Conditions: Asthma
Keywords: Dose-response AMP challenge cortisol suppression dose escalation therapeutic index
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 56
Healthy volunteers: no

Brief summary:
This is a randomized, placebo-controlled, 2-period crossover, escalating repeat dose study, aiming to investigate whether higher potency of different inhaled corticosteroid confers an improvement in the topical efficacy to systemic activity ratio in asthmatic subjects. It will compare the dose response for topical efficacy via airway responsiveness (to adenosine-5'-monophosphate \[AMP\] challenge), and the dose response for systemic activity via 24 hour plasma cortisol suppression, and thereby compare the relative therapeutic index, for the following inhaled corticosteroids: fluticasone furoate (FF), fluticasone propionate (FP) and budesonide (BUD). There will be a screening visit 4 - 42 days before the first dose of study treatment, and AMP challenge Provocative concentration 20 (PC20) of \<=80 milligrams per milliliter (mg/mL) at screening visit 2 i.e. at 4 - 14 days before the first dose of study treatment. Subjects will be randomized to one of 5 or 12 treatment sequences, and will have one or two treatment periods, each comprising 5 consecutive 7-day phases of escalating doses of either FF, FP, BUD or placebo. There will be a 25- to 42-day washout period between treatment periods. The study duration for each subject will be approximately 13 or 24 weeks including the follow-up period.

Detailed description:

Arms:
arm 1: Each treatment period (TP) comprises of 5 consecutive 7-day dosing phases with escalating doses of either FF or FP. In TP 1, subjects will receive evening (PM) dose of 1 puff of FF 25 microgram (mcg) (Total daily dose \[TDD\] = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puff of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puff of FF 200 mcg (TDD = 800 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by morning (AM) and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. Washout period will be of 25-42 days. arm 2: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either FF or BUD. In TP 1, subjects will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD = 100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD = 400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD = 1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. Washout period will be of 25-42 days. arm 3: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either FF or ELLIPTA Placebo. In TP 1, subjects will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of ELLIPTA Placebo in first, second and third phases followed by PM dose of 2 puffs of ELLIPTA Placebo in fourth phase and PM dose of 4 puffs of ELLIPTA Placebo in fifth phase. Washout period will be of 25-42 days. arm 4: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either FP or FF. In TP 1, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. Washout period will be of 25-42 days. arm 5: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either FP or BUD. In TP 1, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD = 400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. Washout period will be of 25-42 days. arm 6: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either FP or DISKUS Placebo. In TP 1, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of DISKUS Placebo in first phase followed by AM and PM doses of 1 puff each DISKUS Placebo in second, third and fourth phase; AM and PM doses of 2 puffs each of DISKUS Placebo in fifth phase. Each TP will be followed by a washout period of 25-42 days. arm 7: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either BUD or FF. In TP 1, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. Washout period will be of 25-42 days. arm 8: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either BUD or FP. In TP 1, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD =500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. Washout period will be of 25-42 days. arm 9: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either BUD or DISKUS Placebo. In TP 1, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of DISKUS Placebo in first phase followed by AM and PM doses of 1 puff each DISKUS Placebo in second, third and fourth phase; and AM and PM doses of 2 puffs each of DISKUS Placebo in fifth phase. Washout period will be of 25-42 days. arm 10: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either ELLIPTA Placebo or FF. In TP 1, subjects will receive PM dose of 1 puff of ELLIPTA Placebo in first, second and third phase followed by PM dose of 2 puffs of ELLIPTA Placebo in fourth phase and PM dose of 4 puffs of ELLIPTA Placebo in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. Washout period will be of 25-42 days. arm 11: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either DISKUS Placebo or FP. TP 1, subjects will receive PM dose of 1 puff of DISKUS Placebo in first phase followed by AM and PM doses of 1 puff each of DISKUS Placebo in second, third and fourth phase; AM and PM doses of 2 puffs each of DISKUS Placebo in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. Washout period will be of 25-42 days. arm 12: Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either ELLIPTA Placebo or BUD. In TP 1, subjects will receive PM dose of 1 puff of ELLIPTA Placebo in first, second and third phase followed by PM dose of 2 puffs of ELLIPTA Placebo in fourth phase and PM dose of 4 puffs of ELLIPTA Placebo in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. Washout period will be of 25-42 days.

Interventions: intervention 1: Fluticasone furoate (FF) Dry Powder Inhaler intervention 2: Fluticasone propionate (FP) Dry Powder Inhaler intervention 3: Budesonide (BUD) Turbuhaler intervention 4: Placebo (ELLIPTA or DISKUS)
Intervention descriptions: intervention 1: Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods intervention 2: Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods intervention 3: Budesonide comprises white to off-white rounded granules, which disintegrate to a fine powder upon slight pressure, will be administered using Turbuhaler for both treatment periods. intervention 4: Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.

Protocol document:
Prot_000.pdf: 
2016N281231_03
CONFIDENTIAL
GlaxoSmithKline group of companies
203162
1
TITLE PAGE
Division:  Worldwide Development
Information Type: Protocol Amendment
Title:
An escalating dose, randomized, placebo-controlled, incomplete-
block, 2 period cross-over study to assess the dose response for 
topical efficacy via airway responsiveness to adenosine-5'-
monophosphate (AMP) challenge and the dose response for 
systemic activity via 24 h plasma cortisol suppression and 
thereby the relative therapeutic index for fluticasone furoate 
(FF), fluticasone propionate (FP) and budesonide (BUD) in 
asthmatic subjects.
Compound Number:
CCI18781 ((FP), fluticasone propionate), GW685698 ((FF), 
fluticasone furoate) and GR160288 (budesonide (BUD))
Development Phase
IIa
Effective Date:
26-APR-2018
Protocol Amendment Number: 03
Author(s):
 
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2016N281231_03
CONFIDENTIAL
GlaxoSmithKline group of companies
203162
2
Revision Chronology
2016N281231_00
2016-SEP-29
Original
2016N281231_01
2017-JAN-16
Amendment No. 1 was to clarify the dose 
rationale, emergency unblinding procedure, 
and approval of substantial amendments 
procedure, as requested by the Medicines and 
Healthcare products Regulatory Agency 
(MHRA), as well as to clarify the blood 
sample time points and volumes and update the 
medical monitor contact details.
2016N281231_02
2017-OCT-03
Amendment No. 2 was to change the 
following:
The protocol design, to allow subjects to 
complete either 1 or 2 treatment periods.
To allow recruitment of subjects taking low-
dose inhaled corticosteroids (ICS) with 
appropriate washout period.
To allow inclusion of light smokers.
Removal of the Run-in and treatment period 2 
baseline visits for adenosine-5’-
monophosphate (AMP) challenge.  
To allow the subjects to leave the unit after 
Day 7 evening procedures.
To allow in-stream data review. 
Changes laid down in MEMOs to protocol 
amendment 1 were also incorporated into this 
protocol amendment.
2016N281231_03
2018-APR-26
Amendment No. 3 is being issued to update the 
serious adverse event (SAE) contact and 
processing information, the pregnancy 
reporting timelines, as well as to include 
administrative changes clarifying the screening 
peak expiratory flow rate (PEFR) procedure.


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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
Site Address
SAE contact 
information 
(PAREXEL Global 
Pharmacovigilance 
Processing Group 
(GPPG)
PAREXEL 
Medical 
Services
Email: 
 and 
 and 
Or Fax: 
 
NA
NA
Primary Medical 
Monitor
GSK, Stockley 
Park West, 
Uxbridge, 
Middlesex, 
UB11 1BT, UK
Secondary Medical 
Monitor
GSK, 709 
Swedeland Rd, 
King of Prussia, 
PA 19406, USA
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical study 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: 2016-003002-14.
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 203162

I confirm agreement to conduct the study in compliance with the protocol, as 
amended by this protocol amendment.

I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in place 
to ensure that site staff receives the appropriate information throughout the study.
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


2016N281231_03
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6
TABLE OF CONTENTS
Page
1.
PROTOCOL SYNOPSIS FOR STUDY 203162......................................................10
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................15
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVES AND ENDPOINTS...........................................................................15
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................17
4.3.
Type and Number of Subjects.....................................................................20
4.4.
Design Justification.....................................................................................20
4.5.
Dose Justification........................................................................................21
4.6.
Benefit:Risk Assessment ............................................................................22
4.6.1.
Risk Assessment .........................................................................24
4.6.2.
Benefit Assessment.....................................................................27
4.6.3.
Overall Benefit: Risk Conclusion..................................................27
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............27
5.1.
Inclusion Criteria.........................................................................................27
5.2.
Exclusion Criteria........................................................................................30
5.3.
Screening/Baseline/Run-in Failures............................................................32
5.4.
Withdrawal/ Stopping Criteria......................................................................32
5.4.1.
Liver Chemistry Stopping Criteria ................................................33
5.4.1.1.
Liver Chemistry Stopping and Increased 
Monitoring Algorithm...................................................33
5.4.1.2.
Study Treatment Restart or Rechallenge....................34
5.4.2.
QTc Stopping Criteria ..................................................................34
5.5.
Subject and Study Completion....................................................................34
6.
STUDY TREATMENT ............................................................................................35
6.1.
Investigational Product and Other Study Treatment....................................35
6.2.
Treatment Assignment................................................................................36
6.3.
Planned Dose Adjustments.........................................................................36
6.4.
Blinding.......................................................................................................36
6.5.
Packaging and Labeling..............................................................................37
6.6.
Preparation/Handling/ Storage/Accountability.............................................37
6.7.
Compliance with Study Treatment Administration.......................................38
6.8.
Treatment of Study Treatment Overdose....................................................38
6.9.
Treatment After the End of the Study..........................................................39
6.10.
Lifestyle and/or Dietary Restrictions............................................................39
6.10.1.
Meals and Dietary Restrictions ....................................................39
6.10.2.
Caffeine, Alcohol, and Tobacco ...................................................39
6.10.3.
Activity .........................................................................................39
6.11.
Concomitant Medications and Non-Drug Therapies....................................39
6.11.1.
Permitted Medications and Non-Drug Therapies..........................39
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................40
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................40
7.1.
Time and Events Table...............................................................................42
7.2.
Screening and Critical Baseline Assessments ............................................45


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7
7.3.
Safety .........................................................................................................45
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........45
7.3.1.1.
Time Period and Frequency for Collecting AE 
and SAE Information ..................................................45
7.3.1.2.
Method of Detecting AEs and SAEs ...........................46
7.3.1.3.
Follow-up of AEs and SAEs........................................46
7.3.1.4.
Cardiovascular and Death Events ..............................46
7.3.1.5.
Regulatory Reporting Requirements for SAEs............47
7.3.2.
Pregnancy ...................................................................................47
7.3.3.
Physical Examinations.................................................................47
7.3.4.
Vital Signs....................................................................................47
7.3.5.
Electrocardiogram........................................................................48
7.3.6.
Clinical Safety Laboratory Assessments ......................................48
7.3.7.
Inhaler Training............................................................................49
7.3.8.
Spirometry ...................................................................................49
7.3.8.1.
Screening Baseline Lung Function .............................50
7.3.8.2.
Pre-dose Baseline Lung Function...............................50
7.3.8.3.
Peak Expiratory Flow Rate (PEFR) 
Measurements............................................................50
7.3.8.4.
Diary Assessments.....................................................51
7.4.
Pharmacodynamics Assessment ................................................................52
7.4.1.
AMP Challenge............................................................................52
7.4.2.
Plasma Cortisol Sample Collection ..............................................53
7.4.3.
Sample Analysis ..........................................................................53
7.5.
Biomarkers .................................................................................................53
7.5.1.
Metabolomic Research ................................................................53
8.
DATA MANAGEMENT ...........................................................................................54
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................54
9.1.
Hypotheses.................................................................................................54
9.2.
Sample Size Considerations.......................................................................54
9.2.1.
Sample Size Assumptions ...........................................................55
9.2.2.
Sample Size Sensitivity................................................................56
9.2.3.
Sample Size Re-estimation or Adjustment...................................58
9.3.
Data Analysis Considerations .....................................................................58
9.3.1.
Analysis Populations....................................................................58
9.3.2.
Interim Analysis ...........................................................................58
9.4.
Key Elements of Analysis Plan ...................................................................58
9.4.1.
Pharmacodynamic Analyses........................................................58
9.4.2.
Safety Analyses...........................................................................60
9.4.3.
Biomarker Analyses.....................................................................60
10. STUDY GOVERNANCE CONSIDERATIONS........................................................60
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............60
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
10.3.
Quality Control (Study Monitoring) ..............................................................61
10.4.
Quality Assurance.......................................................................................62
10.5.
Study and Site Closure ...............................................................................62
10.6.
Records Retention......................................................................................62
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................63


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11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................67
12.1.
Appendix 1: Abbreviations and Trademarks................................................67
12.2.
Appendix 2: Liver Safety Required Actions and Follow-up 
Assessments ..............................................................................................70
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................73
12.3.1.
Definition of Adverse Events........................................................73
12.3.2.
Definition of Serious Adverse Events...........................................74
12.3.3.
Definition of Cardiovascular Events .............................................75
12.3.4.
Recording of AEs and SAEs ........................................................76
12.3.5.
Evaluating AEs and SAEs............................................................76
12.3.6.
Reporting of SAEs .......................................................................78
12.4.
Appendix 4: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................80
12.4.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............80
12.4.2.
Collection of Pregnancy Information ............................................81
12.4.3.
References ..................................................................................82
12.5.
Appendix 5: Low, Medium, and High Daily Doses of Inhaled 
Corticosteroids............................................................................................84
12.6.
Appendix 6: Protocol Amendment Changes................................................85
12.6.1.
Amendment 1 ..............................................................................85
12.6.2.
Amendment 2 (03-OCT-2017) from the Amendment 1 (16-
JAN-2017) ...................................................................................90
12.6.3.
Amendment 3 (26-APR-2018) from the Amendment 2 (03-
OCT-2017).................................................................................116
12.7.
Appendix 7: Country-Specific Requirements.............................................121
LIST OF TABLES
page
Table 1
Treatments regime proposed per dose escalation phase .......................12
Table 2
Doses proposed per dose escalation phase...........................................17
Table 3
Treatments regime proposed per dose escalation phase (total 
daily doses)............................................................................................18
Table 4
Treatments proposed per study period for subjects completing 
2 treatment periods ................................................................................19
Table 5
Treatments proposed for subjects completing 1 treatment period ..........19
Table 6
Study Duration for subjects completing 2 treatment periods...................19
Table 7
Study Duration for subjects completing 1 treatment period.....................20
Table 8
Study treatments....................................................................................35
Table 9
Screening and Follow-up Visit................................................................42


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Table 10
Time and Events Treatment Period 1 and 2 ...........................................43
Table 11
Protocol Required Safety Laboratory Assessments................................48
Table 12
Variability Estimates from Inhaled Steroid Studies with an AMP 
Challenge Model ....................................................................................55
Table 13
Expected Precision of Parameter Estimates for Cross-over and 
Parallel Design Combined; N=18 Subjects Overall for Each 
Treatment...............................................................................................56
Table 14
Variability Estimates from Cortisol Suppression Weighted Mean 
(0-24 hours) model.................................................................................56
Table 15
Simulation Results for Cross-over Design; N=12 Subjects in 
Each Treatment Group...........................................................................57
Table 16
Simulation Results for Parallel Design; N=6 Subjects in Each 
Treatment Group....................................................................................57


2016N281231_03
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1.
PROTOCOL SYNOPSIS FOR STUDY 203162
Rationale
This study aims to investigate whether higher potency confers an improvement in the 
topical efficacy to systemic activity ratio. It will compare the dose response for topical 
efficacy via airway responsiveness to adenosine-5’-monophosphate (AMP) challenge and 
the dose response for systemic activity via 24 hour plasma cortisol suppression and 
thereby the relative therapeutic index for fluticasone furoate (FF), fluticasone propionate 
(FP) and budesonide (BUD) in asthmatic subjects.
Metabolomics will also be included as an exploratory endpoint to study the systemic 
metabolic bioactivity profile of the three inhaled corticosteroids (ICS) with the aim of 
identifying whether qualitative or quantitative differences exists in on-target and 
off-target steroid receptor interactions. This will provide new information that may allow 
the systemic effects of the three ICS to be distinguished quantitatively and qualitatively 
with endpoints not previously identified.
Objectives/Endpoints
Objectives
Endpoints
Primary
To characterize the dose response and relative 
potency for FF, FP and BUD in the adenosine
monophosphate (AMP) challenge model at 12
hours after the last dose on Day 7 
Provocative concentration (PC) of AMP 
causing a 20% fall in forced expiratory 
volume in 1 second (FEV1) (AMP PC20).
To characterize the dose response and relative 
potency for FF, FP and BUD on 24 hour plasma 
cortisol suppression on-treatment from pre-dose 
PM dose on Day 6 to pre-dose PM dose Day 7.
Suppression of 24 hour weighted mean 
plasma cortisol compared to placebo.
To assess the therapeutic index for FF, FP and 
BUD.
(ED20) cortisol suppression (dose at which 
20% cortisol suppression is reached) /ED80
for AMP PC20 (dose at which 80% of the 
maximum AMP PC20 is reached).
Secondary
Safety and tolerability.
Safety and tolerability of all treatments as 
assessed by adverse events (AEs), peak 
expiratory flow rate (PEFR), vital signs, 
physical examinations, laboratory 
assessments, and spirometry.
Exploratory
To estimate the dose of FF and BUD that gives
the same AMP response as the FP doses 
administered in this study.
AMP PC20.
To estimate the dose of FF and BUD that gives
the same cortisol suppression as the FP doses 
administered in this study.
Suppression of 24 hour weighted mean 
plasma cortisol compared to placebo.


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Objectives
Endpoints
To compare the systemic metabolic bioactivity 
profile of FF, FP and BUD with the aim of 
identifying qualitative, quantitative and dose 
related differences in on-target and off-target 
steroid receptor interactions using plasma 
metabolomics.
Metabolic profiling of plasma samples 
collected pre-dose and 12 hour after the last 
dose on Day 7 compared to placebo.
Overall Design
This is a randomized, placebo-controlled, incomplete-block, 2-period cross-over, 7-day 
escalating repeat dose study in subjects with mild asthma.
Subjects will consent to participate in either:

one treatment period; or 

two treatment periods, separated by a washout period of 25-42 days.
Each treatment period will comprise five consecutive 7-day dosing phases with escalating 
doses of one of three ICS products or placebo. Each 7-day period is referred to as an 
escalation phase. In each 7-day escalation phase, subjects will receive study treatment
from the evening of Day 1 to the evening of Day 7. 
Subjects who consent to completing 2 treatment periods will be assigned to one of the 
treatment sequences. Subjects who consent to completing 1 treatment period will be 
randomized to treatment. The randomization schedules will be generated by Clinical 
Statistics prior to the start of the study, using validated internal software.
Treatment Arms and Duration
There will be 5 different study treatments for subjects who consent to 2 treatment 
periods, these treatments will be administered in 12 different treatment sequences with 
2 treatments each. Two subjects will be randomized to each of the 12 treatment 
sequences. Subjects who consent to 1 treatment period will be randomized to treatment, 
6 subjects will be randomized to each active treatment and 3 subjects to each placebo 
treatment.
Study days for subjects who consent to 1 treatment period:

Screening: Day -42 to Day -4.

One treatment period of at least 35 days (i.e. 5 escalating doses administered for 
7 days each).

Follow-up period: 7 to 14 days after the last dose of treatment period 1.


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Study days for subjects who consent to 2 treatment periods:

Screening: Day -42 to Day -4.

Treatment periods: two periods of at least 35 days (i.e. 5 escalating doses 
administered for 7 days each), separated by a washout period of between 25 to 
42 days.

Follow-up period: 7 to 14 days after the last dose of treatment period 2.
The study duration for subjects who consent to 1 treatment period will range from 46 to 
91 days. The study duration for subjects who consent to 2 treatment periods will range 
from 106 to 168 days.
Table 1
Treatments regime proposed per dose escalation phase
Treatment
Ist
escalation 
phase -
7 days
2nd
escalation 
phase -
7 days
3rd 
escalation 
phase -
7 days
4th
escalation 
phase –
7 days
5th
escalation 
phase –
7 days
A
FF 
ELLIPTA™
25 µg
1 puff PM
TDD 
= 25 µg
→
FF 
ELLIPTA™
100 µg
1 puff PM
TDD 
= 100 µg
→
FF 
ELLIPTA™
200 µg
1 puff PM
TDD 
= 200 µg
→
FF 
ELLIPTA™ 
200 µg
2 puff PM
TDD 
= 400 µg
→
FF 
ELLIPTA™
200 µg
4 puff PM
TDD 
= 800 µg
B
FP 
DISKUS™ 
50 µg
1 puff PM
TDD 
= 50 µg
→
FP 
DISKUS™ 
100 µg
1 puff AM
1 puff PM
TDD 
= 200 µg
→
FP 
DISKUS™ 
250 µg
1 puff AM
1 puff PM
TDD 
= 500 µg
→
FP 
DISKUS™ 
500 µg
1 puff AM
1 puff PM
TDD 
= 1000 µg
→
FP 
DISKUS™ 
500 µg
2 puff AM
2 puff PM
TDD 
= 2000 µg
C
BUD
Turbuhaler 
100 µg
1 puff PM
TDD 
= 100 µg
→
BUD
Turbuhaler 
200 µg
1 puff AM
1 puff PM
TDD 
= 400 µg
→
BUD
Turbuhaler 
400 µg
1 puff AM
1 puff PM
TDD 
= 800 µg
→
BUD
Turbuhaler 
400 µg
2 puff AM
2 puff PM
TDD 
= 1600 µg
→
BUD
Turbuhaler 
400 µg
4 puff AM
4 puff PM
TDD 
= 3200 µg
D
ELLIPTA™ 
placebo
1 puff PM
→
ELLIPTA™ 
placebo
1 puff PM
→
ELLIPTA™ 
placebo
1 puff PM
→
ELLIPTA™ 
placebo
2 puff PM
→
ELLIPTA™ 
placebo
4 puff PM
E
DISKUS™ 
placebo
1 puff PM
→
DISKUS™ 
placebo
1 puff AM
1 puff PM
→
DISKUS™ 
placebo
1 puff AM
1 puff PM
→
DISKUS™ 
placebo
1 puff AM
1 puff PM
→
DISKUS™ 
placebo
2 puff AM
2 puff PM
BUD- Budesonide; FF-Fluticasone furoate; FP-Fluticasone propionate; TDD-Total daily dose


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Type and Number of Subjects
Subjects will be recruited such that 48 subjects will complete the study. Twenty-four 
subjects will be enrolled to complete two treatment periods; and a further 24 subjects will 
be enrolled to complete one treatment period. This sample size is based on feasibility.
Analysis
The main purpose of this study is to characterize the dose response and relative potency 
following repeat inhaled doses of FF, FP and BUD on AMP PC20 at 12 hours after the 
last dose on Day 7 and also to characterize the dose response and relative potency for FF, 
FP and BUD on the 24 hour plasma cortisol suppression after 6 days’ dosing.
To achieve these objectives a dose response maximum effect (Emax) model will be fitted 
to the AMP PC20 data and the cortisol suppression 0-24 hours weighted mean data. There 
will be no formal hypothesis tested, but point estimates and corresponding 95% 
confidence intervals will be constructed for each of the three parameters for the Emax
model (response at dose 0 [E0], Emax, and dose at which 50% of the maximum effect is 
reached [ED50]).
2.
INTRODUCTION
Inhaled corticosteroids are the mainstay of asthma treatment with currently eight inhaled 
corticosteroid (ICS) molecules approved for clinical use spanning a wide range of 
potencies and other pharmacological properties. However, the consensus amongst 
prescribers, regulators, treatment guidelines and patients is that the more recently 
approved molecules with greater selectivity, potency and improved targeting to the lung 
may not offer any therapeutic advantages.
One reason for this situation is the widely held assumption that the therapeutic index of 
corticosteroids cannot be improved by increasing their potency via enhanced 
glucocorticoid receptor binding affinity. This is probably valid for systemically 
administered corticosteroids since both the efficacy and safety are attributable to 
circulating drug concentrations and common receptor interactions [Mager, 2003]. 
However, the same rationale is generally applied to ICS and indeed embedded within 
asthma treatment guidelines. Consequently, ICS potency is not considered to affect the 
topical efficacy to systemic activity ratio [Kelly, 1998] and potency differences are 
thought to be overcome by giving larger doses of the less potent drug to achieve 
therapeutic equivalence [Kamada, 1996].
There are several reasons why this rationale may not be valid for ICS. First, they exert 
their anti-inflammatory activity at the site of action in the airways, which is not in 
equilibrium with the downstream systemic drug concentrations responsible for the 
unwanted systemic effects [Daley-Yates, 2010]. Secondly, it assumes that increasing ICS 
potency is not associated with changes in other features of the molecule 
[Hochhaus, 1997]. However, in reality, the molecular structural features that increase 
glucocorticoid receptor binding affinity and selectivity also result in physicochemical and 


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pharmacokinetic changes that together may enhance targeting to the airways and reduce 
systemic exposure [Daley-Yates, 2015].
Fluticasone furoate, ([FF]; GW685698) is a once daily ICS developed for the treatment of 
asthma in adults and adolescents aged 12 years and over. Fluticasone furoate is the most 
potent of the available ICS with a relative glucocorticoid receptor binding affinity ≈30 
times that of dexamethasone. Fluticasone furoate is also a component of a combination 
product for both chronic obstructive pulmonary disease (COPD), and asthma with 
vilanterol (VI; GW642444), a long-acting beta2-agonist (LABA), and is also being 
developed as the ICS component in the following two combination treatments: a dual 
combination with umeclidinium bromide ([UMEC]; GSK573719) a long-acting 
muscarinic antagonist (LAMA) for the treatment of asthma-COPD overlap syndrome; 
and a triple combination with both UMEC and VI for the treatment of COPD [GSK
Document Number GM2004/00283/12].
Fluticasone propionate (FP, CCI18781) is a twice daily ICS approved worldwide for the 
treatment of asthma in adults and children. It is also available as a combination product 
containing the long-acting bronchodilator salmeterol for the treatment of asthma and 
COPD.  FP has a relative glucocorticoid receptor binding affinity ≈18 times that of 
dexamethasone [GSK Document Number RM2002/00280/01].
Budesonide is a twice daily ICS approved worldwide for the treatment of asthma in 
adults and children. It is also available as a combination product containing the 
long-acting bronchodilator formoterol for the treatment of asthma and COPD. 
Budesonide has a relative glucocorticoid receptor binding affinity ≈9 times that of 
dexamethasone. 
Although it is widely recognized that glucocorticoids are the most effective therapy for 
asthma and other allergic and inflammatory diseases, the precise mechanism of action is 
not fully understood. The mode of action for glucocorticoids is through binding to the 
cytosolic glucocorticoid receptor eventually resulting in transactivation or trans 
repression of gene transcription.  Glucocorticoids are therefore able to act as anti-
inflammatory agents via multiple mechanisms to inhibit late phase allergic reactions 
including decreasing the density of mast cells along mucosal surfaces, decreasing 
chemotaxis and activation of eosinophils, decreasing cytokine production by 
lymphocytes, monocytes, mast cells and eosinophils, and inhibiting the metabolism of 
arachidonic acid [Daley-Yates, 2007]. 
The undesirable effects of inhaled corticosteroids comprise a broad range of class-related 
adverse events that include hoarseness/dysphonia, candidiasis of the mouth and throat, 
adrenal suppression, growth retardation in children and adolescents, decreased bone 
mineral density, cataract, glaucoma, hyperglycaemia, contusions and pneumonia (in 
patients with COPD). Some of the commonly reported and minor adverse effects, such 
as hoarseness/dysphonia, are related to local topical activity, whereas adverse effects 
related to systemic exposure, such as adrenal suppression, although more serious, are 
very rarely reported [Mortimer, 2006].


