Clinical trial NCT02712047
Conditions: Asthma
Keywords: Fluticasone furoate/vilanterol Asthma fraction of exhaled nitric oxide cross-over
Sponsor: GlaxoSmithKline
Start date: 2016-04-29; Completion date: 2017-02-21
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
For asthmatic subjects, a combination of inhaled corticosteroid (FF) and long-acting beta2 receptor agonist (VI) is recommended for use (once daily) and fraction of exhaled nitric oxide (FeNO) is a non-invasive airway inflammation marker.

In this randomised, double blind, placebo-controlled, two-period, crossover repeat dose study, the duration of action of fluticasone furoate (FF) will be determined by monitoring the return of FeNO levels to baseline, following the treatment with FF/vilanetrol (VI) in asthmatic subjects.

Subjects who meet the eligibility criteria will participate in the following two treatment periods: FF/VI 100/25 mcg once-daily and placebo once-daily. Approximately 28 subjects will be enrolled in order to achieve 24 evaluable subjects. A 2-week treatment period will be followed by a 21-day monitoring/washout period before crossing over to the next treatment period. Total duration of each subject will be a maximum of 21 weeks. FeNO will be monitored up to 21 days after treatment with FF/VI together with FEV1 (up to 7 days).

Detailed description:

Arms: arm 1: Subjects will receive FF/VI 100/25 mcg each morning (once daily) from Day 1 to Day 14, followed by a 21-day monitoring/washout period arm 2: Subjects will receive placebo each morning (once daily) from Day 1 to Day 14, followed by a 21-day monitoring/washout period
Interventions: intervention 1: Fluticasone furoate (FF) (100 mcg) intervention 2: Vilanterol (VI) (25 mcg) intervention 3: Placebo
Intervention descriptions: intervention 1: First blister strip contains FF blended with lactose, 100 mcg per blister intervention 2: Second blister strip contains vilanterol blended with lactose and magnesium stearate, 25 mcg per blister intervention 3: Matching placebo will have two blister strips, identical in appearance to the inhaler containing active study medication; one containing lactose and the second strip containing lactose and magnesium stearate

Protocol documents:
Prot_000.pdf: 
2015N241692_00
CONFIDENTIAL
GlaxoSmithKline group of companies
201499
1
TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
A randomised, placebo-controlled, double-blind, two period
crossover study to characterise the exhaled nitric oxide time 
profile as a biomarker of airway inflammation in adult asthma 
patients following repeat administration of inhaled Fluticasone 
Furoate (FF)/ Vilanterol (VI) 100/25 mcg
Compound Number:
GW685698+GW642444
Development Phase
IIA
Effective Date:
12-JAN-2016
Author(s):
 (Respiratory TAU); 
 (Respiratory TAU); 
 (CPEMT); 
(Respiratory Medical Franchise); 
 
 (Clinical Statistics).
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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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
Medicines 
Research 
Center, 
Gunnels Wood 
Road, 
Stevenage, 
Hertfordshire, 
SG1 2NY, UK.
Secondary 
Medical 
Monitor
Medicines 
Research 
Center, 
Gunnels Wood 
Road, 
Stevenage, 
Hertfordshire, 
SG1 2NY, UK.
SAE 
contact  
information 
[Medical 
monitor 
as above]
and
[Study 
Manager]
Medicines 
Research 
Center, 
Gunnels Wood 
Road, 
Stevenage, 
Hertfordshire, 
SG1 2NY, UK.
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): Not applicable
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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

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 Signature
Date


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5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201499........................................................8
2.
INTRODUCTION....................................................................................................10
2.1.
Study Rationale/Brief Background ..............................................................10
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................12
4.
STUDY DESIGN ....................................................................................................13
4.1.
Overall Design ............................................................................................13
4.2.
Treatment Arms and Duration.....................................................................14
4.3.
Type and Number of Subjects.....................................................................14
4.4.
Design Justification.....................................................................................15
4.5.
Dose Justification........................................................................................16
4.6.
Benefit:Risk Assessment ............................................................................16
4.6.1.
Risk Assessment .........................................................................17
4.6.2.
Benefit Assessment.....................................................................19
4.6.3.
Overall Benefit:Risk Conclusion...................................................19
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............19
5.1.
Inclusion Criteria.........................................................................................19
5.2.
Exclusion Criteria........................................................................................21
5.3.
Screening Failures......................................................................................23
5.4.
Withdrawal/Stopping Criteria.......................................................................23
5.5.
Subject and Study Completion....................................................................24
6.
STUDY TREATMENT ............................................................................................25
6.1.
Investigational Product................................................................................25
6.2.
Treatment Assignment................................................................................25
6.3.
Blinding.......................................................................................................26
6.4.
Packaging and Labeling..............................................................................26
6.5.
Preparation/Handling/Storage/Accountability..............................................26
6.6.
Compliance with Study Treatment Administration.......................................27
6.7.
Treatment of Study Treatment Overdose....................................................27
6.8.
Treatment after the End of the Study ..........................................................28
6.9.
Lifestyle and/or Dietary Restrictions............................................................28
6.9.1.
Meals and Dietary Restrictions ....................................................28
6.9.1.1.
Nitrate-rich foods........................................................28
6.9.1.2.
Caffeine and Alcohol ..................................................28
6.9.2.
Activity .........................................................................................29
6.10.
Concomitant Medications and Non-Drug Therapies....................................29
6.10.1.
Permitted Medications and Non-Drug Therapies..........................29
6.10.1.1.
Permitted asthma medications ...................................29
6.10.1.2.
Other permitted medications.......................................29
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................29
6.10.2.1.
Prohibited asthma medications...................................29
6.10.2.2.
Prohibited non-asthma medications............................29
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................30
7.1.
Time and Events Table...............................................................................31


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6
7.2.
Screening and Critical Baseline Assessments ............................................33
7.3.
Pharmacodynamics ....................................................................................33
7.3.1.
FeNO measurements...................................................................33
7.3.2.
Spirometry ...................................................................................33
7.3.2.1.
Reversibility testing.....................................................33
7.3.2.2.
FEV1 Stability Limit .....................................................34
7.3.3.
PEF .............................................................................................34
7.3.3.1.
PEF Stability Limit ......................................................34
7.3.3.2.
PEF below Stability Limit ............................................34
7.4.
Safety .........................................................................................................35
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........35
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................35
7.4.1.2.
Method of Detecting AEs and SAEs ...........................35
7.4.1.3.
Follow-up of AEs and SAEs........................................36
7.4.1.4.
Cardiovascular and Death Events ..............................36
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................36
7.4.1.6.
Regulatory Reporting Requirements for SAEs............37
7.4.2.
Pregnancy ...................................................................................37
7.4.3.
Physical Exams ...........................................................................38
7.4.4.
Vital Signs....................................................................................38
7.4.5.
Clinical Safety Laboratory Assessments ......................................38
7.5.
Biomarker(s)/Pharmacodynamic Markers ...................................................39
7.5.1.
Exploratory Biomarkers................................................................39
8.
DATA MANAGEMENT ...........................................................................................39
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................39
9.1.
Hypotheses.................................................................................................39
9.2.
Sample Size Considerations.......................................................................40
9.2.1.
Sample Size Assumptions ...........................................................40
9.2.2.
Sample Size Sensitivity................................................................40
9.2.3.
Sample Size Re-estimation or Adjustment...................................40
9.3.
Data Analysis Considerations .....................................................................41
9.3.1.
Analysis Populations....................................................................41
9.3.2.
Interim Analysis ...........................................................................41
9.4.
Key Elements of Analysis Plan ...................................................................41
9.4.1.
Primary Analyses.........................................................................41
9.4.2.
Secondary Analyses ....................................................................41
9.4.3.
Other Analyses ............................................................................42
10. STUDY GOVERNANCE CONSIDERATIONS........................................................42
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............42
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................42
10.3.
Quality Control (Study Monitoring) ..............................................................42
10.4.
Quality Assurance.......................................................................................43
10.5.
Study and Site Closure ...............................................................................43
10.6.
Records Retention......................................................................................44
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................44


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11. REFERENCES.......................................................................................................45
12. APPENDICES........................................................................................................47
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................47
12.2.
Appendix 2: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................49
12.2.1.
Definition of Adverse Events........................................................49
12.2.2.
Definition of Serious Adverse Events...........................................50
12.2.3.
Definition of Cardiovascular Events .............................................51
12.2.4.
Recording of AEs and SAEs ........................................................52
12.2.5.
Evaluating AEs and SAEs............................................................52
12.2.6.
Reporting of SAEs to GSK...........................................................54
12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................55
12.3.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............55
12.3.2.
Collection of Pregnancy Information ............................................55
12.3.3.
References ..................................................................................56


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1.
PROTOCOL SYNOPSIS FOR STUDY 201499
Rationale
This study will determine the duration of action of FF by monitoring the return of the 
fraction of exhaled nitric oxide (FeNO) levels to baseline following the cessation of 
repeat dose treatment with FF/VI. The study will use a clinical strength of FF/VI (Relvar 
ELLIPTA 100/25 mcg OD) administered for a two week treatment period. FeNO will 
continue to be monitored up to 21 days after treatment with FF/VI together with FEV1 (up 
to 7 days).
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To characterise the fraction of exhaled 
nitric oxide (FeNO) time profile following 
repeat administration of fluticasone 
furoate/vilanterol (FF/VI) 100/25mcg 
combination  in comparison with placebo 
in subjects with asthma.

Change from baseline FeNO over time 
following the cessation of repeat dose 
treatment with FF/VI.
Secondary

Change in FeNO over the treatment 
period following repeat administration of 
FF/VI 100/25mcg combination in 
comparison with placebo in subjects with 
asthma.

To determine the Peak Expiratory Flow 
(PEF) during and following repeat 
administration of FF/VI 100/25mcg 
combination in comparison with placebo 
in subjects with asthma.

To determine forced expiratory volume in 
1 second (FEV1) following repeat 
administration of FF/VI 100/25mcg 
combination in comparison with placebo 
in subjects with asthma

Change from baseline FeNO over the 
FF/VI treatment period.

Measurement of PEF during treatment 
and following cessation of repeat dose 
treatment with FF/VI.

Measurement of FEV1 pre-treatment and 
for up to 7 days after cessation of repeat 
dose treatment with FF/VI.
Exploratory

To investigate the effect of repeat 
administration of FF/VI 100/25mcg 
combination on exploratory biomarkers, 
including but not limited to, blood 
eosinophil levels and serum periostin 
levels, in comparison with placebo in 
subjects with asthma.

Measurement of exploratory biomarkers, 
including but not limited to, blood 
eosinophil and serum periostin levels at 
baseline, and at various time points after 
cessation of repeat dose treatment with 
FF/VI.


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Overall Design
This study will be a randomised, double blind, placebo-controlled, two-period, crossover 
repeat dose study in adult subjects with asthma.
Following screening, subjects will provide AM and PM FeNO and PEF data from Day -7 
of Treatment Period 1.  The Day -7 AM FeNO readings will be used to confirm eligibility 
(FeNO >40ppb).  On Day 1, pre-treatment (AM) FeNO, FEV1 and PEF readings will be
used as baseline for Treatment Period 1.  Subjects will then receive FF/VI 100/25 or 
placebo once daily (AM) for 14 (2) days. All treatments will be taken at the same time 
of day (within 2 hours of the treatment on Day 1).
FeNO will be measured by the subjects AM (pre-dose) and PM for 14 days during each 
treatment period. On Day 14, FEV1 and FeNO will be recorded before the final dose of 
FF/VI or placebo.
FeNO (AM and PM) will be measured for 21 days after the end of treatment (up to Day 
35 for each of the two treatment periods). This will be as an in-patient on Days 14 to 19.  
All FeNO (out-patient and in clinic) measurements will be obtained using the same FeNO 
meter for each subject.
FEV1 will be recorded AM and PM (i.e. every 12 hours) as an in-patient on Days 14 to 
19. Subjects will then be discharged before returning 2 days later (on Day 21) for a 
further measurement of FEV1 (168 hours post-treatment). An FEV1 measurement will 
also be performed on Day 35.
Up to 4 weeks after the final assessment is collected on Day 35 of Treatment Period 1, 
subjects will then be crossed over to the alternative treatment.  Baseline FEV1, PEF and 
FeNO values will be collected pre-treatment in the morning on Day 1: these will be the 
baseline values for Treatment Period 2.  Subjects will then receive FF/VI 100/25 or 
placebo once daily (AM) for 14 (2) days. The second treatment period procedures will 
be identical to the first treatment period.
A single measurement of FeNO will be collected according to American Thoracic 
Society (ATS)/European Respiratory Society (ERS) guidelines at each time point, using a 
NIOX Vero device with electronic data capture. Appropriate dietary and/or lifestyle 
restrictions will be applied.  The order of assessments collected in the clinic will be: 
FeNO, FEV1, and then PEF. When the subjects are at home, FeNO will be collected 
before the PEF measurements. FEV1 measurements taken within 6 hours of short acting 
beta2-receptor agonist (SABA) use will not be analysed.
PEF measurements (best of 3 recordings) will be recorded AM and PM (i.e. every 12 
hours) from Day-7 through to Day 35 of Treatment Period 1, and then from Day 1 of 
Treatment Period 2 through to the follow-up visit. Subjects will be provided with a PEF 
meter and these measurements will be captured electronically whilst they are at home and 
in the clinic.


