47 to 
51 
days
Written Informed Consent
X
Genetics Consent
X1
Subject Demography
X
Medical History (including CV)
X
Disease (Asthma) History 
X
Medication History
X
X
Smoking history/status
X
Inclusion/Exclusion Criteria
X
Evidence of EIB
X
Efficacy Assessments
Spirometry (full FEV1 and FVC)
X
X2
X2
X2
X
X2
X2
X
Exercise Challenge Testing 
(Treadmill)
X3, 17
X4
X5
X4
X5
Post-Challenge Serial FEV1 
Measurements
X3
X6
X6
X6
X6
Asthma Control Questionnaire-5
X
X
X
X
X
Dispense SenseWear15
accelerometer
X
Collect SenseWear accelerometer
X
X
Safety Assessments


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Procedures
Pre-Screen
Screen/
Run-in
Treatment Period 1 
Treatment Period 2
Early
Withdrawal
Visit
Follow-
up
Phone 
Call
Visit/Contact
0
1
212
Randomization
3
412, 14
512
6
712, 14
Week
-4
0
0
2
4
4
6
7
Treatment Day
-26 to -30 
days
0
118
14 (-2/+2) 
days
28 (-2/+2) 
days
2918
42 (-2/+2) 
days
47 to 
51 
days
Concomitant Medication
X
X
X
X
X
X
X
X
X
X7
Physical Examination
X
Vital Signs
X
X8
X8
X8
X
X8
X8
X
12-lead ECG 
X
Adverse Event Assessment
X9
X9
X
X
X
X
X
X
X
X
Issue Medical Conditions Diary 
Card
X
X
X
X
Review Medical Conditions Diary 
Card
X10
X
X10
X10
X
X10
X
Laboratory Assessments
Genetics Saliva Sample
X1
Urine Pregnancy Test
X
X
X
X
X13
Investigational Product
Dispense Fluticasone Propionate
X
X
Collect Fluticasone Propionate
X
X
Dispense Rescue16
Albuterol/salbutamol
X
X
X
X
X
X
Collect Rescue 
Albuterol/salbutamol
X
X
X
X
Dispense IP
X11
X
Assess study drug  compliance
X
X
X
X
X
X
X
Collect IP
X
X
X


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1.
Genetics saliva sample collected at Visit 2 (following Randomization) or at any scheduled visit thereafter. Genetics consent MUST be obtained PRIOR to collection of the Genetics 
sample.  
2.
Pre-exercise spirometry (full FEV1 and forced vital capacity (FVC) testing), conducted immediately pre-exercise (and after vital signs), if applicable. Subject should have withheld 
albuterol/salbutamol within previous 6 hours. 
3.
Performed for determination of eligibility. Serial spirometry performed 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Subjects must demonstrate a decrease in FEV1
of 20% at one time point within 30 minutes of the end of a standardized exercise challenge.  
4.
Exercise challenge testing will be performed at 23 hours following the evening study treatment doses given at Visit 2 and Visit 5 
5.
Exercise challenge testing will be performed at 12 hours and 23 hours following the evening study treatment doses given at the beginning of Visits 4 and 7.
6.
Serial spirometry performed at time points 5, 10, 15, 30, 45 and 60 minutes post- exercise challenges. Longer monitoring may be required for those subjects who do not return to 
95% of baseline FEV1 values within 60 minutes.
7.
Concomitant medications collected for adverse events only between end of treatment and follow-up phone contact. 
8.
Vital signs will be collected before (prior to the pre-exercise spirometry) and after each exercise challenge test.
9.
Adverse Event and Serious Adverse Events to be collected from the start of study Drug (Visit 1) until the follow up contact. However, any SAE related to study participation will be     
recorded from the time of Informed Consent 
10. Review medical conditions diary card, including an assessment of any potential change in exercise capacity
11. An unblinding card will be dispensed along with double blind IP.
12. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear accelerometer for the 7 days preceeding these visits.
13. Pregnancy test will be conducted via home test kit and results will be reported at the Follow-up phone contact.
14. Visit 4 and Visit 7 will begin between 5PM and 11PM and continue over a period of approximately 24 hours. Subjects will return to the clinic at 12 hours (±1 hour) and 23 hours 
(±1 hour) (after the evening dose of study medication from the evening visit) for an exercise challenge procedure.
15. Subjects will be contacted by telephone 8-9 days prior to Visits 2, 4, 5 and 7 and reminded to wear the SenseWear Armband accelerometer for the 7 days preceding these visits.
16.
Collect and re-dispense rescue as needed from Visit 1
17.   Subjects who achieve a decrease in FEV1 of 15% to <20% may continue taking their daily run-in medication and repeat the eligibility exercise challenge and associated 
procedures once within a week of the original procedure.
18.   Visit 3 must be performed on the day immediately following Visit 2.  Visit 6 must be performed on the day immediately following Visit 5.


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10.3.
Appendix 3: Assessment Windows
Clinic visits are scheduled to take place as specified in Section 10.2.1. Individual 
measurements will be reported based on the visits and planned relative times they are 
assigned to in the study database without adjustment.  
If a circumstance should arise where multiple measurements have been collected and 
recorded against the same time point, then the first valid value will be used for that time
point.


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10.4.
Appendix 4: Treatment States
10.4.1.
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. The earliest and latest exposure treatment 
start and stop dates will be used to determine whether an assessment or event was pre-
treatment, on-treatment or post-treatment. If it is not possible to tell whether an 
assessment or event was on-treatment or not it will be considered as on-treatment.
10.4.1.1.
Treatment States for Concomitant Medications
A medication will be summarized in every classification (pre/during/post) in which it was 
taken, so a medication that was started in the run-in and stopped during treatment will 
appear in both the pre-treatment and the during treatment tables.
Medications will be classified by comparing the start date and end dates of the 
medication to the dates of the first and last doses of study medication within the treatment 
periods using the following definitions:. 
Treatment State
Definition
Pre-Treatment
Date medication taken ≤ first dose date of the study
During Treatment
First dose date of treatment period + 1 ≤ date medication taken ≤ last dose date of 
treatment period
During Treatment 
(washout)
Last dose date of treatment period + 1 ≤ date medication taken ≤ first dose date of 
next treatment period
Post-Treatment
Date medication taken ≥ last dose date of study + 1
10.4.1.2.
Treatment States for Adverse Events and Severe Asthma 
Exacerbations
Treatment states for adverse events are described below. Severe asthma exacerbations 
will be treated in the same way, with the exacerbation start date used in place of the AE
start date.
Treatment State
Definition
Pre-Treatment
AE start date first dose date of the study -1
On-Treatment
First dose date of treatment period AE start date last dose date of treatment period
+ 1
Post-Treatment
AE start date last dose date of study + 2
OR
Last dose date of treatment period + 2 ≤ AE start date ≤ first dose date of next 
treatment period - 1