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2.1.
Study Rationale
Fluticasone furoate is the most recently approved ICS for the treatment of asthma and 
COPD. It is also the most potent and hence compared to the other ICS can be 
administered at much lower doses to achieve similar clinical efficacy [Busse, 2014].
There is also evidence from studies in healthy subjects and patients that FF doses in the 
therapeutic dose range are associated with less systemic effects than therapeutic doses of 
other ICS [Allen, 2013a; Allen, 2013b]. Although these findings support the hypothesis 
that higher potency can improve the therapeutic index, there is a need to confirm this in a 
single study that compares both efficacy and systemic safety endpoints for a range of ICS 
potencies in the target patient population.
This study aims to investigate whether higher potency confers an improvement in the 
topical efficacy to systemic activity ratio. It will compare the dose response for topical 
efficacy via airway responsiveness to adenosine-5’-monophosphate (AMP) challenge and 
the dose response for systemic activity via 24 hour plasma cortisol suppression and 
thereby the relative therapeutic index for fluticasone furoate (FF), fluticasone propionate 
(FP) and budesonide (BUD) in asthmatic subjects.
Metabolomics will also be included as an exploratory endpoint to study the systemic 
metabolic bioactivity profile of the three ICS with the aim of identifying whether 
qualitative or a quantitative difference exists in on-target and off-target steroid receptor 
interactions. This will provide new information that may allow the systemic effects of 
the three ICS to be distinguished quantitatively and qualitatively with endpoints not 
previously identified.
2.2.
Brief Background
Asthma is a serious public health problem throughout the world, affecting about
300 million individuals of all ages. Asthma is a chronic inflammatory disorder of the
airways, characterized by recurrent acute attacks of breathlessness and wheezing, in
which many cells and cellular elements play a role [GINA, 2017]. When uncontrolled, 
asthma can place severe limitations on daily life, and is sometimes fatal. Although there 
is no cure, avoidance of asthma triggers and the use of appropriate long- and short-term 
medication offer patients options for control of their disease [WHO, 2015].
Inhaled corticosteroids are recommended as first-line treatment for patients with
persistent asthma, and the addition of an inhaled LABA can be considered to improve 
lung function and symptoms in patients whose asthma is not well controlled on ICS 
alone.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To characterize the dose response and relative 
potency for FF, FP and BUD in the adenosine 
monophosphate (AMP) challenge model at 
Provocative concentration (PC) of AMP 
causing a 20% fall in forced expiratory 
volume in 1 second (FEV1) (AMP PC20).


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Objectives
Endpoints
12 hours after the last dose on Day 7 
To characterize the dose response and relative 
potency for FF, FP and BUD on 24hour plasma 
cortisol suppression on-treatment from pre-dose 
PM dose on Day 6 to pre-dose PM dose Day 7.
Suppression of 24 hour weighted mean 
plasma cortisol compared to placebo.
To assess the therapeutic index for FF, FP and 
BUD.
(ED20) cortisol suppression (dose at which 
20% cortisol suppression is reached) /ED80
for AMP PC20 (dose at which 80% of the 
maximum AMP PC20 is reached).
Secondary
Safety and tolerability.
Safety and tolerability of all treatments as 
assessed by adverse events (AEs), peak 
expiratory flow rate (PEFR), vital signs, 
physical examinations, laboratory 
assessments, and spirometry.
Exploratory:
To estimate the dose of FF and BUD that gives
the same AMP response as the FP doses 
administered in this study.
AMP PC20
To estimate the dose of FF and BUD that gives
the same cortisol suppression as the FP doses 
administered in this study.
Suppression of 24 hour weighted mean 
plasma cortisol compared to placebo.
To compare the systemic metabolic bioactivity 
profile of FF, FP and BUD with the aim of 
identifying qualitative, quantitative and dose 
related differences in on-target and off-target 
steroid receptor interactions using plasma 
metabolomics.
Metabolic profiling of plasma samples 
collected pre-dose and 12 hour after the last 
dose on Day 7 compared to placebo.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized, placebo-controlled, incomplete-block, 2-period cross-over, 7-day 
escalating repeat dose study in subjects with mild asthma.
Screening visit 1 will be conducted 4 – 42 days prior to the first treatment day. Subjects 
who are taking low-dose ICS will have a 4-week ICS washout during which their asthma 
symptoms must remain stable as defined in Section 5.1. Screening visit 2 will be 
conducted 4 – 14 days prior to the first treatment day and at least 4 weeks after screening 
visit 1. Subjects must have an AMP challenge PC20 of ≤80 mg/mL at screening visit 2 to 
be eligible. Procedures from screening visit 1 may be repeated at screening visit 2 as 
deemed necessary by the investigator/delegate.
Subjects who do not have to undergo ICS washout may only have 1 screening visit, and
undergo screening visit 2 procedures at screening visit 1.


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Subjects will consent to participate in either:

one treatment period; or

two treatment periods, separated by a washout period of 25-42 days. 
Each treatment period will comprise five consecutive 7-day dosing phases with escalating 
doses of one of three ICS products or placebo. Each 7-day period is referred to as an 
escalation phase. In each 7-day escalation phase, subjects will receive study treatment
from the evening of Day 1 to the evening of Day 7. 
A follow-up visit will take place within 7-14 days after the last dose of study treatment. 
Time and events tables for screening and follow-up visits (Table 9) and Treatment 
Periods (Table 10) are provided in Section 7.1.
4.2.
Treatment Arms and Duration
The treatments for each dose escalation phase are listed in Table 2 and regime to provide 
each dose in Table 3. Subjects who consent to completing 2 treatment periods will be 
randomized to order of treatments they are included in. Subjects who consent to 
completing 1 treatment period will be randomized to treatment.
Table 2
Doses proposed per dose escalation phase
Treatment
1st
escalation 
phase –
7 days
2nd
escalation 
phase –
7 days
3rd
escalation 
phase –
7 days
4th
escalation 
phase –
7 days
5th
escalation 
phase –
7 days
A
FF 25 µg
→
FF 100 µg
→FF 200 µg →
FF 400 µg →
FF 800 µg
B
FP 50 µg
→
FP 200 µg
→FP 500 µg →
FP 
1000 µg
→
FP 
2000 µg
C
BUD 
100 µg
→
BUD 
400 µg
→BUD 
800 µg
→
BUD 
1600 µg
→
BUD 
3200 µg
D
ELLIPTA™ 
Placebo
→
ELLIPTA™ 
Placebo
→ELLIPTA™ 
Placebo
→
ELLIPTA™ 
Placebo
→
ELLIPTA™ 
Placebo
E
DISKUS™ 
Placebo
→
DISKUS™ 
Placebo
→DISKUS™ 
Placebo
→
DISKUS™ 
Placebo
→
DISKUS™ 
Placebo
BUD- Budesonide; FF-Fluticasone furoate; FP-Fluticasone propionate


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Table 3
Treatments regime proposed per dose escalation phase (total daily 
doses)
Treatment
1st
escalation 
phase -
7 days
2nd
escalatio
n phase -
7 days
3rd 
escalatio
n phase -
7 days
4th
escalatio
n phase –
7 days
5th
escalation 
phase –
7 days
A 
FF 
ELLIPTA™ 
25 µg
1 puff PM
TDD 
= 25 µg
→
FF 
ELLIPTA
™ 100 µg
1 puff PM
TDD 
= 100 µg
→
FF 
ELLIPTA
™ 200 µg
1 puff PM
TDD 
= 200 µg
→
FF 
ELLIPTA
™ 200 µg
2 puff PM
TDD 
= 400 µg
→
FF 
ELLIPTA™ 
200 µg
4 puff PM
TDD 
= 800 µg
B
FP 
DISKUS™ 
50 µg
1 puff PM
TDD 
= 50 µg
→
FP 
DISKUS
™ 100 µg
1 puff AM
1 puff PM
TDD 
= 200 µg
→
FP 
DISKUS
™ 250 µg
1 puff AM
1 puff PM
TDD 
= 500 µg
→
FP 
DISKUS
™ 500 µg
1 puff AM
1 puff PM
TDD 
= 1000 µg
→
FP 
DISKUS™ 
500 µg
2 puff AM
2 puff PM
TDD 
= 2000 µg
C
BUD 
Turbuhaler 
100 µg
1 puff PM;
TDD 
= 100 µg
→
BUD 
Turbuhale
r 200 µg
1 puff AM
1 puff PM
TDD 
= 400 µg
→
BUD 
Turbuhale
r 400 µg
1 puff AM
1 puff PM
TDD 
= 800 µg
→
BUD 
Turbuhale
r 400 µg
2 puff AM
2 puff PM
TDD 
= 1600 µg
→
BUD 
Turbuhaler 
400 µg
4 puff AM
4 puff PM
TDD 
= 3200 µg
D
ELLIPTA™ 
placebo
1 puff PM
→
ELLIPTA
™ 
placebo
1 puff PM
→
ELLIPTA
™ 
placebo
1 puff PM
→
ELLIPTA
™ 
placebo
2 puff PM
→
ELLIPTA™ 
placebo
4 puff PM
E
DISKUS™ 
placebo
1 puff PM
→
DISKUS
™ 
placebo
1 puff AM
1 puff PM
→
DISKUS
™ 
placebo
1 puff AM
1 puff PM
→
DISKUS
™ 
placebo
1 puff AM
1 puff PM
→
DISKUS™ 
placebo
2 puff AM
2 puff PM
BUD- Budesonide; FF-Fluticasone furoate; FP-Fluticasone propionate; TDD-Total daily dose
Twenty-four subjects completing 2 treatment periods will be randomized to one of the 
treatment sequences shown in Table 4.


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Table 4
Treatments proposed per study period for subjects completing 
2 treatment periods
Sequence
Period 1
Period 2
n
1
A
B
2
2
A
C
2
3
A
D
2
4
B
A
2
5
B
C
2
6
B
E
2
7
C
A
2
8
C
B
2
9
C
E
2
10
D
A
2
11
E
B
2
12
D
C
2
Total subjects
24
Subjects per treatment
12
Twenty-four subjects completing 1 treatment period will be randomized to one of the 
treatments shown in Table 5.
Table 5
Treatments proposed for subjects completing 1 treatment period
Treatment
n
A
6
B
6
C
6
D
3
E
3
Total subjects
24
Subjects per treatment
6
Therefore, a total of 48 subjects will complete the study, 18 subjects in total per study 
treatment (for each active treatment and for placebo combined).
Study durations for subjects completing either 2 or 1 treatment periods are shown in 
Table 6 and Table 7.
Table 6
Study Duration for subjects completing 2 treatment periods
Screening
days
Period 1
days
Washout
days
Period 2
days
Follow-Up 
days
Total days
4-42
35
25-42
35
7-14
106-168


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Table 7
Study Duration for subjects completing 1 treatment period
Screening
days
Period 1
days
Follow-Up 
days
Total days
4-42
35
7-14
46-91
4.3.
Type and Number of Subjects
Subjects will be recruited such that 48 subjects will complete the study. Twenty-four 
subjects will be enrolled to complete 2 treatment periods and a further 24 subjects will be 
enrolled to complete 1 treatment period.
This sample size is based on feasibility.
If subjects are replaced they will be assigned to the same treatment or treatment sequence 
as the subject they are replacing. Refer to Section 6.2 for more details.  
4.4.
Design Justification
Three ICS are included in this study; FP which is the most commonly prescribed ICS 
with a glucocorticoid receptor (GR) binding potency in the mid to high range, BUD with 
a GR binding potency in the low to mid-range and FF which has the highest GR binding 
potency. The expected relative potency for efficacy in the AMP challenge model is 2:1 
for FP:BUD. The corresponding relative potency for FF:FP is unknown but expected to 
be in the range 2-5 fold.
This study will assess the activity of FF, FP and BUD in the AMP bronchoprotection 
model to determine the dose response after 7 days of dosing, measured at 12 hours after 
the final dose when genomic actions were considered to be maximal. The study will also 
assess the corresponding dose responses on cortisol suppression, measured as 24 hour
plasma cortisol from pre-dose evening of Day 6 to 24 hours later on Day 7.
The study is not double-blinded or double-dummy but a partially blinded study with the 
following design features mitigated for this aspect. The endpoints are objective rather 
than subjective. Subjects will receive one or two of the four possible treatments not 
knowing which are active or placebo. When receiving placebo they will be assigned 
either a DISKUS™ or an ELLIPTA™ device. There will be no BUD Turbuhaler 
placebo. Subjects assigned to placebo will follow the same dose escalation scheme 
taking the same number of inhalations in each phase as the corresponding active 
treatments. Additionally, this will provide a measure of stability of the AMP and cortisol 
response over the 5 week period where repeated AMP challenges are performed. For a 
completely balanced design there would be 14 treatment sequences for subjects 
completing 2 treatment periods; however, an assumption has been made that ELLIPTA™ 
and DISKUS™ placebo will have the same effect therefore two of the sequences 
including placebo (EC and CD) have been dropped to give an equal number of subjects
on each treatment administered including placebo overall. Similarly, for subjects 
completing one treatment period, 3 subjects will be randomized to ELLIPTA™ and 
DISKUS™ placebo so that 6 subjects in total receive placebo overall, which is equal to 
the subjects on each active treatment.


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In addition to the subjects, the investigators, nurses, technicians and other staff that 
interact with the subjects will also be blinded to the treatment designations. The subjects 
will be provided with one of three different dry powder inhalers for each period either 
active treatment or placebo. The subjects will not be informed which are the active or 
placebo treatments although no Turbuhaler placebo will be used in the study.  The study 
sponsor will be unblinded to study treatment to allow selected sponsor study team 
members to perform unblinded in-stream analysis of available data.  These findings will 
inform on the need for a sample size re-estimation or interim analysis (see Section 9.2.3).
Previous studies have indicated that conducting an AMP challenge may affect subsequent 
AMP challenges when multiple challenges are performed. Therefore by having 5 
consecutive placebo challenges within a subject it will be possible to explore and if 
necessary control for this finding.
Metabolomics will be included as an exploratory endpoint in this study to assess the 
ability of metabolic profiling to provide additional insight into the direct effects of ICS on 
individual responses with a particular focus on dose related changes. The three ICS 
included in this study differ in their receptor binding potency, affinity and specificity for 
the various on-target and off-target steroid receptors. These interactions translate into the 
potential for systemic adverse effects of ICS. Of these the most is commonly measured 
side-effect is suppression the hypothalamic pituitary-adrenal axis, as assessed by 
monitoring changes in plasma cortisol. However, this provides no information about 
qualitative differences in the potential for adverse metabolic effects that may exist for 
different ICS. It is likely that perturbations of adrenal androgen secretion may be a better 
marker than cortisol for the risk of developing osteoporosis. Therefore, for example, it 
may be more appropriate to measure dehydroepiandrosterone sulphate (DHEA-S), an 
adrenal androgen precursor regulated by corticotrophin. 
It also has the advantage of a long half-life (10-12 hours) and concentrations that do not 
fluctuate throughout the day like cortisol. It has also been shown that adrenal androgen 
secretion is more sensitive than cortisol production to the effects of glucocorticoid 
therapy [Kannisto, 2004]. The present study presents an opportunity to study the 
systemic metabolic bioactivity profile of the three ICS with the aim of identifying 
whether qualitative or quantitative differences exists in on-target and off-target steroid 
receptor interactions using metabolomics. Investigations will include the entire 
metabolome with particular focus on any pathways or metabolites detected and related to 
the steroid biome (e.g. DHEA-S). This will provide new information that may allow 
various ICS therapeutic indices to be distinguished quantitatively in class effects and by 
qualitative differences not previously identified.
4.5.
Dose Justification
In order to fully characterize the dose response for the bronchoprotective effect of each 
ICS in the AMP challenge model and simultaneously for cortisol suppression it is 
necessary to study a wide dose range. 
Previous studies have shown that the dose at which 50% of the maximum effect is 
reached (ED50) for FP and BUD are likely to be less than the lowest clinical dose for 


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asthma [Phillips, 2004; GSK Document Number GM2005/00525/00, Study SIG103337]. 
Therefore, the lower doses to be used in the study will be of 25 µg of FF, 50 µg of FP and 
100 µg of BUD administered once daily.
FF (100 and 200 μg per day), is a once daily ICS that is being developed for the treatment 
of asthma, and has been approved in the United States [Food and Drug Administration, 
2014] and 5 other countries (Australia, Canada, Chile, Singapore, and Switzerland) for 
the treatment of asthma in adults and adolescents aged 12 years and over. FF (100 and 
200 μg per day) is also approved worldwide (including the European Union - Relvar 
ELLIPTATM) as the ICS component of a combination product for COPD and asthma, 
with VI (GW642444). In the current study, it is proposed to dose escalate FF, to a 
maximum daily dose of 800 μg. FF has been administered to healthy volunteers at doses 
of 100 to 1600 μg once daily (OD) for 7 days (Study HZA113477, see Section 5.2.2.2 of 
the FF Investigator Brochure and Study FFA103096 [GSK Document Number 
GM2005/00082/00]) and as FF/VI at doses up to 800/100 μg OD for 7 days (Study 
HZA102936 [Kempsford, 2014]). These doses were well tolerated. FF was investigated 
in dose ranging studies in asthmatic subjects over the range 25 to 800 µg once daily for 8 
weeks and was shown to be safe and well tolerated [Bateman, 2012, Bleecker, 2012, 
Busse, 2012].
FP is indicated in the UK and Germany for the treatment of asthma, at doses of up to 
1000 μg twice per day, which also represents the maximum dose that subjects will be 
exposed to in this study.
BUD is indicated in the UK and Germany for the treatment of asthma, at doses up to 
1600 μg in divided doses. In the current study, it is proposed to dose escalate BUD, to a 
maximum daily dose of 3200 μg. BUD has been administered to asthmatic patients at 
doses of up to 3200 μg for up to 6 weeks [Kaiser, 1999]. These doses were well 
tolerated.
For the AMP challenge quadrupling dose increments are expected to show a well-defined 
dose response [Phillips, 2004] for this reason the following total daily doses of 25 µg, 
100 µg, 400 µg for FF; 50 µg, 200 µg, 1000 µg for FP and 100 µg, 400 µg, 1600 µg for 
BUD have been chosen.  However, three doses are insufficient to define the dose 
response for both AMP challenge and cortisol suppression and include all the doses used 
therapeutically since there is little overlap in the doses needed [Daley-Yates, 2015; 
Möllmann, 2001; GSK Document Number GM2005/00082/00]. Therefore, FF 200 
µg/day, FP 500 µg/day, and 2000 µg/day and BUD 800 µg/day are included to ensure the 
dose responses are adequately defined. Likewise, an 800 µg/day FF dose and 3200 
µg/day BUD dose will also be included to fully define the cortisol suppression dose 
response [GSK Document Number GM2005/00082/00] and ensure the dose escalation 
increments are matched between the three ICS under investigation.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and nonclinical studies conducted with
fluticasone propionate, fluticasone furoate and budesonide can be found in the relevant 
Investigator’s Brochure [GSK Document Number RM2002/00280/01 and GSK 


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Document Number GM2004/00283/12] and product label, respectively.  The following 
section outlines the risk assessment and mitigation strategy for this protocol.


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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Corticosteroids:  Fluticasone furoate, fluticasone propionate and budesonide
Exposure to corticosteroid induced side 
effects including, oropharyngeal pain, 
candidiasis, hoarseness and potential 
systemic effect on the hypothalamic-
pituitary-adrenal (HPA) axis including 
adrenal suppression. Other adverse 
effects include eye disorders, respiratory 
infections including pneumonia and 
hypersensitivity.
Inhaled corticosteroids have a number of potential 
side effects, both locally and systemically. Oral 
candidiasis is observed as a common event 
associated with the use of ICS. 
The incidence and severity of oral candidiasis is 
similar for various ICS.
An increased incidence of pneumonia with higher 
doses of ICS cannot be ruled out; however, the 
absolute risk of pneumonia appears to be very small 
and consistent for various ICS.  
Hypersensitivity adverse reactions may include 
anaphylaxis, angioedema, urticaria and rash.
Administered doses in this study will not exceed 
the previous clinical experience for tolerated 
doses of FF, FP and budesonide. Significant 
corticosteroid mediated adverse effects are more 
likely with chronic dosing of high doses; subjects 
will receive at least of 35 days’ continuous 
administration including sub-therapeutic doses.
The highest doses in the doses escalation are 
only administered for 7 days.
Subjects will be informed about the risk of 
candidiasis, adrenal suppression, eye disorders, 
pneumonia and hypersensitivity reactions in the 
informed consent.  If any symptoms appear, 
investigators should implement an appropriate 
treatment while observing the subject’s asthma 
symptoms.
Subjects will be advised to seek medical 
treatment if any signs of eye disorder occur. 
Subjects with concurrent respiratory disease are 
excluded from the study.
Subjects will be advised to seek medical 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
treatment if any signs of hypersensitivity occur. 
Subjects with milk protein allergy or known 
hypersensitivity to ICS will be excluded from 
participating in the study.
AMP Challenge
Exposure to inhaled AMP challenge 
agent
Subject may experience bronchospasm 
Adenosine monophosphate challenges will be 
conducted in specialist clinical units, with trained 
technicians. The normal bronchoconstrictor 
response to AMP disappears within 30 to 45 
minutes after PC20 has been achieved. Subjects 
will remain in the unit until their FEV1 has 
returned to at least 90% of pre-diluent baseline. 
Inhaled salbutamol will be allowed to facilitate 
recovery as needed.
Withdrawal of Inhaled Corticosteroids
Subjects receiving low-dose ICS as 
defined in Appendix 5 may take part after 
a 4 week ICS washout prior to AMP 
challenge.  There is a risk associated with 
withdrawing inhaled corticosteroids in 
these subjects who are currently taking 
them
Subject may experience worsening of asthma 
symptoms
Subjects washing out from ICS will be monitored 
via weekly calls from site, and maintenance of 
diary to capture PEFR and SABA use.
Subjects are instructed to contact the PI/site for 
assessment if they have a deterioration of their 
asthma (refer to Section 7.3.8.4. Diary 
Assessments) or if they have an exacerbation.
Any subject whose asthma is defined as not 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
stable will not be eligible to participate in the 
study.


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4.6.2.
Benefit Assessment
The study procedures e.g. blood samples, are normally associated with low risk of 
short-term tolerability e.g. pain and bruising from blood sampling.
All subjects will be closely monitored during the treatment and during the washout period 
for deterioration of lung function and if necessary withdrawal criteria applied as specified 
in the protocol (Section 5.4).
This is an exploratory study in otherwise healthy asthmatic subjects, to define dose 
equivalence relationships for new and established inhaled corticosteroids. The subjects 
will derive no direct benefit from study participation.
The benefit/risk profile supports the proposed short-term dose escalations of low mid and 
high doses of currently marketed inhaled corticosteroids study in asthmatic subjects
4.6.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in the 
study, the potential risks identified in association with FF, FP and BUD are justified by 
the anticipated benefits that may be afforded to subjects with asthma.
All three study treatments administered in this study are marketed for the treatment of 
asthma, and therefore, they have already clearly demonstrated a favourable benefit: risk 
ratio.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational products or other study 
treatment that may impact subject eligibility is provided in the relevant Investigator 
Brochure (IB) [GSK Document Number RM2002/00280/01 and GSK Document Number
GM2004/00283/12].
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: 18 to 65 years of age inclusive, at the time of signing the informed 
consent.