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Treatment Arms and Duration
Each subject will participate in two treatment periods of 14 (2 days).  FF/VI 100/25 
mcg will be received once daily (AM dosing) in one period and placebo (AM dosing) 
will be administered in the other period.  At the end of each treatment period, there will 
be a monitoring period of 21 days.
Total duration for each subject (from screening to follow-up) will be a minimum of 76 
days, with a maximum of up to 21 weeks, depending on the screening period and the time 
period between Treatment Periods 1 and 2.
A complete subject is one who has completed both treatment periods, all assessments up 
to Day 35 of both treatment periods, and all of the follow-up assessments.
Type and Number of Subjects
Approximately 28 adult subjects with asthma will be enrolled into this study to ensure 
that 24 subjects complete dosing and critical assessments for both treatment periods.
Analysis
Following loge-transformation, primary endpoint of FeNO change from baseline ratio
following cessation of treatment will be analyzed using a mixed effects repeated 
measures model with fixed effect terms for period, treatment, day, time, (period-level 
baseline)*day*time interaction term, treatment*day*time interaction term, period-level 
baseline and subject-level baseline. Day*time interaction term will be fitted as repeated 
measure.
Secondary endpoints of FeNO change from baseline ratio during treatment and FEV1 will 
be analysed similarly to the primary FeNO endpoint.  FEV1 will not be log-transformed.
PEF and safety data will be listed and summarised. Exploratory biomarker data 
(including blood eosinophil and serum periostin data) will be summarized descriptively, 
if available.
2.
INTRODUCTION
2.1.
Study Rationale/Brief Background
Treatment with an inhaled corticosteroid (ICS) is recommended for asthma patients who 
are symptomatic while taking as-needed short acting bronchodilators. In patients who 
remain symptomatic on low to medium doses of ICS, treatment with a combination of a 
long-acting β2 agonists (LABA) and an ICS is recommended. The combination of the 
ICS fluticasone furoate (FF) and the LABA vilanterol (VI) is approved for the once daily 
treatment of asthma (RELVAR ELLIPTA or BREO ELLIPTA; 100/25 and 200/25 mcg).
The FF/VI asthma clinical development program demonstrated efficacy over the 24 hour 
dosing interval resulting in regulatory approvals for once-daily administration. The 
duration of bronchodilation produced by a single dose of FF/VI 100/25 mcg beyond the 


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24 hour dosing interval was assessed [GlaxoSmithKline Document Number 
2014N194756_00] and showed clinically significant bronchodilation over 48 hours with 
effects still apparent up to 72 hours post-dose. This effect was predominantly attributed 
to the LABA (VI) component. The persistence of the anti-inflammatory effect of the ICS 
(FF) component of FF/VI following cessation of dosing has not been determined.
In subjects with asthma the fraction of exhaled nitric oxide (FeNO) is a non-invasive 
marker of airway inflammation. In symptomatic subjects high FeNO levels (>50ppb) 
indicate significant airway eosinophilia which is likely to respond to ICS (Taylor, 2006; 
Smith, 2005).  The onset of action for ICS in reducing FeNO occurs within one week and 
is maintained with chronic dosing (Kharitonov, 2002; Nolte, 2013). Dose-related 
reductions in FeNO have been shown with low dose ICS (Kharitonov, 2002; Silkoff, 
2001), while fluticasone propionate (FP) produced comparable near-maximal reductions 
in FeNO across a wide dose range (50-2,000 mcg/5 days) with a maximum possible 
effect for the agonist (Emax) of 63% reduction and an effective dose for 50% of people 
receiving the drug (ED50) of 18 mcg which is below the minimal approved clinical dose 
[GSK Document Number GM2005/00525/00]. A limited investigation (3 days 
treatment) of the effects of high doses of FF (250 mcg and 1000 mcg) in comparison with 
FP (1000 mcg) on FeNO was conducted during the early clinical development of FF 
[GSK Document Number GM2003/00418/00]. Both FF and FP reduced FeNO with a 
greater effect seen with FF 1000 mcg compared with either FF 250 mcg or FP 1000mcg.  
However, the overall response to FP was approximately half that produced by the same 
dose administered for 5 days [GSK Document Number GM2005/00525/00] indicating 
that the 3 day treatment duration may have been insufficient to produce maximal
reductions in FeNO. In a study with mometasone furoate (Nolte, 2013) a greater effect 
on FeNO was seen after 14 days compared with the response at 7 days across all doses 
(100, 200 and 400 mcg), although the difference was minimal (approximately 90% of the 
Day 14 response was apparent by Day 7).  This indicates a treatment with ICS for at least 
14 days is necessary for the optimal effect on airway inflammation as measured by 
FeNO.
Following the cessation of ICS treatment FeNO levels progressively return to pre-
treatment baseline levels, suggesting a return of inflammation.  FeNO levels returned to 
baseline 7 days after cessation of treatment with budesonide (Kharitonov, 2002) and two 
weeks after administration of FP 1000 mcg/day for one month, although earlier time-
points were not assessed (Van Rensen, 1999).  Following short term FF treatment (3 
days) FeNO levels remained lowered for 72 hours after the last dose [GSK Document 
Number GM2003/00418/00]; later time-points were not investigated.  
FF demonstrates a number of characteristics that could result in a prolonged anti-
inflammatory action including a greater glucocorticoid receptor binding and higher tissue 
uptake and retention than other ICS molecules (Salter, 2007; Valotis, 2007) together with 
a longer lung retention than FP in man (Allen, 2013).  The duration of anti-inflammatory 
activity of the FF component of FF/VI beyond the 24 hour dosing interval is not known.
This study will determine the duration of action of FF by monitoring the return of FeNO 
levels to baseline following the cessation of repeat dose treatment with FF/VI. The study 
will use a clinical strength of FF/VI (RELVAR ELLIPTA 100/25 mcg Once Daily (OD)) 
administered for a two week treatment period. FeNO will continue to be monitored up to 


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21 days after treatment with FF/VI together with forced expiratory volume in 1 second 
(FEV1) (up to 7 days).
Information on the physical, chemical and pharmaceutical properties of FF/VI is 
available in the Investigator Brochure (IB) [GlaxoSmithKline Document Number 
RM2008/00012/07] and also in the BREO ELLIPTA datasheet on the New Zealand 
Medsafe website: 
http://www.medsafe.govt.nz/profs/datasheet/b/breoelliptainhalation.pdf.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To characterise the fraction of exhaled 
nitric oxide (FeNO) time profile following 
repeat administration of fluticasone 
furoate/vilanterol (FF/VI) 100/25mcg 
combination  in comparison with placebo 
in subjects with asthma.

Change from baseline FeNO over time 
following the cessation of repeat dose 
treatment with FF/VI.
Secondary

Change in FeNO over the treatment 
period following repeat administration of 
FF/VI 100/25mcg combination in 
comparison with placebo in subjects with 
asthma.

To determine the Peak Expiratory Flow 
(PEF) during and following repeat 
administration of FF/VI 100/25mcg 
combination in comparison with placebo 
in subjects with asthma.

To determine FEV1 following repeat 
administration of FF/VI 100/25mcg 
combination in comparison with placebo 
in subjects with asthma

Change from baseline FeNO over the 
FF/VI treatment period.

Measurement of PEF during treatment 
and following cessation of repeat dose 
treatment with FF/VI.

Measurement of FEV1 pre-treatment and 
for up to 7 days after cessation of repeat 
dose treatment with FF/VI.
Exploratory

To investigate the effect of repeat 
administration of FF/VI 100/25mcg 
combination on exploratory biomarkers, 
including but not limited to, blood 
eosinophil levels and serum periostin 
levels, in comparison with placebo in 
subjects with asthma.

Measurement of exploratory biomarkers, 
including but not limited to, blood 
eosinophil and serum periostin levels at 
baseline, and at various time points after 
cessation of repeat dose treatment with 
FF/VI.


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4.
STUDY DESIGN
4.1.
Overall Design
This study will be a randomised, double blind, placebo-controlled, two-period, crossover 
repeat dose study in adult subjects with asthma.
Following screening, subjects will provide AM and PM FeNO and PEF data from Day -7 
of Treatment Period 1.  The Day -7 AM FeNO readings will be used to confirm eligibility 
(FeNO >40ppb).  On Day 1, pre-treatment (AM) FeNO, FEV1 and PEF readings will be 
used as baseline for Treatment Period 1.  Subjects will then receive FF/VI 100/25 or 
placebo once daily (AM) for 14 (2) days. All treatments will be taken at the same time 
of day (within ± 2 hours of the treatment on Day 1).
FeNO will be measured by the subjects AM (pre-dose) and PM for 14 days during each 
treatment period. On Day 14, FEV1 and FeNO will be recorded before the final dose of 
FF/VI or placebo.
FeNO (AM and PM) will be measured for 21 days after the end of treatment (up to Day 
35 for each of the two treatment periods). This will be as an in-patient on Days 14 to 19.  
All FeNO (out-patient and in clinic) measurements will be obtained using the same FeNO 
meter for each subject.
FEV1 will be recorded AM and PM (i.e. every 12 hours) as an in-patient on Days 14 to 
19. Subjects will then be discharged before returning 2 days later (on Day 21) for a 
further measurement of FEV1 (168 hours post-treatment). An FEV1 measurement will 
also be performed on Day 35.
Up to 4 weeks after the final assessment is collected on Day 35 of Treatment Period 1, 
subjects will then be crossed over to the alternative treatment.  Baseline FEV1, PEF and 
FeNO values will be collected pre-treatment in the morning on Day 1: these will be the 
baseline values for Treatment Period 2.  Subjects will then receive FF/VI 100/25 or 
placebo once daily (AM) for 14 (2) days. The second treatment period procedures will 
be identical to the first treatment period.
A single measurement of FeNO will be collected according to ATS/ERS guidelines at 
each time point, using a NIOX Vero device with electronic data capture. Appropriate 
dietary and/or lifestyle restrictions will be applied.  The order of assessments collected in 
the clinic will be: FeNO, FEV1, and then PEF. When the subjects are at home, FeNO will 
be collected before the PEF measurements. FEV1 measurements taken within 6 hours of 
SABA use will not be analysed.
PEF measurements (best of 3 recordings) will be recorded AM and PM (i.e. every 12 
hours) from Day-7 through to Day 35 of Treatment Period 1, and then from Day 1 of 
Treatment Period 2 through to the follow-up visit. Subjects will be provided with a PEF 
meter and these measurements will be captured electronically whilst they are at home and 
in the clinic.


2015N241692_00
4.2.
Treatment Ar
Each subject will participate 
mcg will be received once da
will be administered in the ot
be a monitoring period of 21 
Treatment Period 1, there ma
start Treatment Period 2.
A schematic is shown below:
Total duration for each subjec
days, with a maximum of up 
period between Treatment Pe
Day -7 visit if convenient. Lik
and Treatment Period 2, the D
the Day 1 visit of Treatment P
A complete subject is one wh
to Day 35 of both treatment p
4.3.
Type and Num
Approximately 28 adult subje
that 24 subjects complete dos
If more than 4 subjects prema
at the discretion of the sponso
subject would be assigned to 
subject.
CONFIDENTIAL
14
ms and Duration
in two treatment periods of 14 (2 days). FF/V
aily (AM dosing) in one period and placebo (AM
ther period.  At the end of each treatment period
days. At the end of this monitoring period follo
ay be a period of up to a further 4 weeks before t
:
ct (from screening to follow-up) will be a minim
to 21 weeks, depending on the screening period
eriods 1 and 2. The screening visit can be combin
kewise, if no gap is required between Treatment
Day 35 visit for Treatment Period 1 can be comb
Period 2.
ho has completed both treatment periods, all asse
periods, and all of the follow-up assessments.
mber of Subjects
ects with asthma will be enrolled into this study 
sing and critical assessments for both treatment p
aturely discontinue the study, these subjects may
or, in consultation with the investigator.  A repla
the same treatment sequence as the original wit
201499
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d and the time 
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thdrawn 


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4.4.
Design Justification
Treatment period. The characterisation of the FeNO time profile following 
administration of FF is not known and its determination is the primary objective of this 
study. The onset of action of ICS on FeNO occurs within a few days with significant and 
near maximal effects seen after one week. In subjects with asthma and elevated FeNO 
(mean baseline eNO >65ppb) treatment with FP for 5 days reduced FeNO by 47-60% 
with a similar effect produced across a 40-fold dose range (50-2,000 mcg twice daily 
(BD); GSK Document Number GM2005/00525/00). A lesser reduction of approximately 
33% from baseline was seen with FP 1,000 mcg BD for 3 days [GSK Document Number 
GM2003/00418/00] suggesting that this treatment duration may have been sub-optimal.  
Approximately 90% of the maximal effect of mometasone furoate on FeNO was seen 
after 7 days treatment compared with 14 days treatment (Nolte, 2013) These data suggest 
that the selected treatment period of 14 days should be associated with a near maximal 
effect of FF on eNO and that a longer treatment duration would be unlikely to result in 
further substantial effects.
Washout. As the duration of action of FF on eNO is not known, the washout period of at 
least 21 days represents a pragmatic balance between a likely duration of action and 
successful and timely study completion. A washout period of 14-28 days was 
successfully used in a previous study with repeat dose FP [GSK Document Number 
GM2005/00525/00]. There is a minimum of a 21 day washout period from the end of 
Treatment Period 1 to the start of Treatment Period 2. This is expected to be a sufficient 
washout for FeNO levels to return to baseline. However, to provide flexible scheduling 
for Treatment Period 2, there may be a further period of up to 4 weeks after the end of 
this initial 21 day washout period has finished before the subject commences Treatment 
Period 2.
Design Rationale. A placebo-controlled double-blind crossover study is preferred to a 
parallel group as this will require fewer subjects.  Screening failure rates in a similar 
study [GSK Document Number 2014N194756_00] at the same site were in the order of 
90% and a parallel group study is not considered to be feasible.  The drop-out rate 
predicted for this study is considered to be low (based on the previous study HZA116592 
conducted at the same site) [GSK Document Number 2014N194756_00].
Baseline FeNO (for eligibility). Based on the ATS FeNO 2011 guidelines [ATS, 2011],
the lower limit of 40ppb to be used in this study is classified as ‘intermediate’ (range 25-
50ppb). Patients with intermediate FeNO values respond to ICS treatment and clinical 
cut-offs between 35 and 50ppb have been linked with a high likelihood of asthma 
diagnosis as well as an increased risk of worsening symptoms and exacerbations 
(Bjermer, 2014).  FeNO >40ppb is considered to be elevated and this lower limit has 
previously been successfully used by the study site. In a previous study with repeat dose 
FP in AMP sensitive asthmatics receiving SABA only [GSK Document Number 
GM2005/00525/00], mean baseline FeNO across the treatments ranged between 66 and 
85ppb.
Dietary and smoking restrictions. In healthy subjects, eNO increased by 60% two hours 
after a nitrate-rich meal and was still 22% higher than baseline after 15 hours before 