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AEs occurring during the washout period or during the follow-up period are therefore 
classified as post-treatment and will be summarized under the treatment from the 
previous period.
Note: Time Since 1st Dose will be derived as follows:

If the First Dose Date or the AE Onset Date are missing then => missing

If First Dose Date ˃ AE Onset Date then => AE Onset Date – First Dose Date

If First Dose Date ≤ AE Onset Date then => AE Onset Date - First Dose Date +1


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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
FF/VI 100/25mcg OD
FF/VI 100/25 OD
1
B
FP 250mcg BD
FP 250 BD
2
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
If a subject attends at least one scheduled clinic visit for a treatment period, then they will 
be counted as having taken part in that treatment period and will contribute to the 
population numbers (i.e. “Big N” numbers) for the treatment that they were randomized 
to receive in that period.
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definitions
In general, the subject level baseline (or study baseline) is defined as the value taken at 
visit 2 (randomization), and the period level baseline is defined as the pre-treatment value 
taken at the start of each treatment period (visit 2 and visit 5). Using these definitions the 
period baseline for treatment period 1 is the same as the subject level baseline.
For FEV1 and Vital Signs, the baseline value at visit 2 will be taken from the “Pre 
Challenge” planned time. 
The primary analysis will include as a covariate, the period baseline value as well as 
including as a covariate, the mean of the two period baseline values.
For the physical activity measures assessed by the biosensor, the period baseline will be 
derived using all the available data from the last 7 calendar days prior to, but not 
including the first clinic visit of the treatment period (Visit 2/5). For example, if the 
randomisation visit (Visit 2) was on the 18th May then the period baseline for treatment 
period 1 would be derived as the average of the non-missing data that is available from
the 11th May to the 17th May inclusive. 
10.5.2.2.
Derivations and Handling of Missing Baseline Data
Change from baseline will be defined as the difference between the value of the endpoint 
at the time point of interest and the baseline value as defined in Section 10.5.2.1.


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If the baseline for an endpoint is missing it will not be imputed using a different time
point or derivation but will remain missing. 
10.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Area
: /arenv/arprod/gw685698_gw642444/mid201832/final/
QC Spreadsheet
: \\hlwdsntv006a\med_ds_rgm\Projects\Respiratory & 
Inflammation\Horizon\201832 (Exercise study)\Statistics\QC Tracking\
Analysis Datasets 

Analysis and reporting (A&R) datasets will be created according to Integrated Data Standards 
Library (IDSL) standards.
Generation of RTF Files

RTF files will be generated.
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 treatment the subject was randomized to unless
otherwise stated.

Numeric data will be reported at the precision collected on the eCRF or recorded in the raw 
dataset if from non eCRF sources.

For summaries and analyses the decimal places shown below will be applied in the data 
displays:


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Reporting Standards
Specification of Number of Decimal Places for Descriptive Statistics
Label 
Description
No. of decimal places (dp) 
more than raw data
N 
Number of subjects in the 
treatment group
Always present to 0 dp 
n 
Number of subjects with non-
missing values
Always present to 0 dp 
Mean
Arithmetic Mean
1 dp 
SD
Standard Deviation
2 dp 
Median
Median
1 dp 
Min.
Minimum
0 dp 
Max.
Maximum
0 dp 
Specification of Number of Decimal Places for Statistical Analysis
Label 
Description
No. of decimal places (dp) 
more than raw data
LS Mean
Adjusted mean for the 
treatment group
1 dp
LS Mean Change
Adjusted mean change from 
baseline for the treatment 
group
1 dp
Std Err
Standard error
2 dp
Difference
Treatment difference
1 dp
Odds Ratio
Treatment odds ratio
Always present to 2 dp
95% CI 
95% Confidence interval 
around treatment 
difference/ratio
Same number of dp as the 
difference/ratio
p-value 
p-value
Always present to 3 dp 
(or <0.001 or >0.999)
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time will be used in figures, summaries, statistical analyses and calculation of any 
derived parameters, unless otherwise stated.

Reporting for Data Listings: 

Planned and actual time will be shown in listings (Refer to IDSL Statistical Principle 
5.05.1).

Unscheduled or unplanned measurements will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables or 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, %


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Reporting Standards
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.

The programs for statistical analysis tables will create SAS datasets with the unrounded 
numbers from the statistical models to be used in any graphs. This will included all LS means, 
standard errors, treatment differences or ratios and confidence intervals. This will be done for 
all analysis tables regardless of whether or not a figure is planned as part of SAC.

The programs for all graphical displays will additionally create a CSV file with the final data that 
is used in the graph in order to allow the graph to be redrawn for any potential publication 
requirement in the future.


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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Time Point

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.
Time Since Study First Dose / Time Since Period First Dose

Calculated as the number of days from the date of first dose:

Ref Date = Missing                  → Time Since First Dose = Missing 

Ref Date < First Dose Date    → Time Since First Dose = Ref Date – First Dose Date    

Ref Data ≥ First Dose Date   → Time Since First Dose = Ref Date – (First Dose Date) + 1   
Study Day / Period Day

Study day will be calculated as the number of days from the Visit 1 (Screening) visit:

Ref Date = Missing                → Study Day = Missing 

Ref Date < Visit 1 Date          → Study Day = Ref Date – Visit 1 Date    

Ref Data ≥ Visit 1 Date         →Study Day = Ref Date – (Visit 1 Date) + 1 

For a treatment period, the dates of the first and last clinic visits for that treatment period will be 
used as the period start date and the period end date.

For the washout period, imputed dates will be used. The washout period start date will be the 
day after the period end date for the previous treatment period and the washout period end 
date will be the day before the period start date for the next treatment period. 

Period day will be calculated as the number of days from the period start date:

Ref Date = Missing                    → Period Day = Missing 

Ref Date < Period Start Date     → Period Day = Ref Date – Period Start Date    

Ref Data ≥ Period Start Date    → Period Day = Ref Date – (Period Start Date) + 1 
10.6.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Completely missing dates of birth will remain as missing, with no imputation applied. 
Consequently, the age of the subject will not be calculated and will remain missing.

Age, in whole years, will be calculated with respect to the date of screening (Visit 1).