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TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Asthma: Documented history of bronchial asthma, first diagnosed at least 6 months 
prior to the screening visit.
3. Severity of disease:  
a) Pre-bronchodilator FEV1 ≥65% of predicted at screening. 
b) The pre-dose baseline FEV1 should not have changed significantly in the opinion 
of the investigator from the screening baseline value and should be ≥ 65% 
predicted for the subject to continue.
c) Documented sensitivity to AMP with a provocative concentration of AMP 
resulting in a fall of ≥20% FEV1 with a PC20 AMP ≤80 mg/mL at the screening 
visit.
4. Current Therapy:

Short-Acting Beta2-Agonists (SABA): prescribed SABA for at least 12 weeks 
prior to screening, if needed.

Subjects receiving low-dose ICS as defined in Appendix 5 may take part after a 
4-week ICS washout prior to AMP challenge. The subject’s asthma symptoms
must remain stable during this 4-week period as assessed at screening visit 2.
Stable asthma is defined as:

No more than 2 consecutive days where ≥12 inhalations/day of salbutamol 
were used.

No severe asthma exacerbations requiring use of systemic corticosteroids 
(tablets, suspension, or injection) or an in-patient hospitalization or 
emergency department visit due to asthma that required systemic 
corticosteroids.

No clinical asthma worsening which in the opinion of the investigator 
requires additional asthma treatment other than study medication or 
salbutamol.

Subjects taking LABA, LAMA, leukotriene receptor antagonist (LTRA) therapy 
within 3 months prior to the start of the study are not eligible.

Subjects taking biological therapies within 6 months prior to start of the study
are not eligible.
WEIGHT
5. Bodyweight and Body Mass Index (BMI): Bodyweight ≥ 50 kg and BMI within the 
range 18.0-35.0 kg/m2 (inclusive)


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SEX
6. Gender: Male and 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 prior to randomization:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation.
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion.
Hysterectomy.
Documented Bilateral Oophorectomy.
Postmenopausal defined as 12 months of spontaneous amenorrhea, in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
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 postmenopausal 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 from 30 days prior to the first dose of study medication and 
until at least five terminal half-lives after the last dose of study medication (Appendix 
4).
The investigator is responsible for ensuring that subjects understand how to properly 
use these methods of contraception.
OTHER
7. Liver criteria: Aspartate aminotransferase (AST) and Alanine transaminase (ALT) 
< 2x upper limit of normal (ULN); alkaline phosphatase and bilirubin 1.5x ULN 
(isolated bilirubin > 1.5x ULN is acceptable if bilirubin is fractionated and direct 
bilirubin < 35%).
8. Light smokers, who smoke ≤ 20 cigarettes per week or equivalent unit dose of other 
tobacco products or e-cigarettes, are eligible for the study. Smokers who intend to 
stop, reduce or increase their smoking habit during the study period are not eligible.
INFORMED CONSENT
9. Having provided written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form.


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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND CORRECTED QT (QTc) INTERVAL) 
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): severe 
pneumonia within 6 months of the screening visit, pneumothorax, atelectasis, 
pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, 
emphysema, chronic obstructive pulmonary disease, tuberculosis 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 within 4 weeks of 
screening that:

In the opinion of the investigator, is expected to affect the subject’s asthma status 
or the subject’s ability to participate in the study.
4. Oropharyngeal examination: A subject will not be eligible if he/she has clinical 
visual evidence of oral candidiasis at screening.
5. 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 randomization.
CONCOMITANT MEDICATIONS
6.
Use of prohibited medications:
Any other medications including, anti-depressant drugs, and anti-asthma drugs (other 
than short-acting inhaled β-agonists supplied as rescue medication, oral 
contraceptives not listed in Appendix 4, non-steroidal anti-inflammatory drugs, 
stable doses of antihistamines, and paracetamol) for 1 week prior to screening and 
throughout the course of the study. Antihistamines should be withheld 4 days prior 
to AMP challenge.

Subjects must also be able to abstain from short-acting inhaled β-agonists, for 
8 hours prior to spirometry.
7.
Subjects undergoing de-sensitization therapy.
RELEVANT HABITS
8.
Tobacco Use: Current smokers who smoke > 20 cigarettes per week or the 
equivalent unit dose of other tobacco products or e-cigarettes, or smokers with a 
smoking history of 10 pack years. 
9.
History of regular alcohol consumption exceeding 21 units/week for men and 


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14 units/week for females (1 unit = 5 ounces (150 mL) of wine or 12 ounces 
(360 mL) of beer or 1.5 ounces (45 mL) of spirits) within 6 months of screening.
10. All subjects who are currently or in the last month have worked night-shifts are 
excluded from the study.
CONTRAINDICATIONS 
11. Previous Participation: Exposure to more than four new chemical entities within 12 
months prior to the first dosing day or received an investigational product within 30 
days of study start, or 5 half-lives of study drug if that is longer.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
12. 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. (e.g. stroke or myocardial infarction within 3 months, uncontrolled 
hypertension, congestive heart failure, uncontrolled diabetes mellitus.)
13. Evidence of cancer or history of cancer in the past 5 years other than adequately 
treated basal or squamous cell carcinoma of the skin or adequately treated in situ 
carcinoma of the cervix.
14. Pregnancy and Lactating Females:

Pregnant females as determined by positive urine HCG test at screening or by 
positive urine HCG test prior to dosing.

Lactating females.
15. Subjects with active or chronic infections including hepatitis B or C, human 
immunodeficiency virus (HIV). A positive serology at screening.
16. Allergies:

Milk Protein Allergy: History of severe milk protein allergy.

Drug Allergy: Any adverse reaction including immediate or delayed 
hypersensitivity to intranasal, inhaled, or systemic corticosteroid therapy.  
Known or suspected sensitivity to the constituents of FF, FP or BUD (i.e., 
lactose or magnesium stearate, etc).

Historical Allergy: History of drug or other allergy that, in the opinion of the 
investigator or GSK Medical Monitor, contraindicates their participation.
17. 12-Lead electrocardiogram (ECG) abnormality: Significant abnormality in the 
12-lead ECG performed at screening. The mean of the three individual ECGs will be 
taken.
Mean QT interval corrected for heart rate (QTc) > 450 msec for males or QTc 
> 470 msec for female subjects and > 480 in subjects with bundle branch block.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF).


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5.3.
Screening/Baseline/Run-in Failures
Subjects who fail the initial screening visit may be rescreened once, after discussion with 
the sponsor. In order to be rescreened, subjects must have demonstrated AMP sensitivity 
and meet the spirometry and respiratory test results as described in inclusion criterion 3. 
Subjects must not have met any of the exclusion criteria. If AMP sensitivity was not 
established at screening, subjects known to be insensitive to AMP will not be rescreened.
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 publishing 
requirements, and respond to queries from regulatory authorities, a minimal set of screen 
failure information is required including Demography, Screen Failure details, Eligibility 
Criteria, and Serious Adverse Events (see Section 7.3.1.5).
5.4.
Withdrawal/ Stopping Criteria
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”.

Subjects who are not eligible to perform an AMP challenge at any of the specified 
time during the treatment periods (i.e. for reasons of safety) will be withdrawn from 
the study. One repeat attempt is permitted within 1-3 days.
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.
Worsening asthma: The following criteria will be used to aid the investigator in 
determining asthma stability. A randomized subject who meets any of the following 
stopping criteria will be withdrawn from the study:


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
Clinic FEV1 > 35% below the FEV1 value calculated at pre-treatment Day 1, 
treatment period 1.
During the study, the subject experienced:

At least 3 consecutive days in which 12 inhalations/day of 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) 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 salbutamol.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology (in alignment with the Food and Drug 
Administration premarketing clinical liver safety guidance) [FDA, 2009].
5.4.1.1.
Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
AST- Aspartate aminotransferase; ALT-Alanine transaminase; INR- International normalized ratio; ULN-
Upper limit of normal.
Liver Safety Required Actions and Follow-up Assessments Section can be found in 
Appendix 2.


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5.4.1.2.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria
The ECGs are only recorded at screening thus any QTc stopping criteria are not 
applicable.
5.5.
Subject and Study Completion
A completed subject is one who has completed the number of treatment periods they 
consented to, including the follow-up visit.
The end of the study is defined as the last subject’s last visit.


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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any 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.
Table 8
Study treatments
Study Treatment
Product name:
FF (GW685698) 
25 µg, 100 µg, 
and 200 µg Dry 
Powder Inhaler
FP (CCI18781) 
50 µg, 100 µg, 
250 µg, and 
500 µg
Dry Powder 
Inhaler
Placebo
BUD Turbuhaler
Formulation 
description:
Dry Powder 
Inhaler
Dry Powder 
Inhaler
Dry Powder 
Inhaler
See label for details.
Dosage form:
Dry Powder 
Inhaler
Dry Powder 
Inhaler
Dry Powder 
Inhaler
Dry Powder Inhaler
Unit dose 
strength(s)/Do
sage level(s):
25, 100, and 200 
µg per blister
50, 100, 250, 
and 500 µg per 
blister
Lactose
100, 200 and 400 μg 
per dose
Route of 
Administration
Inhaled
Inhaled
Inhaled
Inhaled
Dosing 
instructions:
Per Protocol
Per Protocol
Per Protocol
Per Protocol
Physical 
description:
Dry White 
Powder
Dry White 
Powder
Dry White 
Powder
White to off-white 
rounded granules, 
which disintegrate to 
a fine powder upon 
slight pressure
Storage 
conditions
Store up to 25°C 
(77°F)
Store at 2-25°C 
(36-77F)
ELLIPTA™: 
Store up to 25°C 
(77°F)
DISKUS™: Store 
at 2-25°C (36-
77°F)
Per commercial
Label:
Do not store above 
30°C or See label 
for details
Device:
ELLIPTA™
DISKUS™
ELLIPTA™ and 
DISKUS™
Turbuhaler
Method for 
individualizing 
dosage:
Inhalation (oral)
Inhalation (oral)
Inhalation (oral)
Inhalation (oral)
BUD- Budesonide; FF – Fluticasone furoate; FP – Fluticasone propionate


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6.2.
Treatment Assignment
Subjects will be assigned to one of the treatment sequences in accordance with the 
randomization schedule, generated by Clinical Statistics prior to the start of the study, 
using validated internal software.
Randomization numbers will be assigned to subjects using the randomization schedule.
Subjects should be randomized before they receive their first dose of study medications 
on the same day (Day 1).
A description of each regimen is provided in Table 3.
Withdrawn subjects may be replaced. Replacement subjects will be assigned to the same 
treatment sequence as the subject they are replacing. 
For subjects completing two treatment periods:

Each subject will receive 2 different treatments, one in treatment period 1, and one in 
treatment period 2; the possible treatment sequences are pre-defined in Table 4. Two 
subjects will be randomized to each of the 12 treatment sequences (Table 4).

If a subject withdraws during treatment period 1, the replacement subject will start 
from the beginning of period 1 of the same treatment sequence. If a subject 
withdraws after period 1 or during period 2, the replacement subject may start from 
period 2; a maximum of 2 subjects can be replaced from the start of period 2.  If more 
than 2 subjects withdraw after period 1 or during period 2, they will be replaced from 
the beginning of period 1.
For subjects completing one treatment period:

Each subject will receive one treatment, as defined in Table 5. Six subjects will be 
randomized to each treatment, including placebo overall (Table 5).

Replacements for withdrawn subjects will start from the beginning of period 1 of the 
same treatment.
6.3.
Planned Dose Adjustments
No dose adjustments are planned for this study.
6.4.
Blinding
The study is not double-blinded or double-dummy but a partially blinded study by the use 
of DISKUS™ placebo and ELLIPTA™ placebo, but no Turbuhaler placebo will be used.
In addition to the subjects, the investigators, nurses, technicians and other staff that 
interact with the subjects will also be blinded to the treatment designations. The subjects 
will be provided with a dry powder inhaler for each dose escalation phase either active 


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treatment or placebo. The subjects will not be informed which are the active or placebo 
treatments although no Turbuhaler placebo will be used in the study.
The following will also 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.

Selected sponsor study team members may be unblinded to perform the in-stream 
analysis. This may include the study statistician, study programmer (and delegates) 
and study DMPK scientist. Access to unblinded data will be kept to the minimum set 
of individuals required to implement any in-stream or interim analyses, but may 
include GSK management/review committees if alterations to the study conduct are 
required. Details of who were unblinded to what data and when will be included in 
the clinical study report.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
All supplies will be Packaged and Labelled in an Open-Label fashion. An unblinded site 
pharmacist will blind the supplies before dispensing them to the subjects.
6.6.
Preparation/Handling/ Storage/Accountability
No special preparation of study treatment is required. An unblinded site pharmacist will 
blind the supplies (by over-labelling) before dispensing them to the subjects.

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.


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
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 labeled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment are 
provided in the Study Reference Manual (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.
Precaution will be taken to avoid direct contact with the study treatment. A MSDS 
describing occupational hazards and recommended handling precautions will be provided 
to the investigator. In the case of unintentional occupational exposure notify the monitor, 
Medical Monitor and/or GSK study contact.
6.7.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.
When subjects self-administer study treatments at home, compliance with FF or FP or 
BUD or placebo will be assessed through querying the subject during the site visits
regarding the completion of subject’s diary and then this can be transcribed into
electronic case report form (eCRF). A record of the number of FF or FP or BUD or 
placebo dry powder inhalers dispensed to and taken by each subject must be maintained 
and reconciled with study treatment and compliance records.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of FF or FP or BUD above the highest doses defined in the 
protocol within a 24 hour time period will be considered an overdose.
In the event of an overdose the investigator should:


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1. Inform the Medical Monitor(s).
2. Monitor the subject for adverse events (AEs)/serious adverse events (SAEs) and 
laboratory abnormalities as considered appropriate by the investigator. Further 
medical management of overdose cases is at the discretion of investigator.
3. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
6.9.
Treatment After the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available.
6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions

Refrain from consumption of chocolate and chocolate drinks, fish, Seville oranges, 
products containing St John’s Wort, grapefruit or grapefruit juice or pummelos, 
exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first 
dose of study medication until after the final dose.
6.10.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, subjects will abstain from ingesting caffeine-or 
xanthine-containing products (e.g., coffee, tea and cola drinks) for 24 hours prior to 
and during all visits. 

During each dosing session, subjects will abstain from alcohol for 24 hours prior to 
and during all visits. 

Light smokers may continue to use inhaled or non-inhaled nicotine containing 
products as long as they do not exceed 20 cigarettes or equivalent per week from 
screening until after the final follow-up visit. To ensure subjects maintain the same 
degree of AMP sensitivity, they must not intend to increase, reduce or stop the 
amount they smoke during the course of the study. Subjects must refrain from 
smoking for at least 1 hour before lung function tests.
6.10.3.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests. Subjects will abstain from vigorous exercise at least 
30 minutes before lung function tests.
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
The following medications are allowed during the study:


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
Short-Acting Beta2-Agonists (SABA) (except within 8 hours prior to spirometry).

Paracetamol (except within 24hours of metabolomics plasma sample).

Non-steroidal anti-inflammatory drugs (except within 24 hours of metabolomics 
plasma sample).

Use of antihistamines is allowed, however subjects should not take antihistamines 
within 96 hours of each AMP challenge.

HRT, hormonal contraception with highly effective contraception methods (see 
inclusion criterion 6- Section 5.1).
Any medication, herbal therapy or vitamin which is not listed as prohibited is 
permitted at the discretion of the investigator.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Prohibited medications and non-drug therapies are as follows:

The subject should be able to abstain from short-acting inhaled β-agonists, for 
8 hours prior to spirometry and AMP challenges.

Use of anti-depressant drugs for 1 week prior to screening and throughout the course 
of the study.

Subjects undergoing de-sensitization therapy.

Use of LABA, LAMA, LTRA therapy for 3 months prior to the start of the study and 
use of ICS, LABA, LAMA, LTRA therapy throughout the course of the study.
Subjects currently receiving low-dose ICS will be consented and perform screening 
visit 1, then if the subject is eligible for the study they will undergo a 4-week 
washout period for ICS.  If the subject’s condition remains stable they will attend 
screening visit 2 and progress to randomization, if eligible.

Use of biological therapies for at least 6 months prior to start of the study and 
throughout the course of the study.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1.
The following points must be noted:

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File which is approved by the relevant GSK study 
team member and then archived in the study sponsor and site study files, but this will 
not constitute a protocol amendment.


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


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7.1.
Time and Events Table
Table 9
Screening and Follow-up Visit
Procedure
Screening Visit 1
Screening Visit 2
Treatment Period 
1
Washoutd
Treatment Period 
2d
FU
Day
Day -42 to 
Day -4b
Day -14 to 
Day -4c
Assessments during treatment period are detailed in 
Table 10
Washout will be a minimum of 25 days to maximum of 42 days
Assessments during treatment period are detailed in 
Table 10
7 to 14 daysg
Outpatient visit
X
X
X
Informed consenta
X
Inclusion and exclusion criteria
X
X
Demography
X
Full physical examination including height and weight
X
Urine drugs of abuse and alcohol breath test
X
Brief physical
X
Medical history (includes substance usage)
X
Urine pregnancy test (all female subjects)
X
X
HIV, Hep B and Hep C screen 
X
Safety labs: chemistry, hematology and urinalysis
X
X
12-lead ECG
X
Vital signs
X
PEFR
Xb
AMP challenge
Xf
Spirometry (FEV1 and FVC) 
X
X
X
AE/SAEe
X
X
X
Concomitant medicatione
X
X
X
AE – Adverse event; AMP- Adenosine 5 monophosphate; ECG – Electrocardiogram; FEV1 – Forced expiratory volume in 1 second; FVC – Forced vital capacity; FU – Follow-up; HIV-
Human immunodeficiency virus; Hep B –Hepatitis B; Hep C – Hepatitis C; PEFR –Peak expiratory flow rate; SAE – Serious adverse event;.
a Informed consent may be obtained on a separate visit prior to screening visit 1.
b Baseline PEFR values will be captured for all subjects at screening visit 1. Subjects who are receiving low-dose ICS may take part after a 4-week washout and screening procedures 
will be completed in two screening visits. For these subjects, screening visit 2 will be at least 28 days after screening visit 1.  During the 4-week ICS washout subjects will keep a diary
(from screening visit 1 to randomization) to record twice daily PEFR (subject to contact site if there is a 20% decrease) and SABA use (subject to contact site if SABA intake is 
increased). Salbutamol will be dispensed for rescue use. The reference PEFR value will be obtained at screening visit 1 and an alert value recorded in subject diary by site staff.
c Subjects who do not require an ICS washout may have only one screening visit, these procedures may then be done at screening visit 1. Screening visit 1 procedures may be 
repeated at screening visit 2 as deemed necessary by the Investigator or delegate.
d Subjects who consent to only 1 treatment period will not undergo the washout period or treatment period 2.
e AEs and concomitant medication will be documented on all days throughout the study, but review will only occur when the subject is in the unit.


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f The screening visit 2 AMP challenge can be repeated only once; at least 72h after the first attempt.
g 7 to 14 days after the last dose of study treatment.
Table 10
Time and Events Treatment Period 1 and 2
Treatment period 1 and 2
Day 1, pre-
dosea
Day 1 
dosing and 
post-dose, 
Days 8, 15, 
22, 29
Days 2, 9, 
16, 23, 30
Days 3, 10, 
17, 24, 31
Days 4, 11, 
18, 25, 32
Days 5, 12, 
19, 26, 33
Days 6, 13, 
20, 27, 34
Days 7, 14, 
21, 28, 35
Day 36b
Study treatment dispensingc
X
X
X
Outpatient visitd
X
X
Confinemente
X
X
Randomizationf
X
Urine pregnancy test (all female subjects)
X
X
X
Vital signsg
X
X
Use of inhaler trainingh
X
Peak expiratory flow ratei
X
X
X
X
X
X
X
Study Treatmentj
X
X
X
X
X
X
X
Patient diaryk
X
X
X
X
X
X
X
AMP challengel
X
X
Spirometry (FEV1 and FVC)
X
Blood sampling for plasma cortisolm
X
X
X
Metabolomics samplen
X
X
X
AE/SAEo
X
X
X
X
X
X
X
X
X
Concomitant medicationo
X
X
X
X
X
X
X
X
X
AE – Adverse event; AMP- Adenosine monophosphate; FEV1 – Forced expiratory volume in 1 second; FVC – Forced vital capacity; SAE – Serious adverse event.
a Day 1 pre-dose completed at start of treatment period 1 and 2, respectively.  Urine pregnancy test (where applicable), Vital signs, Spirometry (FEV1 and FVC), blood sampling for 
plasma cortisol,metabolomics sample, AE/SAEreview, restriction checks and concomitant medication reviewwill be performed on the morning of Day 1 (Pre-dose) of each treatment 


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period.  Use of inhaler training, randomization (treatment period 1 only), AE/SAEreview, restriction checks, concomitant medication review and study treatment dispensing will be 
performed in the evening of Day 1, prior to study treatment administration.
b Day 36 completed following completion of treatment period 1 and 2, respectively.
c Subjects are dispensed study treatments for the first dose level on Day 1 prior to evening dose. Study treatments for the subsequent 4 dose levels are dispensed prior to release after 
completion of the AMP challenge on Days 8, 15, 22, and 29.
d Subjects receive first dose for treatment Period 1 and 2 during the outpatient visit.
e Subject will be admitted to unit prior to evening dose on Days 6, 13, 20, 27 and 34 of each treatment period. Subjects will be confined in the unit until they have recovered from the
AMP challenge on Days 8, 15, 22, 29, and 36, but may leave the unit on the evenings of Days 7, 14, 21, 28, and 35 after their last plasma cortisol sample and return the following 
morning, if they prefer.
fPrior to first dose of treatment period 1 only.
g Performed on Days 1 and 36.
h Reinforcement by the investigator on the proper use of the inhaler.
i Peak expiratory flow reading must be taken before each dose of study treatment at home. Three PEFR manoeuvres should be performed in each session. The highest PEFR of the 3 
efforts from any session will be the one that will be recorded in a paper diary.
j Subjects will take doses of study treatment in the evening only (for all ELLIPTA FF/placebo doses, and the first escalation phase for FP [50 mcg dose] and BUD [100 mcg dose]) or in 
the morning and evening, 12 hours apart (for all other dose regimens).  There will be no dosing in the mornings of Days 1, 8, 15, 22 and 29. When subjects are not at the unit, they will 
take their study treatments at home.
k On Days 1, 8, 15, 22, and 29, subjects will receive a patient diary to document day and time of each dose, the peak expiratory flow rate (PEFR) recording and any AEs or concomitant 
medication including the number of SABA doses. The subject will enter their data in a paper diary.
l The AMP challenges will be done in the morning of Days 8, 15, 22, 29, 36 and 12 hours after the preceding evening dose. If subjects cannot perform the AMP challenge, this may be 
rescheduled 1-3 days later, in this case; the subjects will continue dosing at the same level until the rescheduled AMP challenge and the study schedule will be shifted.
m Blood samples for plasma cortisol will be taken on Day 1 pre-dose (baseline) and at the following time points related to evening study drug administration on Days 6, 13, 20, 27, 34: 
pre-dose and at 1, 2, 3, 5, 10, 12 (before morning dose), 14, 16, 18 and 24 hours post-dose.
n The plasma metabolomics will be taken on Day 1 pre-dose (baseline) and on Days 8, 15, 22, 29 and 36, at the end of each dose escalation phase, at 12 hour after the last evening 
dose (before AMP challenge procedure).
o AEs and concomitant medication will be documented on all days throughout the study, but review will only occur when the subject is in the unit.


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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.
Subjects who are receiving low-dose ICS may take part after a 4-week ICS washout. For 
these subjects, screening visit 2 will be at least 28 days after screening visit 1. During the 
4-week ICS washout and up to randomization, subjects will keep a diary to record twice 
daily PEFR measurements and SABA use. The site will also contact the subjects weekly 
to monitor their asthma symptoms and may ask the subject to attend the site if necessary.
The subject must contact the site if the PEFR measurement is below the 20% decrease 
value calculated by the sites, if there is an increase in SABA use, or if they experience an 
exacerbation.
Salbutamol will be dispensed to all subjects for rescue use from screening and throughout 
the study as required.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1). Additional time points for safety tests such as vital signs, physical 
examinations and laboratory safety tests may be added during the course of the study 
based on newly available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
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 consent until the follow-up contact (see Section 
7.3.1.3), 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 eCRF.


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
All SAEs will be recorded and reported to PAREXEL within 24 hours, as indicated 
in Appendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify PAREXEL.
NOTE: The method of recording, evaluating, and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to PAREXEL are provided 
in Appendix 3.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.3.1.3.
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 3.
7.3.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they 
are considered SAEs, specific cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs 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 eCRF within one week of receipt of 
a CV event data query prompting its completion. 
The Death eCRF 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.


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7.3.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to PAREXEL 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 by GSK. 
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.
7.3.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects
will be collected after the start of dosing and until follow-up contact that is 7-14 days 
after the final dose of the study.

If a pregnancy is reported, then the investigator should inform PAREXEL within 24 
hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.
7.3.3.
Physical Examinations

A complete physical examination will include, at a minimum, assessment of the 
cardiovascular, respiratory, gastrointestinal, skin, abdomen (liver and spleen), and 
neurological systems. Height and weight will also be measured and recorded.

A brief physical examination will include, at a minimum assessments of the skin,
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.3.4.
Vital Signs
Vital signs will be measured after subjects have been rested in supine position for at least 
5 minutes and will include temperature, systolic and diastolic blood pressure, pulse rate 
and respiratory rate. The measurement may be repeated twice if out of range.


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7.3.5.
Electrocardiogram

A triplicate 12-lead ECGs will be obtained at screening using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTcF 
intervals.  The triplicate ECGs will be recorded within a period of 10 minutes. Refer 
to Section 5.2 (see exclusion criterion 17).