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returning to baseline at 20 hours [Vints, 2005]. Therefore, avoidance of nitrate-rich foods 
is a restriction in this study.
Smoking can reduce FeNO by 30-60%, dependent on daily cigarette consumption
(Bjermer, 2014).  Consequently, all subjects will be non-smokers.
4.5.
Dose Justification
FF/VI 100/25 mcg represents the lower approved dose for asthma (RELVAR ELLIPTA 
and BREO ELLIPTA) and is likely to be the most frequently prescribed strength. The 
predicted effects of FF/VI 200/25 on FeNO would either be of comparable or of longer 
duration and therefore the 100/25 mcg dose represent the ‘worst case’ in terms of 
duration. The dose response for FF reduction in eNO is not known. However, repeat 
dose FP for 5 days [GSK Document Number GM2005/00525/00] produced similar 
reductions in FeNO (ranging from 47% [50 mcg BD] to 60% [2,000 mcg BD] with an 
ED50 of 18 mcg and an Emax of 63%). Given the greater potency, higher glucocorticoid 
receptor selectivity, greater tissue uptake and longer intracellular and lung retention of FF 
compared with FP it is considered to be reasonable to assume that FF 100 mcg for 14 
days will produce a maximal or near maximal reduction of eNO.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with FF/VI
can be found in the Investigator’s Brochure) [GlaxoSmithKline Document Number 
RM2008/00012/07] and also in the BREO ELLIPTA datasheet on the New Zealand 
Medsafe website: 
http://www.medsafe.govt.nz/profs/datasheet/b/breoelliptainhalation.pdf.
The study is considered low risk. The dose of FF/VI to be used in this study (100/25mcg) 
is an approved dose world-wide and has been administered on an out-patient basis in 
phase III studies in both asthma and chronic obstructive pulmonary disease (COPD) and 
was well tolerated.  The asthma patients to be included in this study are comparable to 
those in the asthma phase III studies.  There are some low risks associated with the study 
design and procedures and these are summarised below:


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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Mitigation Strategy
Monitoring implemented
Investigational Product (IP)
There is a potential risk of worsening asthma as 
subjects will receive placebo in one treatment 
arm and no treatments during the washout 
periods (however access to SABA rescue 
medication will be available throughout the entire 
study).
Stopping criteria will be applied for both FEV1
(during the clinic stays/visits) and PEF (out-
patient and in-clinic) which will be monitored 
throughout the study treatment and washout 
periods.
Stopping criteria will be applied for both FEV1
(during the clinic stays) and PEF (out-patient and 
in-clinic) which will be monitored throughout the 
study treatment and washout periods.
As with any inhaled medication paradoxical 
bronchospasm may occur with an immediate 
wheeze after dosing.
If bronchospasm occurs following dosing, 
immediate administration of a short-acting (i.e., 
quick relief) inhaled bronchodilator (e.g., 
albuterol) is recommended. If this treatment fails 
to provide relief, a physician should be contacted 
immediately and/or emergency treatment should 
be sought.
First dose of the study medication in each 
treatment period will be administered in the clinic 
under the supervision of a physician.
FF/VI is contraindicated in subjects with severe 
milk protein allergy or known hypersensitivity or 
any ingredient of the preparation.
These subjects will be excluded from the study.
Not applicable.
Cardiovascular effects, such as cardiac 
arrhythmias e.g. supraventricular tachycardia 
and extrasystoles may be seen with 
sympathomimetic drugs, including fluticasone 
furoate/vilanterol. Therefore fluticasone 
furoate/vilanterol should be used with caution in 
patients with severe cardiovascular disease.
Caution is needed in patients with pre-existing 
cardiovascular (CV) disease, especially severe 
CV disease. Patients with severe CV disease will
be excluded.
Not applicable


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Potential Risk of Clinical Significance
Mitigation Strategy
Monitoring implemented
Investigational Product (IP)
There is limited experience of inhaled FF/VI, FF, 
and VI exposure during pregnancy in clinical 
studies. The use of FF/VI is not recommended 
during pregnancy or lactation
Pregnant/ lactating females will be excluded from 
the study. 
Highly effective methods of contraception are 
required by the protocol in females of 
childbearing potential 


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4.6.2.
Benefit Assessment
Benefit considerations for each individual subject may include:

Potential benefit of receiving FF/VI combined inhaled therapy during the study

Contributing to the process of developing new asthma therapies

Medical evaluations/assessments associated with study procedures e.g. PEF, 
FEV1, physical examinations and vital signs.
4.6.3.
Overall Benefit:Risk Conclusion
The study is considered low risk. The dose of FF/VI to be used in this study (100/25mcg) 
is an approved dose world-wide and has been administered on an out-patient basis in 
phase III studies in both asthma and COPD and was well tolerated.  The asthma patients 
to be included in this study are comparable to those in the asthma phase III studies.
Taking into account the measures taken to minimise risk to patients participating in this 
study, the potential low risks identified in association with inhaled FF/VI are justified by 
the anticipated benefits that will be afforded to subjects with asthma.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events
(AEs), and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the BREO ELLIPTA
datasheet on the New Zealand Medsafe website: 
http://www.medsafe.govt.nz/profs/datasheet/b/breoelliptainhalation.pdf.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Age of subject: Between 18 and 65 years of age inclusive, at the time of signing the 
informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Asthma: A doctor diagnosis of asthma for at least 6 months prior to the start of the 
study.
3. Severity of disease: A screening pre-bronchodilator FEV1 ≥ 60% of predicted


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NOTE: Predicted values will be based upon NHANES III [Hankinson, 1999]
4. Reversibility of disease:
Demonstrated presence of reversible airway disease at screening (repeat testing of 
eligibility can be undertaken following the screening visit up to Day -7).
OR
The presence of reversible airways disease can have been demonstrated historically 
within 6 months of the screening visit.
NOTE: Reversible airway disease is defined as increase in FEV1 of ≥ 12% over baseline 
and an absolute change of ≥ 200 mL within 30 minutes following 4 inhalations of 
albuterol/salbutamol inhalation aerosol/spacer (or equivalent nebulised treatment with 
albuterol/salbutamol solution).
5. Current Therapy:

Short-Acting Beta2-Agonists (SABA): prescribed SABA for at least 12 weeks 
prior to screening. 
No ICS, LABA, long acting muscarinic anatagonist (LAMA), leukotriene receptor 
antagonist (LTRA) therapy for three months prior to the start of the study.
6. Non-smoker or ex-smoker (no smoking in previous 12 weeks, ≤10 pack years).
7. Screening and Day -7 AM FeNO values > 40ppb.
NOTE: Both screening and Day -7 AM FeNO values for Treatment Period 1 need to 
be > 40ppb for the subject to be eligible.
WEIGHT
8. Bodyweight and BMI: Bodyweight  ≥ 50 kg and Body Mass Index (BMI) within the 
range 18.0-40.0 kg/m2 (inclusive)
SEX
9. Male OR Female
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one 
of the following conditions applies:Non-reproductive potential defined as:
Pre-menopausal females reporting one of the following:

Tubal ligation

Hysteroscopic tubal occlusion procedure with follow-up confirmation of 
bilateral tubal occlusion 

Hysterectomy


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
Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 3) from 30 days prior to the first dose of 
study medication and until after the last dose of study medication and completion of 
the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
10. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY
1. A history of life-threatening asthma.
NOTE: Life-threatening asthma is defined as an asthma episode that required intubation 
and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the 
last 5 years
2. Other significant pulmonary diseases to include (but not limited to): pneumonia, 
pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, 
chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or other 
respiratory abnormalities other than asthma.
3. 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 screening 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 


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the subject’s ability to participate in the study.
However, subjects can be rescreened to allow for an adequate time period (of at least 4
weeks) between resolution of the infection and the date of randomisation.
4. Asthma Exacerbation: Any asthma exacerbation requiring oral corticosteroids 
within 12 weeks of screening or that resulted in overnight hospitalization requiring 
additional treatment for asthma within 6 months prior to screening.
CONCOMITANT MEDICATIONS
5. Concomitant Medications: These are listed in detail in Section 6.9 of the protocol.
Restrictions of nitrate-rich foods are listed in detail in Section 6.9.1.1 of the protocol.
RELEVANT HABITS
6. Tobacco Use: Current smokers or a smoking history of 10 pack years. A subject 
may not have used any inhaled tobacco products in 12 weeks preceding the screening 
visit.
CONTRAINDICATIONS 
7. Previous Participation: Exposure to more than four new chemical entities within 12 
months prior to the first dosing day.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
8. Other concurrent Diseases/Abnormalities: A subject has 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 study results if the condition/disease exacerbated during the 
study.
The list of additional excluded conditions/diseases includes, but is not limited to the 
following:
Congestive heart failure
Known aortic aneurysm
Clinically significant coronary heart disease
Clinically significant cardiac arrhythmia
Stroke within 3 months of Visit 1
Uncontrolled hypertension*
Recent or poorly controlled peptic ulcer
Haematologic, hepatic**, or renal disease
Immunologic compromise
Current malignancy***
Tuberculosis (current or untreated)****
Cushing’s disease
Addison’s disease
Uncontrolled diabetes mellitus
Liver cirrhosis
Systemic Lupus Erythematosus
Uncontrolled thyroid disorder
Recent history of drug or alcohol abuse


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*Two or more measurements with systolic BP>160mmHg, or diastolic BP >100mmHg 
**Subjects with chronic stable hepatitis B and C are acceptable provided their screening ALT is < 2x upper limit of 
normal (ULN) and the subject otherwise meets the entry criteria. Subjects who have chronic co-infection with both 
hepatitis B and hepatitis C are not eligible.
***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)
****Subjects with a history of tuberculosis infection who have completed an appropriate course of antituberculous 
treatment may be suitable for study entry provided that there is no clinical suspicion of active or recurrent 
disease.
9. Oropharyngeal examination: A subject will not be eligible if he/she has clinical 
visual evidence of oral candidiasis at screening.
10. Pregnancy and Lactating Females:

Pregnant females as determined by positive serum hCG test at screening or by 
positive urine hCG test prior to dosing.

Lactating females
11. Allergies:

Milk Protein Allergy: History of severe milk protein allergy.

Drug Allergy: Any adverse reaction including immediate or delayed 
hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, 
inhaled, or systemic corticosteroid therapy.  Known or suspected sensitivity to 
the constituents of the Dry Powder Inhaler (DPI) (i.e., lactose or magnesium 
stearate).

Historical Allergy: History of drug or other allergy that, in the opinion of the 
investigator or GSK Medical Monitor, contraindicates their participation.
5.3.
Screening Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (SAEs) (see Section 7.4.1.6).
Subjects who initially fail screening based on not meeting one of the inclusion/exclusion 
criteria may be rescreened subsequently. A limited rescreen checking this parameter 
against the inclusion/exclusion criteria may be performed, and if the subject then meets 
all the eligibility criteria, they would be allowed to be enrolled onto the study. However, 
repeat Day -7 visits cannot be performed.
5.4.
Withdrawal/Stopping Criteria
Worsening asthma: The following criteria will be used to aid the Investigator in 
determining asthma stability. A randomised subject who meets any of the following 
stopping criteria will be withdrawn from the study:


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
Clinic PEF and FEV1 below the stability limit values calculated at pre-treatment Day 
1, Treatment Period 1.  Subjects must have completed a minimum of at least 10 out 
of 14 peak flow measurements during the one week prior to randomisation (Day -7 
to Day 1).

During the study, the subject experienced:
1.
At least 4 consecutive days in which the PEF (either AM, PM or both) 
has fallen below the PEF Stability Limit calculated at pre-treatment Day 
1, Treatment Period 1 OR
2.
At least 3 days in which 12 inhalations/day of albuterol/salbutamol 
were used.

Subjects who experience a protocol-defined 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 visit due to asthma that required systemic corticosteroids.

Clinical asthma worsening which in the opinion of the investigator requires 
additional asthma treatment other than study medication or study supplied albuterol/ 
salbutamol.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.5.
Subject and Study Completion
A complete subject is one who has completed both treatment periods, all assessments up 
to Day 35 of both treatment periods, and all of the follow-up assessments.


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The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
FF/Vilanterol Inhalation Powder ,
100/25 mcg per blister
Placebo To Match FF/Vilanterol 
Inhalation Powder
Formulation 
description:
First strip: FF blended with lactose, 
100 mcg per blister
Second strip: Vilanterol  blended 
with lactose and magnesium 
stearate1, 25 mcg per blister2
First strip: lactose
Second strip: lactose and magnesium 
stearate1
Dosage form:
Dry Powder Inhaler
Dry Powder Inhaler
Unit dose 
strength(s)/Dosa
ge level(s):
FF/Vilanterol
100/25 mcg2
N/A
Route of
Administration/
Duration:
Inhaled/ Taken once a day for 14 ± 2 
days
Inhaled/Taken once a day for 14 ± 2 
days
Dosing 
instructions:
1 inhalation 
1 inhalation
Physical 
description:
Dry powder Inhaler 
Manufacturer/
source of 
procurement:
GSK
GSK
1.
Magnesium stearate 1% w/w of total drug product
2.
40 mcg of Vilanterol trifenatate (triphenylacetate salt) is equivalent to 25 mcg of Vilanterol (free base).
6.2.
Treatment Assignment
Subjects will be assigned to one of two treatment sequences (AB or BA, where A is 
placebo and B is FF/VI 100/25 mcg) in accordance with the randomization schedule 
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software.
If more than 4 subjects prematurely discontinue the study, these subjects may be replaced 
at the discretion of the Sponsor, in consultation with the investigator. A replacement 
subject would be assigned to the same treatment sequence as the original withdrawn 
subject.