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Demographics
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
Race
The high level FDA race categories and designated Asian subcategories are:
1.
African American/African Heritage
2.
American Indian or Alaska Native
3.
Asian
a.
Central/South Asian Heritage
b.
Japanese/East Asian Heritage/South East Asian Heritage
c.
Mixed Asian Heritage (only required if data exists)
4.
Native Hawaiian or other Pacific Islander
5.
White
These will be summarized along with all combinations of high level categories which exist in the 
data. All five of the high level race categories and the two Asian subcategories must appear on the 
display even if there are no subjects in a particular category, but combinations that do not exist in 
the data do not need to be represented. Combinations will be represented as the concatenation of 
the high level category terms, e.g., “White & Asian.” The designated Asian subcategories will not be 
summarized as combinations with other categories.
In addition the twelve standard race categories collected on the IDSL eCRF page will be 
summarized along with categories for mixed race. The categories are:
1.
African American/African Heritage
2.
American Indian or Alaska Native
3.
Asian - Central/South Asian Heritage
4.
Asian – East Asian Heritage
5.
Asian – Japanese Heritage
6.
Asian – South East Asian Heritage
7.
Asian – Mixed Race
8.
Native Hawaiian or other Pacific Islander
9.
White – Arabic/North African Heritage
10. White – White/Caucasian/European Heritage
11. White – Mixed Race
12. Mixed Race
“Asian – Mixed Race” is only used if more than one Asian category is selected, but no non-Asian 
races. Similarly, “White – Mixed Race” is only used if both of the White categories are selected, and 


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Demographics
no non-White races. If multiple races of different types are selected, then the overall “Mixed Race” 
category is used.
A subject will only be represented in a single category. A subject who selects a combination of 
races will be counted as “Asian – Mixed Race,” “White – Mixed Race,” or “Mixed Race,” but not in 
each of the constituent terms. Therefore the counts will add up to the total number of subjects with a 
response, and the percentages will add to 100%.
Extent of Exposure
Exposure will be calculated for each type of inhaler (DISKUS and ELLIPTA) separately. The number 
of days on study drug for each subject and treatment period will be calculated as (date treatment 
stopped – date treatment started) + 1. The treatment start and stop dates used will be the earliest 
and latest of all dates recorded for the subject and treatment period in question.
Treatment Compliance
Overall percentage treatment compliance for every subject will be calculated for each type of inhaler 
(DISKUS and ELLIPTA) and for each treatment period separately.
Compliance for the DISKUS and ELLIPTA will be based on the total number of inhalations taken 
from each type of inhaler and the expected number of inhalations to be taken. The expected 
number of inhalations will be derived as the expected number of inhalations per day (from each 
inhaler) multiplied by the number of days on study drug for the treatment period in question based 
on the subjects treatment start and stop date for that type of inhaler. 
The total number of inhalations taken will be based on the dose counter for each type of inhaler. If 
there is no dose counter information at all for a given treatment period then the compliance will be 
missing, however, as long as the information from one dose counter is present, the compliance for 
that treatment period will be calculated. If a dose counter start count is missing then it will be 
assumed to be 30 for the ELLIPTA and 60 for the DISKUS. 
In each calculation, all inhalers dispensed will be used, provided the dose counter stop counts are 
non-missing. The following formula will be used:
100
)1
_
_
(
_
_
_
_
_
_











Date
Start
Date
Stop
s
Inhalation
Expected
Taken
s
Inhalation
of
Number
Total
Compliance
Overall
Where 
Taken
s
Inhalation
of
Number
Total
_
_
_
_
is the total number of doses taken from all 
DISKUS or ELLIPTA inhalers in the treatment period in question,
s
Inhalation
Expected _
is equal 
to 2 for the DISKUS and 1 for the ELLIPTA and 
Date
Start _
and 
Date
Stop _
are the earliest 
treatment start date and the latest treatment stop date recorded for all of the inhalers used in the 
calculation.


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10.6.3.
Efficacy
Primary Endpoint
Maximal % Decrease from Pre-Exercise FEV1 Following 12 Hour Challenge at Day 14
The primary endpoint will be derived as follows:
Where pre-exercise FEV1 will be defined as the FEV1 value collected immediately prior to the 
exercise challenge.
And the minimum post exercise FEV1 will be the smallest FEV1 value recorded from the planned 
post-challenge time points (5, 10, 15, 30, 45 and 60 minutes) using only those with an actual time 
that is no more than 65 minutes after the challenge stop time.
The minimum post exercise FEV1 will only be calculated if there are at least the following non-
missing FEV1 values:

A post-exercise measurement with an actual time of ≤17 minutes

A post-exercise measurement with an actual time of ≥25 and ≤50 minutes
If there are not values meeting both of these criteria available then the endpoint will not be 
calculated and will be treated as missing.
Secondary and Other Endpoints
Maximal % Decrease from Pre-Exercise FEV1 Following Exercise Challenge
Maximal percent decrease from pre-exercise FEV1 will be derived for other time points in the same 
way as for the primary endpoint.
Maximal Decrease from Pre-Exercise FEV1 (L) Following Exercise Challenge
Maximal decrease from pre-exercise FEV1 (L) will be derived as:
Where pre-exercise FEV1 and minimum post-exercise FEV1 are defined in the same way as for the 
primary endpoint and the same minimum number of non-missing FEV1 values are required for the 
endpoint to be calculated.
Maximal % Decrease from Period Baseline FEV1 Following Exercise Challenge
Maximal percent decrease from period baseline FEV1 will be derived as:
Where minimum post-exercise FEV1 is defined in the same way as for the primary endpoint and the 
same minimum number of non-missing FEV1 values are required for the endpoint to be calculated.


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Secondary and Other Endpoints
Maximal Decrease from Period Baseline FEV1 (L) Following Exercise Challenge
Maximal decrease from period baseline FEV1 (L) will be derived as:
Where minimum post-exercise FEV1 is defined in the same way as for the primary endpoint and the 
same minimum number of non-missing FEV1 values are required for the endpoint to be calculated.
Proportion of Subjects With a Post-Challenge FEV1 No More Than 5% Lower Than Their Pre-
Exercise FEV1
Subjects meeting the criteria will be those who had a post-challenge FEV1 ≥95% of their pre-
exercise FEV1. For the time point in question, each subject’s post-challenge FEV1 as a percentage 
of their pre-exercise FEV1 will be derived as follows:
If this number is ≥ 95% then the subject will have met the criteria.
% of Subjects with a Decrease from Pre-Exercise FEV1 in 3 Categories
For the time point in question, each subject’s percentage decrease from pre-exercise FEV1 will be 
derived as follows:
Subjects will then be allocated to one of the 3 categories.
Weighted Mean 0-60 Minutes for % Decrease from Pre-Exercise FEV1 Following Exercise 
Challenge
For each time point, the percentage decrease from pre-exercise FEV1 will be derived as follows:
The weighted mean will then be calculated as the average area under the curve (AAUC) using the 
trapezoidal rule, and dividing by the relevant time interval. The 0 minute value, coming from the pre-
exercise measurement, will be 0 by definition and actual times will be used for all other 
measurements in the calculation of the AAUC.  
The AAUC will be calculated from the first non-missing time point to the last non-missing time point. 
If one or more observations are missing between two non-missing observations, the value(s) will be 
linearly interpolated between the two non-missing values. 
The AAUC (
Lt
t 
0
mins) will be calculated as follows:


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Secondary and Other Endpoints
AAUC (
Lt
t 
0
mins) =  
0
1
0
1
1
)
)(
(
2
1
t
t
t
t
C
C
L
L
i
i
i
i
i








Where, 
i = collected measurement
L = last collected measurement 
Ci = result of collected measurement i 
ti = actual time of assessment for collected measurement i
For the weighted mean over 0-60 minutes, only scheduled planned times (5, 10, 15, 30, 45 and 60 
minutes) will be used for the post-exercise time points and only those with an actual time that is less 
than or equal to 65 minutes after the challenge stop time. The AAUC will only be calculated if there 
are at least the following non-missing values:

The 0 hour (pre-exercise) measurement

A post-exercise measurement with an actual time of ≤17 minutes

A post-exercise measurement with an actual time of ≥25 and ≤50 minutes

A post-exercise measurement with an actual time of ≥55 and ≤65 minutes
If any of these values are missing then the AAUC will not be calculated, and the endpoint will be 
treated as missing.
ACQ-5
The Asthma Control Questionnaire-5 (ACQ-5) is a five-item questionnaire and there are 7 answers 
to each question that are associated with the numbers 0-6, where 0 represents no impairment and 6 
represents maximum impairment. The ACQ-5 score is the mean of the 5 items and therefore gives 
a value between 0 (well controlled) and 6 (extremely poorly controlled). The ACQ-5 score will only 
be calculated if all 5 items of the questionnaire are non-missing.
Physical Activity Measures Assessed by Biosensor
For the physical activity measures assessed by the biosensor, the week 2 time point will be derived 
using all the available data from the last 7 calendar days prior to, but not including the last 
scheduled clinic visit of the treatment period (Visit 4/7). For example, if Visit 4 was on the 18th May 
then the week 2 time point for treatment period 1 would be derived as the average of the non-
missing data that is available between the 11th May and the 17th May inclusive.


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10.6.4.
Safety
Adverse Events

Adverse events will be coded using the MedDRA coding dictionary, to give a preferred term and 
a system organ class.
Adverse Events of Special Interest

The adverse events of special interest terms, their subgroups and the preferred terms which will 
be counted towards each of them will be agreed upon prior to unblinding the study.
Pneumonia and Chest X-rays

A chest x-ray will be considered to be associated with a pneumonia assessment if it was 
performed within -7 to +14 days of the date of onset. If more than one chest x-ray is within that 
window then the data displays will use the worst case from the answers to “Was an infiltrate 
present?” i.e. “Yes” will be taken over “Unknown” and “Unknown” will be taken over “No”.


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10.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion is defined in the protocol as completing all phases of 
the study including the follow-up phone contact.

Withdrawn subjects will not be replaced in the study.

All available data from subjects who were withdrawn from the study is included 
in listings and where possible any available data from withdrawn subjects is 
included in any summaries or analyses
10.7.2.
Handling of Missing Data
Element
Reporting Detail
Maximal % 
Decrease / 
Maximal 
Decrease

As detailed in Section 10.6.3, the only post-exercise FEV1 values that will be 
used will be those recorded against the planned post-challenge time points (5, 
10, 15, 30, 45 and 60 minutes) and only those with an actual time that is no 
more than 65 minutes after the challenge stop time. 

These endpoints will only calculated if there are at least the following non-
missing FEV1 values:
o
A post-exercise measurement with an actual time of ≤17 minutes
o
A post-exercise measurement with an actual time of ≥25 and ≤50 
minutes
If there are not values meeting both of these criteria available then the endpoint 
will not be calculated and will be treated as missing.
Weighted 
Mean 0-60 
Minutes

As detailed in Section 10.6.3, only scheduled planned times (5, 10, 15, 30, 45 
and 60 minutes) will be used for the post-exercise time points and only those 
with an actual time that is less than or equal to 65 minutes after the challenge 
stop time.

The weighted mean will only be calculated if there are at least the following non-
missing values:
o
The 0 hour (pre-exercise) measurement
o
A post-exercise measurement with an actual time of ≤17 minutes
o
A post-exercise measurement with an actual time of ≥25 and ≤50 
minutes
o
A post-exercise measurement with an actual time of ≥55 and ≤65 
minutes
If any of these values are missing then the weighted mean will not be calculated, 
and the endpoint will be treated as missing.
Physical 
Activity 
Measures 

For the physical activity measures assessed by the biosensor, all time periods 
including baseline, will be calculated from all available data over the time period 
of interest. No imputations will be performed on missing data.


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Element
Reporting Detail
Assessed 
by 
Biosensor

A day will only be considered valid if the biosensor was worn for at least 21.5 
hours in that day. Any day where the biosensor was worn for less than 21.5 
hours will not be used and the data from that day will be considered missing.

All time periods including baseline, will be considered missing if less than 3 valid
days are recorded in the time-period of interest.
ACQ-5

For ACQ-5, all questions must be answered to generate an overall score; if any 
individual questions are missing then the overall score will be missing.
10.7.2.1.
Handling of Missing/Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Concomitant 
Medications

The eCRF allows partial dates to be captured for concomitant medications.

The methods for dealing with partial drug start and stop dates will be the same 
for all medications and will be to include each drug in every period in which it 
could conceivably have been taken. For example, if we only know that the 
month and year for the drug start date is the same as the month and year of 
the treatment start date, then the drug will be considered to have started pre-
treatment. Similarly if we only know that the year the drug was stopped is the 
same as the year that the treatment was stopped then the drug will be 
considered to have stopped post-treatment.

The answers to the questions “Taken Prior to Study?” and “Ongoing?” which 
are recorded on the eCRF will also be taken into consideration to determine if 
the medication was started pre-treatment or continued post-treatment. In each 
case, should the answers suggest a different classification than the dates, the 
medication will be summarized in all possible classifications (pre/during/post) 
and in all possible periods (treatment period 1, washout, treatment period 2) in 
which it could conceivably have been taken.
Adverse 
Events

The eCRF does not allow partial dates to be captured for AEs. All dates will 
either be complete or missing.