The ECG measurements will be made with the subject in a supine position having 
rested in this position for at least 5 minutes.
7.3.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 11, must be conducted 
in accordance with the SRM, and Protocol Time and Events Schedule. Details for the 
preparation and shipment of samples will be provided by the laboratory and are detailed 
in the SRM. 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 eCRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a local laboratory. The 
result of each test has to enter into the eCRF.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 11.
Table 11
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
Blood urea 
nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase
(AST or serum 
glutamic-oxaloacetic 
transaminase)
Total and direct 
bilirubin


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Laboratory 
Assessments
Parameters
Creatinine
Sodium
Alanine 
aminotransferase
(ALT or serum 
glutamic-pyruvic 
transaminase)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
BUN
Routine 
Urinalysis
Specific gravity.
pH, glucose, protein, blood and ketones by dipstick.
Microscopic examination (if blood or protein is abnormal) for casts (cellular, 
granular, hyaline); WBC and RBC.
Other 
Screening Tests
HIV
Hepatitis B (HbsAg)
Hepatitis C (Hep C antibody)
FSH and estradiol (if needed to confirm postmenopausal status in women of 
non-child bearing potential only)
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines).
Urine HCG Pregnancy test (all female subjects) 2
NOTES :
1Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments 
after liver stopping or monitoring event are given in Section 5.4.1 and Appendix 2 (Section 12.2).
2Local urine pregnancy testing will be standard for the protocol unless serum testing is required by 
local regulation or ethics committee.
MCH-Mean cell hemoglobin; MCV- Mean corpuscular volume; RBC- Red blood cell count; WBC – White blood cell 
count.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline. If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
7.3.7.
Inhaler Training
Inhaler training using paper-training materials will be performed at Day 1, with 
reinforcement of proper technique at subsequent visits. At each subsequent visit, the 
correct inhalation technique will be reinforced by the investigator prior to dose 
administration.
7.3.8.
Spirometry
Spirometry will be performed using a spirometer calibrated/maintained in accordance 
with the manufacturer’s guidance, which meets American Thoracic Society 
(ATS)/European Respiratory Society (ERS) standards.


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Spirometry (FEV1 and FVC) will be measured with subjects in a sitting position using a 
calibrated spirometer in accordance with ATS guidelines using ERS guidelines for 
predicted values [Quanjer, 2012]. Measurements will be made at the screening visit, on 
Day 1, and follow-up visit and as a part of the AMP challenge procedures.
7.3.8.1.
Screening Baseline Lung Function
Measurements will be made in triplicate and the best recordings (i.e. the highest FEV1
and the highest FVC) from 3 technically acceptable maneuvers will be recorded in the 
eCRF. To fulfil the entry criteria, FEV1 should be ≥ 65% of predicted. This 
measurement will be the screening baseline value.
7.3.8.2.
Pre-dose Baseline Lung Function
Baseline measurements of trough FEV1 will be made prior to dosing on Day 1 of the 
treatment period(s). These measures should be made at the same time of day during the 
treatment period(s). Three technically acceptable measures will be obtained and the 
highest of these three measurements will be recorded in the eCRF and will constitute the 
pre-dose baseline value. This pre-dose baseline FEV1 should not have changed 
significantly in the opinion of the investigator from the screening baseline value and ≥ 
65% predicted for the subject to continue.
7.3.8.3.
Peak Expiratory Flow Rate (PEFR) Measurements
Baseline PEFR values will be captured for all subjects at screening visit 1. Subjects who 
undergo low-dose ICS washout will be provided with a peak flow meter at screening visit 
1 for use at home, until randomization. Subjects will also be provided with a diary to 
record their measurements and symptoms, and will be instructed to contact the site if 
their PEFR measurement is below the 20% decrease value calculated by the sites, if there 
is an increase in SABA use, or if they experience an exacerbation.
During each treatment period, subjects will be given a peak flow meter for use at home to 
measure PEFR. The paper diary will have a place for subjects to record their PEFR 
measurements that must be taken before each dose. Three PEFR maneuvers should be 
performed in each session. The highest PEFR of the 3 efforts from any session will be 
the one that will be recorded in a paper diary.
All PEFR measurements should be taken before subjects take their study drug. Subjects 
should not, whenever possible, use SABA reliever therapies for 6 hours before 
performing PEFR.
Subjects who consented to 2 treatment periods will also be provided with a peak flow 
meter and a patient diary to record their asthma symptoms at home during the washout 
period. Subjects will be instructed to contact the site if their PEFR measurement is below 
the 20% decrease value calculated by the sites, if there is an increase in SABA use, or if 
they experience an exacerbation.


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7.3.8.4.
Diary Assessments
Subjects who wash-out from low-dose ICS prior to screening visit 2 will be provided 
with a patient diary to document the following until randomization:

Any AEs

Any medical problems the subject may have experienced and any medications used 
to treat those medical problems

PEFR measurements twice daily

Number of occasions rescue salbutamol used over the previous 24 hours
Subjects who wash-out from low-dose ICS prior to screening visit 2 will be instructed to 
perform PEFR measurements twice daily and to contact the site if there is a 20% fall in 
PEFR, if there is an increase in SABA use, or if they experience an exacerbation at any 
point during the study.
Subjects who participate in two treatment periods will be provided with a patient diary 
during the wash-out period to document:

Any AEs

Any medical problems the subject may have experienced and any medications used 
to treat those medical problems.

Number of occasions rescue salbutamol used over the previous 24 hours.

PEFR measurements if their asthma symptoms are getting worse or if they are using 
their salbutamol more than usual. 
Subjects should complete their daily diary pages during the treatment periods. On 
Days 1, 8, 15, 22, and 29, subjects will receive a patient diary to document:

Day and time of each dose.

PEFR measurements.

Any AEs or medical problems the subject may have experienced and any 
medications used to treat those medical problems.

Number of occasions rescue salbutamol used over the previous 24 hours.
Reminding or retraining of the subject on proper paper diary documentation will be 
conducted if there is a discrepancy between the device metrics and paper diary entries.


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7.4.
Pharmacodynamics Assessment
Pharmacodynamics assessments will be performed at the time points presented in the 
Time and Events Table (Section 7.1).
7.4.1.
AMP Challenge
The AMP challenge agent to be used for the procedure is Good Manufacturing Practice 
(GMP)-grade product and will be sourced by the investigator site from Stockport 
Pharmaceuticals. A certificate of analysis will be provided for each batch of the AMP 
challenge agent to ensure its quality and safety.
After each 7-day dose escalation phase of each treatment period an AMP challenge 
[Joos, 1998] 12 hour post-evening dose on Day 7 will be performed.
All subjects will wear a nose-clip during the procedures. Three technically acceptable 
recordings of FEV1 will be taken at 1-min intervals prior to administration of diluent. 
The highest of these three measurements will be used as the pre-diluent baseline. The 
challenge will not to take place if the subject demonstrates an FEV1 < 65% predicted or 
has significant asthma symptoms of wheeze, chest tightness or cough. Following this 
baseline assessment, subjects will inhale five breaths of 0.9% diluent, nebulised from a 
breath-activated dosimeter of known output, by inspiring slowly from functional residual 
capacity to total lung capacity (i.e., at the beginning of deep inhalation) over 3 seconds 
and then breath holding for 6 seconds. Two FEV1 measurements will be taken, the first 
at 60 seconds and the second at 180 seconds after inhalation of diluent. The higher of the 
two measurements will be used as the post-diluent FEV1 to calculate the PC20 value (i.e., 
80% of post-diluent FEV1). In the event of a post-diluent fall in FEV1 of more than 10% 
from baseline, subjects will be rested for at least 20 minutes before the diluent
administration procedure is repeated. If, after three diluent administrations the subject 
still has a fall in FEV1 of greater than 10% from the original baseline value, the procedure 
will be abandoned. If subjects cannot perform an on-treatment AMP challenge, this may 
be rescheduled 1-3 days later and the subjects will then continue dosing at the same level 
until the rescheduled AMP challenge and the study schedule will be shifted. If a subject 
fails to perform the repeated AMP challenge, the subject will be withdrawn from the 
study.
If post-diluent FEV1 is equal to10% from pre-diluent, then subjects will inhale doubling 
increments of AMP until a ≥20% fall in FEV1 from the post-diluent value is achieved or 
the highest permitted dose of AMP is achieved (320 mg/mL). Doubling concentrations 
of AMP to be used in the challenge are: 0.04, 0.08, 0.16, 0.32, 0.63, 1.25, 2.5, 5.0, 10.0, 
20.0, 40.0, 80.0, 160.0 and 320.0 mg/mL. For the screening visit, the maximum dose of 
AMP to be used for documenting AMP sensitivity is ≤ 80 mg/mL.
FEV1 will be recorded 60 seconds and 180 seconds after each administration of AMP. If 
the best FEV1 is still less than 20% below the post-saline FEV1 reference subjects will 
progress immediately within 5 minutes of the previous dose to receiving the next highest 
concentration of AMP.


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The normal bronchoconstrictor response to AMP disappears within 30 to 45 minutes after 
PC20 has been achieved. Subjects are to remain in the unit until their FEV1 has returned 
to ≥90% of pre-diluent baseline with the use of salbutamol rescue as needed. 
7.4.2.
Plasma Cortisol Sample Collection
Blood samples (approximately 3 mL) for measurement of plasma cortisol will be taken at 
the time points indicated in Section 7 (Time and Events Table).
The actual date and time of each blood sample collection will be recorded. The timing of 
cortisol samples may be altered and/or cortisol samples may be obtained at additional 
time points to ensure thorough cortisol monitoring.
Processing, storage and shipping procedures are provided in the SRM.
7.4.3.
Sample Analysis
Plasma cortisol analysis will be performed under the control of Platform Technology and 
Science - Drug Metabolism and Pharmacokinetics (PTS-DMPK)/Scinovo, 
GlaxoSmithKline, the details of which will be included in the SRM. Concentrations of 
plasma cortisol will be determined using the currently approved bioanalytical 
methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).
Once the plasma cortisol has been analyzed any remaining plasma may be analyzed for 
other cortisol-related metabolites and the results reported under a separate 
PTS-DMPK/Scinovo, GlaxoSmithKline protocol.
7.5.
Biomarkers
7.5.1.
Metabolomic Research
Biofluid [plasma] metabolome studies will be performed by mass spectrometry (LC-MS). 
This may include analysis of identified or uncharacterized metabolites and lipids that are 
known to be or emerge in the future as being important in the pathogenesis of asthma, or 
a related medical condition, the subject’s response to study treatment or adverse events.
Subjects will abstain from eating or drinking (except water) for a minimum of 8 hours via 
overnight fasting prior to each blood collection for metabolomics analysis.
Blood samples (approximately 1 ml) for measurement of plasma metabolomics will be 
taken on Day 1 pre-dose (baseline) and on Days 8, 15, 22, 29 and 36, at the end of each 
dose escalation phase, at 12 hour after the last evening dose (before morning dose and 
AMP challenge procedure).
Plasma samples will be prepared and handled according to Metabolon Sample 
Preparation Guidelines as follows:

Collect whole blood in tubes (e.g. Vacutainer or Vacuette) containing Ethylene di 
amine tetra acetic acid (EDTA) anti-coagulant and follow tube manufacturer’s 
processing instructions. Immediately aliquot the collected plasma/serum/whole blood 


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into chilled, polypropylene tubes and flash-freeze.  Store samples at approximately 
-80°C until shipment. For each sample 2 x 150 microL aliquots will be prepared and 
stored for analysis. If possible one or more back-up aliquots will also be prepared 
and stored at approximately -80°C.
8.
DATA MANAGEMENT

For this study, subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) and an internal validated medication 
dictionary, GSK Drug.

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The main purpose of this study is to characterize the dose response and relative potency 
following repeat inhaled doses of FF, FP and BUD on AMP PC20 at 12 hours after the last 
dose on Day 7 and also to characterize the dose response and relative potency for FF, FP 
and BUD on 24 hour plasma cortisol suppression (pre-dose PM dose on Day 6 to pre-
dose PM dose Day 7).
To achieve these objectives a dose response maximum effect (Emax) model will be fitted 
to the AMP PC20 data and the cortisol suppression 0-24 hour weighted mean data. There 
will be no formal hypothesis tested, but point estimates and corresponding 95% 
confidence intervals will be constructed for each of the three parameters for the Emax
model (response at dose 0 [E0], Emax, and ED50).
9.2.
Sample Size Considerations
Subjects will be recruited such that 48 subjects complete the study. Twenty-four subjects 
will be enrolled to complete 2 treatment periods; a further 24 subjects will be enrolled to 
complete 1 treatment period. This sample size is based on feasibility.
If subjects are replaced they will be assigned to the same treatment or treatment sequence 
as the subject they are replacing. If a subject withdraws during treatment period 1 then 
the replacement subject will start from the beginning of period 1 of the same treatment or 
treatment sequence. If a subject withdraws after period 1 or during period 2 then the 


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subject may be replaced just to do period 2.  A maximum of 2 subjects can be replaced 
from the start of period 2; if more than 2 subjects on the study withdraw after period 1 or 
during period 2, the replacements must start from the beginning of period 1.
9.2.1.
Sample Size Assumptions
The response to AMP (as measured by PC20) has been measured for FP in study 
SIG103337 [GSK Document Number GM2005/00525/00] and the estimated placebo 
response rate has ranged from 0.8 to 1.8 Doubling Dose (DD). ED50 is assumed to be 
around the lowest dose being studied for each active treatment. The maximum effect 
observed for BUD in a previous study was 4DD [Phillips, 2004] and it is expected that 
the same maximum effect (Emax) will be observed for all active treatments. The Slope 
(=0.9) value is also kept as constant for all treatments this estimate has been considered 
from the study SIG103337 [GSK Document Number GM2005/00525/00] in which FP 
was studied. The results in this study are expected to be between the 2 hour and 14 hour 
data from the study SIG103337 [GSK Document Number GM2005/00525/00], hence, the 
selected slope of 0.9 which is between the two estimated slopes.
Variability estimates have been considered from in-house studies utilizing the AMP 
challenge model for inhaled steroids. These are shown in Table 12.
Table 12
Variability Estimates from Inhaled Steroid Studies with an AMP 
Challenge Model
Study
Compound
Analysis/ 
Model
Variability Estimate
Within Subject 
SD
Total between Subject 
SD
SIG102335 
GW870086X
ANOVA
1.628
2.040
SIG103337 
FP
Emax
1.151
2.343
SIG103337 
FP
ANOVA
1.221
2.441
All AMP challenges at steady state
All challenges at 2 hours post-dose 
ANOVA – Analysis of variance; FP – Fluticasone propionate; SD – Standard deviation
Based on these assumptions, four subjects being assigned to each of the sequences 
detailed in Table 4. Table 13 details the precision to which this study can estimate each of 
the three Emax model parameters, and thus ultimately the dose response curve for FP, FF 
and BUD. The below table was generated based on stimulations performed incorporating 
the variability estimates from the Emax model from study SIG103337 (see Table 12) and 
the initial assumptions on the parameters based on expert opinion and information on 
doubling doses and ED50 from reference studies.


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Table 13
Expected Precision of Parameter Estimates for Cross-over and 
Parallel Design Combined; N=18 Subjects Overall for Each 
Treatment
Doses
Assumptions
Sample Size
Predicted Width of 95% CI
E0(DD)
Emax(DD)
ED50 (mcg) 
FF
E0 = 0.8
Emax = 4 DD
ED50 = 25 mcg
Slope = 0.9
18
0.51
0.55
15.7
FP
E0 = 0.8
Emax = 4 DD
ED50 = 50 mcg
Slope = 0.9
18
0.51
0.54
30.3
BUD
E0 = 0.8
Emax = 4 DD
ED50 = 100 mcg
Slope = 0.9
18
0.51
0.55
62.1
BUD- Budesonide; CI- Confidence interval; FF – Fluticasone furoate; FP – Fluticasone propionate
In previous studies the variability for the cortisol suppression endpoint was observed to 
be less than for the AMP challenge endpoint. Therefore it is assumed that the sample 
size deemed to provide sufficient precision estimates for AMP will also be sufficient for 
cortisol. The variability estimates of cortisol suppression endpoints are shown in Table 
14.
Table 14
Variability Estimates from Cortisol Suppression Weighted Mean 
(0-24 hours) model
Study
Compound
Analysis/ Model
Variability Estimate
Within Subject SD
FFA103096
FP/ GW685698X
ANOVA
0.385
HZA102940
GW685698X/ 
GW642444M
ANOVA
0.158
HZA105871
GW685698X/ 
GW642444M
ANOVA
0.120
HZA108799
GW685698X
ANOVA
0.129
ANOVA – Analysis of variance; SD – Standard deviation
9.2.2.
Sample Size Sensitivity
The predicted widths of the confidence interval for the parameters of the model depend 
on the assumed model parameters. A sensitivity analysis was performed to assess the 
importance of the assumptions on the results. A range of values observed from the 
reference studies [GSK Document Number GM2005/00525/00, GSK Document Number
GM2007/00123/00, GSK Document Number GM2005/00082/00] have been considered.
The results in this study are expected to be somewhere between the 2 hour and 14 hour 


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data from the SIG10337 study [GSK Document Number GM2005/00525/00] hence, the 
selected slope of 0.9 which is between the two estimated slopes, and 1.5 DD for Emax
which is also between the two time points. 
The study will include 2 groups of subjects; 1 in which the subjects participate in 
2 treatment periods in a cross-over design, and the other in which subjects complete only 
1 treatment period in a parallel design. Precision estimates were calculated on the 
feasible sample size per study treatment, based on 12 subjects in a cross-over design and 
6 subjects in a parallel design, and the combined estimates for 18 subjects in total per 
treatment (Table 15, and Table 16).
Table 15
Simulation Results for Cross-over Design; N=12 Subjects in Each 
Treatment Group
Doses
Assumptions
Sample Size
Predicted Width of 95% CI
E0(DD)
Emax(DD)
ED50 (mcg) 
FF
E0 = 0.8
Emax = 4 DD
ED50 = 25 mcg
Slope = 0.9
12
0.67
0.61
19.0
FP
E0 = 0.8
Emax = 4 DD
ED50 = 50 mcg
Slope = 0.9
12
0.67
0.59
37.1
BUD
E0 = 0.8
Emax = 4 DD
ED50 = 100 mcg
Slope = 0.9
12
0.67
0.61
72.6
Table 16
Simulation Results for Parallel Design; N=6 Subjects in Each 
Treatment Group
Doses
Assumptions
Sample Size
Predicted Width of 95% CI
E0(DD)
Emax(DD)
ED50 (mcg) 
FF
E0 =0.8
Emax =4 DD
ED50=25 mcg
Slope =0.9
6
0.61
1.18
37.9
FP
E0 =0.8
Emax =4 DD
ED50=50 mcg
Slope =0.9
6
0.61
1.15
74.6
BUD
E0 =0.8
Emax =4 DD
ED50=100 mcg
Slope =0.9
6
0.61
1.19
152.5


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9.2.3.
Sample Size Re-estimation or Adjustment
The need for sample size re-estimation will be reviewed by in-stream data review (see
Section 4.4).
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All subjects’ population: All subjects’ population will consist of all subjects who are 
randomized and who receive at least one dose of trial medication.
Pharmacodynamic (PD) population: The PD population is defined as all subjects in All 
Subjects population who received at least one dose of study treatment and who also have 
at least one PD measurement.
9.3.2.
Interim Analysis
The need for interim analysis will be reviewed by in-stream data review (see Section 4.4).
9.4.
Key Elements of Analysis Plan
9.4.1.
Pharmacodynamic Analyses
AMP PC20
To characterize the dose response of FF, FP and BUD on AMP PC20 at 12 hours after the
last dose on Day 7, a non-linear mixed model will be fitted. AMP PC20 will be 
log-transformed (base 2) and then the following model will be fitted.  


ijk
i
ijk
ijk
ij
BUD
ijk
ijk
ij
FP
ijk
ijk
ij
FF
j
ijk
s
ED
BUD
Dose
Dose
E
BUD
I
ED
FP
Dose
Dose
E
FP
I
ED
FF
Dose
Dose
E
FF
I
Period
E
PC




















50
_
*
_
*
50
_
*
_
*
50
_
*
_
*
log
max
,
max
,
max
,
0
20
2
where:
i= Subject (i=1 to N), j= Period (j=1 to 2), k= Escalation phase within jth period (k=1 to 
5), Doseijk = Dose received by ith subject in the jth period and kth escalation phase (if this 
corresponds to Placebo then set Dose to zero).
IFF,ij, IFP,ij and IBUD,ij are indicator functions that take the value 1 if the ith subject in the jth 
period was on the associated study drug and zero otherwise.
Period
=Main effect of period
E0
= Response at dose 0
FF_Emax
= Maximum effect for FF treatment
FF_ED50
= Dose at which 50% of the maximum effect is reached for FF treatment


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FP_Emax
= Maximum effect for FP treatment
FP_ED50
= Dose at which 50% of the maximum effect is reached for FP treatment
BUD_Emax
= Maximum effect for BUD treatment
BUD_ED50
= Dose at which 50% of the maximum effect is reached for BUD treatment

= Slope constant (fixed at 1 in the first instance)
si
= Subject effect
εijk
= Residual error
The slope parameter gamma will be assumed to be 1 (i.e. first intent is to fit three 
parameter Emax models to each treatment, but four parameter Emax formulae are 
presented as gamma may be fitted as an additional model parameter as part of sensitivity 
analyses).
The subject term will be fitted as a random effect. This is equivalent to adding a random 
coefficient to the E0 parameter. All other terms (except the residual error) in the model 
will be fitted as fixed effects. The dose will be set to zero for all placebo data.  Random 
coefficients may also be fitted to the other parameters in the model (Emax and ED50) if 
possible. The suitability of such models will be explored.
Prior to analysis, the AMP challenge results for placebo across the five dose escalation 
phases will be investigated.  If there appears to be an effect of repeated AMP challenge 
on placebo (e.g. a linear trend through time, or evidence contradicting the assumption that 
each of the placebo responses in the five escalation phases are the same) then the dose 
response modelling may be performed on an adjusted version of the dataset (adjustments 
made to active data points to account for the varying placebo data points). Further details 
will be given in the Reporting and Analysis Plan (RAP).
From the analysis, the predicted value for the 3 parameters of interest (E0, Emax and ED50) 
for each of the treatments will be calculated and back transformed onto the original scale.  
The 95% confidence interval for each of the predicted values will also be calculated and 
back transformed.
Predicted AMP PC20 values and 95% confidence intervals will be plotted against dose for 
each of the active treatments. The potency of FF and BUD relative to FP will be assessed 
by comparing the estimates for ED50.
The Emax model will also be used to address the exploratory endpoint to assess the dose of 
FF and BUD that gives the same AMP response as the FP doses administered in the 
study.
Details of the in-stream data review and analysis will be presented in the RAP.
Plasma Cortisol
Similar dose response Emax model as mentioned for the AMP PC20 data will be 
constructed to characterize the dose response of FF, FP and BUD on cortisol suppression 
0-24 hours weighted mean after Day 6 dose. The cortisol 0-24 hours weighted mean will 
be log-transformed using natural logs (i.e. base e).


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The Emax model will also be used to address the exploratory endpoint to assess the dose of 
FF and BUD that gives the same cortisol response as the FP doses administered in the 
study.
Therapeutic Index (TI)
Emax models as described above will also be used to obtain the ED20 0-24 hr weighted 
mean cortisol suppression and the ED80 for AMP PC20. The TI is then calculated as ED20
cortisol suppression /ED80 for AMP PC20.
9.4.2.
Safety Analyses
Safety data will be summarized descriptively according to GSK’s Integrated Data 
Standards Library standards.
Further details regarding the safety analyses will be given in the RAP.
9.4.3.
Biomarker Analyses
Further details regarding the metabolomic analyses will be given in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International
Council for Harmonization (ICH) Good Clinical Practice (GCP) and applicable country-
specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
Substantial amendments to the protocol will be approved by the regulatory agency and/or 
ethics committee, as applicable, before implementation.
The study will also be conducted in accordance with ICH 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.


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
Obtaining signed informed consent.

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC).

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
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.

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRFs or entered in the eCRFs that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study; also current medical records must be 
available.

Definition of what constitutes source data can be found in the SRM.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.