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6.3.
Blinding
This will be a double-blind study and the following will apply. 

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the CRF.
The patients, site staff and GSK will remain blinded for the duration of the study.
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
Sealed code break envelopes will be provided to the site, in case of unblinding.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment.  All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the 
investigator and authorized site staff. 


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
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.
6.6.
Compliance with Study Treatment Administration
When subjects are dosed at the site (on Day 1 and Day 14 of each treatment period), they 
will receive study treatment directly from the investigator or designee, under medical 
supervision.  The date and time of each dose administered in the clinic will be recorded in 
the source documents.  The dose of study treatment and study subject identification will 
be confirmed at the time of dosing by a member of the study site staff other than the 
person administering the study treatment.  
When subjects self-administer study treatment at home (on Days 2 to 13 of each 
treatment period), dosing details will be completed by the subjects in individual paper
diaries, and then later transcribed by the site into the CRF. Dosing compliance will be 
assessed through querying the subject during the subsequent site visits and this will be 
documented in the source documents and CRF.  A dosing record for each subject must be 
maintained and reconciled with study treatment and compliance records.
Subject compliance with study treatment administered at home will be reinforced by the 
site using various methods including the use of daily text reminders and weekly 
telephone contact. More details will be given in the SRM.
6.7.
Treatment of Study Treatment Overdose
An overdose for this study will be considered as any dose of study drug more than the 
planned dose on each dosing occasion. In the event of an overdose, there are no 
recommended medications or non-drug therapies for treatment. GSK is not 
recommending specific treatment guidelines for overdose and toxicity management. The 
investigator should contact the GSK Medical Monitor, and is advised to refer to the 
relevant documents for detailed information regarding warnings, precautions, 
contraindications, adverse events, and other significant data pertaining to the study 
drug(s) being used in this study. Such documents may include, but not limited to, the 
Investigator’s Brochure (IB) or equivalent document provided by GSK, the approved 
product label if applicable, or both. Clinical judgment should be used in treating the 


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overdose. Management should be supportive and the investigator should use his/her 
clinical judgement in treating any overdose situation.  Subjects experiencing such adverse 
events will be followed up clinically until the event has resolved.
6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and/or other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.9.
Lifestyle and/or Dietary Restrictions
6.9.1.
Meals and Dietary Restrictions
6.9.1.1.
Nitrate-rich foods
Nitrate-rich foods should be avoided as much as possible from Day -7 throughout the 
duration of the study until completion of the follow-up visit. Details of nitrate-rich foods 
are given in the table below:
Nitrate-rich Food*
Beetroot
Celery
Cabbage
Aubergine
Spinach
Radish
Broccoli
Cauliflower
Carrot
Lettuce
Radish
Turnip/swede
*Vegetables such as beetroot, celery, lettuce, radishes and spinach contribute about 85 to 
90% of an adult’s dietary intake of nitrate, with nitrate levels ranging from 1700 to 2400 
mg/kg food [Vints, 2005]. This food should be avoided as much as possible for the 
duration of the study.  Specially prepared food will be given to the subjects whilst in-
clinic and subjects will be reminded about this restriction for all other periods.
6.9.1.2.
Caffeine and Alcohol

From the screening visit until the follow up visit, subjects must not drink more than 
the equivalent of 4 standard cups of coffee/tea per day (e.g. 4 single shot cups or 2 


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double shot cups) and they must not drink more than 2 standard alcoholic drinks per 
day (e.g. 2 standard glasses of wine, where a standard glass = 175 mL).

Subjects must abstain completely from coffee, tea, and alcohol within 2 hours of any 
of the lung function measurements.
6.9.2.
Activity
Patients should avoid rigorous exercise for at least 2 hours before each FeNO and lung 
function measurement.
6.10.
Concomitant Medications and Non-Drug Therapies
6.10.1.
Permitted Medications and Non-Drug Therapies
6.10.1.1.
Permitted asthma medications
The current asthma therapy for the patients enrolled in this study will be Short-Acting 
Beta2-Agonists (SABA), and patients must have been prescribed SABA for at least 12 
weeks prior to screening.
6.10.1.2.
Other permitted medications
Regarding subjects with any upper respiratory disorders including allergic rhinitis (both 
seasonal and perennial) and chronic rhinosinusitis (with or without nasal polyps), any 
subject who is on chronic maintenance therapies for these conditions will continue on 
their current standard of care medications (i.e. intranasal corticosteroids, antihistamines, 
cromones) throughout the entire duration of the study.
6.10.2.
Prohibited Medications and Non-Drug Therapies
6.10.2.1.
Prohibited asthma medications
Inhaled corticosteroids (ICS), long acting beta agonists (LABA), leukotriene receptor 
antagonists (LTRA), long acting muscarinic anatagonists (LAMA), oral steroids,
omalizumab (Xolair) and mepolizumab (Nucala) are prohibited from 3 months prior to 
the start of the study until after the study follow-up visit.
6.10.2.2.
Prohibited non-asthma medications
The following medications may not be used during the study from first dosing to the end 
of Treatment Period 2 inclusive:

Anticonvulsants (barbiturates, hydantoins, and carbamazepine)

Polycyclic antidepressants

β-adrenergic blocking agents

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Phenothiazines


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
Monoamine oxidase (MAO) inhibitors
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1.
Additional detailed procedures for obtaining each assessment are provided in the Study
Reference Manual (SRM) where specified.
The timing and number of planned study assessments, including safety and spirometry 
assessments may be altered during the course of the study to ensure appropriate 
monitoring. The change in timing or addition of time points for any planned study 
assessments must be approved and documented by GSK, but this will not constitute a 
protocol amendment. The Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) will be informed of any safety issues that require alteration of the safety 
monitoring scheme. 
A subject may attend an unscheduled visit at any time if the investigator deems necessary 
for safety reasons.


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7.1.
Time and Events Table
Procedure
Screening 
(up to 42 
days prior to 
Day 1)
Study Day (each treatment period)
Follow-up 
(Days 35-
42)13
Notes
Day -7
(start of 
run-in)1
Day 
1
Days 2-
13
Days 
14-19
Day 
21
Day 
35
Out-patient visit to the unit
X
X
X
X
X
X
1 Day -7 is the start of the one 
week run-in period and therefore 
this visit and the assessments on 
this day only apply to Treatment 
Period 1
Admission to the unit
X
Informed consent
X
Inhaler, PEF meter and FeNO device 
practice
X
Inclusion and exclusion criteria/eligibility
review
X
X
X2
2 Treatment Period 1 only
Demography
X
Full physical exam including height and 
weight
X
Medical history (includes substance usage  
[and family history of premature CV 
disease])
X
Substances: [Drugs, Alcohol, 
tobacco and caffeine]
Past and current medical conditions  
[including cardiovascular medical history]
X
Urine pregnancy test (WCBP)
X
X3
X
X
3 Collected pre-dose
Vital signs
X
Set up PEF and FeNO monitoring
X
Study Treatment
X4
X5
4Dosing every morning; dosing in 
the unit on Days 1 and 14 and at 
home on Days 2-13
5 Dosing on the morning of Day 14 
only


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Procedure
Screening 
(up to 42 
days prior to 
Day 1)
Study Day (each treatment period)
Follow-up 
(Days 35-
42)13
Notes
Day -7
(start of 
run-in)1
Day 
1
Days 2-
13
Days 
14-19
Day 
21
Day 
35
Exploratory biomarker sampling6
X
X
X
X
6These measurements are taken 
at baseline (Day 1 pre-dose), at 
the end of treatment (Day 15), on 
Day 21 and on Day 35.
FEV1 readings7
X
X8
X9
X10
X10
7 Measured in the unit only
8Taken pre-dose
9 Collected AM (pre-dose on Day 
14) and PM
10Collected AM only
FeNO assessment11
X
==============================================
11 Start of collection 7 days before 
Day 1 (Day -7), then collected 
every day AM and PM through to 
Day 35 of each treatment period.
PEF12
======================================================
12Collected AM and PM every day 
from Day -7 through to Day 35 for 
Treatment Period 1, and from Day 
1 through to follow up for 
Treatment Period 2.
AE/SAE review
===========================================================
Concomitant medication review
===========================================================
13 Follow up visit only after 
Treatment period 2. The follow-up 
visit can be combined with the 
Day 35 visit for Treatment Period 
2.
Issue of diary card
X
X14
14 Second diary card given out on 
Day 21 of Treatment Period 1, to 
capture data for Treatment Period 
2


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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
7.3.
Pharmacodynamics
7.3.1.
FeNO measurements
Fractionated exhaled nitric oxide (FeNO) measurements will be collected from 7 days 
before Day 1 (start of treatment) (Day -7), and then every morning and evening all the 
way through to Day 35 of each treatment period (see Time and Events Table in Section 
7.1).  Additional time points may be added during the course of the study based on newly 
available information.
Single FeNO measurements will be collected at each time-point in accordance with 
ATS/ERS guidelines. These measurements will be recorded using a NIOX Vero device
which will be supplied to the patient on Day -7 by the site. Measurements will be 
captured electronically and regularly downloaded by the site at each clinic visit.
Training and practice with these devices will be given to each patient at the screening 
visit.
More details will be given in the SRM.
7.3.2.
Spirometry
Three technically acceptable FEV1 measurements will be made at the time points outlined 
in the Time and Events table (Section 7.1) and the highest values will be recorded.
Spirometry assessments must be performed in accordance with ATS/ERS guidelines 
[ATS/ERS Task Force, 2005]. The Forced Expiratory Volume during the first 6 seconds 
(FVC6), rather than the full Forced Vital Capacity (FVC) will be measured.
Screening FEV1 must be measured between 7am-10am.
7.3.2.1.
Reversibility testing
The presence of reversible airways disease can have been demonstrated historically 
within 6 months of the screening visit.
OR
It must be demonstrated at the screening visit.


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Following the spirometry assessment at screening, administer a single dose of 400 g 
inhaled albuterol / salbutamol using a metered dose inhaler (MDI) and spacer device.  
The bronchodilator will be withheld for 6 hours prior to the screening visit. At any time 
point between 15 and 30 minutes post administration of albuterol / salbutamol, take 
triplicate FEV1 measurements and record the highest.
Reversibility is shown if there is an increase in FEV1 of 12.0% over baseline and an 
absolute change of 200 mL between the highest pre and post salbutamol FEV1.
7.3.2.2.
FEV1 Stability Limit
Calculate a FEV1 Stability Limit as follows:
Best pre-dose FEV1 x 80%
The FEV1 Stability Limit value will be calculated at the pre-dose time point of treatment 
period 1 and used as reference until the pre-dose time point of treatment period 2. The 
stability limit will be re-calculated at the pre-dose time point of treatment period 2 and
used for the remainder of the study.
7.3.3.
PEF
Each subject will be given a PEF meter by the site on Day -7. Data will be captured 
electronically.
Subjects must measure morning and evening PEF as indicated in the time and events 
table. Three technically acceptable PEF measurements will be collected at each time 
point and the highest values will be recorded.
7.3.3.1.
PEF Stability Limit
Subjects must have completed a minimum of at least 10 out of 14 peak flow 
measurements during the one week prior to randomisation (Day -7 to Day 1).
Calculate a PEF Stability Limit as follows:
Mean AM PEF from the available 7 days preceding Day 1 dose x 80%
The AM PEF from the morning of Day 1 will be included in the calculation of the PEF 
stability limit.
The PEF Stability Limit value will be used for the remainder of the study.
PEF devices will be set to alert the subject if their PEF drops below this limit.
7.3.3.2.
PEF below Stability Limit
Should the PEF fall below the PEF stability limit, the subject should contact the site. The 
investigator must monitor the subject and withdraw the subject is he/she meets any of the 
criteria in Section 5.4.


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7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs and physical 
examinations) may be added during the course of the study based on newly available data 
to ensure appropriate safety monitoring.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 2.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

AEs will be collected from the start of the run-in period (Day -7) until the follow-up 
contact (see Section 7.4.1.3), at the time-points specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 2.

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 2.
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”


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
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 2.
7.4.1.4.
Cardiovascular and Death Events
Investigators will be required to fill out event specific data collection tools for the
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thrombosis

Deep Venous Thrombosis

Revascularization
For these cardiovascular events detailed above and for all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be 
required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in subjects with asthma and 
can be serious/life threatening:


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1.
Wheezing
2.
Chest tightness or chest heaviness
3.
Coughing
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of a SAE).  These events will be recorded 
on the DRE page in the subject’s CRF within 5 working days.
NOTE: However, if either of the following conditions apply, then the event must be 
recorded and reported as an SAE (instead of a DRE): 

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, or

The investigator considers that there is a reasonable possibility that the event 
was related to treatment with the investigational product
7.4.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until the follow-up visit.

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix
3.


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7.4.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses
7.4.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure (BP) and pulse rate. 
7.4.5.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments as detailed in Table 1 must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled
with the subject number, protocol number, site/centre number, and visit date. Reference 
ranges for all safety parameters will be provided to the site by the laboratory responsible 
for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Parameters to be tested are listed in Table 1.
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Other 
Screening 
Tests

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential)1
NOTES :
1.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.


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7.5.
Biomarker(s)/Pharmacodynamic Markers
7.5.1.
Exploratory Biomarkers
With the subject’s consent, blood samples will be collected during this study and used for 
the purposes of measuring exploratory biomarkers, including but not limited to, blood 
eosinophil and serum periostin levels on Day 1 pre-dose (baseline) and following inhaled 
administration of FF/VI.
Samples will be collected at the time-points indicated in the Time and Events Table in 
Section 7.1. The timing of the collections may be adjusted on the basis of emerging data 
from this study or other new information in order to ensure optimal evaluation of the PD 
endpoints. Analyses of these biomarker data may be reported separately. Further details 
will be provided in the SRM.
8.
DATA MANAGEMENT

For this study, subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Subject paper diaries will also be used for when the subjects are at home, for 
collection of dosing information, details of any AEs/SAEs and concomitant 
medications.  These will then be transcribed into the CRF by clinic staff.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
No formal hypothesis will be tested, an estimation approach will be adopted to address 
the primary objective. A point estimate and corresponding 95% CI will be constructed for 
the treatment ratio of test treatment, (test) and reference treatment(reference), where 
FF/VI 100/25mcg is the test treatment and placebo the reference treatment.