Where AE onset dates are missing then the AE will be considered on-
treatment unless there is evidence to the contrary.
Severe 
Asthma 
Exacerbations

Exacerbations are treated in the same way as adverse events.


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10.8.
Appendix 8: Multicenter Studies
10.8.1.
Definition of Country

Country is determined by the location of the centre, as entered into GSK systems by 
the site monitor.


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10.9.
Appendix 9: Examination of Covariates, Subgroups & Other 
Strata
10.9.1.
Covariates

The primary efficacy analysis will be adjusted for period baseline, the mean of the 
two period baselines, period, smoking history (number of pack years), sex, age, and 
treatment group. Subject will be fitted as a random effect. 
10.9.2.
Subgroups

The statistical analysis for selected endpoints will be repeated for the ITT (15 Years 
or Older) population.

Selected summary tables will be repeated for the ITT (15 Years or Older) population.

Selected summary tables will be repeated for the ITT (12-17 Years Old) population.


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10.10.
Appendix 10: Multiple Comparisons & Multiplicity
10.10.1.
Handling of Multiple Comparisons & Multiplicity
A 2-sided 5% risk associated with incorrectly rejecting any of the null hypotheses 
(significance level) is considered acceptable for this study. In order to account for 
multiplicity, the hypothesis test for the FF/VI versus FP treatment comparison using the 
primary ITT analysis on the primary endpoint will act as a gatekeeper for all other 
hypothesis tests using the secondary endpoints, where these tests will proceed in the pre-
defined order shown below. If a given statistical test fails to reject the null hypothesis of 
no treatment difference at the significance level of 0.05, then all tests lower down in the 
hierarchy will be interpreted as descriptive only.
Primary Efficacy Endpoint (Gatekeeper)
1. Test at the 5% level the null hypothesis that the true population difference 
between the treatment group means in maximal percent decrease from pre-
exercise FEV1 following exercise challenge at 12 hrs post-dose at the end of the 
2-week treatment period is zero.
Secondary Efficacy Endpoints
2. If 1 is significant then test at the 5% level the null hypothesis that the true odds 
ratio between the two treatment groups of recovering to within 5% of pre-exercise 
FEV1 at the 30 minute post-exercise time point following the exercise challenge at 
12 hours post evening dose is equal to one.
3. If 2 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in maximal percent 
decrease from pre-exercise FEV1 following exercise challenge at 23 hrs post-dose 
at the end of the 2-week treatment period is zero.
4. If 3 is significant then test at the 5% level the null hypothesis that the true odds 
ratio between the two treatment groups of recovering to within 5% of pre-exercise 
FEV1 at the 30 minute post-exercise time point following the exercise challenge at 
23 hours post evening dose is equal to one.
5. If 4 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in weighted mean 0-60 
minutes for percentage decrease from pre-exercise FEV1 following the exercise 
challenge at 12 hrs post-dose at the end of the 2-week treatment period is zero.
6. If 5 is significant then test at the 5% level the null hypothesis that the true 
population difference between the treatment group means in weighted mean 0-60 
minutes for percentage decrease from pre-exercise FEV1 following the exercise 
challenge at 23 hrs post-dose at the end of the 2-week treatment period is zero.


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If either the gatekeeper hypothesis or any of the other above null hypotheses are not 
rejected, then although all of the subsequent analyses will still be performed, the results
and the associated p-value, will be used for descriptive purposes only. 
The treatment comparisons defined as part of the multiple testing strategy will be limited 
to the specified key comparisons above. Other pairwise comparisons will be performed, 
but will not form part of the multiple testing strategy. Analyses of other efficacy 
measures for the FF/VI versus FP treatment comparison are nested under the secondary 
efficacy measures and no multiplicity adjustment is planned for these other efficacy 
endpoints.
If significance is achieved for the FF/VI versus FP treatment comparison on the primary 
efficacy endpoint, then the secondary endpoints will be tested in a closed-testing manner 
using the hierarchy of comparisons. If significance is also achieved for each of the 
secondary efficacy endpoints, then all other efficacy endpoints will be tested for the 
FF/VI versus FP treatment comparison without further multiplicity adjustment.


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10.11.
Appendix 11: Model Checking and Diagnostics for 
Statistical Analyses
10.11.1.
Model Checking
Analysis

MMRM

The Kenward-Roger method [Kenward MG, Roger, JH, 1997] for approximating the 
denominator degrees of freedom and correcting for bias in the estimated variance-covariance 
of the fixed effects will be used in the analyses. This will be achieved by specifying the 
DDFM=KR option in the MODEL statement within PROC MIXED.

Appropriate graphs will be reviewed as part of the model checking process to ensure that 
distributional assumptions hold. These will include a normal probability plot of the residuals and 
a plot of the residuals versus the fitted values.

Interactions with treatment will be explored for all covariates and tests for interactions will be at 
the 2-sided 10% significance level. Any significant interactions that are found will be thoroughly 
investigated and where necessary, extra outputs will be produced.


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10.12.
Appendix 12: Abbreviations & Trade Marks
10.12.1.
Abbreviations
Abbreviation
Description
A&R
Analysis and reporting
AAUC
Average area under the curve
ACQ
Asthma control questionnaire
AE
Adverse event
ATC
Anatomical therapeutic chemical
BD
Bis in die (twice daily)
BMI
Body mass index
CI
Confidence interval
CS
Clinical statistics
CSR
Clinical study report
CSV
Comma-separated values
CV
Cardiovascular
DBF
Database freeze
dp
Decimal places
eCRF
Electronic case record form
FDA
US food and drug administration
FEV1
Forced expiratory volume in 1 second
FF/VI
Fluticasone furoate/vilanterol
FP
Fluticasone propionate
FVC
Forced vital capacity
GEE
Generalized estimating equation
HARP
Harmonisation for analysis and reporting program
hr
Hour
ICH
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use
IDSL
Integrated data standards library
IP
Investigational product
ITT
Intent-To-Treat
GSK
GlaxoSmithKline
GUI
Guidance
L
Litre
LS
Least squares
Max.
Maximum
mcg
Microgram
MedDRA
Medical dictionary for regulatory activities
METs
Metabolic equivalent of tasks
Min.
Minimum
MMRM
Mixed model repeated measures
N
Number of subjects in the treatment group
n
Number of subjects with non-missing values