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


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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, Schenkenberger I, Trivedi R, Cole J, Hicks W, Gul N, et al. Inhaled fluticasone 
furoate/vilanterol does not affect hypothalamic-pituitary-adrenal axis function in 
adolescent and adult asthma: randomised, double-blind, placebo-controlled study. Clin 
Respir J. 2013b; 7(4):397-406.
Allen A. The relationship between fluticasone furoate systemic exposure and cortisol 
suppression. Clin Pharmacokinet 2013a; 52:885-96.
Bateman ED, Bleecker ER, Lötvall J, Woodcock A, Forth R, Medley H et al. Dose effect 
of once-daily fluticasone furoate in persistent asthma: a randomized trial. Respir Med. 
2012;106(5):642-650.
Bleecker ER, Bateman ED, Busse WW, Woodcock A, Frith L, House KW et al. Once-
daily fluticasone furoate is efficacious in patients with symptomatic asthma on low-dose 
inhaled corticosteroids. Ann Allergy Asthma Immunol. 2012;109(5):353-358.
Busse W, Bateman E, O’Byrne PM, Lötvall J, Woodcock A, Medley H et al. Once-daily 
fluticasone furoate 50mcg in mild to moderate asthma: a 24-week placebo-controlled 
randomized trial: Allergy. 2014; Nov; 69(11):1522-30.
Busse WW, Bleecker ER, Bateman ED, Lötvall J, Forth R, Davis AM et al. Fluticasone 
furoate demonstrates efficacy in patients with asthma symptomatic on medium doses of 
inhaled corticosteroid therapy: an 8-week, randomised, placebo-controlled trial. Thorax. 
2012;67(1):35-41.
Daley-Yates PT. Pharmacological aspects of glucocorticoid therapy. In: Exogenous 
Glucocorticoids in Paediatric Asthma, ed. Wolthers OD, Kerala: Transworld Research, 
Network, 2007; 1–18.
Daley-Yates PT. The clinical utility of pharmacokinetics in demonstrating bioequivalence 
of locally acting orally inhaled drugs. In: Respiratory Drug Delivery eds Dalby RN, 
Byron PR, Peart J, Suman JD, Farr SJ, Young PM, et al. Healthcare International 
Publishing 2010; 1: 273-283.
Daley-Yates, P. Inhaled corticosteroids: potency, dose equivalence and therapeutic index. 
British J Clin Pharmacol. 2015 Published online:http://onlinelibrary.wiley.com 
/doi/10.1111/bcp.12637/pdf.
FDA CBER Guidance for industry, “Drug-induced liver injury: Premarketing clinical 
evaluation”. U.S. FDA; July 2009.
Food and Drug Administration. Arnuity Ellipta Highlights of Prescribing Information.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205625s000lbl.pdf (accessed 
on 11 Jan 2017). 
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Global Initiative for Asthma (GINA). Global strategy for Asthma Management and 
Prevention, 2017.  Available from: www.ginasthma.org.
GSK Document Number GM2004/00283/12 Fluticasone Furoate (GW685698) Oral 
Inhalation Powder Investigator’s Brochure, version dated 15 August 2017.
GSK Document Number GM2005/00082/00 FFA103096. A randomised, double-blind, 
placebo controlled, incomplete block, five-way cross-over study to investigate the effect 
of one week repeat dosing of fluticasone furoate (GW685698X) and fluticasone 
propionate (FP) on twenty-four hour serum cortisol in healthy subjects. dated 09 
December 2005.
GSK Document Number GM2005/00525/00 SIG103337. A randomised, 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. dated 20 October 2006.
GSK Document Number GM2007/00123/00 SIG102335, A double-blind, placebo-
controlled, randomised, 4-way crossover single dose escalation and a double-blind, 
placebo-controlled, randomised, parallel group, 7-days repeat once daily dose study to 
investigate the safety, tolerability, pharmacodynamics and pharmacokinetics of 
GW870086X administered via DISKHALER™ in healthy male subjects followed by a 
double-blind, placebo controlled, 3-way crossover study to investigate the effect of 7-
days repeat once daily inhaled doses of GW870086X administered via DISKHALER on 
airway responsiveness to AMP in mild steroid-naïve male asthmatics. dated 18 June 
2007.
GSK Document Number RM2002/00280/01 Clinical Investigator’s Brochure: 
Fluticasone Propionate for Inhalation Including: Fluticasone Propionate HFA Inhalation 
Aerosol, Fluticasone Propionate CFC MDI, Fluticasone Propionate ROTADISK & 
Fluticasone Propionate DISKUS, version dated 22 Aug 2006.
Hochhaus G, Möllmann H, Derendorf H, Gonzalez-Rothi RJ. Pharmacokinetic and 
pharmacodynamics aspects of aerosol therapy using glucocorticoids as a model. J Clin 
Pharmacol 1997; Oct;37: 881-892.
Joos GF, O´Connor B, Anderson SD, et al. Indirect airway challenges. Eur Respir J. 
1998;21:1050-1068.
Kaiser H, Aaronson D, Dockhorn R, Edsbäcker S, Korenblat P, Källén A. Dose-
proportional pharmacokinetics of budesonide inhaled via Turbuhaler. Br J Clin 
Pharmacol. 1999;48(3):309-316.
Kamada AK, Szefler SJ, Martin RJ, Boushey HA, Chinchilli VM , Drazen JM, et al. 
Issues in the use of inhaled glucocorticoids. The Asthma Clinical Research Network. 
American Journal of Respiratory and Critical Care Medicine, Vol. 153, No. 6 (1996), pp. 
1739-1748.


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Kannisto S, Laatikainen A, Taivainen A, Savolainen K, Tukiainen H, Voutilainen R. 
Serum dehydroepiandrosterone sulfate concentration as an indicator of adrenocortical 
suppression during inhaled steroid therapy in adult asthmatic patients. European Journal 
of Endocrinology (2004) 150 687–690.
Kelly HW. Establishing a therapeutic index for the inhaled corticosteroids: Part I. 
Pharmacokinetic/pharmacodynamics comparison of the inhaled corticosteroids. J Allergy 
Clin Immunol 1998;102:S36-S51.
Kempsford R, Allen A, Kelly K, Saggu P, Crim C. A repeat-dose thorough QT study of 
inhaled fluticasone furoate/vilanterol combination in healthy subjects. Br J Clin 
Pharmacol. 2014;77(3):466-479.
Mager DE, Lin SX, Blum RA, Lates CD, Jusko WJ. Dose equivalency evaluation of 
major corticosteroids: pharmacokinetics and cell trafficking and cortisol dynamics. J Clin 
Pharmacol 2003; 43:1216–1227.
Möllmann H, Wagner M, Krishnaswami S.  Single dose and steady state pharmacokinetic 
and pharmacodynamics evaluation of equipotent doses of inhaled fluticasone propionate 
and budesonide in healthy subjects. J Clin Pharmacol  2001;41:1329-1338 (FLTB1006).
Mortimer KJ, Tata LJ, Smith CJP, West J, Harrison TW, Tattersfield AE, et al. Oral and 
inhaled corticosteroids and adrenal insufficiency: a case-control study. Thorax 2006; 61: 
405–408.
Phillips K, Oborne J, Harrison TW, Tattersfield AE. Use of sequential quadrupling dose 
regimens to study efficacy of inhaled corticosteroids in asthma. Thorax 2004;59:21–25. 
Doi: 10.1136/thx.2003.015289.
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Enright PL, et al. On behalf of the 
ERS Global Lung Function Initiative. Multi-ethnic reference values for spirometry for the 
3-95 year age range: the global lung function 2012 equations. Eur Respir J. 
2012;40:1324-1343.
World Health Organization (WHO). Asthma fact sheet; Number 307. 
http://www.who.int/mediacentre/factsheets/fs307/en/. Updated November 2013. 
Accessed June 6, 2015.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase
AMP
Adenosine-5-monophosphate
AMP PC20
Provocative concentration of AMP causing a 20% fall in 
forced expiratory volume in 1 second
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
ATS
American Thoracic Society
BMI
Body mass index
BUD
Budesonide
BUN
Blood urea nitrogen
CI
Confidence interval
COPD
Chronic obstructive pulmonary disease
CPK
Creatinine phosphokinase
CRF
Case report form
CV
Cardiovascular
DD
Doubling dose
DHEA-S
Dehydroepiandrosterone sulphate
ECG
Electrocardiogram
eCRF
Electronic case report form
E0
Response at dose 0
ED20
Dose at which 20% of the maximum effect is reached
ED50
Dose at which 50% of the maximum effect is reached
ED80
Dose at which 80% of the maximum effect is reached
EDTA
Ethylene di amine tetra acetic acid
Emax
Maximum effect
ERS
European Respiratory Society
FF
Fluticasone furoate
FP
Fluticasone propionate
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FSH
Follicle stimulating hormone
FU
Follow-up
FVC
Forced vital capacity
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GPPG
Global Pharmacovigilance Processing Group
GR
Glucocorticoid receptor
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen


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HCG
Human chorionic gonadotropin
Hep B
Hepatitis B
Hep C
Hepatitis C
HIV
Human immunodeficiency virus
HPA
Hypothalamic pituitary-adrenal
HRT
Hormone replacement therapy
IB
Investigator Brochure
ICH
International Conference on Harmonization
ICS
Inhaled corticosteroids
IEC
Independent ethics committee
IgM
Immunoglobulin M
INR
International normalized ratio
IRB
Institutional review board
ITT
Intention-to-treat
LABA
Long-acting beta2-agonist
LAMA
Long-acting muscarinic antagonist
LC-MS
Liquid chromatography-Mass spectroscopy
LDH
Lactate dehydrogenase
LS
Least square
LTRA
Leukotriene receptor antagonist
MedDRA
Medical Dictionary for Regulatory Activities
mcg
Microgram
MCH
Mean cell haemoglobin
MCV
Mean corpuscular volume
MS
Mass spectrometry
MSDS
Material safety data sheet
PC
Provocative concentration
PD
Pharmacodynamic
PEFR
Peak expiratory flow rate
PK
Pharmacokinetic
PTS-DMPK
Platform Technology and Science - Drug Metabolism and 
Pharmacokinetics
QTc
Corrected QT interval
QTcF
QT interval with Fridericia's correction 
RAP
Reporting analysis plan
RBC
Red blood cell
SABA
Short-Acting Beta2-Agonists
SAE
Serious adverse event
SD
Standard deviation
SRM
Study reference manual
TDD
Total doubling dose
TI
Therapeutic index
ULN
Upper limit normal
UMEC
Umeclidinium bromide
VI
Vilanterol
WBC
White blood cell


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12.2.
Appendix 2: Liver Safety Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase II liver chemistry stopping criteria and required follow-up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (> 35% direct bilirubin)
INR2
ALT 3xULN and INR> 1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow-up Assessments following ANY Liver Stopping Event
Actions
Follow-Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver chemistry event follow-up 
assessments 

Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted.

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained up to 24h post-dose 
after last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 


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treatment and may continue subject in the study 
for any protocol specified follow-up 
assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 24-
72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG)or gamma globulins

Serum acetaminophen-adduct High 
performance liquid chromatography 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]).

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (> 35% direct bilirubin) or ALT 3xULN and INR> 1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants.
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody.
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.


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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and < 5xULN and
bilirubin < 2xULN, without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety 

Subject can continue study treatment 

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT < 3xULN and 
bilirubin < 2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.3.
Appendix 3: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 


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investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting.  Complications that occur during hospitalization are AEs.  
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.


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d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (> 35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 2 for the required liver chemistry follow-up instructions
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:


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
Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF.

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the 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 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.
12.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 


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everyday activities.

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to PAREXEL.  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 PAREXEL.

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 PAREXEL 
and/or 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 


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care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide PAREXEL 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 PAREXEL within the 
designated reporting time frames.
12.3.6.
Reporting of SAEs
SAE reporting

GSK has contracted PAREXEL GPPG to handle the collection and initial processing 
of SAEs.

On discovery, all SAEs should be immediately reported (latest within 24 hours of 
knowledge of the event) to PAREXEL Global Medical Services (GMS) /GSK 
Medical Monitors by:
1-Completing the paper SAE report form which will be emailed/faxed/ (whatever is 
more convenient for the site, e-mail would be preferred) to PAREXEL GPPG and to GSK 
medical monitor, for all sites globally via:
E-mail to: 
 and 
and 
Or FAX: 
AND
2-Entering the adverse event in the appropriate section of the eCRF, indicating that 
the event is considered serious and providing all the details per the eCRF 
completion guidelines at the same time the event is entered.

Note: Email should be used preferentially. Fax to be used in case of email failure.

The reporting of the serious adverse event should be done immediately in the e-CRF 
even though the paper SAE report is completed. Thus, one alert email will be 
triggered and the safety team will be aware that one SAE has been notified.

In the event that the site is unable to complete the SAE report form, the investigators 
may report the SAE over the telephone via the SAE answering service, and then 
provide the completed SAE form via email/fax, (within the next 24 hours). If 
questions arise regarding the reporting procedures or the specifics of the reporting of 
an event, sites may notify PAREXEL utilizing the following numbers:
Paris: Tel: 
PPD
PPD
PPD
PPD
PPD


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Paris: Fax: 
 or 

GPPG will check the eCRF/SAE form and source documents (if submitted) for 
validity, completeness, accuracy, legibility, signature, compliance with patient data 
protection, and investigator’s causality assessment. GPPG may interact with the site, 
as needed, to clarify information and/or obtain missing or additional information.

Follow-up SAE reports and support documents should be reported in the same 
manner as the initial report.
PPD
PPD


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12.4.
Appendix 4: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.4.1.
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.
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable).
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until [at least five half-lives of study medication OR for a cycle of spermatogenesis 
following five terminal half-lives] after the last dose of study medication.
1.
Vasectomy with documentation of azoospermia. The documentation on male 
sterility can come from the site personnel’s: review of subject’s medical records,
medical examination and/or semen analysis, or medical history interview.
2.
Male condom plus partner use of one of the contraceptive options below that meets 
the SOP effectiveness criteria including a < 1% rate of failure per year, as stated in 
the product label:

Contraceptive subdermal implant


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
Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
The definition of ‘non-reproductive’ for male subject’s female partners is either 
postmenopausal, or pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of 
bilateral tubal occlusion

Hysterectomy

Documented Bilateral Oophorectomy Female
12.4.2.
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 PAREXEL
within 24 hours 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 PAREXEL. Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy that is considered 
reasonably related to the study treatment by the investigator will be reported to 
PAREXEL as described in Appendix 3. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of an 
SAE through spontaneous reporting.


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Any female subject who becomes pregnant while participating will discontinue 
study medication 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 PAREXEL within 24 hours 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 PAREXEL. 

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.
12.4.3.
References
CHMP, 2005 - EMA - Guideline on Adjuvants in Vaccines for Human Use, 
(CHMP/VEG/134716/2004), January 2005.
Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy 
tests at the time of missed menses. Am J Ob Gyn 2004(190):100-5.
EMA/CHMP/ICH/449035/2009: General principles to address virus and vector shedding. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002680.pdf Accessed 28 Nov 2014.
EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
Before First Clinical Use of Gene Therapy Medicinal Products [2008]
FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. FDA; 
Feb. 2006. 
FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
(hCG) assays: What laboratorians should know about false-positive results”, 
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceS
afety/ucm109390.htm, accessed 17 Nov 2014.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, et aleditors. 
Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc. 2011: 50.
Table 3-2.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 


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Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998]
WHO, 2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants 
and Adjuvanted Vaccines, 2013
World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9.
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.


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12.5.
Appendix 5: Low, Medium, and High Daily Doses of Inhaled 
Corticosteroids
Low, medium, and high daily dosage of inhaled corticosteroids in adults and 
adolescents (12 years and older)
Drug
Daily dose (mcg)
Low
Medium
High
Beclometasone dipropionate 
(CFC)
200-500
>500-1000
>1000
Beclometasone dipropionate 
(HFA)
100-200
>200-400
>400
Budesonide (DPI)
200-400
>400-800
>800
Ciclesonide (HFA)
80-160
>160-320
>320
Fluticasone furoate (DPI)
100
NA
200
Fluticasone propionate (DPI)
100-250
>250-500
>500
Fluticasone propionate (HFA)
100-250
>250-500
>500
Mometasone furoate
110-220
>220-440
>440
Triamicolone acetonide
400-1000
>1000-2000
>2000
Abbreviations: CFC: chlorofluorocarbon propellant, DPI: dry powder inhaler; HFA: 
hydrofluroalkane propellant; NA: not applicable.
Source: 2017 Global Initiative for Asthma (GINA 2017) Report


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12.6.
Appendix 6: Protocol Amendment Changes
12.6.1.
Amendment 1
Summary of Amendment Changes with Rationale
This amendment is to justify the use of higher doses of budesonide and fluticasone 
furoate than the recommended doses. Specific sections of the protocol have also been 
updated to clarify that investigators have direct access to unblinding of treatment in an 
emergency, and to clarify that the amendments to the protocol will be approved by the 
regulatory agency and/or ethics committee, as applicable, before implementation. Those 
changes were requested by the UK MHRA. Text has also been updated to clarify blood 
sample instructions and time points, and to update the medical monitor contact details.
List of Specific Changes
CHANGE 1
Updated medical monitor contact details.
REVISED TEXT
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Site Address
Primary Medical 
Monitor (Parexel) 
(urgent medical 
questions, subject 
eligibility 
questions, etc)
Herman 
Heijermansweg 
20  
1077 WL 
Amsterdam, 
The 
Netherlands 
GlaxoSmithKl
ine Stockley 
Park West, 
Uxbridge, 
Middlesex, 
UB11 1BT, 
UK
PPD


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Secondary 
Medical Monitor
GlaxoSmithKlin
e Stockley Park 
West, Uxbridge, 
Middlesex, 
UB11 1BT, UK
GSK, 709 
Swedeland Rd, 
King of Prussia, 
PA 19406, USA
SAE contact  
information 
(PAREXEL)
PAREXEL 
Medical 
Services
NA
SAE contact 
information (GSK)
[SecondaryPrim
ary Medical 
monitor, details 
as above]
Central Safety 
Department
FAX: 
 
EMAIL: 
CHANGE 2
Updated Dose Justification Section to justify the use of higher doses of budesonide and 
fluticasone furoate than the recommended doses.
Section 4.5, Dose Justification
REVISED TEXT
FF (100 and 200 μg per day), is a once daily ICS that is being developed for the treatment 
of asthma, and has been approved in the United States (Arnuity ELLIPTA Highlights of 
Prescribing Information, 2014) and 5 other countries (Australia, Canada, Chile, 
Singapore, and Switzerland) for the treatment of asthma in adults and adolescents aged 
12 years and over. FF (100 and 200 μg per day) is also approved worldwide (including 
the European Union - Relvar ELLIPTATM) as the ICS component of a combination 
product for COPD and asthma, with VI (GW642444). In the current study, it is proposed 
to dose escalate FF, to a maximum daily dose of 800 μg. FF has been administered to 
healthy volunteers at doses of 100 to 1600 μg once daily (OD) for 7 days (Study 
HZA113477, see Section 5.2.2.2 of the FF Investigator Brochure and Study FFA103096 
[GSK Document Number GM2005/00082/00]) and as FF/VI at doses up to 800/100 μg 
OD for 7 days (Study HZA102936 [Kempsford, 2014]). These doses were well tolerated.
FF was investigated in dose ranging studies in asthmatic subjects over the range 25 to 
800 µg once daily for 8 weeks and was shown to be safe and well tolerated [Bateman
2012, Bleecker 2012, Busse 2012].
PPD
PPD
PPD
PPD
PPD


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FP is indicated in the UK for the treatment of asthma, at doses of up to 1000 μg twice per 
day, which also represents the maximum dose that subjects will be exposed to in this 
study.
BUD is indicated in the UK for the treatment of asthma, at doses up to 1600 μg in 
divided doses. In the current study, it is proposed to dose escalate BUD, to a maximum 
daily dose of 3200 μg. BUD has been administered to asthmatic patients at doses of up to 
3200 μg for up to 6 weeks [Kaiser, 1999]. These doses were well tolerated.
For the AMP challenge quadrupling dose increments are expected to show a well-defined 
dose response [Phillips, 2004] for this reason the following total daily doses of 25 µg, 
100 µg, 400 µg for FF; 50 µg, 200 µg, 1000 µg for FP and 100 µg, 400 µg, 1600 µg for 
BUD have been chosen.  However, three doses are insufficient to define the dose 
response for both AMP challenge and cortisol suppression and include all the doses used 
therapeutically since there is little overlap in the doses needed [Daley-Yates, 2015; 
Möllmann, 2001; Study FFA103096 [GSK Document Number GM2005/00082/00]]. 
Therefore, FF 200 µg/day, FP 500 µg/day, and 2000 µg/day and BUD 800 µg/day are 
included to ensure the dose responses are adequately defined. Likewise, an 800 µg/day 
FF dose and 3200 µg/day BUD dose will also be included to fully define the cortisol 
suppression dose response (Study FFA103096) [GSK Document Number 
GM2005/00082/00] and ensure the dose escalation increments are matched between the 
three ICS under investigation.
CHANGE 3
Updated Blinding Section to clarify that investigators have direct access to unblinding of 
treatment in case of an emergency.
Section 6.4, Blinding
ADDED TEXT
The following will also 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. 


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
The date and reason for the unblinding must be fully documented in the CRF.
CHANGE 4
Updated footnote in Time and Events Table to reflect different timepoints for the 
collection of metabolomic sample.
REVISED TEXT
Section 7.1, Time and Events Table 8 Footnotes
Change made to Table 10 to clarify that the plasma metabolomic sample will be collected 
on Day 36. 
Table 19
Time and Events Treatment Period 1 and 2
Treatment period 1 and 2
Day 1, 
pre-
dosea
Day 1 
dosing 
and 
post-
dose, 
Days 
8, 15, 
22, 29
Days 
2, 9, 
16, 
23, 30
Days 
3, 10, 
17, 
24, 31
Days 
4, 11, 
18, 
25, 32
Days 
5, 12, 
19, 
26, 33
Days 
6, 13, 
20, 
27, 34
Days 
7, 14, 
21, 
28, 35
Day 
36b
Metabolomics samplem
X
X
X
m
The plasma metabolomics will be taken on Day 1 pre-dose (baseline) and on Days 8, 15, 22, 29 
and 36, at the end of each dose escalation phase, at 12 hour after the last evening dose (before 
morning dose and AMP challenge procedure) pre-dose before the start of each period and on Day 
8 at the end of each dose escalation phase at 12 hour after the last evening dose and prior to the 
AMP challenge procedure.
CHANGE 5
Corrected errors in the sample analysis section for plasma cortisol.
Section 7.4.3, Sample Analysis 
REVISED TEXT 
Plasma cortisol analysis will be performed under the control of Platform Technology and 
Science - Drug Metabolism and Pharmacokinetics (PTS-DMPK)/Scinovo, 
GlaxoSmithKline, the details of which will be included in the SRM.  Concentrations of 
FF, FP, and BUD plasma cortisol will be determined in plasma cortisol samples using the 
currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site (detailed in the SRM).


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Once the plasma cortisol has been analyzed for FF, FP, and BUD any remaining plasma 
cortisol may be analyzed for other compoundcortisol-related metabolites and the results 
reported under a separate PTS- DMPK/Scinovo, GlaxoSmithKline protocol.
CHANGE 6
Updated Metabolomic Research Section to reflect blood sample volume and different 
timepoints for the collection of metabolomic sample.
Section 7.5.1, Metabolomic Research
REVISED TEXT 
Blood samples (approximately 0.5 1 ml) for measurement of plasma metabolomics will 
be taken on Day 1 pre-dose (baseline) and on Days 8, 15, 22, 29 and 36, at the end of 
each dose escalation phase, at 12 hour after the last evening dose (before morning dose 
and AMP challenge procedure). pre-dose before the start of each period and on Day 8 at 
the end of each dose escalation phase at 12 hour after the last evening dose and prior to 
the AMP challenge procedure.
CHANGE 7
Added the text to clarify that the amendments to the protocol will be approved by the 
regulatory agency and/or ethics committee, as applicable, before implementation.
Section 10.2, Regulatory and Ethical Considerations, Including the Informed 
Consent Process
ADDED TEXT 
Substantial amendments to the protocol will be approved by the regulatory agency and/or 
ethics committee, as applicable, before implementation.


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12.6.2.
Amendment 2 (03-OCT-2017) from the Amendment 1 (16-JAN-
2017)
Protocol Amendment 2 applies to all sites participating in the conduct of the study.
Summary of Amendment Changes with Rationale
This amendment is to improve subject recruitment by reducing the requirements and 
increasing the flexibility of the study for the subjects. The protocol is amended to allow 
subjects to complete either 1 or 2 treatment periods, who are currently taking low-dose
ICS and/or are light smokers. 
Changes laid down in previous MEMOs from protocol amendment 1 were also 
incorporated into this protocol amendment.
List of Specific Changes
CHANGE 1
Synopsis, Overall Design
Rationale for change: The subjects’ consent to complete either 1 or 2 treatment periods.
REVISED TEXT
Subjects will be required consent to participate in either:

one treatment period; or

two treatment periods, separated by a washout period of 25-42 days.
Each treatment period will comprise five consecutive 7-day dosing phases with escalating 
doses of one of three ICS products or placebo. Each 7-day period is referred to as an 
escalation phase. In each 7-day phase of the dose escalation period phase, subjects will 
receive investigational product study treatment from the evening of Day 1 to the evening 
of Day 7. Each treatment period will be followed by a washout period of 25-42 days.
There will be at least 21 days between the last dose of the Treatment Period 1 and the 
baseline AMP challenge of Treatment Period 2.
Subjects who consent to completing 2 treatment periods will be assigned to one of the 
treatment sequences in accordance with the. Subjects who consent to completing 1 
treatment period will be randomized to treatment. The randomization schedule schedules 
will be generated by Clinical Statistics prior to the start of the study, using validated 
internal software.


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CHANGE 2
Synopsis, Treatment Arms and Duration
Rationale for change: The study duration text was changed as the study duration will be 
shorter for subjects who consent to 1 treatment period compared to those who consent to 
2 treatment periods. 
REVISED TEXT
There will be 5 different study treatments administered for subjects who consent to 
2 treatment periods, these treatments will be in 12 different treatment sequences with 
2 treatments each. Four Two subjects will be randomized to each of the 12 treatment 
sequences.  Subjects who consent to 1 treatment period will be randomized to treatment, 
6 subjects will be randomized to each active treatment and 3 subjects to each placebo 
treatment.
Study days for subjects who consent to 1 treatment period:

Screening: Day -2842 to Day -74.

One treatment period of at least 35 days (i.e. 5 escalating doses administered for 
7 days each).

Run-in-AMP challengeFollow-up period: 7 to 14 days after the last dose of treatment 
period 1.
Study days for subjects who consent to 2 treatment periods:

Screening: Day -17 42 to Day -4 days.

Treatment periods: two periods of at least 35 days (i.e. 5 escalating doses 
administered for 7 days each), separated by a washout period of between 25 to 
42 days.

Wash-out AMP challenge: At least 21 days after the last dose in Treatment Period 1 
and no later than 4 days prior to the start of Treatment Period 2.