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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Approximately 28 subjects will be recruited to ensure 24 evaluable subjects.  An 
evaluable subject is defined as a subject who completes dosing and critical assessments in 
both treatment periods.
A re-analysis of FeNO data from the FFA10028 study [GlaxoSmithKline Document 
Number GM2003/00418/00] was carried out to estimate the within-subject coefficient of 
variation (CVw) from a repeated measures analysis using the treatments and time-points 
most relevant to this study (i.e. FF and placebo treatments and all pre-dose, 12 hour and 
24 hour time-points on all days assessed (Days 1-5).  A mixed effects repeated measures 
model was fitted with fixed effect terms for period, treatment, day, time, period-level 
baseline, subject-level baseline, (period-level baseline)*day*time interaction term and the 
treatment*day*time interaction term. Day*time interaction term was fitted as a repeated 
measure.  FeNO was loge-transformed prior to deriving subject-level baseline and period-
level baseline.  The CVw from the re-analysis was 21.6%.
Based upon a CVw of 21.6% and a sample size of 24 subjects, it is estimated that the 
lower and upper bounds of the 95% confidence interval for the treatment ratio (FF/VI vs 
Placebo) for FeNO will be approximately 14% of the point estimate.
9.2.2.
Sample Size Sensitivity
A sensitivity analysis was conducted in the event that the variability deviates from that 
estimated from the FFA10028 study [GlaxoSmithKline Document Number 
GM2003/00418/00]. The table below shows precision estimates for varying within 
subject coefficient of variability keeping all other variables constant.
Confidence Level
Sample Size (N)
CVw%
Half Width (%)
0.95
24
15%
10%
20%
13%
25%
16%
30%
20%
The precision estimates are deemed acceptable to assess the study objectives.
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation or adjustment will be performed.


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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Statistical analyses of the pharmacodynamic parameter data will be the responsibility of 
Clinical Statistics, GlaxoSmithKline.
Subjects excluded from any analyses will be fully documented and justified within the 
clinical study report. All analyses will be based on the actual treatment that each subject 
received. Any departures from the planned treatment according to the randomisation 
schedule will be documented in the clinical study report.
The ‘All Subjects’ population will consist of all subjects randomised to treatment who 
received at least one dose of study treatment.
The ‘Pharmacodynamic’ (PD) population will consist of all subjects from the ‘All 
Subjects’ population who had at least one PD assessment.
9.3.2.
Interim Analysis
No interim analysis is planned.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
Following loge-transformation, primary endpoint of FeNO change from baseline ratio
following cessation of treatment will be analyzed using a mixed effects repeated 
measures model with fixed effect terms for period, treatment, day, time, (period-level 
baseline)*day*time interaction term, treatment*day*time interaction term, period-level 
baseline and subject-level baseline. Day*time interaction term will be fitted as repeated 
measure. FeNO will be loge-transformed prior to deriving subject-level baseline and 
period-level baseline.  Point estimates and their associated 95% confidence intervals will 
be constructed for the difference [FF/VI 100/25mcg] – [Placebo] at each timepoint 
(AM/PM i.e. pre-dose & 12 hours) on each day. The point estimates and their associated 
95% confidence intervals will then be back-transformed to provide point estimates and 
95% confidence intervals for the ratios, [FF/VI 100/25mcg]/[Placebo] for each day and 
AM/PM timepoint. Further details will be provided in the Reporting and Analysis Plan
(RAP) regarding the model to be fitted and model checking.
9.4.2.
Secondary Analyses
Secondary endpoints of FeNO change from baseline ratio during treatment and FEV1 will 
be analysed similarly to the primary FeNO endpoint.  FEV1 will not be log-transformed.
PEF data will be listed and summarised.
Further details will be provided in the RAP.


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9.4.3.
Other Analyses
Safety data will be listed and summarised. Exploratory biomarker data (including blood 
eosinophil and serum periostin data) will be summarized descriptively, if available.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
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 the International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (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.  
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.


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GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.


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


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11.
REFERENCES
Allen A, Bareille PJ, Rousell VM. Fluticasone Furoate, a Novel Inhaled Corticosteroid, 
Demonstrates Prolonged Lung Absorption Kinetics in Man Compared with Inhaled 
Fluticasone Propionate. Clin Pharmacokinet. 2013;52:37–42
ATS/ERS Task Force:Standardisation of Lung Function testing. Standardization of 
spirometry. Eur Respir J. 2005.26:319-338.
ATS, 2011. An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric 
Oxide Levels (FENO) for Clinical Applications. Am J Respir Crit Care Med Vol 184. Pp 
602–615.
Bjermer L, Alving K, Diamant Z, et al. Current evidence and future research needs for 
FeNO measurement in respiratory disease. Resp Med. 2014;108:830-841.
GlaxoSmithKline Document Number 2014N194756_00. Study Number HZA116592. A 
Randomised, Double-Blind, Placebo-Controlled Cross-Over Study to Determine the 
Bronchodilator Effect of A Single Dose of Fluticasone Furoate (FF)/ Vilanterol (VI) 
100/25 mcg Combination Administered in the Morning in Adult Patients With Asthma. 
29th January 2015.
GlaxoSmithKline Document Number GM2003/00418/00. Study Number FFA10028. A 
45andomized, double-blind, placebo-controlled, balanced incomplete block, multiple 
dose crossover study to investigate the effect of 3 days repeat dosing of GW685698X 
(250 and 1000 µg) and fluticasone propionate (1000 µg) on exhaled nitric oxide in mild 
to moderate asthmatic patients. 21st June 2004.
GlaxoSmithKline Document Number GM2005/00525/00. Study Number SIG103337. A 
45andomized, double-blind, placebo-controlled, incomplete block, 4-period crossover 
study to investigate the effects of 5-day repeat inhaled doses of fluticasone propionate 
(BID, 50-2000 mcg) on airway responsiveness to adenosine-5’-monophosphate (AMP) 
challenge when delivered after the last dose in mild asthmatic subjects. 20th October 
2006.
GlaxoSmithKline Document Number RM2008/00012/07. Fluticasone Furoate + 
Vilanterol Investigator Brochure (IB). 7th August 2015.
Hankinson J L, Odencrantz, JR; Feden, KB. Spirometric Reference Values from a 
Sample of the General U.S. Population. AM J Respir Crit care Med. 1999;159:179-187.
Kharitonov SA, Donnelly LE, Montuschi P, Corradi M, Collins JV, Barnes PJ. Dose-
dependent onset and cessation of action of inhaled budesonide on exhaled nitric oxide. 
Thorax. 2002;57:889-896.
Nolte H, Pavord I, Backer V, et al. Dose-dependent anti-inflammatory effect of inhaled 
mometasone furoate/formoterol in subjects with asthma. Respir Med. 2013;107:656-664


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Salter M, Biggadike K, Matthews JL,. Pharmacological properties of the enhanced-
affinity glucocorticoid fluticasone furoate in vitro and in an in vivo model of respiratory 
inflammatory disease. Am J Physiol Lung Cell Mol Physiol. 2007;293:L660–L667.
Silkoff P, McClean P, Spino M, Erlich L, Slutsky AS, Zamel N. Dose-response 
relationship and reproducibility of the fall in exhaled nitric oxide after inhaled 
beclomethasone dipropionate therapy in asthma patients. Chest. 2001;119:1322-1328.
Smith AD, Cowan JO, Brassett KP, et al. Exhaled nitric oxide: a predictor of steroid 
response. Am J Resp Crit Care Med. 2005;172:453-459.
Taylor DR, Pijnenburg MW, Smith AD, Jongste JCD. Exhaled nitric oxide 
measurements: clinical application and interpretation and symptoms in mild asthma. 
Thorax. 2006;61:817-827.
Valotis A, Hogger P. Human receptor kinetics and lung tissue retention of the enhanced-
affinity glucocorticoid fluticasone furoate. Respir Res. 2007;8:54.
Van Rensen EL, Straathof KC, Veselic-Charvat MA, Zwinderman AH, Bel EH, Sterk 
PJ.. Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils and 
exhaled nitric oxide levels in patients with asthma. Thorax. 1999; 54: 403-408.
Vints AM, Oostveen E, Eeckhaut G, Smolders M, De Backer WA. Time-dependent 
effect of nitrate-rich meals on exhaled nitric oxide in healthy subjects. Chest. 2005 
Oct;128(4):2465-70.


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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
µg
Microgram
AE
Adverse Event
ATS
American Thoracic Society
BD
Twice daily
BMI
Body mass index
BP
Blood pressure
COPD
Chronic obstructive pulmonary disease
CPEMT
Clinical Pharmacology Experimental Medicine and Technologies
CRF
Case Report Form
CV
Cardiovascular
DPI
Dry powder Inhaler 
ED50
Effective dose for 50% of people receiving the drug
Emax
Maximum possible effect for the agonist
eNO
Exhaled Nitric Oxide
ERS
European Respiratory Society
FeNO
Fraction of exhaled nitric oxide
FEV1
Forced expiratory volume in 1 second
FF
Fluticasone furoate
FP
Fluticasone proprionate
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
FVC6
Forced Vital Capacity in 6 seconds
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilence
GSK
GlaxoSmithKline
hCG
Human chorionic gonadotropin
HIV
Human Immunodeficiency Virus
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
ICS
Inhaled Corticosteriods
IEC
Independent Ethics Committee 
IP
Investigational Product
IRB
Institutional Review Board
Kg
Kilogram
L
Liter
LABA
Long-acting, beta2-receptor agonist
LAMA
long acting muscarinic anatagonist


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LTRA
leukotriene receptor antagonist
MAO
Monoamine oxidase
mcg
Micrograms
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
mmHg
Millimeter of mercury
MSDS
Material Safety Data Sheet
N
Number
OD
Once daily
PEF
Peak Expiratory Flow 
ppb
Parts per billion
RAP
Reporting and Analysis Plan
SABA
Short acting beta2-receptor agonist
SAE
Serious adverse event(s)
SRM
Study Reference Manual
TAU
Therapeutic Area Unit
UK
United Kingdom
ULN
Upper limit of normal
VI
Vilanterol
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
BREO ELLIPTA
SAS
RELVAR ELLIPTA


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12.2.
Appendix 2: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.2.1.
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).
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 


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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.2.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

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


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e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.2.3.
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


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
Revascularization
12.2.4.
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.
12.2.5.
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 


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the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
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.


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12.2.6.
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 and the GSK Study 
Manager

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the GSK Study Manager by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.3.
Appendix 3: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.3.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.3.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.


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
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 2. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication or be withdrawn from the study.

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.
12.3.3.
References
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
201499
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 201499 : A 
randomised, placebo-controlled, double-blind, two period 
crossover study to characterise the exhaled nitric oxide time 
profile as a biomarker of airway inflammation in adult asthma 
patients following repeat administration of inhaled 
Fluticasone Furoate (FF)/ Vilanterol (VI) 100/25 mcg
Compound Number 
:
GW685698+GW642444
Effective Date 
:
11-Apr-2017
Description :

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 2015N241692_00

The planned analyses and output to be included in Clinical Pharmacology Study 
Report for Protocol 201499. This RAP is intended to describe the pharmacodynamic, 
biomarker, safety and tolerability analyses required for the study which will be 
provided to the study team members to convey the content of the reporting efforts, 
specifically Statistical Analysis Complete (SAC). 
Author’s Name and Functional Area: 
 
31-Mar-2017
Associate Statistician (QSI)
Approved by: 
11-Apr-2017
Manager, Statistics
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


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TABLE OF CONTENTS
PAGE NO.
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................4
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................7
2.4.
Statistical Hypotheses...................................................................................8
3.
PLANNED ANALYSES ............................................................................................8
3.1.
Interim Analyses ...........................................................................................8
3.2.
Final Analyses ..............................................................................................8
4.
ANALYSIS POPULATIONS .....................................................................................9
4.1.
Protocol Deviations.......................................................................................9
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................10
6.
STUDY POPULATION ANALYSES .......................................................................11
6.1.
Overview of Planned Analyses ...................................................................11
7.
PRIMARY STATISTICAL ANALYSES....................................................................12
7.1.
Pharmacodynamic Analyses.......................................................................12
7.1.1.
Overview of Planned Pharmacodynamic Analyses ......................12
7.1.1.1.
Statistical Analysis of Pharmacodynamic 
Parameters.................................................................12
7.1.2.
Planned Primary Pharmacodynamic Statistical Analyses.............13
8.
SECONDARY STATISTICAL ANALYSES .............................................................13
8.1.
Pharmacodynamic Analyses.......................................................................13
8.1.1.
Overview of Planned Pharmacodynamic Analyses ......................13
8.1.2.
Planned Secondary Pharmacodynamic Statistical Analyses .................14
9.
OTHER STATISTICAL ANALYSES .......................................................................15
9.1.
Overview of Planned Biomarker Analyses ..................................................15
9.1.1.
Overview of Planned Analyses ....................................................15
9.2.
Overview of Safety Analyses ......................................................................16
9.2.1.
Overview of Planned Adverse Events Analyses...........................16
9.2.2.
Overview of Planned Clinical Laboratory Analyses ......................16
9.2.3.
Overview of Planned Other Safety Analyses................................17
10. REFERENCES.......................................................................................................18
11. APPENDICES........................................................................................................19
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................20
11.2.
Appendix 2: Data Management...................................................................21
11.3.
Appendix 3: Time & Events.........................................................................22
11.4.
Appendix 4: Treatment States and Phases.................................................25