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Abbreviation
Description
OD
Once daily
PBO
Placebo
PM
Post-meridian (evening)
PP
Per Protocol
PT
Preferred term
QC
Quality control
RAP
Reporting & analysis plan
RAMOS NG
Randomization & medication ordering system next generation
RTF
Rich text format
SAC
Statistical analysis complete
SAE
Serious adverse events
SD
Standard deviation
SOC
System organ class
SOP
Standard operation procedure
Std Err
Standard error
TFL
Tables, figures & listings 
10.12.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
DISKUS
SAS
ELLIPTA


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10.13.
Appendix 13: List of Data Displays
10.13.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.40
-
Efficacy
2.1 to 2.36
2.1 to 2.16
Safety
3.1 to 3.28
-
Section
Listings
ICH Listings
1 to 18
Other Listings
19 to 30


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10.13.2.
Study Population Tables
Study Population Tables
No.
Population
IDSL 
Basis
Title
Subject Disposition
1.1.
Total
-
Summary of Subject Populations
1.2.
Total
ES6
Summary of Reasons For Screen Failure
1.3.
Total
ES6
Summary of Reasons For Run-in Failure
1.4.
ITT
ES1
Summary of End of Study Record
1.5.
ITT
-
Summary of Treatment Completion
1.6.
ITT
-
Summary of Attendance at Each Clinic Visit
1.7.
ITT
-
Summary of Number of Subjects by Centre - Intent-to-Treat
1.8.
Total
-
Summary of Number of Subjects by Centre - Total
Protocol Deviations
1.9.
ITT
IE2
Summary of Inclusion/Exclusion Criteria Deviations Recorded in the 
eCRF
1.10.
ITT
DV1
Summary of Important Protocol Deviations Recorded in the eCRF
1.11.
ITT
-
Summary of Protocol Deviations Impacting the Per Protocol Population
Demographic and Baseline Characteristics
1.12.
ITT
DM3
Summary of Demographic Characteristics - Intent-to-Treat
1.13.
PP
DM3
Summary of Demographic Characteristics - Per Protocol
1.14.
Total
DM3
Summary of Demographic Characteristics - Total 
1.15.
ITT (12-17 
Years Old)
DM3
Summary of Demographic Characteristics - ITT (12-17 Years Old)
1.16.
ITT (15 
Years or 
Older)
DM3
Summary of Demographic Characteristics - ITT (15 Years or Older)
1.17.
ITT
DM5
Summary of Race and Racial Combinations
1.18.
ITT
DM6
Summary of Race and Racial Combination Details
1.19.
ITT
-
Summary of History of Tobacco Use at Screening
1.20.
ITT
-
Summary of Duration of Asthma and Exacerbation History - Intent-to-
Treat
1.21.
ITT (12-17 
Years Old)
-
Summary of Duration of Asthma and Exacerbation History - ITT (12-17 
Years Old)
1.22.
ITT (15 
Years or 
Older)
-
Summary of Duration of Asthma and Exacerbation History - ITT (15 Years 
or Older)
1.23.
ITT
MH4
Summary of Current Medical Conditions
1.24.
ITT
MH4
Summary of Past Medical Conditions
1.25.
ITT
FH1
Summary of Family History of Cardiovascular Risk Factors


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Study Population Tables
No.
Population
IDSL 
Basis
Title
1.26.
ITT
-
Summary of Screening and Study Baseline Lung Function Test Results -
Intent-to-Treat
1.27.
ITT (12-17 
Years Old)
-
Summary of Screening and Study Baseline Lung Function Test Results -
ITT (12-17 Years Old)
1.28.
ITT (15 
Years or 
Older)
-
Summary of Screening and Study Baseline Lung Function Test Results -
ITT (15 Years or Older)
1.29.
ITT
-
Summary of Study Baseline Serial FEV1
1.30.
ITT
-
Summary of Maximal Percent Decrease from Pre-Exercise FEV1 at Study 
Baseline - Intent-to-Treat
1.31.
ITT (15 
Years or 
Older)
Summary of Maximal Percent Decrease from Pre-Exercise FEV1 at Study 
Baseline - ITT (15 Years or Older)
1.32.
ITT
-
Summary of Study Baseline Lung Function Test Results by Completion 
Status
Exposure and Treatment Compliance
1.33.
ITT
-
Summary of Exposure
1.34.
ITT
-
Summary of Treatment Compliance
Concomitant Medications
1.35.
ITT
CM8b
Summary of Asthma Concomitant Medications Taken Pre-Treatment
1.36.
ITT
CM8b
Summary of Asthma Concomitant Medications Taken During Treatment
1.37.
ITT
CM8b
Summary of Asthma Concomitant Medications Taken Post Treatment
1.38.
ITT
CM8b
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
1.39.
ITT
CM8b
Summary of Non-Asthma Concomitant Medications Taken During 
Treatment
1.40.
ITT
CM8b
Summary of Non-Asthma Concomitant Medications Taken Post 
Treatment


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10.13.3.
Efficacy Tables
Efficacy: Tables
No.
Population
Title
Primary Endpoint
2.1.
ITT
Summary of Maximal Percent Decrease from Pre-Exercise FEV1 Following 12 Hour 
Exercise Challenge - Intent-to-Treat
2.2.
ITT
Statistical Analysis of Maximal Percent Decrease from Pre-Exercise FEV1 Following 
12 Hour Exercise Challenge - Intent-to-Treat
2.3.
ITT (15 
Years or 
Older)
Statistical Analysis of Maximal Percent Decrease from Pre-Exercise FEV1 Following 
12 Hour Exercise Challenge - ITT (15 Years or Older)
2.4.
PP
Summary of Maximal Percent Decrease from Pre-Exercise FEV1 Following 12 Hour  
Exercise Challenge - Per Protocol
2.5.
PP
Statistical Analysis of Maximal Percent Decrease from Pre-Exercise FEV1 Following 
12 Hour Exercise Challenge - Per Protocol
2.6.
ITT (12-17 
Years Old)
Summary of Maximal Percent Decrease from Pre-Exercise FEV1 Following 12 Hour 
Exercise Challenge - ITT (12-17 Years Old)
2.7.
ITT
Summary of Maximal Decrease from Pre-Exercise FEV1 (L) Following 12 Hour  
Exercise Challenge
2.8.
ITT
Statistical Analysis of Maximal Decrease from Pre-Exercise FEV1 (L) Following 12 
Hour Exercise Challenge - Intent-to-Treat
2.9.
ITT (15 
Years or 
Older)
Statistical Analysis of Maximal Decrease from Pre-Exercise FEV1 (L) Following 12 
Hour Exercise Challenge - ITT (15 Years or Older)
Secondary and Other Endpoints
2.10.
ITT
Summary of Maximal Percent Decrease from Pre-Exercise FEV1 Following 23 Hour 
Exercise Challenge - Intent-to-Treat
2.11.
ITT (12-17 
Years Old)
Summary of Maximal Percent Decrease from Pre-Exercise FEV1 Following 23 Hour 
Exercise Challenge - ITT (12-17 Years Old)
2.12.
ITT
Statistical Analysis of Maximal Percent Decrease from Pre-Exercise FEV1 Following 
23 Hour Exercise Challenge - Intent-to-Treat
2.13.
ITT (15 
Years or 
Older)
Statistical Analysis of Maximal Percent Decrease from Pre-Exercise FEV1 Following 
23 Hour Exercise Challenge - ITT (15 Years or Older)
2.14.
ITT
Summary of Maximal Decrease from Pre-Exercise FEV1 (L) Following 23 Hour 
Exercise Challenge
2.15.
ITT
Statistical Analysis of Maximal Decrease from Pre-Exercise FEV1 (L) Following 23 
Hour Exercise Challenge - Intent-to-Treat
2.16.
ITT (15 
Years or 
Older)
Statistical Analysis of Maximal Decrease from Pre-Exercise FEV1 (L) Following 23 
Hour Exercise Challenge - ITT (15 Years or Older)
2.17.
ITT
Summary of Maximal Percent Decrease from Period Baseline FEV1 Following 
Exercise Challenge