Follow-up period: 7 to 14 days after the last dose of treatment period 2.
The study duration for each subjectsubjects who consent to 1 treatment period will range 
from 46 to 91 days. The study duration for subjects who consent to 2 treatment periods
will range from 106 to 168 days. 
CHANGE 3
Synopsis, Type and Number of Subjects
Rationale for change: The section was updated to clarify how many subjects will 
consent to 2 treatment periods and how many will consent to 1 treatment period.


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REVISED TEXT
Forty-eight adult subjects with asthma will be enrolled into this study. Subjects will be 
recruited such that 48 subjects will complete the study Twenty-four subjects will be 
enrolled to complete two treatment periods; and a further 24 subjects will be enrolled to 
complete one treatment period. This sample size is based on feasibility. If the number of 
withdrawals results in less than 18 subjects per treatment (considering placebo overall) 
then subjects may be replaced at the discretion of the investigator and key GSK study 
team members. If subjects are replaced they will be assigned to the same treatment 
sequence as the subject they are replacing.
CHANGE 4
Section 4.1, Study Design
Rationale for change: The subjects are now given the option to complete 2 or 1 
treatment periods. 
REVISED TEXT
A run-in AMP challenge will be conducted 4-17 days prior to first dose. There will be a 
minimum of 4 days between the run-in visit and the first treatment day. Subjects will be 
required to respond with a PC20 of ≤80 mg/mL AMP at screening and run in AMP PC20
has to be within 1.25 doubling concentrations of the screening PC20.
Screening visit 1 will be conducted 4 – 42 days prior to the first treatment day. Subjects 
who are taking low-dose ICS will have a 4-week ICS washout during which their asthma 
symptoms must remain stable as defined in Section 5.1. Screening visit 2 will be 
conducted 4 – 14 days prior to the first treatment day and at least 4 weeks after screening 
visit 1. Subjects must have an AMP challenge PC20 of ≤80 mg/mL at screening visit 2 to 
be eligible. Procedures from screening visit 1 may be repeated at screening visit 2 as 
deemed necessary by the investigator/delegate.
Subjects who do not have to undergo ICS washout may only have 1 screening visit, and
undergo screening visit 2 procedures at screening visit 1.
Subjects will consent to participate in either:

one treatment period; or

two treatment periods; separated by a washout period of 25-42 days.
Each treatment period will comprise five consecutive 7-day dosing phases with escalating 
doses of one of three ICS products or placebo. Each 7-day period is referred to as an 
escalation phase. In each 7-day phase of the dose escalation period phase, subjects will 
receive investigational product study treatment from the evening of Day 1 to the evening 
of Day 7. Each treatment period will be followed by a washout period of 25-42 days.
Before the second treatment period a baseline AMP challenge will be conducted at least 
21 days after the last dose of Treatment Period 1 and at least 4 days prior to the first day 


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of Treatment Period 2. The AMP PC20 has to be within 1.25 doubling concentrations of 
the Run-in PC20.
A follow-up visit will take place within 7-14 days after the last dose of the second study
treatment period. Time and events tables for Screening, Run-Inscreening and Follow 
follow-up Visits visits (Table 7 Table 9) and Treatment Periods (Table 8Table 10) are 
provided in Section 7.1.
CHANGE 5
Section 4.2 Treatment Arms and Duration
Rationale for change: The study duration text was changed as the study duration will be 
shorter for subjects who consent to 1 treatment period compared to those who consent to 
2 treatment periods
REVISED TEXT
The treatments for each part of the study dose escalation phase are listed in Table 2 and 
regime to provide each dose in Table 3. Subjects who consent to completing 2 treatment 
periods will be randomized to order of treatments they are included in; the treatment 
sequences shown in Table 4. Subjects who consent to completing 1 treatment period will 
be randomized to treatment.
Twenty-four subjects completing 2 treatment periods will be randomized to one of the 
treatment sequences shown in Table 4.
Table 4
Treatments proposed per study period for subjects completing 
2 treatment periods
Sequence
Period 1
Period 2
n
n [1]
1
A
B
42
3
2
A
C
42
3
3
A
D
42
3
4
B
A
42
3
5
B
C
42
3
6
B
E
42
3
7
C
A
42
3
8
C
B
42
3
9
C
E
42
3
10
D
A
42
3
11
E
B
42
3
12
D
C
42
3
Total subjects
4824
36
Subjects per treatment
2412
18
[1]: If there are considerable numbers of dropouts in the study then there should be at least 36 completers such that 
there are at least 18 subjects in each active treatment group and overall for Placebo. For a completely balanced design  
there would be 14 sequences  however an assumption has been made that ELLIPTA™ and DISKUS™ placebo will 
have the same effect  therefore two of the sequences including placebo (EC and CD)  have been dropped to give an 
equal number of subjects on each treatment administered overall.


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Twenty-four subjects completing 1 treatment period will be randomized to one of the 
treatments shown in Table 5.
Table 5
Treatments proposed for subjects completing 1 treatment period
Treatment
n
A
6
B
6
C
6
D
3
E
3
Total subjects
24
Subjects per treatment
6
Therefore, a total of 48 subjects will complete the study, 18 subjects in total per study 
treatment (for each active treatment and for placebo combined).
Study durations for subjects completing either 2 or 1 treatment periods are shown in 
Table 6 and Table 7.
Table 56
Study Duration for subjects completing 2 treatment periods
Screening
days
Period 1
days
Washout
days
Period 2
days
Follow-Up 
days
Total days
7-284-42
35
2125-42
35
7-14
105-154 106-
168
Table 7
Study Duration for subjects completing 1 treatment period
Screening
days
Period 1
days
Follow-Up 
days
Total days
4-42
35
7-14
46-91
CHANGE 6
Section 4.3, Type and Number of Subjects
REVISED TEXT
Subjects will be recruited such that 48 subjects will complete the study.  Twenty-four 
subjects will be enrolled to complete 2 treatment periods; and a further 24 subjects will 
be enrolled to complete 1 treatment period. Forty-eight adult subjects with asthma will be 
enrolled into this study.  
If the number of withdrawals results in less than 18 subjects per treatment (considering 
placebo overall) then subjects may be replaced at the discretion of the investigator, GSK 
clinical investigation leader and GSK statistician.  This sample size is based on 
feasibility.


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If subjects are replaced they will be assigned to the same treatment or treatment sequence 
as the subject they are replacing.   If a subject withdraws during period 2 then the subject 
can be replaced just to do period 2, unless the withdrawal results in less than 2 subjects 
on the same sequence. If this scenario occurs then the subject will have to begin from 
period 1 of the same sequence.  Refer to Section 6.2 for more details.
CHANGE 7
Section 4.4, Design Justification
Rationale for change: The design justification section was updated to make it clearer 
that the subjects may receive treatment in either 1 or 2 treatment periods. Text was also 
added to indicate that the sponsor could be unblinded to study treatment to allow sample 
size re-estimation.
REVISED TEXT
The study is not double-blinded or double-dummy but a partially blinded study with the 
following design features mitigated for this aspect. The endpoints are objective rather 
than subjective. Subjects will receive one or two of the four possible treatments not 
knowing which are active or placebo. When receiving placebo they will be assigned 
either a DISKUS™ or an ELLIPTA™ device. There will be no BUD Turbuhaler 
placebo. Subjects assigned to placebo will follow the same dose escalation scheme 
taking the same number of inhalations in each phase as the corresponding active 
treatments. Additionally, this will provide a measure of stability of the AMP and cortisol 
response over the 5 week period where repeated AMP challenges are performed. For a 
completely balanced design there would be 14 treatment sequences for subjects 
completing 2 treatment periods; however, an assumption has been made that ELLIPTA™ 
and DISKUS™ placebo will have the same effect therefore two of the sequences 
including placebo (EC and CD) have been dropped to give an equal number of subjects 
on each treatment administered including placebo overall. Similarly, for subjects 
completing one treatment period, 3 subjects will be randomized to ELLIPTA™ and 
DISKUS™ placebo so that 6 subjects in total receive placebo overall, which is equal to 
the subjects on each active treatment.
In addition to the subjects, the investigators, nurses, technicians and other staff that 
interact with the subjects will also be blinded to the treatment designations.  The subjects 
will be provided with one of three different dry powder inhalers for each period either 
active treatment or placebo.  The subjects will not be informed which are the active or 
placebo treatments although no Turbuhaler placebo will be used in the study.  The study 
sponsor will be unblinded to study treatment to allow selected sponsor study team 
members to perform unblinded in-stream analysis of available data.  These findings will 
inform on the need for a sample size re-estimation or interim analysis (see Section 9.2.3).


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CHANGE 8
Section 4.5, Dose Justification
REVISED TEXT (4th paragraph)
FP is indicated in the UK and Germany for the treatment of asthma, at doses of up to 
1000 μg twice per day, which also represents the maximum dose that subjects will be 
exposed to in this study.
BUD is indicated in the UK and Germany for the treatment of asthma, at doses up to 
1600 μg in divided doses.  
CHANGE 9
Section 4.6.1, Risk Assessment
Rationale for change: To add risk assessment for subjects who are withdrawn from low-
dose ICS treatment.
ADDED TEXT
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Withdrawal of Inhaled Corticosteroids
Subjects receiving low-dose ICS 
as defined in Appendix 5 may 
take part after a 4 week ICS 
washout prior to AMP challenge.  
There is a risk associated with 
withdrawing inhaled 
corticosteroids in these subjects 
who are currently taking them
Subject may experience 
worsening of asthma symptoms
Subjects washing out from ICS 
will be monitored via weekly calls 
from site, and maintenance of 
diary to capture PEFR and SABA 
use.
Subjects are instructed to contact 
the PI/site for assessment if they 
have a deterioration of their 
asthma (refer to section 
7.3.8.4.Diary Assessments) or if 
they have an exacerbation.
Any subject whose asthma is 
defined as not stable will not be 
eligible to participate in the study.
CHANGE 10
Section 5.1, Inclusion Criteria
Rationale for change: Inclusion criterion 2 was updated to remove short acting β 2-
agonist therapy by inhalation.


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REVISED TEXT
2.
Asthma: Documented history of bronchial asthma, first diagnosed at least 6 
months prior to the screening visit and being treated only with intermittent short-acting 
β2-agonist therapy by inhalation.
CHANGE 11
Section 5.1, Inclusion Criteria
Rationale for change: Clarification was given for the severity of disease in inclusion 
criterion 3.
REVISED TEXT
3. Severity of disease:  
a) Pre-bronchodilator FEV1 ≥65% of predicted at screening. 
b) The pre-dose baseline FEV1 should be ± 15% of the not have changed significantly in 
the opinion of the investigator from the screening baseline value and should be ≥ 65% 
predicted for the subject to continue.
c) Documented sensitivity to AMP with a provocative concentration of AMP resulting 
in a fall of ≥20% FEV1 with a PC20 AMP ≤80 mg/mL at the screening visit.
d) Demonstrated stable bronchoconstriction in response to inhaled AMP at the run-in 
visit. The run-in PC20 to be within 1.25 doubling concentration of the screening PC20.
CHANGE 12
Section 5.1, Inclusion Criterion Number 4
Rationale for change: To allow recruitment of subjects currently taking low-dose ICS.
REVISED TEXT

NoSubjects receiving low-dose ICS, as defined in Appendix 5 may take part 
after a 4-week ICS washout prior to AMP challenge. The subject’s asthma 
symptoms must remain stable during this 4-week period as assessed at screening 
visit 2. Stable asthma is defined as:

No more than 2 consecutive days where ≥12 inhalations/day of salbutamol 
were used.

No severe asthma exacerbations requiring use of systemic corticosteroids 
(tablets, suspension, or injection) or an in-patient hospitalization or 
emergency department visit due to asthma that required systemic 
corticosteroids.


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
No clinical asthma worsening which in the opinion of the investigator 
requires additional asthma treatment other than study medication or 
salbutamol.

Subjects taking LABA, LAMA, leukotriene receptor antagonist (LTRA) therapy
for three within 3 months prior to the start of the study are not eligible.

No Subjects taking biological therapies for at least within 6 months prior to start 
of the study are not eligible.
CHANGE 13
Section 5.1, Inclusion Criterion Number 8
Rationale for change: The inclusion criteria were changed to allow light smokers
ADDED TEXT
Light smokers, who smoke ≤20 cigarettes per week or equivalent unit dose of other 
tobacco products or e-cigarettes, are eligible for the study. Smokers who intend to stop, 
reduce or increase their smoking habit during the study period are not eligible.
CHANGE 14
Section 5.2, Exclusion Criterion Number 8
Rationale for change: The exclusion criteria were changed to allow light smokers.
REVISED TEXT
Tobacco Use: Current smokers who smoke >20 cigarettes per week or the equivalent 
unit dose of other tobacco products or e-cigarettes, or smokers with a smoking history of 
10 pack years. A subject must not have used any inhaled tobacco products in the 12 
month period preceding the screening visit.
CHANGE 15
Section 5.3, Screening/Baseline/Run-in Failures
Rationale for change: Text was added to allow subjects to rescreen after discussion with 
the sponsor.
ADDED TEXT
Subjects who fail the initial screening visit may be rescreened once, after discussion with 
the sponsor. In order to be rescreened, subjects must have demonstrated AMP sensitivity 
and meet the spirometry and respiratory test results as described in inclusion criterion 3. 
Subjects must not have met any of the exclusion criteria. If AMP sensitivity was not 
established at screening, subjects known to be insensitive to AMP will not be rescreened.


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CHANGE 16
Section 5.4, Withdrawal/Stopping Criteria
Rationale for change: The period of time where a rescheduled AMP challenge could be 
performed was extended from 2 to 3 days.
REVISED TEXT
Subjects who are not eligible to perform an AMP challenge at any of the specified time 
during the treatment periods (i.e. for reasons of safety) will be withdrawn from the study.  
One repeat attempt is permitted within 21-3 days.
CHANGE 17
Section 5.4, Withdrawal/Stopping Criteria
Rationale for change: There is no longer an AMP PC20 measurement during the 
washout period so the withdrawal criterion linked to this measurement was removed.
DELETED TEXT

Subjects who do not meet the AMP PC20 reproducibility criteria prior to Treatment 
Period 2 Day 1 will be withdrawn. One repeat attempt is permitted.
CHANGE 18
Section 5.4, Withdrawal/Stopping Criteria
Rationale for change: Clarification that salbutamol will not be supplied as a study 
medication. This is to incorporate a change from a MEMO dated 30 MAY 2017.
REVISED TEXT

Clinical asthma worsening which in the opinion of the investigator requires 
additional asthma treatment other than study medication or study 
supplied/salbutamol
CHANGE 19
Section 5.5 Subject and Study Completion
Rationale for change: The definition of a completed subject was updated.
REVISED TEXT
A completed subject is one who has completed all phases of the study the number of 
treatment periods they consented to, including the follow-up visit.


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CHANGE 20
Section 6.2, Treatment Assignment
Rationale for change: The treatment assignment section was updated to include details 
for subjects who consent to 2 or 1 treatment periods.
DELETED TEXT
If the number of withdrawals results in less than 18 subjects per active treatment and 
placebo overall then subjects may be replaced at the discretion of the investigator, GSK 
clinical investigation leader and GSK statistician. 
If subjects are replaced they will be assigned to the same treatment sequence as the 
subject they are replacing or during period 2 then the subject can be replaced just to do 
period 2, unless the withdrawal results in less than 2 subjects on the same sequence. If 
this scenario occurs then the subject will have to begin from period 1 of the same 
sequence. The replacement will be at the discretion of the investigator, GSK clinical 
investigation leader and GSK statistician.
Each subject will receive 2 different treatments, one in treatment period 1, and one in 
treatment period 2; the possible treatment sequences pre-defined in Table 4. Four subjects 
will be randomized to each of the 12 treatment sequences (Table 4).
The study statistician will monitor the withdrawals with regards to treatment sequence 
assigned and treatments administered. As it is standard procedure to keep the treatment 
schedule concealed within the randomisation system until DBF regardless of blinding 
status, the study statistician will request approval from the Clinical Statistics Head to 
access the treatment and sequence information early in order to monitor the withdrawals 
on an ongoing basis.  The study statistician will alert the study team when the number of 
withdrawals results in less than 18 subjects on a treatment (considering placebo overall) 
or if the number of withdrawals is greater than two subjects on a sequence.  Subjects will 
be replaced at the discretion of the key GSK study team members (including study 
statistician, medical monitor and CIL) along with the investigator. The investigator will 
remain blinded to the treatments the withdrawn subjects were assigned.
ADDED TEXT
Withdrawn subjects may be replaced. Replacement subjects will be assigned to the same 
treatment sequence as the subject they are replacing.
For subjects completing two treatment periods:

Each subject will receive 2 different treatments, one in treatment period 1, and one in 
treatment period 2; the possible treatment sequences are pre-defined in Table 4. Two 
subjects will be randomized to each of the 12 treatment sequences (Table 4).

If a subject withdraws during treatment period 1, the replacement subject will start 
from the beginning of period 1 of the same treatment sequence.  If a subject 


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withdraws after period 1 or during period 2, the replacement subject may start from 
period 2; a maximum of 2 subjects can be replaced from the start of period 2.  If more 
than 2 subjects withdraw after period 1 or during period 2, they will be replaced from 
the beginning of period 1.
For subjects completing one treatment period:

Each subject will receive one treatment, as defined in Table 5. Six subjects will be 
randomized to each treatment, including placebo overall (Table 5).
Replacements for withdrawn subjects will start from the beginning of period 1 of the 
same treatment. 
CHANGE 21
Section 6.4, Blinding
Rationale for change: Text was added to the blinding section to indicate that key 
sponsor team members can be unblinded to allow in-stream analysis.
ADDED TEXT
Selected sponsor study team members may be unblinded to perform the in-stream 
analysis. This may include the study statistician, study programmer (and delegates) and 
study DMPK scientist. Access to unblinded data will be kept to the minimum set of 
individuals required to implement any in-stream or interim analyses, but may include 
GSK management/review committees if alterations to the study conduct are required. 
Details of who were unblinded to what data and when will be included in the clinical 
study report.
CHANGE 22
Section 6.10.2, Caffeine, Alcohol, and Tobacco
Rationale for change: The restriction on the use of nicotine containing products was 
updated as the protocol now allows light smokers to join the study.
REVISED TEXT

Use of Light smokers may continue to use inhaled or non-inhaled nicotine
containing products (including nicotine patches and electronic cigarettes)as long as 
they do not exceed 20 cigarettes)is not allowed or equivalent per week from 
screening until after the final follow-up visit. To ensure subjects maintain the same 
degree of AMP sensitivity, they must not intend to increase the amount they smoke 
during the course of the study.  Subjects must refrain from smoking for at least 1 
hour before lung function tests.


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CHANGE 23
Section 6.11.2, Prohibited Medications and Non-Drug Therapies
Rationale for change: The restriction on ICS was updated to allow subjects who were 
receiving low-dose ICS.
REVISED TEXT

No ICS, Use of LABA, LAMA, LTRA therapy for three 3 months prior to the start 
of the study and use of ICS, LABA, LAMA, LTRA therapy throughout the course of 
the study. Subjects currently receiving low-dose ICS will be consented and perform 
screening visit 1, then if the subject is eligible for the study they will undergo a 4-
week washout period for ICS.  If the subject’s condition remains stable they will 
attend screening visit 2 and progress to randomization, if eligible.

No Use of biological therapies for at least 6 months prior to start of the study and 
throughout the course of the study.
CHANGE 24
Section 7.1, Time and Events Table
Rationale for change: The Time and Events Table was updated to remove the Run-in, to 
add a second screening visit to assess subjects who have a 4-week ICS washout, and to 
extend the screening period to -42 to -4 days prior to the first dose of study treatment.


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REVISED TEXT
Table 79
Screening, Run-in, and Follow-up Visit
Procedure
Screening
Visit 1
Run in 
visitScreening 
Visit 2
Treatment 
Period 1
Washoutd
Baseline visit prior to 
Treatment Period 2
Treatment 
Period 2d
FU
Day
Day -28 -
-42 to 
Day -7 -4b
Day -17 -14
to Day -4c
Assessments during treatment period are detailed in 
Table 10
Washout will be a minimum of 25 days to maximum of 42days
At least 21 days after 
the last dose in TP 1 
and no later than 
4 days prior to the 
start of TP 2 Day 1
Assessments during treatment period are detailed in 
Table 10
7 to 14 
daysdg
Outpatient visit
X
X
X
Informed consenta
X
Inclusion and exclusion criteria
X
X
Demography
X
Full physical examination including 
height and weight
X
Urine drugs of abuse and alcohol 
breath test
X
X
X
Brief physical
X
Medical history (includes 
substance usage)
X
Urine pregnancy test (all female 
subjects)
X
X
X
X
HIV, Hep B and Hep C screen 
X
Safety labs: chemistry, hematology
and urinalysis
X
X
12-lead ECG
X
Vital signs
X
Peak expiratory flow rate
Xb
Xb
Baseline AMP challenge
Xf
Spirometry (FEV1 and FVC) 
X
X
X
AE/SAEce
X
X
X
Concomitant medicationce
X
X
X
AE – Adverse event; AMP- Adenosine 5 monophosphate; ECG – Electrocardiogram; FEV1 – Forced expiratory volume in 1 second; FVC – Forced 
vital capacity; FU – Follow-up; HIV- Human immunodeficiency virus; Hep B –Hepatitis B; Hep C – Hepatitis C; SAE – Serious adverse event;.
a Informed consent may be obtained on a separate visit prior to screening visit 1.
b There will be a baseline AMP challenge during run-in and at least 21 days after the last dose of Treatment Period 1 and at least 4 days prior to the 
first day of Treatment Period 2b Subjects who are receiving low-dose ICS may take part after a 4-week washout. For these subjects, screening visit 
2 will be at least 28 days after screening visit 1.  During the 4-week ICS washout subjects will keep a diary (from screening visit 1 to pre-dose Day 1)
to record twice daily peak expiratory flow (subject to contact site if there is a 20% decrease) and SABA use (subject to contact site if SABA intake is 
increased). Salbutamol will be dispensed for rescue use.
c Subjects who do not require an ICS washout may have only one screening visit, these procedures may then be done at screening visit 1. 
Screening visit 1 procedures may be repeated at screening visit 2 as deemed necessary by the Investigator or delegate.
d Subjects who consent to only 1 treatment period will not undergo the washout period or treatment period 2.
ce AEs and concomitant medication will be documented on all days throughout the study, but review will only occur when the subject is in the unit.
f The screening visit 2 AMP challenge can be repeated only once; at least 72h after the first attempt.
dg7 to 14 days after the last dose of Treatment Period 2 study treatment.
CHANGE 25
Section 7.1, Time and Events Table
Rationale for change: The Time and Events Table for treatment periods 1 and 2 was 
updated to include PEFR measurements and to allow subjects to leave the study site after 
the Day 7 study procedures and return on Day 8 rather than staying at the unit overnight.
The table was also updated to incorporate changes from a MEMO dated 04 APR 2017. 
The AMP challenge for Day 36 is now indicated and footnote ‘c’ has ‘and Day 36’ 
deleted as study drug is not dispensed on this day.