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11.4.1.
Treatment States for AE Data......................................................25
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................26
11.5.1.
Study Treatment & Sub-group Display Descriptors......................26
11.5.2.
Baseline Definition & Derivations .................................................26
11.5.2.1.
Baseline Definitions....................................................26
11.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................26
11.5.3.
Reporting Process & Standards...................................................27
11.6.
Appendix 6: Derived and Transformed Data ...............................................29
11.6.1.
General........................................................................................29
11.6.2.
Study Population..........................................................................29
11.6.3.
Pharmacodynamic.......................................................................30
11.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............31
11.7.1.
Premature Withdrawals................................................................31
11.7.2.
Handling of Missing Data.............................................................31
11.7.2.1.
Handling of Missing Dates..........................................31
11.7.2.2.
Handling of Partial Dates............................................32
11.7.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................32
11.8.
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................33
11.8.1.
Statistical Analysis Assumptions..................................................33
11.9.
Appendix 9 – Abbreviations & Trade Marks ................................................34
11.9.1.
Abbreviations...............................................................................34
11.9.2.
Trademarks .................................................................................34
11.10. Appendix 10: List of Data Displays..............................................................35
11.10.1. Data Display Numbering..............................................................35
11.10.2. Mock Example Shell Referencing ................................................35
11.10.3. Deliverable [Priority].....................................................................35
11.10.4. Study Population Tables..............................................................36
11.10.5. Pharmacodynamic Tables ...........................................................38
11.10.6. Pharmacodynamic Figures ..........................................................39
11.10.7. Safety Tables...............................................................................40
11.10.8. Biomarker Tables.........................................................................40
11.10.9. Biomarker Figures .......................................................................41
11.10.10.ICH Listings .................................................................................41
11.10.11.Non-ICH Listings..........................................................................43
11.11. Appendix 11: Example Mock Shells for Data Displays ................................44


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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this RAP is to describe the planned analyses and output 
to be included in the Clinical Study Report for Protocol 
GlaxoSmithKline Document Number 2015N241692_00

The planned analyses and output to be included in Clinical 
Pharmacology Study Report for Protocol 201499. This RAP is 
intended to describe the pharmacodynamic, biomarker, safety and 
tolerability analyses required for the study which will be provided to 
the study team members to convey the content of the reporting efforts, 
specifically Statistical Analysis Complete (SAC).
Protocol

Reporting and Analysis Plan is based on original protocol (Dated: [12-
JAN-2016]) for study 201499 [GlaxoSmithKline Document Number: 
2015N241692_00]                                                                                     
Primary 
Objective /
Endpoint
To characterise the fraction of exhaled nitric oxide (FeNO) time profile 
following repeat administration of fluticasone furoate/vilanterol (FF/VI) 
100/25mcg combination  in comparison with placebo in subjects with 
asthma as measured by :

Change from baseline FeNO over time following the cessation 
of repeat dose treatment with FF/VI.
Secondary 
Objective/
Endpoint
Change in FeNO over the treatment period following repeat administration 
of FF/VI 100/25mcg combination in comparison with placebo in subjects 
with asthma  measured by:

Change from baseline FeNO over the FF/VI treatment period.
To determine the Peak Expiratory Flow (PEF) during and following repeat 
administration of FF/VI 100/25mcg combination in comparison with 
placebo in subjects with asthma  measured by:

Measurement of PEF during treatment and following cessation 
of repeat dose treatment with FF/VI.
To determine forced expiratory volume in 1 second (FEV1) following 
repeat administration of FF/VI 100/25mcg combination in comparison with 
placebo in subjects with asthma as measured by:

Measurement of FEV1 pre-treatment and for up to 7 days after 
cessation of repeat dose treatment with FF/VI.


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Overview
Key Elements of the RAP
Exploratory
Objective / 
Endpoint
To investigate the effect of repeat administration of FF/VI 100/25mcg 
combination on exploratory biomarkers, including but not limited to, blood 
eosinophil levels and serum periostin levels, in comparison with placebo in 
subjects with asthma as measured by:

Measurement of exploratory biomarkers, including but not 
limited to, blood eosinophil and serum periostin levels at baseline, and 
at various time points after cessation of repeat dose treatment with 
FF/VI
Study 
Design
Randomised, double blind, placebo-controlled, two-period, crossover 
repeat dose study in adult subjects with asthma. 
Approximately twenty eight adult asthmatic subjects will be enrolled to 
ensure 24 subjects complete dosing and critical assessments for both 
treatment periods.
Each subject will participate in two treatment periods of 14 (+ 2 days).  
FF/VI 100/25mcg will be received once daily (AM dosing) in one period 
and placebo (AM dosing) will be administered in the other period. At the 
end of each treatment period , there will be a monitoring period of 21 days.  
Following the 21 day monitoring period following treatment period 1, there 
may be a period of up to a further 4 weeks before the subjects start 
treatment period 2. 
Planned 
Analyses

No interim analysis is planned.

The final planned analyses will be performed after database freeze has 
been declared.
Analysis 
Population

All Subjects Population comprise of all subjects randomised to 
treatment who received at least one dose of study medication

Pharmacodynamic Population comprise of all  Subjects in the 
‘All Subjects’ population who had at least one PD assessment
Hypothesis
No formal hypothesis will be tested, an estimation approach will be 
adopted to address the primary objective. A point estimate and 
corresponding 95% CI will be constructed for the treatment ratio of test 
treatment, μ(test) and reference treatment, µ(reference), where FF/VI 
100/25mcg is the test treatment and placebo the reference treatment
Primary 
Analyses
FeNO, change from baseline ratio will be formally analysed following loge-
transformation.  A mixed effects repeated measures model will be fitted 
with fixed effect terms for period, treatment, day, time, (period-level 
baseline)*day*time interaction term, treatment*day*time interaction term, 
period-level baseline and subject-level baseline. Day*time interaction term 
will be fitted as repeated measure. FeNO will be loge-transformed prior to 
deriving subject-level baseline and period-level baseline.  


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Overview
Key Elements of the RAP
Secondary 
Analyses
FeNO change from baseline ratio during treatment and FEV1 will be 
analysed similarly to the primary FeNO endpoint. FEV1 will not be log-
transformed prior to analysis.
PEF will be summarised.
Safety 
Analyses
Safety data will  be summarized
Biomarker 
Analyses
Exploratory endpoints of biomarkers will be summarized
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol [Dated: 12-JAN-2016].
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary (Pharmacodynamic)
Primary (Pharmacodynamic)
To characterise the fraction of exhaled nitric 
oxide (FeNO) time profile following repeat 
administration of fluticasone 
furoate/vilanterol (FF/VI) 100/25mcg 
combination  in comparison with placebo in 
subjects with asthma.
Change from baseline FeNO over time 
following the cessation of repeat dose 
treatment with FF/VI.
Secondary (Pharmacodynamic)
Secondary (Pharmacodynamic)
Change in FeNO over the treatment period 
following repeat administration of FF/VI 
100/25mcg combination in comparison with 
placebo in subjects with asthma.
Change from baseline FeNO over the FF/VI 
treatment period
To determine the Peak Expiratory Flow 
(PEF) during and following repeat 
administration of FF/VI 100/25mcg 
combination in comparison with placebo in 
subjects with asthma.
Measurement of PEF during treatment and 
following cessation of repeat dose treatment 
with FF/VI.
To determine FEV1 following repeat 
administration of FF/VI 100/25mcg 
combination in comparison with placebo in 
subjects with asthma
Measurement of FEV1 pre-treatment and for 
up to 7 days after cessation of repeat dose 
treatment with FF/VI


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Objectives
Endpoints
Exploratory (Biomarker)
Exploratory (Biomarker)
To investigate the effect of repeat 
administration of FF/VI 100/25mcg 
combination on exploratory biomarkers, 
including but not limited to, blood 
eosinophil levels and serum periostin levels, 
in comparison with placebo in subjects with 
asthma
Measurement of exploratory biomarkers, 
including but not limited to, blood 
eosinophil and serum periostin levels at 
baseline, and at various time points after 
cessation of repeat dose treatment with 
FF/VI
2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features
This study is a randomized, double-blind, placebo-controlled, two-period, 
crossover repeat dose study to characterise the exhaled nitric oxide time 
profile as a biomarker of airway inflammation in adult asthmatics.
Dosing
Each subject will participate in two treatment periods of 14 (+/- 2 days).  
FF/VI 100/25 mcg will be received once daily (AM dosing) in one period and 
placebo (AM dosing) will be administered in the other period.  At the end of 
each treatment period, there will be a monitoring period of 21 days.  
Following the 21 day monitoring period following treatment period 1, there 
may be a period of up to a further 4 weeks before the subjects start treatment 
period 2.
Total duration for each subject (from screening to follow-up) will be a 
minimum of 11 weeks, with a maximum of up to 21 weeks, depending on the 
screening period and the time period between Treatment Periods 1 and 2


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Overview of Study Design and Key Features
Treatment 
Assignment
Subjects will be randomized to one of two sequences AB or BA.
Where, A=Placebo and B=FF/VI 100/25mcg.  
Subjects will be administered the first treatment in the sequence in the first 
period and the second treatment in the sequence in the second period.  
2.4.
Statistical Hypotheses
No formal hypothesis will be tested, an estimation approach will be adopted to address 
the primary objective. A point estimate and corresponding 95% CI will be constructed for 
the treatment ratio of test treatment, µ (test) and reference treatment, µ (reference), 
where, FF/VI 100/25mcg is the test treatment and placebo the reference treatment.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned.
3.2.
Final Analyses
Analysis
Details
Final Analyses 
The final planned analyses will be performed after all subjects have 
completed the study and after database freeze/unblinding. See Section 6
Section 9 for all final planned analyses for this study.
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1. All subjects have completed the study as defined in the protocol 
2. All required database cleaning activities have been completed and final database 
release has been declared by Data Management.
3. All protocol deviations have been confirmed
4. All criteria for unblinding the randomisation codes have been met. 
5. Randomisation codes have been distributed according to RandAll NG procedures.
6. Database freeze has been declared by Data Management.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses/Endpoint(s) 
Evaluated
Screened Subjects 

Comprise of all subjects who 
attended the screening visit 

Study Population
All Subjects 
Population

Comprise of all subjects randomised 
to treatment who received at least 
one dose of study medication.

Study Population

Biomarker

Safety
Pharmacodynamic  
Population

Subjects in the ‘All Subjects’
population who had at least one PD 
assessment

Pharmacodynamic

FeNO

FEV1

PEF
NOTES: Please refer to Appendix 10which details the population to be used for each display 
being generated.
4.1.
Protocol Deviations

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed by the study team prior to database release to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset. 
o
The SI dataset will include all protocol deviations, the analysis dataset will 
include only important protocol deviations.  The analysis   dataset will be used for 
the listing and summary of important protocol deviations.

A separate listing of all inclusion/exclusion criteria deviations will also be provided.

The study endpoints will be reported using the populations detailed in Section 4 of 
this document regardless of whether the subjects deviate from the protocol.

If there are subjects with protocol deviations that may potentially impact the PD 
endpoints which needs to be confirmed prior to unblinding, exploratory sensitivity 
analyses may be considered. It further sensitivity analyses of the data are produced, 
they will be detailed in the clinical study report.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
11.2
Appendix 2: Data Management
11.3
Appendix 3: Time and Event
11.4
Appendix 4: Treatment States and Phases
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
11.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses
11.9
Appendix 9: Abbreviations & Trade Marks
11.10
Appendix 10: List of Data Displays
11.11
Appendix 11: Example Mock Shells for Data Displays


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the “All Subjects” population, unless 
otherwise specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 10: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Endpoint 
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition for the Subject Conclusion Record
Y
Reasons for Subject Withdrawal
Y
Screening Status and Reasons for Screen Failure
Y
Y
Subjects Enrolled by Country and Site ID
Y
Subjects for Whom the Treatment Blind was Broken
Y
Planned and Actual Treatments
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Subjects with Inclusion/Exclusion Criteria Deviations
Y
Populations Analysed
Study Populations
Y
Subjects Excluded from Any Population
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y[1]
Y
Age Ranges
Y
Race and Racial Combinations
Y
Y[2]
Prior and Concomitant Medications
Current & Past Medical Conditions
Y
Concomitant Medications
Y
Exposure
Exposure to Study Treatment
Y
Y
NOTES :

Y = Yes display generated.
[1] Conditional Display for PD Population.
[2] Listing of race.


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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Pharmacodynamic Analyses
Statistical Analysis of Pharmacodynamic endpoints will be performed by or under the 
direct auspices of, Clinical Statistics, GlaxoSmithKline.    
7.1.1.
Overview of Planned Pharmacodynamic Analyses
The primary Pharmacodynamic analyses will be based on the “Pharmacodynamic (PD)” 
population, unless otherwise specified.
Table 3 provides an overview of the planned Pharmacodynamic analyses, with full details 
of data displays being presented in Appendix 10: List of Data Displays.
Table 3
Overview of Planned Pharmacodynamic Analyses
Endpoint 
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
FeNo
Y
Y
Y
Endpoint
Loge transformed
Stats Analysis
Summary
Individual
T
F
L
T
F
L
F
L
FeNO
Y
Y
Y
Y
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TF related to any summaries (descriptive statistics) of the observed raw data.
Individual = Represents FL related to any displays of individual subject observed raw data.    
7.1.1.1.
Statistical Analysis of Pharmacodynamic Parameters
For the PD parameter of FeNO, the following summary statistics will be calculated and 
tabulated by treatment:

Untransformed Data : N, n, arithmetic mean, 95% confidence interval (CI) for the 
arithmetic mean, SD, median, minimum, maximum

Loge-transformed Data:  Geometric mean, 95% CI for the geometric mean, SD of 
loge-transformed data and %CVb


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7.1.2.
Planned Primary Pharmacodynamic Statistical Analyses
Primary Statistical Analyses
Endpoint

Change from baseline ratio of loge transformed FeNO over time following the 
cessation of repeat dose treatment with FF/VI.
Model Specification
Endpoints will be statistically analysed using a mixed models repeated measures 
(MMRM) model.
Terms fitted in the MMRM model will include:
Fixed effect terms: Period, Treatment, Day, Time, Period-level baseline*Day*Time 
interaction term, Treatment*Day*Time interaction term, Period-level baseline and 
Subject-level baseline. 
Repeated: Day*Time interaction term.
Note: FeNO will be loge-transformed prior to deriving subject-level baseline and period-
level baseline.
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics will be performed for 
mentioned Statistical Analyses as required.
Model Results Presentation

Point estimates and their associated 95% confidence intervals will be constructed for 
the difference [FF/VI 100/25mcg] – [Placebo] at each timepoint (AM and PM i.e. 
pre-dose & 12 hours) on each day. The point estimates and their associated 95% 
confidence intervals will then be back-transformed to provide point estimates and 
95% confidence intervals for the ratios, [FF/VI 100/25mcg]/[Placebo] for each day 
and AM/PM timepoint.