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Efficacy: Tables
No.
Population
Title
2.18.
ITT
Statistical Analysis of Maximal Percent Decrease from Period Baseline FEV1 
Following Exercise Challenge
2.19.
ITT
Summary of Maximal Decrease from Period Baseline FEV1 (L) Following Exercise 
Challenge
2.20.
ITT
Statistical Analysis of Maximal Decrease from Period Baseline FEV1 (L) Following 
Exercise Challenge
2.21.
ITT
Summary of Change from Period Baseline in Individual Serial FEV1 Measurements 
(L)
2.22.
ITT
Statistical Analysis of Change from Period Baseline in Individual Serial FEV1 
Measurements (L) - Intent-to-Treat
2.23.
ITT (15 
Years or 
Older)
Statistical Analysis of Change from Period Baseline in Individual Serial FEV1 
Measurements (L)  - ITT (15 Years or Older)
2.24.
ITT
Statistical Analysis of Proportion of Subjects with a Post-Challenge FEV1 No More 
Than 5% Lower Than Pre-Exercise FEV1 - Intent-to-Treat
2.25.
ITT (15 
Years or 
Older)
Statistical Analysis of Proportion of Subjects with a Post-Challenge FEV1 No More 
Than 5% Lower Than Pre-Exercise FEV1 - ITT (15 Years or Older)
2.26.
ITT (12-17 
Years Old)
Summary of Proportion of Subjects with a Post-Challenge FEV1 No More Than 5% 
Lower Than Pre-Exercise FEV1
2.27.
ITT
Summary of Weighted Mean 0-60 min for Percentage Decrease from Pre-Exercise 
FEV1 Following Exercise Challenge - Intent-to-Treat
2.28.
ITT
Statistical Analysis of Weighted Mean 0-60 min for Percentage Decrease from Pre-
Exercise FEV1 Following Exercise Challenge - Intent-to-Treat
2.29.
ITT (15 
Years or 
Older)
Statistical Analysis of Weighted Mean 0-60 min for Percentage Decrease from Pre-
Exercise FEV1 Following Exercise Challenge - ITT (15 Years or Older)
2.30.
ITT (12-17 
Years Old)
Summary of Weighted Mean 0-60 min for Percentage Decrease from Pre-Exercise 
FEV1 Following Exercise Challenge - ITT (12-17 Years Old)
2.31.
ITT
Statistical Analysis of Percentage of Subjects with a Decrease from Pre-Exercise 
FEV1 in 3 Categories
2.32.
ITT
Summary of Change from Period Baseline in ACQ-5 Score
2.33.
ITT
Statistical Analysis of Change from Period Baseline in ACQ-5 Score
2.34.
ITT
Statistical Analysis of Percentage of Subjects Controlled (ACQ-5 Score <=0.75)
2.35.
ITT
Statistical Analysis of Percentage of Subjects Achieving an Improvement of >=0.5 in 
ACQ-5 Score
2.36.
ITT
Summary of Change from Period Baseline in Physical Activity Measures Over Week 2 
of Treatment Period


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10.13.4.
Efficacy Figures
Efficacy: Figures
No.
Population
Title
Primary Endpoint
2.1.
ITT/PP
Adjusted Treatment Differences for Maximal Percent Decrease from Pre-Exercise 
FEV1 Following Exercise Challenge
2.2.
ITT (15 
Years or 
Older)
Adjusted Treatment Differences for Maximal Percent Decrease from Pre-Exercise 
FEV1 Following Exercise Challenge - ITT (15 Years or Older)
Secondary and Other Endpoints
2.3.
ITT
Adjusted Treatment Differences for Maximal Decrease from Pre-Exercise FEV1 (L) 
Following Exercise Challenge - Intent-to-Treat
2.4.
ITT (15 
Years or 
Older)
Adjusted Treatment Differences for Maximal Decrease from Pre-Exercise FEV1 (L) 
Following Exercise Challenge - ITT (15 Years or Older)
2.5.
ITT
Adjusted Treatment Differences for Maximal Percent Decrease from Period Baseline 
FEV1 Following Exercise Challenge
2.6.
ITT
Adjusted Treatment Differences for Maximal Decrease from Period Baseline FEV1 (L) 
Following Exercise Challenge
2.7.
ITT
Adjusted Mean Change from Period Baseline in Individual Serial FEV1 Measurements 
(L) - Intent-to-Treat
2.8.
ITT (15 
Years or 
Older)
Adjusted Mean Change from Period Baseline in Individual Serial FEV1 Measurements 
(L) - ITT (15 Years or Older)
2.9.
ITT
Adjusted Treatment Ratios for Proportion of Subjects with a Post-Challenge FEV1 No 
More Than 5% Lower Than Pre-Exercise FEV1 - Intent-to-Treat
2.10.
ITT (15 
Years or 
Older)
Adjusted Treatment Ratios for Proportion of Subjects with a Post-Challenge FEV1 No 
More Than 5% Lower Than Pre-Exercise FEV1 - ITT (15 Years or Older)
2.11.
ITT
Adjusted Treatment Differences for Weighted Mean 0-60 min for Percentage 
Decrease from Pre-Exercise FEV1 Following Exercise Challenge - Intent-to-Treat
2.12.
ITT (15 
Years or 
Older)
Adjusted Treatment Differences for Weighted Mean 0-60 min for Percentage 
Decrease from Pre-Exercise FEV1 Following Exercise Challenge - ITT (15 Years or 
Older)
2.13.
ITT
Adjusted Treatment Ratios for Percentage of Subjects with a Decrease from Pre-
Exercise FEV1 in 3 Categories
2.14.
ITT
Adjusted Treatment Differences and Ratios for ACQ-5 Endpoints at Day 14
Forest Plot Across Endpoints
2.15.
ITT
Adjusted Treatment Differences and Ratios for Primary and Secondary Efficacy 
Endpoints at Day 14 - Intent-to-Treat
2.16.
ITT (15 
Years or 
Older)
Adjusted Treatment Differences and Ratios for Primary and Secondary Efficacy 
Endpoints at Day 14 - ITT (15 Years or Older)