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REVISED TEXT
Table 810
Time and Events Treatment Period 1 and 2
Treatment period 1 and 2
Day 1, 
pre-
dosea
Day 1 
dosing 
and 
post-
dose, 
Days 8, 
15, 22, 
29
Days 2, 
9, 16, 
23, 30
Days 3, 
10, 17, 
24, 31
Days 4, 
11, 18, 
25, 32
Days 5, 
12, 19, 
26, 33
Days 6, 
13, 20, 
27, 34
Days 7, 
14, 21, 
28, 35o
Day 36b
Study drug treatment dispensingc
X
X
X
Outpatient visitd
X
X
Confinemente
X
X
Randomizationf
X
Urine pregnancy test prior to AMP 
challenge (all female subjects)
X
X
X
Vital signsg
X
X
Use of inhaler trainingh
X
X
Peak expiratory flow ratei
X
X
X
X
X
X
X
Study treatmentij
X
X
X
X
X
X
X
Patient diaryjk
X
X
X
X
X
X
X
AMP challengekl
X
X
Spirometry (FEV1 and FVC)
X
Blood sampling for plasma cortisollm
X
X
X
Metabolomics samplemn
X
X
X
AE/SAEno
X
X
X
X
X
X
X
X
X
Concomitant medicationno
X
X
X
X
X
X
X
X
X
AE – Adverse event; AMP- Adenosine monophosphate; FEV1 – Forced expiratory volume in 1 second; FVC – Forced vital capacity; SAE – Serious 
adverse event.
a Day 1 Pre-dose completed at start of treatment period 1 and 2, respectively.  Urine pregnancy test (where applicable), Vital signs, Spirometry 
(FEV1 and FVC), blood sampling for plasma cortisol, metabolomics sample, AE/SAE review, restriction checks and concomitant medication review 
will be performed on the morning of Day 1 (pre-dose) of each treatment period.  Use of inhaler training, randomization (treatment period 1 only), 
AE/SAE review, restriction checks, concomitant medication review and study treatment dispensing will be performed in the evening of Day 1, prior to 
study treatment administration.
b Day 36 completed following completion of Treatment Period treatment period 1 and 2, respectively.
c Subjects are dispensed drug study treatments for the first dose level on Day 1 prior to evening dose. Drug Study treatments for the subsequent 4 
dose levels are dispensed prior to release after completion of the AMP challenge on Days 8, 15, 22, and 29, and 36.
d Subjects receives first treatment for first dose for each of treatment period 1 and 2 during the outpatient visit.
e Subject will be admitted to unit prior to evening dose on Days 6, 13, 20, 27 and 34 of each treatment period. Subjects will be confined in the unit 
until they have recovered from the AMP challenge on Days 8, 15, 22, 29, and 36, but may leave the unit on the evenings of Days 7, 14, 21, 28, and 
35 after their last plasma cortisol sample and return the following morning, if they prefer.
f Prior to first dose of Treatment Period treatment period 1 only.
g Performed on first and last day of each Days 1 and 36 Treatment period.
h Reinforcement by the investigator on the proper use of the inhaler.
i Peak expiratory flow reading must be taken before each dose of study treatment at home. Three PEFR manoeuvres should be performed in each 
session. The highest PEFR of the 3 efforts from any session will be the one that will be recorded in a paper diary.
ij On Days 1,8,15, 22, and 29 of the Treatment period, the subjects do not receive a morning dose. This does not apply to the following: all of the FF 
doses, the Ellipta placebo doses and the first week of the dose escalations for FP (50mcg dose) and bud (100mcg dose), since these are all PM only 
dosing regimens. On all other days where the subjects receive a morning and an evening dose of FP or BUD the doses will be administered 12 
hours apart. Subjects will take doses of study treatment in the evening only (for all ELLIPTA FF/placebo doses, and the first escalation phase for FP 
[50 mcg dose] and BUD [100 mcg dose]) or in the morning and evening, 12 hours apart (for all other dose regimens).  There will be no dosing in the 
mornings of Days 1, 8, 15, 22 and 29. When subjects are not at the unit, they will take their study treatments at home.
jkOn Days 1, 8, 15, 22, and 29, subjects will receive a patient diary to document day and time of each dose, the peak expiratory flow rate (PEFR) 
recording and the any AEs or concomitant medication including the number of SABA doses. The subject will enter their data in a paper diary.
Rescue medication will also be captured in the diary.
kl There will be a baseline AMP challenge during the Run-in visit and at least 21 days after the last dose of Treatment Period 1 and prior to Treatment 
Period 2. A baseline AMP challenge can be repeated only once at least 72 hours after the initial challenge. or concomitant medication including the 
number of SABA doses.  The subject will enter their data in a paper diary.
The AMP challenges will be done in the morning of Days 8, 15, 22, 29, 36 and 12 hours after the preceding evening dose. If subjects cannot 
perform the AMP challenge, this may be repeated rescheduled 1-23 days later; in this case, and the subjects will then continue dosing at the same 
level until the rescheduled AMP challenge and the study schedule will be shifted.
lm Blood samples for plasma cortisol will be taken on Day 1 pre-dose (baseline) and at the following time points related to evening study drug 
administration on Days 6, 13, 20, 27, 34: pre-dose and at 1, 2, 3, 5, 10, 12 (before morning dose), 14, 16, 18 and 24 hours post-dose.
nThe plasma metabolomics will be taken on Day 1 pre-dose (baseline) and on Days 8, 15, 22, 29 and 36, at the end of each dose escalation phase, 
at 12 hour after the last evening dose (before morning dose and AMP challenge procedure).


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oAEs and concomitant medication will be documented on all days throughout the study, but review will only occur when the subject is in the unit.
CHANGE 26
Section 7.2 Screening and Critical Baseline Assessments
Rationale for change: Text was added to the section to describe the 2 screening periods.
ADDED TEXT
Subjects who are receiving low-dose ICS may take part after a 4-week ICS washout.  For 
these subjects, screening visit 2 will be at least 28 days after screening visit 1.  During the 
4-week ICS washout and up to randomization, subjects will keep a diary to record twice 
daily PEFR measurements and SABA use.  The site will also contact the subjects weekly 
to monitor their asthma symptoms and may ask the subject to attend the site if necessary.  
The subject must contact the site if the PEFR measurement is below the 20% decrease 
value calculated by the sites, if there is an increase in SABA use, or if they experience an 
exacerbation.  
Salbutamol will be dispensed all subjects for rescue use from screening and throughout 
the study as required.
CHANGE 27
Section 7.3.7, Inhaler training
Rationale for change: Paper training materials will be used instead of dummy/placebo 
devices for inhaler training. This is to incorporate a change from a MEMO dated 04 APR 
2017.
REVISED TEXT
Inhaler training using dummy/placebo devices paper training materials will be performed 
at Day 1, with reinforcement of proper technique at subsequent visits. At each 
subsequent visit, the correct inhalation technique will be reinforced by the investigator 
prior to dose administration.
CHANGE 28
Section 7.3.8.2, Pre-dose Baseline Lung Function
Rationale for change: The method for obtaining the pre-dose lung function was updated 
for clarity.
REVISED TEXT
Baseline measurements of trough FEV1 will be made prior to dosing on Day 1 of eachthe 
treatment period(s).  These measures should be made at the same time of day for all two 
periods during the treatment period(s).  Three technically acceptable measures will be 


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obtained and the highest of these three measurements will be recorded in the eCRF and 
will constitute the pre-dose baseline value.  This pre-dose baseline FEV1 should be ± 
15% not have changed significantly in the opinion of the investigator from of the 
screening baseline value and ≥65% predicted for the subject to continue.  The baseline 
for period 2 should be within 15% of the baseline for period 1 and ≥ 65% predicted for 
the subject to continue.
CHANGE 29
Section 7.3.8.3, Peak expiratory flow rate (PEFR) measurements
Rationale for change: The frequency of PEFR measurements was updated to remove 
‘twice daily’. On days where the subjects receive one dose of study drug this statement is 
not true. This is to incorporate a change from a MEMO dated 04 APR 2017. The text 
was also updated to reflect the PEFR measurements that will be made during the ICS 
washout and PEFR were added to the wash-out period between periods 1 and 2.
REVISED TEXT
Subjects who undergo low-dose ICS washout, will be provided with a peak flow meter at 
Screening Visit 1, for use at home, until randomization. Subjects will also be provided 
with a diary to record their measurements and symptoms, and will be instructed to 
contact the site if their PEFR measurement is below the 20% decrease value calculated by 
the sites, if there is an increase in SABA use, or if they experience an exacerbation.
During each treatment period, Ssubjects will be given a peak flow meter for use at home 
to measure PEFR. The paper diary will have a place for patientssubjects to record their 
PEFR measurements that must be taken before each dose. Three PEFR maneuvers 
should be performed in each session, twice daily. The highest PEFR of the 3 efforts from 
any session will be the one that will be recorded in a paper diary.
All PEFR measurements should be taken before subjects take their study drug.  Patients
Subjects should not, whenever possible, use SABA reliever therapies for 6 hours before 
performing PEFR.
Subjects should completewho consented to 2 treatment periods will also be provided with 
a peak flow meter and a patient diary to record their asthma symptoms at home during the
washout period.  Subjects will be instructed to contact the site if their PEFR measurement 
is below the 20% decrease value calculated by the sites, if there is an increase in SABA 
use, or if they experience an exacerbation.
CHANGE 30
Section 7.3.8.4, Diary Assessments
Rationale for change: The diary assessments section was updated to include the patient 
diary for subjects who undergo wash-out from low-dose ICS.


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ADDED TEXT
Subjects who wash-out from low-dose ICS prior to screening visit 2 will be provided 
with a patient diary to document the following until randomization:

Any AEs. 

Any medical problems the subject may have experienced and any medications used 
to treat those medical problems

PEFR measurements twice daily

Number of occasions rescue salbutamol used over the previous 24 hours
Subjects who wash-out from low-dose ICS prior to screening visit 2 will be instructed to 
perform PEFR measurements twice daily and to contact the site if there is a 20% fall in 
PEFR if there is an increase in SABA use, or if they experience an exacerbation at any 
point during the study.
Subjects who participate in two treatment periods will be provided with a patient diary 
during the wash-out period to document:

Any AEs

Any medical problems the subject may have experienced and any medications used 
to treat those medical problems.

Number of occasions rescue salbutamol used over the previous 24 hours.

PEFR measurements if their asthma symptoms are getting worse or if they are using 
their salbutamol more than usual. 
Subjects should complete their daily diary pages during the treatment periods.  On 
Days 1, 8, 15, 22, and 29, subjects will receive a patient diary to document:

Day and time of each dose.

PEFR measurements.

Any AEs or medical problems the subject may have experienced and any 
medications used to treat those medical problems.

Number of occasions rescue salbutamol used over the previous 24 hours.
Reminding or retraining of the subject on proper paper diary documentation will be 
conducted if there is a discrepancy between the device metrics and paper diary 
entries.


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CHANGE 31
Protocol Section 7.4.1, AMP Challenge
Rationale for change: Clarifications to the AMP dose to be used during AMP challenge 
at screening visit. This is to incorporate a change from a MEMO dated 30 MAY 2017.
The text was also revised to extend the period of time where a rescheduled AMP 
challenge could be performed.
ADDED TEXT, 4th paragraph 3rd sentence
For the screening visit, the maximum dose of AMP to be used for documenting AMP 
sensitivity is ≤80 mg/mL.
REVISED TEXT
If subjects cannot perform an on-treatment AMP challenge, this may be repeated
rescheduled 1-23 days later and the subjects will then continue dosing at the same level 
until the rescheduled AMP challenge and the study schedule will be shifted.  
CHANGE 32
Section 9.2, Sample Size Considerations
Rationale for change: The sample size considerations section was updated to include the 
number of patients who can consent to 2 treatment periods and 1 treatment period as well 
as clarifying that subjects who withdraw after treatment period 1 may be replaced.
REVISED TEXT
Subjects will be recruited such that 48 Forty eight subjects will be recruited into this
complete the study. Twenty-four subjects will be enrolled to complete 2 treatment 
periods; a further 24 subjects will be enrolled to complete 1 treatment period. This 
sample size is based on feasibility. If the number of withdrawals results in less than 18 
subjects per active treatment and placebo overall then subjects may be replaced at the 
discretion of the investigator and key GSK study team members.
If subjects are replaced they will be assigned to the same treatment or treatment sequence 
as the subject they are replacing . If a subject withdraws during treatment period 1 then 
the replacement subject will start from the beginning of period 1 of the same treatment 
sequence. i.e, if If a subject withdraws after period 1 or during period 2 then the subject 
can may be replaced just to do period 2, unless the withdrawal results in more than 2 
subjects from the same sequence. If this scenario occurs then the subject will have to 
begin from period 1 of the same sequence.  A maximum of 2 subjects can be replaced 
from the start of period 2; if more than 2 subjects on the study withdraw after period 1 or 
during period 2, the replacements must start from the beginning of period 1.


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CHANGE 33
Section 9.2.1, Sample Size Assumptions
Rationale for change: The expected precision of parameter estimates was updated to 
reflect a sample size of 18 subjects per study treatment.
REVISED TEXT
Table 1113
Expected Precision of Parameter Estimates for Cross-over and Parallel 
Design Combined; N=18 Subjects Overall for Each Treatment
Doses
Assumptions
Sample Size
Predicted Width of 95% CI
E0(DD)
Emax(DD)
ED50 (mcg) 
FF
E0 = 0.8
Emax = 4 DD
ED50 = 25 mcg
Slope = 0.9
4818
0.470.51
0.430.55
13.315.7 
FP
E0 = 0.8
Emax = 4 DD
ED50 = 50 mcg
Slope = 0.9
4818
0.470.51
0.420.54
26.130.3 
BUD
E0 = 0.8
Emax = 4 DD
ED50 = 100 mcg
Slope = 0.9
4818
0.470.51
0.430.55
53.262.1
BUD- Budesonide; CI- Confidence interval; FF – Fluticasone furoate; FP – Fluticasone propionate
CHANGE 34
Section 9.2.2, Sample Size Sensitivity
Rationale for change: Precision estimates were updated based on a sample size per 
study treatment of 12 subjects in a cross-over design and 6 subjects in a parallel design, 
and the combined estimates for 18 subjects.
REVISED TEXT
The predicted widths of the confidence interval for the parameters of the model depend 
on the assumed model parameters.  A sensitivity analysis was performed to assess the 
importance of the assumptions on the results.  A range of values observed from the 
reference studies (SIG103337, SIG102335 and FFA103096) [GSK Document Number 
GM2005/00525/00, GSK Document Number GM2007/00123/00 and GSK Document 
Number GM2005/00082/00, respectively] have been considered for a sample size of 48 
subjects.  The results in this study are expected to be somewhere between the 2 hour and 
14 hour data from the SIG103337 study [GSK Document Number GM2005/00525/00], 
hence, the selected slope of 0.9 which is between the two estimated slopes, and 1.5 DD 


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for Emax which is also between the two time points. Table 13 gives the estimate for 
different scenarios with an Emax 1.5DD to 4DD.
The study will include 2 groups of subjects; 1 in which the subjects participate in 
2 treatment periods in a cross-over design, and the other in which subjects complete only 
1 treatment period in a parallel design. Precision estimates were calculated on the 
feasible sample size per study treatment, based on 12 subjects in a cross-over design and 
6 subjects in a parallel design, and the combined estimates for 18 subjects in total per 
treatment (Table 16 and Table 17).
Table 15
Simulation Results for Cross-over Design; N=12 Subjects in Each 
Treatment Group
Doses
Assumptions
Sample Size
Predicted Width of 95% CI
E0(DD)
Emax(DD)
ED50 (mcg) 
FF
E0 =0.8
Emax =4 DD
ED50=25 mcg
Slope =0.9
12
0.67
0.61
19.0
FP
E0 =0.8
Emax =4 DD
ED50=50 mcg
Slope =0.9
12
0.67
0.59
37.1
BUD
E0 =0.8
Emax =4 DD
ED50=100 mcg
Slope =0.9
12
0.67
0.61
72.6
Table 16
Simulation Results for Parallel Design; N=6 Subjects in Each Treatment 
Group
Doses
Assumptions
Sample Size
Predicted Width of 95% CI
E0(DD)
Emax(DD)
ED50 (mcg) 
FF
E0 =0.8
Emax =4 DD
ED50=25 mcg
Slope =0.9
6
0.61
1.18
37.9
FP
E0 =0.8
Emax =4 DD
ED50=50 mcg
Slope =0.9
6
0.61
1.15
74.6
BUD
E0 =0.8
Emax =4 DD
ED50=100 mcg
Slope =0.9
6
0.61
1.19
152.5


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Table 13
Sample Size Sensitivity Analysis (N=48)
Doses
Parameters
n
Predicted Width of 95% CI
E0(DD)
Emax(DD)
ED50 (mcg) 
FF
E0 =0.8
48
0.47
0.43
35.3 
Emax =1.5 DD
ED50=25 mcg
=0.9
E0 =1.8
48
0.47
0.43
13.3 
Emax =4 DD
ED50=25 mcg
=0.9
E0 =1.8
48
0.47
0.43
34.7
Emax =1.5 DD
ED50=25 mcg
=0.9
FP
E0 =0.8
48
0.47
0.42
67.7
Emax =1.5 DD
ED50=50 mcg
=0.9
E0 =1.8
48
0.47
0.42
26.0 
Emax =4 DD
ED50=50 mcg
=0.9
E0 =1.8
48
0.47
0.42
67.9
Emax =1.5 DD
ED50=50 mcg
=0.9
BUD
E0 =0.8
48
0.47
0.43
140.3 
Emax =1.5 DD
ED50=100 mcg
=0.9
E0 =1.8
48
0.47
0.43
53.3 


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Doses
Parameters
n
Predicted Width of 95% CI
E0(DD)
Emax(DD)
ED50 (mcg) 
Emax =4 DD
ED50=100 mcg
=0.9
E0 =1.8
48
0.47
0.43
136.2
Emax =1.5 DD
ED50=100 mcg
=0.9
BUD- Budesonide; DD- Doubling dose; FF – Fluticasone furoate; FP – Fluticasone propionate; mcg–microgram
To assess the impact of withdrawals sample size sensitivity has also been performed 
based on a sample size of 36 subjects. The same assumptions have been used as for N=48 
for the scenarios where E0=0.8. The E0=0.8 scenarios give the best representation of how 
the predicted width of the ED50 95% confidence interval is expected to vary, whereas the 
E0 and Emax predicted confidence intervals remained consistent.
Table 14
Sample Size Sensitivity Analysis (N=36)
Doses
Parameters
n
Predicted Width of 95% CI
E0(DD)
Emax(DD)
ED50 (mcg) 
FF
E0 =0.8
36
0.54
0.50
15.5 
Emax =4 DD
ED50=25 mcg
=0.9
E0 =0.8
36
0.54
0.50
40.2
Emax =1.5 DD
ED50=25 mcg
=0.9
FP
E0 =0.8
36
0.54
0.48
30.1 
Emax =4 DD
ED50=50 mcg
=0.9
E0 =0.8
36
0.54
0.48
77.0
Emax =1.5 DD


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Doses
Parameters
n
Predicted Width of 95% CI
E0(DD)
Emax(DD)
ED50 (mcg) 
ED50=50 mcg
=0.9
BUD
E0 =0.8
36
0.54
0.50
61.5 
Emax =4 DD
ED50=100 mcg
=0.9
E0 =0.8
36
0.54
0.50
157.2 
Emax =1.5 DD
ED50=100 mcg
..=0.9
CHANGE 35
Section 9.2.3, Sample Size Re-estimation or Adjustment
Rationale for change: The sample size re-estimation or adjustment section was updated 
to indicate that the sample size can be re-estimated.
REVISED TEXT
Sample The need for sample size re-estimation is not planned. will be reviewed by in-
stream data review (see Section 4.4).
CHANGE 36
Section 9.3.2, Interim Analysis
Rationale for change: The possibility of an interim analysis was included.
REVISED TEXT
The need for interim analysis will be reviewed by in-stream data review (see Section 4.4).  
No interim analysis is planned for this study.
CHANGE 37
Section 9.4.1, Pharmacodynamic Analyses
Rationale for change: The analysis plan for the in-stream data review was added.


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ADDED TEXT, 8th paragraph
Details of the in-stream data review and analysis will be presented in the RAP.
CHANGE 38
Section 12.4.1, Contraceptive requirements for male subjects with female partners 
of reproductive potential (when applicable)
Rationale for change: A definition of ‘non-reproductive’ for male subject’s female 
partners was added to Appendix 12.4.1. This is to incorporate a change from a MEMO 
dated 30 MAY 2017.
ADDED TEXT
The definition of ‘non-reproductive’ for male subject’s female partners is either 
postmenopausal or pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of 
bilateral tubal occlusion

Hysterectomy

Documented Bilateral Oophorectomy Female
CHANGE 39
Section 12.5, Appendix 5: Low, Medium and High Daily Doses of Inhaled 
Corticosteroids
Rationale for change: An Appendix was added from the GINA report 2017 to present 
equivalent dose for low-dose ICS.
ADDED TEXT
Low, medium, and high daily dosage of inhaled corticosteroids in adults and adolescents 
(12 years and older)
Drug
Daily dose (mcg)
Low
Medium
High
Beclometasone dipropionate 
(CFC)
200-500
>500-1000
>1000
Beclometasone dipropionate 
(HFA)
100-200
>200-400
>400


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Low, medium, and high daily dosage of inhaled corticosteroids in adults and adolescents 
(12 years and older)
Drug
Daily dose (mcg)
Low
Medium
High
Budesonide (DPI)
200-400
>400-800
>800
Ciclesonide (HFA)
80-160
>160-320
>320
Fluticasone furoate (DPI)
100
NA
200
Fluticasone propionate (DPI)
100-250
>250-500
>500
Fluticasone propionate (HFA)
100-250
>250-500
>500
Mometasone furoate
110-220
>220-440
>440
Triamicolone acetonide
400-1000
>1000-2000
>2000
Abbreviations: CFC: chlorofluorocarbon propellant, DPI: dry powder inhaler; HFA: 
hydrofluroalkane propellant; NA: not applicable.
Source: 2017 Global Initiative for Asthma (GINA 2017) Report


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12.6.3.
Amendment 3 (26-APR-2018) from the Amendment 2 (03-OCT-
2017)
Protocol Amendment 3 applies to all sites participating in the conduct of the study.
Summary of Amendment Changes with Rationale
This amendment is being issued to update the SAE contact information, as well as to 
include an administrative change clarifying the screening PEFR procedure.
List of Specific Changes
CHANGE 1
Medical Monitor/SAE Contact Information 
Rationale for change: Contact information has been updated.
REVISED TEXT
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Site Address
SAE contact 
information 
(PAREXEL Global 
Pharmacovigilance 
Processing Group 
(GPPG)
PAREXEL 
Medical 
Services
Email: 
 and 
 and 
Or Fax: 
NA
 
NA
Primary Medical 
Monitor
GSK, Stockley 
Park West, 
Uxbridge, 
Middlesex, 
UB11 1BT, UK
Secondary Medical 
Monitor
GSK, 709 
Swedeland Rd, 
King of Prussia, 
PA 19406, USA
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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SAE contact 
information (GSK)
[Primary 
Medical 
monitor, details 
as above]
Central Safety 
Department
FAX: 
 
EMAIL: 
CHANGE 2
SAE Reporting and Processing Information
Rationale for change: SAE Management Plan has been updated.
REVISED TEXT

SAE processing information was updated for alignment with the SAE management 
plan. It was clarified that PAREXEL GPPG will handle the collection and initial 
processing of SAEs. In Section 7.3.1.1, Section 7.3.1.5 and Section 12.3.5, GSK has 
been replaced by PAREXEL. 
CHANGE 3
Section 12.3.6 Reporting of SAEs
Rationale for change: SAE Management Plan has been updated.
REVISED TEXT
SAE reporting

WithinGSK has contracted PAREXEL GPPG to handle the collection and initial 
processing of SAEs.

On discovery, all SAEs should be immediately reported (latest within 24 hours of 
being notified of the SAE, knowledge of the event) to PAREXEL Global Medical 
Services (GMS) /GSK Medical Monitors by:
1-Completing the paper SAE report form which will be emailed/faxed/ (whatever is 
more convenient for the site(s) will contact the Parexel Safety Group either by phone or 
email, and they must also contact the , e-mail would be preferred) to PAREXEL GPPG and 
to GSK medical monitor, the GSK Study Manager and the GSK Central Safety 
Department.for all sites globally via:

Paper SAE data collection forms can be used and faxed to the GSK Central Safety 
Department, the GSK Medical Monitor and the GSK Study Manager.

The site(s) must also enter the serious adverse event data into the Parexel electronic 
PPD
PPD
PPD


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data capture system.

After the study is completed at a given site, the electronic data collection tool 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 must report this information on a paper SAE form to the Parexel 
Safety Group and also to the GSK Central Safety Department, the GSK Medical 
Monitor and GSK Study Manager.
Contacts for SAE receipt for both PAREXEL and GSK can be found at the beginning of 
this protocol on the sponsor/Medical Monitor Contact Information page.E-mail to: 
and 
and 
Or FAX: 
AND
2-Entering the adverse event in the appropriate section of the eCRF, indicating that 
the event is considered serious and providing all the details per the eCRF 
completion guidelines at the same time the event is entered.

Note: Email should be used preferentially. Fax to be used in case of email failure.

The reporting of the serious adverse event should be done immediately in the e-CRF 
even though the paper SAE report is completed. Thus, one alert email will be 
triggered and the safety team will be aware that one SAE has been notified.

In the event that the site is unable to complete the SAE report form, the investigators 
may report the SAE over the telephone via the SAE answering service, and then 
provide the completed SAE form via email/fax, (within the next 24 hours). If 
questions arise regarding the reporting procedures or the specifics of the reporting of 
an event, sites may notify PAREXEL utilizing the following numbers:
Paris: Tel: 
Paris: Fax: 
 or 

GPPG will check the eCRF/SAE form and source documents (if submitted) for 
validity, completeness, accuracy, legibility, signature, compliance with patient data 
protection, and investigator’s causality assessment. GPPG may interact with the site, 
as needed, to clarify information and/or obtain missing or additional information.

Follow-up SAE reports and support documents should be reported in the same 
manner as the initial report.
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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CHANGE 4
Section 7.3.2 Pregnancy
Rationale for change: Change in reporting pregnancy information within 24 hours.
REVISED TEXT
• If a pregnancy is reported, then the investigator should inform GSKPAREXEL within 2 
weeks24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.
CHANGE 5
Section 12.4.2 Collection of Pregnancy Information
Rationale for change: Change in reporting pregnancy information within 24 hours.
REVISED TEXT

Information will be recorded on the appropriate form and submitted to PAREXEL
within 2 weeks24 hours of learning of a subject's pregnancy.
CHANGE 6
Time and Events, Table 9 
Screening and Follow-up Visit
Rationale for change: Administrative change clarifying that baseline PEFR will be 
captured for all subjects and that PEFR will not be performed at screening visit 2.
REVISED TEXT
The Time and Events Table was updated to reflect that PEFR will not be performed at 
screening visit 2. In addition, table footnote b provides further detail as follows:
Table footnote b
Baseline PEFR values will be captured for all subjects at screening visit 1. Subjects who 
are receiving low-dose ICS may take part after a 4-week washout and screening 
procedures will be completed in two screening visits. For these subjects, screening visit 2 
will be at least 28 days after screening visit 1. During the 4 week ICS washout subjects 
will keep a diary (from screening visit 1 to randomization) to record twice daily PEFR 
(subject to contact site if there is a 20% decrease) and SABA use (subject to contact site 
if SABA intake is increased). Salbutamol will be dispensed for rescue use. The reference 
PEFR value will be obtained at screening visit 1 and an alert value recorded in subject 
diary by site staff.
CHANGE 7
Section 7.3.8.3- Peak Expiratory Flow Rate (PEFR) Measurements


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Rationale for change: Change clarifying that baseline PEFR will be captured for all 
subjects at screening visit 1.
REVISED TEXT
Baseline PEFR values will be captured for all subjects at screening visit 1. Subjects who 
undergo low-dose ICS washout will be provided with a peak flow meter at screening visit 
1 for use at home, until randomization.
CHANGE 8
Section 11 References 
Rationale for change: Added one reference and cited in Section 7.4.1
REVISED TEXT
Joos GF, O´Connor B, Anderson SD, et al. Indirect airway challenges. Eur Respir J. 
1998;21:1050-1068.