Estimates of within-subject variability for FeNO will also be provided, where 
CVw(%) = SQRT(exp(MSE) – 1)×100 and MSE is the residual mean squared error 
from the model. CVw represents a pooled measure of within-subject variability across 
the regimens FF/VI 100/25mcg, Placebo and timepoints.
8.
SECONDARY STATISTICAL ANALYSES
8.1.
Pharmacodynamic Analyses
8.1.1.
Overview of Planned Pharmacodynamic Analyses
The secondary Pharmacodynamic analyses will be based on the “Pharmacodynamic 
(PD)” population, unless otherwise specified.
Table 4 provides an overview of the planned Pharmacodynamic analyses, with further 
details of data displays being presented in Appendix 10: List of Data Displays.


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Table 4
Overview of Planned Pharmacodynamic Analyses
Endpoint 
Absolute
Change from Baseline
Summary
Individual
Stats Analysis
Summary 
Individual
T
F
F
L
T
F
L
T
F
F
L
FeNO[1]
Y
Y
Y
FEV1
Y
Y
Y
Y
Y
Y
PEF
Y
Y
NOTES:
[1] FeNO will be loge transformed prior to analysis. 

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TF related to any summaries (descriptive statistics) of the 
observed raw data.
Individual = Represents FL related to any displays of individual subject observed raw 
data. 
8.1.2.
Planned Secondary Pharmacodynamic Statistical Analyses
Secondary Statistical Analyses
Endpoint

Change from baseline ratio of loge transformed FeNO during treatment with FF/VI.
Model Specification
Endpoints will be statistically analysed using a mixed models repeated measures 
(MMRM) model.
Terms fitted in the MMRM model will include:
Fixed effect terms: Period, Treatment, Day, Time, Period-level baseline*Day*Time 
interaction term, Treatment*Day*Time interaction term, Period-level baseline and 
Subject-level baseline. 
Repeated: Day*Time interaction term. 
Note: FeNO will be loge-transformed prior to deriving subject-level baseline and period-
level baseline.
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics will be performed for 
mentioned Statistical Analyses as required.
Model Results Presentation

Point estimates and their associated 95% confidence intervals will be constructed for 
the difference [FF/VI 100/25mcg] – [Placebo] at each timepoint (AM/PM i.e. pre-
dose & 12 hours) on each day. 

Estimates of within-subject variability for FeNO will also be provided, where 
CVw(%) = SQRT(exp(MSE) – 1)×100 and MSE is the residual mean squared error 
from the model. CVw represents a pooled measure of within-subject variability across 
the regimens FF/VI 100/25mcg, Placebo and timepoints.
Endpoint

Change from baseline of FEV1 during treatment with FF/VI.


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Secondary Statistical Analyses
Model Specification
Endpoints will be statistically analysed using a mixed models repeated measures 
(MMRM) model.
Terms fitted in the MMRM model will include:
Fixed effect terms: Period, Treatment, Day, Time, Period-level baseline*Day*Time 
interaction term, Treatment*Day*Time interaction term, Period-level baseline and 
Subject-level baseline. 

Repeated: Day*Time interaction term.
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics will be performed for 
mentioned Statistical Analyses as required.
Model Results Presentation

Point estimates and their associated 95% confidence intervals will be constructed for 
the difference [FF/VI 100/25mcg] – [Placebo] at each timepoint (AM/PM i.e. pre-
dose & 12 hours) on each day.

Estimates of within-subject variability for FEV1 will also be provided, where 
CVw(%) = SQRT(exp(MSE) – 1)×100 and MSE is the residual mean squared error 
from the model. CVw represents a pooled measure of within-subject variability across 
the regimens FF/VI 100/25mcg, Placebo and timepoints.
9.
OTHER STATISTICAL ANALYSES
9.1.
Overview of Planned Biomarker Analyses
Blood Eosinophil and Serum Periostin levels will be listed and summarised if data is 
available.  The biomarker displays will be based on the “All Subjects” population.  
9.1.1.
Overview of Planned Analyses
Table 5 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 10: List of Data Displays.
Table 5
Overview of Planned Biomarker Analyses
Endpoint
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Biomarker 
Biomarker Parameters
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Summary = Represents TFL related to any summaries (descriptive 
statistics) of the observed raw data.


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Endpoint
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L

Individual = Represents FL related to any displays of individual subject 
observed raw data.
9.2.
Overview of Safety Analyses
9.2.1.
Overview of Planned Adverse Events Analyses
The safety analyses will be based on the “All Subjects” population, unless otherwise 
specified.
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays.
Table 6
Overview of Planned Adverse Event Analyses
Endpoint 
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AEs by SOC and PT
Y
Y
Drug-Related AEs  by SOC and PT
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT and Verbatim Text
Y
Serious AEs by SOC and PT 
Y
AEs Leading to Withdrawal from Study / Permanent 
Discontinuation of Study Treatment by SOC and PT
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System 
Organ Class, PT = Preferred Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the 
observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw 
data. 
9.2.2.
Overview of Planned Clinical Laboratory Analyses
The safety analyses will be based on the “All Subjects” population, unless otherwise 
specified.
Table 7 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays.


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Table 7
Overview of Planned Clinical Laboratory Analyses
Summary
Individual
T
F
L
Lab Parameters 
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated

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.
9.2.3.
Overview of Planned Other Safety Analyses
The safety analyses will be based on the “All Subjects” population, unless otherwise 
specified.
Table 8 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays.
Table 8
Overview of Planned Other Safety Analyses
Summary
Individual
T
F
L
Vital Signs by Visit
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated.

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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10.
REFERENCES
GlaxoSmithKline Document Number 2015N241692_00 (Original – 12-JAN-2016):
A randomised, placebo-controlled, double-blind, two period crossover study to 
characterise the exhaled nitric oxide time profile as a biomarker of airway inflammation 
in adult asthma patients following repeat administration of inhaled Fluticasone Furoate 
(FF)/ Vilanterol (VI) 100/25 mcg.


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


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11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
As detailed in Section 4.1, Protocol deviations will be tracked by the study team 
throughout the conduct of the study in accordance with the Protocol Deviation 
Management Plan and a listing and summary of important Protocol Deviations will be 
provided.   A separate listing and summary of inclusion/exclusion criteria deviations will 
also be produced based on the eligibility eCRF page.
A Per Protocol Population is not being defined for this study.  However additional 
exploratory sensitivity summaries may be considered, if there are protocol deviations that 
may affect the primary PD endpoint analysis will be confirmed prior to unblinding. Any 
additional sensitivity summaries will be documented in the CSR


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11.2.
Appendix 2: Data Management
Data Type
Source 
Format 
of Data
Planned Date of 
Final File1
Responsibility
Study Population
Database
IDSL
DBF
CPSSO
Safety
Database
IDSL
DBF
CPSSO
Pharmacodynamic
Database
IDSL
DBF
CPSSO
Biomarker
Database
IDSL
DBF
CPSSO
1. Provided source data is clean


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11.3.
Appendix 3: Time & Events
Procedure
Screening (up to 
42 days prior to 
Day 1)
Study Day (each treatment period)
Follow-up 
(Days 35-
42)12
Notes
Day -7 (start 
of run-in)1
Day 1
Days 
2-13
Days 
14-19
Day 
21
Day 35
Out-patient visit to the 
unit
X
X
X
X
X
X
1 Day -7 is the start of 
the one week run-in 
period and therefore 
this visit and the 
assessments on this day 
only apply to Treatment 
Period 1
Admission to the unit
X
Informed consent
X
Inhaler, PEF meter and 
FeNO device practice
X
Inclusion and exclusion 
criteria/eligibility review
X
X
X
Demography
X
Full physical exam 
including height and 
weight
X
Medical history (includes 
substance usage  [and 
family history of 
premature CV disease])
X
Substances: [Drugs, 
Alcohol, tobacco and 
caffeine]
Past and current medical 
conditions  [including 
cardiovascular medical 
history]
X


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Procedure
Screening (up to 
42 days prior to 
Day 1)
Study Day (each treatment period)
Follow-up 
(Days 35-
42)12
Notes
Day -7 (start 
of run-in)1
Day 1
Days 
2-13
Days 
14-19
Day 
21
Day 35
Urine pregnancy test 
(WCBP)
X
X2
X
X
2 Collected pre-dose
Vital signs
X
Set up PEF and FeNO 
monitoring
X
Study Treatment
X3
X4
3 Dosing every 
morning; dosing in the 
unit on Days 1 and 14 
and at home on Days 2-
13
4 Dosing on the 
morning of Day 14 
only
Exploratory biomarker 
sampling5
X
X
X
X
5 These measurements 
are taken at baseline 
(Day -7), at the end of 
treatment (Day 15), on 
Day 21 and on Day 35.
FEV1 readings6
X
X7
X8
X9
6 Measured in the unit 
only
7 Taken pre-dose
8 Collected AM (pre-
dose on Day 14) and 
PM
9 Collected AM only
FeNO assessment10
X
==============================================
10 Start of collection 7 
days before Day 1 (Day 
-7), then collected 
every day AM and PM 
through to Day 35 of 
each treatment period.


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Procedure
Screening (up to 
42 days prior to 
Day 1)
Study Day (each treatment period)
Follow-up 
(Days 35-
42)12
Notes
Day -7 (start 
of run-in)1
Day 1
Days 
2-13
Days 
14-19
Day 
21
Day 35
PEF11
======================================================
11 Collected AM and 
PM every day from 
Day -7 through to Day 
35 for Treatment Period 
1, and from Day 1 
through to follow up 
for Treatment Period 2.
AE/SAE review
===========================================================
Concomitant medication 
review
===========================================================
12 Follow up visit only 
after Treatment period 
2. The follow-up visit 
can be combined with 
the Day 35 visit for 
Treatment Period 2.
Issue of diary card
X
X13
13 Second diary card 
given out on Day 21 of 
Treatment Period 1, to 
capture data for 
Treatment Period 2


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11.4.
Appendix 4: Treatment States and Phases
11.4.1.
Treatment States for AE Data
Treatment 
State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment 
stop date.
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date [+ 
Lag Time]
Post-Treatment
If AE onset date is after the treatment stop date.
AE Start Date > Study Treatment Stop Date 
Onset Time  
Since 1st Dose
(Days)
If Treatment Start Date ˃ AE Onset Date = AE Onset Date - Treatment Start 
Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start 
Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on [Inform/CRF OR value is missing].
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.


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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
Placebo
Placebo
1
B
FF/VI 100/25 mcg
FF/VI 100/25 mcg
2
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
11.5.2.
Baseline Definition & Derivations
11.5.2.1.
Baseline Definitions
For all endpoints (expect as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment. 
Parameter
Study Assessments Considered As Baseline
Baseline Used in Data 
Display
Screening
Day -7
Day 1 (Pre-Dose)
PD
FeNO
X
X
X
Day  1 (Pre-dose)
FEV1
X
X
Day  1 (Pre-dose)
PEF
X
X
Day  1 (Pre-dose)
Biomarker
X
Day  1 (Pre-dose)

Note: Baseline definitions are applicable to each period 
For FeNO, FEV1 analyses:

Subject level baseline is defined as the mean of baseline across periods for each 
subject.

Period level baseline is defined as the difference between the baseline and subject 
level baseline for each period and each subject.
11.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 11.5.2.1 Baseline Definitions 
will be used for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to 
missing.

The baseline definition will be footnoted on all change from baseline displays.


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11.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175-HARP PROD-UK
HARP Area
: \ARPROD\ GW685698+GW642444\mid201499\Final
QC Spreadsheet
: \ARWORK\ GW685698+GW642444\mid201499\Final\Documents
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards
Generation of RTF Files

RTF files will be generated for summary displays.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for 
reporting, unless otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be 
adopted for reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical 
principles but may be adjusted to a clinically interpretable number of DP’s.


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Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time relative to dosing will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or 
scheduled visit days on the analyses and interpretation of the results will be 
assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings 
(Refer to IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol 
deviations) will be included in listings but omitted from figures, summaries and 
statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables. 

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacodynamic Parameters
Descriptive Summary 
Statistics (Log 
Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard 
deviation (SD) of logged data and [between and or within]
geometric coefficient of variation (CVb/w (%)) will be reported.
[1] CVb (%) = √(exp(SD2) - 1) * 100
(SD = SD of log transformed data)
[2] CVw (%) = √ (exp(MSE) - 1) * 100
(MSE = mean square error from mixed effect model of 
loge-transformed data).
Parameters Not Being 
Log Transformed
FEV1
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented.