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10.13.5.
Safety Tables
Safety : Tables
No.
Population
IDSL 
Basis
Title
Adverse Events Including Pneumonia
3.1.
ITT
-
Adverse Event Overview
3.2.
ITT
AE1
Summary of On-Treatment Adverse Events - Intent-to-Treat
3.3.
ITT (15 
Years or 
Older)
AE1
Summary of On-Treatment Adverse Events - ITT (15 Years or Older)
3.4.
ITT (12-17 
Years Old)
AE1
Summary of On-Treatment Adverse Events - ITT (12-17 Years Old)
3.5.
ITT
AE1
Summary of Post-Treatment Adverse Events
3.6.
ITT
AE3
Summary of Most Frequent On-Treatment Adverse Events
3.7.
ITT
-
Summary of the Most Frequent On-treatment Adverse Events - Top Ten
Most Commonly Reported On-treatment Adverse Events Per Treatment 
Group
3.8.
ITT
AE1
Summary of Drug-Related Adverse Events
3.9.
ITT
AE1
Summary of Drug-Related Serious Adverse Events
3.10.
ITT
AE1
Summary of Adverse Events Leading to Permanent Discontinuation of 
Study Drug or Withdrawal From the Study
3.11.
ITT
AE1
Summary of On-Treatment Serious Adverse Events
3.12.
ITT
AE1
Summary of Post-Treatment Serious Adverse Events
3.13.
ITT
-
Summary of Common On-Treatment Non-Serious Adverse Events (>=3% 
without rounding)
3.14.
ITT
-
Summary of On-Treatment Serious Adverse Events
3.15.
ITT
-
Summary of On-Treatment Fatal Adverse Events
3.16.
ITT
-
Summary of Post-Treatment Fatal Adverse Events
3.17.
ITT
-
Summary of On-Treatment and Post-Treatment Adverse Events of 
Special Interest - Intent-to-Treat
3.18.
ITT (12-17 
Years Old)
-
Summary of On-Treatment and Post-Treatment Adverse Events of 
Special Interest - ITT (12-17 Years Old)
3.19.
ITT
-
Summary of On-Treatment and Post-Treatment Serious Adverse Events 
of Special Interest - Intent-to-Treat
3.20.
ITT
-
Summary of On-Treatment Pneumonia
3.21.
ITT
-
Summary of Post-Treatment Pneumonia
3.22.
ITT
AE2
Relationship of Adverse Event System Organ Class, Preferred Term and 
Verbatim Text
3.23.
ITT
-
Record of all Preferred Terms That Could Have Mapped to Special 
Interest Terms


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Safety : Tables
No.
Population
IDSL 
Basis
Title
Severe Asthma Exacerbations
3.24.
ITT
-
Summary of Subjects with Severe Asthma Exacerbations - Intent-to-Treat
3.25.
ITT (15 
Years or 
Older)
-
Summary of Subjects with Severe Asthma Exacerbations - ITT (15 Years 
or Older)
3.26.
ITT (12-17 
Years Old)
-
Summary of Subjects with Severe Asthma Exacerbations - ITT (12-17 
Years Old)
Other
3.27.
ITT
VS1
Summary of Vital Signs
3.28.
ITT
VS1
Summary of Change from Baseline in Vital Signs


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10.13.6.
ICH Listings
ICH : Listings
No.
Population
IDSL 
Basis
Title
Study Population
1.
ITT
ES3
Listing of Reasons for Premature Withdrawal
2.
ITT
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations Recorded 
in the eCRF
3.
ITT
BL2
Listing of Subjects for Whom the Treatment Blind was Broken During the 
Study
4.
ITT
DM4
Listing of Demographic Characteristics
5.
ITT
DM10
Listing of Race
6.
ITT
-
Listing of Randomized and Actual Treatments
7.
ITT
-
Listing of Exposure and Compliance Data
Efficacy
8.
ITT
-
Listing of Clinic Lung Function Data
Safety
9.
ITT
AE7
Listing of Subject Numbers for Individual Adverse Events
10.
ITT
AE9
Listing of Pre-Treatment Adverse Events
11.
ITT
AE9
Listing of On-Treatment Adverse Events
12.
ITT
AE9
Listing of Post-Treatment Adverse Events
13.
ITT
AE9
Listing of Adverse Events Leading to Permanent Discontinuation of Study 
Drug or Withdrawal From the Study
14.
ITT
AE9
Listing of Non-Fatal Serious Adverse Events
15.
ITT
AE9
Listing of Fatal Adverse Events
16.
Not in ITT
AE9
Listing of Adverse Events for Subjects not in Intent-to-Treat Population
17.
ITT
-
Listing of Pneumonia Data
18.
ITT
-
Listing of Chest X-ray Data


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10.13.7.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL 
Basis
Title
Study Population
19.
ITT
-
Listing of Important Protocol Deviation Recorded in the eCRF
20.
ITT
-
Listing of Protocol Deviations Impacting the Per Protocol Population
21.
ITT
-
Listing of Subjects who Received Incorrect Medication
22.
ITT
-
Listing of History of Tobacco Use
23.
ITT
-
Listing of Duration of Asthma and Exacerbation History
24.
ITT
MH2
Listing of Medical Conditions
25.
ITT
-
Listing of Family History of Cardiovascular Risk Factors
26.
ITT
CM3
Listing of Concomitant Medications
27.
ITT
CM6
Listing of Relationship Between ATC Level 1, Ingredient and Verbatim 
Text
Safety
28.
ITT
-
Listing of Severe Asthma Exacerbations
29.
ITT
VS5
Listing of Vital Signs
30.
ITT
-
Listing of IP Inhaler Malfunctions


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10.14.
Appendix 14: Example Mock Shells for Data Displays
The data display shells are contained in separate documents which are available on 
request.