If there are two values within a time window the value closest to the target day for 
that window will be used. If values are the same distance from the target then the 
mean will be taken.
Study Day

Calculated as the number of days from randomisation date :

Ref Date = Missing                     → Study Day = Missing 

Ref Date < Treatment start Date → Study Day = Ref Date – Treatment start Date    

Ref Data ≥ Treatment start Date → Study Day = Ref Date – (Treatment start
Date) + 1    
11.6.2.
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’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = (Treatment Stop Date – Treatment Start Date) + 1

Subjects who were randomized but did not report a treatment start date will be 
categorised as having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)


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11.6.3.
Pharmacodynamic
FeNO
Period level baseline

The Period-Specific Baseline value is the pre-dose assessment collected on day 1 of 
each treatment period

Period level baseline is defined as the difference between the baseline and subject 
level baseline for each period and each subject.
Subject level baseline

Subject level baseline is defined as the mean of baseline across periods for each 
subject.
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, 
has a non-detectable level reported in the database, where the numeric value is 
missing, but typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less 
than x or greater than x in the comment field) is present, the number of significant 
digits in the observed values will be used to determine how much to add or subtract in 
order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    


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11.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined 
as subject is one who has completed both treatment periods, all 
assessments up to Day 35 of both treatment periods, and all of the 
follow-up assessments. The end of the study is defined as the last 
subject’s last visit.

Withdrawn subjects were not replaced in the study.

All available data from subjects who were withdrawn from the study 
will be listed and all available planned data will be included in summary 
tables and figures, unless otherwise specified.
11.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to 
blank fields on the collection instrument :
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case 
the data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses 
will be documented along with the reason for exclusion in the clinical 
study report.
11.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and 
year) to be recorded for AE start and end dates; that is, the day of the 
month may be missing. In such a case, the following conventions will be 
applied for calculating the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is 
before the start date of study treatment; in this case the study 
treatment start date will be used and hence the event is considered 
On-treatment as per Appendix 4: Treatment States and Phases.
o
Missing Stop Day: Last day of the month will be used, unless this is 
after the stop date of study treatment; in this case the study treatment
stop date will be used.


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Element
Reporting Detail

Completely missing start or end dates will remain missing, with no 
imputation applied. Consequently, time to onset and duration of such 
events will be missing.

Start or end dates which are completely missing (i.e. no year specified) 
will remain missing, with no imputation applied.
11.7.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will 
be imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 
'Jan' will be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the 
day (dependent on the month and year) and 'Dec' will be used for 
the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. 
If the full date cannot be ascertained, the following assumptions will be 
made:
o
If the partial date is a start date, a '01' will be used for the day and 
'Jan' will be used for the month. 
o
However, if these results in a date prior to Week 1 Day 1 and the 
event could possibly have occurred during treatment from the 
partial information, then the Week 1 Day 1 date will be assumed to 
be the start date. 
o
The AE will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a '28/29/30/31' will be used for the 
day (dependent on the month and year) and 'Dec' will be used for 
the month.

The recorded partial date will be displayed in listings.
11.7.2.3.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Outliers

Any subjects excluded from the summaries and/or statistical analyses 
will be documented along with the reason for exclusion in the clinical 
study report.


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11.8.
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses
11.8.1.
Statistical Analysis Assumptions
Endpoint(s)

Loge (FeNO) and FEV1
Analysis

MMRM

Model assumptions will be applied, but appropriate adjustments maybe made based 
on the data.

The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used.

An unstructured covariance structure for the R matrix will be used by specifying 
‘type=UN’ on the REPEATED line.
o
In the event that this model fails to converge, alternative correlation structures 
may be considered such as CSH or CS. 
o
Akaike's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure.

Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable.

If there are any departures from the distributional assumptions, alternative models 
will be explored using appropriate transformed data.


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11.9.
Appendix 9 – Abbreviations & Trade Marks
11.9.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CI
Confidence Interval
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
GUI
Guidance
MMRM
Mixed Model Repeated Measures
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
QC
Quality Control
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
GSK
GlaxoSmithKline
11.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of 
Companies
HARP
SAS


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11.10.
Appendix 10: List of Data Displays
11.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.10
-
Pharmacodynamic
2.1 to 2.8
2.1 to 2.6
Safety
3.1 to 3.3
Biomarker
4.1 to 4.2
4.1
Section
Listings
ICH Listings
1 to 18
Other Listings
19 to 25
11.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
N/A
POP_Tn
POP_Ln
Pharmacodynamic/Biomarker
PD_Fn
PD_Tn
PD_Ln
Safety
N/A
SAFE_Tn
SAFE_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ 
column as ‘[Non-Standard] + Reference.’
11.10.3.
Deliverable [Priority]
Delivery Priority
Description
Headline [1]
Headline Results
SAC [2]
Final Statistical Analysis Complete


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11.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition 
1.1.
All Subjects
ES1A
Summary of Subject Disposition for the Subject 
Conclusion Record
Headline [1]
SAC [2]
1.2.
Screened 
Subjects
ES6
Summary of Screening Status and Reasons for 
Screen Failure
SAC [2]
1.3.
Screened 
Subjects
NS1
Summary of Number of Subjects by Country and 
Site ID
SAC [2]
Protocol Deviation
1.4.
All Subjects
DV1
Summary of Important Protocol Deviations
SAC [2]
Population Analysed
1.5.
Screened 
Subjects
SP1
Summary of Study Populations
SAC [2]
Demographics
1.6.
All Subjects
DM3
Summary of  Demographic characteristics
Include BMI
Headline [1]
SAC [2]
1.7.
PD
DM3
Summary of  Demographic characteristics
Include BMI.
Conditional Display
SAC [2]
1.8.
All Subjects
DM11
Summary of Age Ranges
Include only Adult (18-
64) and (65-84) years 
category
SAC [2]


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Study Population Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.9.
All Subjects
DM5
Summary of  Race and Racial Combinations
SAC [2]
Exposure
1.10.
All Subjects
EX1
Summary of Exposure Data
SAC [2]


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11.10.5.
Pharmacodynamic Tables
Efficacy: Tables
No.
Population
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacodynamic Parameters
2.1.
PD
LB1
Summary of Exhaled Nitric Oxide Data 
Parameter with units, both 
untransformed and transformed
Headline [1]
SAC [2]
2.2.
PD
LB1
Summary of Change  from Baseline  Exhaled Nitric 
Oxide Data
Parameter with units for 
untransformed data 
SAC [2]
2.3.
PD
LB1
Summary of Ratio  from Baseline  Exhaled Nitric 
Oxide Data
Parameter with units for 
transformed data
Headline [1]
SAC [2]
2.4.
PD
PD_T1
Summary of Repeated Measures Statistical Analysis 
of Ratio from Baseline Exhaled Nitric Oxide Data  
after cessation of repeat dose of treatment
Headline [1]
SAC [2]
2.5.
PD
PD_T1
Summary of Repeated Measures Statistical Analysis 
of Ratio from Baseline Exhaled Nitric Oxide Data  
SAC [2]
2.6.
PD
LB1
Summary of Spirometry data
SAC [2]
2.7.
PD
LB1
Summary of Change from Baseline in Spirometry 
data
SAC [2]
2.8.
PD
PD_T1
Summary of  Repeated Measures Statistical Analysis 
of  Change from Baseline FEV1 Data
SAC [2]


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11.10.6.
Pharmacodynamic Figures
Pharmacodynamic: Figures
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacodynamic Parameters
2.1.
PD
PD_F1
Plot of Individual Subject of Exhaled Nitric Oxide 
Time-Profile after cessation of repeat dose 
treatment
SAC [2]
2.2.
PD
PD_F2
Plot of Adjusted Geometric Mean Exhaled Nitric 
Oxide Ratio from Baseline Time-Profile by 
Treatment
With confidence intervals taken from 
repeated measures analysis.
Plot to present Day & AM/PM on x-axis 
and change from baseline ratio on y-axis.  
One line for each treatment.
Headline [1]
SAC [2]
2.3.
PD
PD_F2
Plot of Exhaled Nitric Oxide Ratio from Baseline 
Treatment Ratios Against Time
With confidence interval taken from 
repeated measures analyses.
Similar to Figure 2.02 but present 
treatment ratio instead of adjusted mean.   
Include horizontal line through 1.
SAC [2]
2.4.
PD
PD_F1
Plot of Individual Subject of FEV1 Time-Profile
SAC [2]
2.5.
PD
PD_F2
Plot of Adjusted Mean FEV1 Change from 
Baseline Time-Profile by Treatment
With confidence interval taken from 
repeated measures analysis.
Present as for FeNO except present for 
change from baseline instead of change 
from baseline ratio.
SAC [2]
2.6.
PD
PD_F2
Plot of FEV1 Change from Baseline Treatment 
Differences Against Time
With confidence intervals taken from 
repeated measures analysis.
Present as for FeNO except present for 
change from baseline instead of change 
from baseline ratio.
SAC [2]


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11.10.7.
Safety Tables
Safety : Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
All Subjects
AE1CP
Summary of Adverse Events by System Organ Class 
and Preferred Term
Headline [1]
SAC [2]
3.2.
All Subjects
AE1CP
Summary of All Drug-Related Adverse Events by 
System Organ Class and Preferred Term
SAC [2]
3.3.
All Subjects
AE1CP
Summary of AEs Leading to Permanent Discontinuation 
of Study Drug or Withdrawal from Study
SAC [2]
11.10.8.
Biomarker Tables
Biomarker Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarker parameter
4.1. 
All Subjects
LB1
Summary of Biomarker Data
SAC [2]
4.2.
All Subjects
LB1
Summary of Change from Baseline Biomarker Data
SAC [2]


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201499
41
11.10.9.
Biomarker Figures
Biomarker: Figure
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarker Parameter
4.1
PD
PD_F3
Plot of Histogram of Biomarker Data by 
Treatment
SAC [2]
11.10.10. ICH Listings
ICH : Listings
No.
Population
IDSL /
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened 
Subjects 
ES7
Listing of Reasons for Screening Failure
SAC [2]
2.
All Subjects
ES3
Listing of Reasons for Withdrawal
SAC [2]
3.
All Subjects
BL2
Listing of Subjects for Whom the Treatment Blind was Broken 
During the Study
SAC [2]
4.
All Subjects
TA2
Listing of Randomised and Actual Treatments
SAC [2]
Protocol Deviations
5.
All Subjects
DV2A
Listing of all Protocol Deviations
SAC [2]
6.
All Subjects
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
SAC [2]


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201499
42
ICH : Listings
No.
Population
IDSL /
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Subject Disposition
7.
Screened 
Subjects
SP3A
Listing of Subjects Excluded from Any Population
SAC [2]
Demographics
8.
All Subjects
DM4
Listing of Demographic Characteristics
SAC [2]
9.
All Subjects
DM10
Listing of Race
SAC [2]
Prior and Concomitant Medication
10.
All Subjects
MH2
Listing of Medical Conditions
SAC [2]
11.
All Subjects
CP_CM4
Listing of Concomitant Medications by Generic Terms
SAC [2]
Exposure
12.
All Subjects
EX4
Listing of Exposure Data
SAC [2]
AE
13.
All Subjects
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC [2]
14.
All Subjects
AE9CP
Listing of All Adverse Events
SAC [2]
15.
All Subjects
AE9CP
Listing of Serious Adverse Events
SAC [2]
16.
All Subjects
AE9CP
Listing of AEs Leading to Withdrawal from Study 
SAC [2]
Vitals/LAB
17.
All Subjects
VS5
Listing of Vital Signs
SAC [2]
18.
All Subjects
CP_LB6
Listing of Laboratory Data for Subjects
SAC [2]


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201499
43
11.10.11. Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL /
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
AE
19.
All Subjects
AE2
Listing of Relationship between System Organ Class and 
Verbatim Text
SAC [2]
Pharmacodynamic/Biomarker
20.
PD
EG4
Listing of Exhaled Nitric Oxide Data 
SAC [2]
21.
PD
EG4
Listing of Spirometry  Data
SAC [2]
22.
PD
EG4
Listing of Biomarker Data
SAC [2]
23.
PD
Raw SAS Output from Repeated Measures Statistical Analysis 
of Change from Baseline RatioExhaled Nitric Oxide Data after 
cessation of repeat dose treatment
SAC [2]
24.
PD
Raw SAS Output from Repeated Measures Statistical Analysis 
of Change from Baseline RatioExhaled Nitric Oxide Data
SAC [2]
25.
PD
Raw SAS Output from Repeated Measures Statistical Analysis 
of Change from Baseline FEV1
SAC [2]


CONFIDENTIAL
201499
44
11.11.
Appendix 11: Example Mock Shells for Data Displays
Example 
: PD_T1
                      
   Page 1 of 2
Protocol
: 201499
Population
: PD
Table 2.3
Summary of Repeated Measures Statistical Analysis of Ratio from Baseline Exhaled Nitric Oxide Data after cessation of repeat dose of 
treatment
Parameter
Visit
Planned 
Timepoint 
Comparison
Adjusted Geometric 
Mean
Ratio
(Test/Ref)
95% Confidence Interval 
for Ratio
%CVw
n    Test     n    Ref
FeNO   
Test vs Ref
x
xx.xx
x
xx.xx
x.xxxx
(x.xxxx, x.xxxx)             
xx.x
Example 
: PD_F1
            
  Page 1 of 1


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201499
45
Protocol
: 201499
Population
: PD
Figure 2.1.
Plot of Individual Subject of Exhaled Nitric Oxide Time-Profile after cessation of repeat dose treatment      
Plot to present Day & AM/PM on x-axis and PD endpoints on y-axis. One line for each treatment.
Example 
: PD_F2
Page 1 of 1
Exhaled Nitric Oxide 


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201499
46
Protocol
: 201499
Population
: PD
Figure 2.2
Plot of Adjusted Geometric Mean Exhaled Nitric Oxide Ratio from Baseline Time-Profile by Treatment
Plot to present Day & AM/PM on x-axis but change from baseline ratio on y-axis. One line for each treatment.
Example 
: PD_F3
Page 1 of 1


CONFIDENTIAL
201499
47
Protocol
: 201499
Population
: PD
Figure 4.1
Plot of Histogram of Biomarker Data by Treatment
Biomarker result (units)
V1 
     V2              V3          V4 
      V5            V6          V7           V8 
Visit