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12.7.
Appendix 7: Country-Specific Requirements
No country-specific requirements exist.

SAP_001.pdf: 
CONFIDENTIAL
GlaxoSmithKline group of companies
203162
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for study 203162: An escalating dose, 
randomized, placebo-controlled, incomplete-block, 2-period cross-
over study to assess the dose response for topical efficacy via 
airway responsiveness to adenosine-5'-monophosphate (AMP) 
challenge and the dose response for systemic activity via 24h 
plasma cortisol suppression and thereby the relative therapeutic 
index for fluticasone furoate (FF), fluticasone propionate (FP) and 
budesonide (BUD) in asthmatic subjects.
Compound Number 
:
CCI18781 ((FP), Fluticasone Propionate), GW685698 ((FF), 
Fluticasone Furoate) and GR160288 ((BUD) Budesonide)
Effective Date 
:
05-FEB-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be included in the 
Clinical Study Report for Protocol 203162 (2016N281231_03).

This RAP will be provided to the study team members to convey the content of the Statistical 
Analysis Complete (SAC) deliverables 
Author(s)
Author
Date
Lead
Associate Statistician, RD Respiratory, Biostatistics – India
05-FEB-2019
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  Unauthorized
copying or use of this information is prohibited.
 
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GlaxoSmithKline group of companies
203162
2
RAP Team Review Confirmations:
(Method: E-mail)
Approver
Date
 
28- JAN -2019
Principal Clinical Research Scientist [RD PCPS CPSSO]
 
31- JAN -2019
Clinical Development Director, RD Respiratory HUP 
 
24- JAN -2019
Statistics Leader, RD Respiratory, Biostatistics 
Associate Manager - Programming, RD Respiratory, Biostatistics – India
29- JAN -2019
 
29- JAN -2019
Physician Director, RD Respiratory HUP CPDM 
Senior Clinical Data Scientist, Data Management
25- JAN -2019
SERM Scientist, CMO GCSP SERM 
30- JAN -2019
Medical Director, CMO GCSP SERM
28-JAN-2019
Clinical Statistics & Clinical Programming Line Approvals:
(Method: Pharma TMF eSignature)
Approver
Date
05-FEB-2019
Director, Clinical statistics, Biostatistics RD Respiratory
(e-signed on behalf of 
 Senior Manager - Statistics, 
Biostatistics, RD Respiratory)
05-FEB-2019
Senior Manager - Programming, Biostatistics, RD Respiratory
 
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TABLE OF CONTENTS
1.
INTRODUCTION......................................................................................................5
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 ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................12
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
5.1.
Study Treatment & Sub-group Display pooled treatment dose 
Descriptors .................................................................................................14
5.1.1.
Study Treatment & Sub-group Display Descriptors for 
displays other than pooled treatment dose Descriptors................14
5.2.
Baseline Definitions ....................................................................................15
5.3.
Multicenter Studies .....................................................................................15
5.4.
Examination of Covariates, Other Strata and Subgroups............................15
5.4.1.
Covariates and Other Strata ........................................................15
5.5.
Multiple Comparisons and Multiplicity .........................................................16
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................16
6.
STUDY POPULATION ANALYSES .......................................................................17
6.1.
Overview of Planned Study Population Analyses........................................17
6.1.1.
Subject Disposition ......................................................................17
6.1.2.
Medical Conditions ......................................................................17
7.
PHARMACODYNAMIC AND BIOMARKER ANALYSES........................................17
7.1.
Primary Pharmacodynamic Analyses..........................................................17
7.1.1.
Endpoint / Variables.....................................................................17
7.1.2.
Summary Measure ......................................................................17
7.1.3.
Population of Interest...................................................................18
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................18
7.1.5.
Statistical Analyses / Methods .....................................................18
7.1.5.1.
Statistical Methodology Specification..........................18
7.2.
Exploratory Pharmacodynamic and Biomarker Analyses............................22
7.2.1.
Endpoint / Variables.....................................................................22
7.2.2.
Summary Measure ......................................................................22
7.2.3.
Population of Interest...................................................................23
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................23
7.2.5.
Statistical Analyses / Methods .....................................................23
8.
SAFETY ANALYSES .............................................................................................23
 
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8.1.
Adverse Events Analyses ...........................................................................23
8.2.
Adverse Events of Special Interest Analyses..............................................23
8.3.
Clinical Laboratory......................................................................................24
8.4.
Other Safety Analyses ................................................................................24
9.
REFERENCES.......................................................................................................25
10. APPENDICES........................................................................................................26
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................26
10.2.
Appendix 2: Schedule of Activities ..............................................................27
10.2.1.
Protocol Defined Schedule of Events...........................................27
10.3.
Appendix 3: Assessment Windows .............................................................30
10.3.1.
Definitions of Assessment Windows for Analyses........................30
10.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................31
10.4.1.
Treatment States .........................................................................31
10.4.2.
Treatment States for AE Data......................................................31
10.4.2.1.
Study Phases for Concomitant Medication .................31
10.4.3.
Treatment Emergent Flag for Adverse Events .............................32
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................33
10.5.1.
Reporting Process .......................................................................33
10.5.2.
Reporting Standards....................................................................33
10.6.
Appendix 6: Derived and Transformed Data ...............................................35
10.6.1.
General........................................................................................35
10.6.2.
Study Population..........................................................................35
10.6.3.
Pharmacodynamic derivation.......................................................36
Calculation of Weighted Means ...........................................................................38
10.6.4.
Safety ..........................................................................................39
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................40
10.7.1.
Premature Withdrawals................................................................40
10.7.2.
Handling of Missing Data.............................................................40
10.7.2.1.
Handling of Missing and Partial Dates ........................42
10.8.
Appendix 8: Abbreviations & Trade Marks ..................................................43
10.8.1.
Abbreviations...............................................................................43
10.8.2.
Trademarks .................................................................................44
10.9.
Appendix 9: List of Data Displays ...............................................................45
10.9.1.
Data Display Numbering..............................................................45
10.9.2.
Mock Example Shell Referencing ................................................45
10.9.3.
Deliverables.................................................................................45
10.9.4.
Study Population Tables..............................................................46
10.9.5.
Pharmacodynamic Tables ...........................................................49
10.9.6.
Pharmacodynamic and Biomarker Figures ..................................52
10.9.7.
Safety Tables...............................................................................53
10.9.8.
ICH Listings .................................................................................55
10.9.9.
Non-ICH Listings..........................................................................58
10.10. Appendix 10: Example Mock Shells for Data Displays ................................60
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be included in 
the Clinical Study Report for Protocol 203162 (2016N281231_03):
Revision Chronology:
2016N281231_00
29-SEP-2016
Original
2016N281231_01
16-JAN-2017
Amendment No. 1 was to clarify the dose rationale, 
emergency unblinding procedure, and approval of 
substantial amendments procedure, as requested by the 
Medicines and Healthcare Products Regulatory Agency 
(MHRA), as well as to clarify the blood sample time points 
and volumes and update the medical monitor contact 
details.
2016N281231_02
03-OCT-2017
Amendment No. 2 was to change the following:
The protocol design, to allow subjects to complete either 1 
or 2 treatment periods.
To allow recruitment of subjects taking low- dose inhaled 
corticosteroids (ICS) with appropriate washout period.
To allow inclusion of light smokers.
Removal of the Run-in and treatment period 2 baseline 
visits for adenosine-5’- monophosphate (AMP) challenge.
To allow the subjects to leave the unit after Day 7 evening 
procedures.
To allow in-stream data review.
Changes laid down in MEMOs to protocol amendment 1 
were also incorporated into this protocol amendment.
2016N281231_03
26-APR-2018
Amendment No. 3 is being issued to update the serious 
adverse event (SAE) contact and processing information, 
the pregnancy reporting timelines, as well as to include 
administrative changes clarifying the screening peak 
expiratory flow rate (PEFR) procedure.
2016N281231_04
27-APR-2018
Applies to Germany only
Amendment 3 is being issued to:

exclude enrolment of vulnerable subjects, employees 
and relatives of employees

clarify the informed consent process as it relates to 
the 2013 version of the Declaration of Helsinki

clarify the criteria for partial or complete 
discontinuation of the study
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were deviations to the “Analysis population” as outlined in Table 1. However, no changes
were made to the originally planned statistical analysis specified in the protocol amendment 3
[(Dated: 26/APR/2018)].
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical 
Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Not Defined 

Screened: All Subjects 
screened and for whom a 
record exists on the study 
database

Enrolled: All Subjects who are 
enrolled into the study (i.e. 
passed screening, regardless 
of whether they are 
randomized or receive 
treatment)

These populations are required for 
Study Population displays

PD 
Population

Subjects in All Subjects 
population who also have at 
least one post dose PD 
measurement.

This change is to avoid assigning a 
Subject to the PD population if the 
Subject has received one dose and 
withdrawn before collecting at least 
one post dose PD (Escalation Phase 
1 FEV1/Cortisol) measurement
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To characterize the dose response 
and relative potency for FF, FP and 
BUD in the adenosine 
monophosphate (AMP) challenge 
model at 12 hours after the last dose 
on Day 7

Provocative concentration (PC) of AMP causing a 
20% fall in forced expiratory volume in 1 second 
(FEV1) (AMP PC20)
To characterize the dose response 
and relative potency for FF, FP and 
BUD on 24hour plasma cortisol 
suppression on treatment from pre-

Suppression of 24 hour weighted mean plasma 
cortisol compared to placebo
 
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Objectives
Endpoints
dose PM dose on Day 6 to pre-dose 
PM dose Day 7 

To assess the therapeutic index for 
FF, FP and BUD

ED20 cortisol suppression (dose at which 20% 
cortisol suppression is reached) /ED80 for AMP 
PC20 (dose at which 80% of the maximum AMP 
PC20 is reached)
Secondary Objectives
Secondary Endpoints

Safety and tolerability

Safety and tolerability of all treatments as 
assessed by adverse events (AEs), peak 
expiratory flow rate (PEFR), vital signs, physical 
examinations, laboratory assessments, and 
spirometry
Exploratory Objectives
Exploratory Endpoints

To estimate the dose of FF and BUD 
that gives the same AMP response 
as the FP doses administered in this 
study.

AMP PC20

To estimate the dose of FF and BUD 
that gives the same cortisol 
suppression as the FP doses 
administered in this study.

Suppression of 24 hour weighted mean plasma 
cortisol compared to placebo.

To compare the systemic metabolic 
bioactivity profile of FF, FP and BUD 
with the aim of identifying qualitative, 
quantitative and dose related
differences in on-target and off-target 
steroid receptor interactions using 
plasma metabolomics.

Metabolic profiling of plasma samples collected 
pre-dose and 12 hours after the last dose on Day 
7 compared to placebo.
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design Features

This is a randomized, placebo-controlled, incomplete-block, 2-period cross-over, 7-day escalating repeat dose study in 
subjects with mild asthma
Dosing

Subjects will consent to participate in either:
o
one treatment period; or
o
two treatment periods, separated by a washout period of 25-42 days.

Subjects who are taking low-dose ICS will have a 4-week ICS washout during which their asthma symptoms must remain 
stable.

Each treatment period will comprise five consecutive 7-day dosing phases with escalating doses of one of three ICS products 
or placebo.

Each 7-day period is referred to as an escalation phase. In each 7-day escalation phase, subjects will receive study treatment 
from the evening of Day 1 to the evening of Day 7.

Blood samples for plasma cortisol will be taken on pre-dose evening of Day 6 to 24 hours later Day 7.

After each 7-day dose escalation phase of each treatment period an AMP challenge 12-hour post-evening dose on Day 7 will 
be performed.

Subjects who consent to completing 2 treatment periods will be assigned to one of the treatment sequences. Subjects who 
consent to completing 1 treatment period will be randomized to treatment.

A follow-up visit will take place within 7-14 days after the last dose of study treatment.
Time & Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment
For subjects who consent to completing two treatment periods each Subject will receive 2 different treatments, one in treatment 
period 1, and one in treatment period 2; the possible treatment sequences are pre-defined in Table 3. Two Subjects will be 
randomized to each of the 12 treatment sequences (Table 3).
For subjects who consent to completing one treatment period: Each subject will receive one treatment, as defined in Table 4 . Six 
Subjects will be randomized to each treatment, including placebo overall (Table 4).
 
 
 
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Overview of Study Design and Key Features
Table 2
Doses proposed per dose escalation phase
Treatment
1st 
escalation 
phase –
7 days
2nd 
escalation 
phase –
7 days
3rd 
escalation 
phase –
7 days
4th 
escalation 
phase –
7 days
5th 
escalation 
phase –
7 days
A
FF 25 µg →FF 100 µg →FF 200 µg →FF 400 µg →FF 800 µg
B
FP 50 µg →FP 200 µg →FP 500 µg →FP
1000 µg
→FP
2000 µg
C
BUD
100 µg
→BUD
400 µg
→BUD
800 µg
→BUD
1600 µg
→BUD
3200 µg
D
ELLIPTA™
Placebo
→ELLIPTA™
Placebo
→ELLIPTA™
Placebo
→ELLIPTA™
Placebo
→ELLIPTA™
Placebo
E
DISKUS™
Placebo
→
DISKUS™
Placebo
→
DISKUS™
Placebo
→
DISKUS™
Placebo
→
DISKUS™
Placebo
Twenty-Four Subjects completing 2 treatment periods will be randomized to one of the treatment sequences
 
 
 
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Overview of Study Design and Key Features
Table 3
Sequence and number of Subjects for two period treatment allocation
Sequence
Period 1
Period 2
n
1
A
B
2
2
A
C
2
3
A
D
2
4
B
A
2
5
B
C
2
6
B
E
2
7
C
A
2
8
C
B
2
9
C
E
2
10
D
A
2
11
E
B
2
12
D
C
2
Total subjects
24
Subjects per treatment
12
Twenty-Four Subjects completing 1 treatment period will be randomized to one of the treatments 
 
 
 
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Overview of Study Design and Key Features
Table 4
Sequence and number of Subjects for single period treatment allocation
Sequence
Treatment
N
13
A
6
14
B
6
15
C
6
16
D
3
17
E
3
Total Subjects
24
Subjects per treatment
6
Therefore, a total of 48 Subjects will be randomized, 18 Subjects in total per study treatment (for each active treatment and for 
placebo combined).
Interim Analysis

No interim analysis is planned for this study
 
 
 
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2.4.
Statistical Hypotheses / Statistical Analyses
No formal hypothesis will be tested.
The main purpose of this study is to characterize the dose response and relative potency following 
repeat inhaled doses of FF, FP and BUD on AMP PC20 at 12 hours after the last dose on Day 7 as 
well as to characterize the dose response and relative potency for FF, FP and BUD on 24-hour
plasma cortisol suppression (pre-dose PM dose on Day 6 to pre-dose PM dose Day 7). To achieve 
these objectives a dose response maximum effect (Emax) model will be fitted to the AMP PC20
data and the cortisol suppression 0-24 hour weighted mean data. There will be no formal 
hypothesis tested but point estimates and corresponding 95% confidence intervals will be 
constructed for each of the three parameters for the Emax model (Placebo response [E0], Emax, and 
ED50).
3.
PLANNED ANALYSES
3.1.
Interim Analyses
In-Stream Data Review will be carried out to assess the need for a sample size re-estimation or 
interim analysis based on the below graphs
1.
Percentage change in FEV1 vs Doubling dose for each subject and for each treatment
2.
AMP PC20 vs Each Escalation phases for each subject including screening AMP PC20 
data
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the following 
sequential steps:
1.
All Subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database release
and database freeze has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened Population

All subjects screened and for whom a 
record exists on the study database.  

Study Population
Enrolled Population

All subjects who are enrolled into the 
study (i.e. passed screening, regardless 
of whether they are randomized or 
receive treatment)

Study Population
All Subjects Population

All subjects population will consist of all 
subjects who are randomized and who 
receive at least one dose of trial 
medication.

Study Population

Safety
Pharmacodynamic 
(PD) population

Subjects in All Subjects population who 
also have at least one post dose PD 
measurement.

PD
1. NOTES:
2. Please refer to Appendix 9: List of Data Displays which details the population to be used for 
each display being generated.
4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized and listed.

Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with PAREXEL’s Protocol Deviation Specification, as outlined in the study 
Data Management Plan.

Data will be reviewed by study team members prior to unblinding and freezing the 
database to ensure all important deviations and deviations which may lead to exclusion 
from the analysis are captured and categorized on the protocol deviations dataset. 

The SDTM dataset will include all protocol deviations, the analysis dataset (ADAM) will 
include only important protocol deviations.  The analysis dataset will be used for the listing 
and summary of important protocol deviations.

A separate summary and 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 except those 
mentioned in Appendix 1.

If there are subjects with protocol deviations that may potentially impact the PD endpoints
other than those mentioned in Appendix 1, exploratory sensitivity analyses may be 
considered. If 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
5.1.
Study Treatment & Sub-group Display pooled treatment 
dose Descriptors
5.1.1.
Study Treatment & Sub-group Display Descriptors for displays 
other than pooled treatment dose Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1,2]
A
FF 25 mcg/FF 100 mcg/FF 200 
mcg/FF 400 mcg/FF 800 mcg
FF
2
B
FP 50 mcg/FP 200 mcg/FP 500 
mcg/FP 1000 mcg/FP 2000 mcg
FP
3
C
BUD 100 mcg/BUD 400 mcg/BUD 
800 mcg/BUD 1600 mcg/BUD 
3200 mcg
BUD
4
D
ELLIPTA Placebo/ELLIPTA 
Placebo/ELLIPTA 
Placebo/ELLIPTA 
Placebo/ELLIPTA Placebo
Placebo
1
E
DISKUS Placebo/DISKUS 
Placebo/DISKUS 
Placebo/DISKUS 
Placebo/DISKUS Placebo
Placebo
1
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
FF 25 mcg/FF 100 mcg/FF 200 mcg/FF 400 
mcg/FF 800 mcg
FF 25 mcg
6
FF 100 mcg  
7
FF 200 mcg
8
FF 400 mcg
9
FF 800 mcg
10
B
FP 50 mcg/FP 200 mcg/FP 500 mcg/FP 1000 
mcg/FP 2000 mcg
FP 50 mcg
11
FP 200 mcg
12
FP 500 mcg
13
FP 1000 mcg
14
FP 2000 mcg
15
 
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In displays “Subjects” will be used to refer to “Participants”.
5.2.
Baseline Definitions
For all endpoints except Cortisol Suppression the baseline value will be the latest pre-dose 
assessment including unscheduled visits with a non-missing value. Baseline definitions are 
applicable to each period except for Dose response model.
For the calculation of AMP PC20 the latest pre-diluent FEV1 values will be considered as the 
baseline for each AMP challenge.
5.3.
Multicenter Studies
In this multicenter study, enrolment will be presented by country and center. All other data will be 
pooled in the data displays and no adjustments will be made for country or center in the analyses.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
Category
Details
Covariates
Fixed effects: AMP escalation phase, dose and Period 
Random effects: subject 
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
C
BUD 100 mcg/BUD 400 mcg/BUD 800 
mcg/BUD 1600 mcg/BUD 3200 mcg
BUD 100 mcg
16
BUD 400 mcg
17
BUD 800 mcg
18
BUD 1600 mcg
19
BUD 3200 mcg
20
D
E
ELLIPTA Placebo/ELLIPTA Placebo/ELLIPTA 
Placebo/ELLIPTA Placebo/ELLIPTA Placebo
DISKUS Placebo/DISKUS Placebo/DISKUS 
Placebo/DISKUS Placebo/DISKUS Placebo
Placebo 1
1
Placebo 2
2
Placebo 3
3
Placebo 4
4
Placebo 5
5
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
2.
For Safety and Study Population displays, the Placebo data should be pooled and 
reported except in exposure displays. For study pop summaries, only total column 
is required unless otherwise specified.
1.
 
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5.5.
Multiple Comparisons and Multiplicity
No formal hypothesis is being tested in this study and so no adjustments will be made for 
multiplicity.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7:  Reporting Standards for Missing Data
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population will be based on the All Subjects population, unless otherwise specified. All 
the study population displays will be based on planned treatment.
Study population analyses including analyses of subject disposition, protocol deviations, 
demographic and baseline characteristics, concomitant medications, smoking history, 
inclusion/exclusion criteria deviations and treatment exposure will be summarized and listed based 
on GSK Core Data Standards. Details of the planned displays are presented in Appendix 9: List 
of Data Displays.
6.1.1.
Subject Disposition 
The study population summary will show the number of subjects overall who were enrolled, the 
number of screen failures and the number with each reason for screen failure.
The end of study record summary will show the number of subjects who complete the study in 
each escalation phase as well as the number who withdrew early from the study along with 
reasons for early withdrawal.
6.1.2.
Medical Conditions
The number and percentage of subjects reporting each current medical condition will be presented. 
All medical conditions must be summarized in this table regardless of frequency. 
This will be repeated for past medical conditions.
7.
PHARMACODYNAMIC AND BIOMARKER ANALYSES
7.1.
Primary Pharmacodynamic Analyses
7.1.1.
Endpoint / Variables
Primary endpoints:

Provocative concentration (PC) of AMP causing a 20% fall in forced expiratory volume in 1 
second (FEV1) (AMP PC20).

Suppression of 24 hour weighted mean plasma cortisol compared to placebo.

ED20 cortisol suppression (dose at which 20% cortisol suppression is reached) /ED80 for 
AMP PC20 (dose at which 80% of the maximum AMP PC20 is reached).
7.1.2.
Summary Measure

Predicted dose response for AMP PC20. (Emax Parameters)

Predicted dose response for 24 hour weighted mean plasma cortisol.

ED20 for cortisol suppression/ ED80 for AMP PC20 as a Therapeutic Index.
 
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7.1.3.
Population of Interest
The primary efficacy analyses will be based on the PD population and actual treatment, unless 
otherwise specified.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
The intercurrent event is treatment discontinuation. The dose response to be predicted will be 
the hypothetical effect with the assumption that any subjects who withdraw would have 
behaved the same as those who completed. Missing data due to any intercurrent events will 
not be imputed; all data will be analyzed as collected.
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays.
7.1.5.1.
Statistical Methodology Specification
Primary Statistical Analyses
Endpoints

Provocative Concentration of AMP causing a 20% fall in FEV1 (AMP PC20).

Suppression of 24 hour weighted mean plasma cortisol compared to placebo.

ED20 cortisol suppression (dose at which 20% cortisol suppression is reached) /ED80 for AMP 
PC20 (dose at which 80% of the maximum AMP PC20 is reached).
Model Specification
where:
IFF,ij ,IFP,ij and IBUD,ij are indicator functions that take the value 1 if the ith subject in the jth period was 
associated study drug and its corresponding screening and zero otherwise.
E0 = Response at dose 0 (Placebo response)
FF_Emax = Maximum effect for FF treatment
FF_ED50 = Dose at which 50% of the maximum effect is reached for FF treatment
FP_Emax = Maximum effect for FP treatment
FP_ED50 = Dose at which 50% of the maximum effect is reached for FP treatment
BUD_Emax = Maximum effect for BUD treatment
BUD_ED50 = Dose at which 50% of the maximum effect is reached for BUD treatment
i= Subject (i=1 to N), j= Period (j=1 to 2), k= Escalation phase within jth period (k=1 to
5), 
 
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Primary Statistical Analyses
Doseijk = Dose received by ith subject in the jth period and kth escalation phase (if this corresponds 
to Placebo or screening (Pre-dose) then set Dose to zero).
γ= Slope constant (fixed as 1, converting four parameter model to three parameter Emax model)
si = Subject effect
εijk = Residual error
Starting values for the iterations will be chosen based on the observed data as appropriate.  For 
example:
E0: Mean in placebo response (AMP PC20/Cortisol Suppression) or Screening/Pre-dose response 
based on the model we are fitting.
Emax: Mean of difference between the response from Maximum dose and E0
ED50= Median dose of each ICS.
b2: Between Subject variability: Estimate of between-subject variance from MMRM fitted with the 
random intercept model for the interested parameter (log2 AMP PC20) with Treatment (FF, FP and 
BUD), Escalation phase and period as a fixed effect and subject as a random effect. The 
assumption for covariance structure to be used in the model will be CS where subjects are nested 
within period.  
w2 Within Subject variability: Estimate of within-subject variance from MMRM fitted with the 
random intercept model for the interested parameter (log2 AMP PC20) with Treatment (FF, FP and 
BUD), Escalation phase and period as a fixed effect and subject as a random effect. The 
assumption for covariance structure to be used in the model will be CS where subjects are nested 
within period.
In case of convergence issues in the dose response model, alternative starting values for the 
model parameters (E0, ED50, Emax, b2 and w2) will be considered. If appropriate, a grid of values 
will be used as initial values for the model and variance parameters.
The slope (hill) parameter gamma will be assumed to be 1 (i.e. if necessary to fit three parameter 
Emax model to each treatment, but four parameter Emax formulae are presented as gamma may be 
fitted as an additional model parameter as part of sensitivity analyses and will be detailed in the 
clinical study report). The subject term will be fitted as a random effect. This is equivalent to adding 
a random coefficient to the E0 parameter. All other terms (except the residual error) in the model 
will be fitted as fixed effects. 
The model initially will be fitted with three different Emax parameters (ie one for each ICS). If the 
estimated Emax values are appear similar, then the model will be re-fitted with a single Emax
parameter. 
 
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Primary Statistical Analyses
RM-ANOVA Model:
Prior to dose response analysis, the AMP challenge/Cortisol suppression results for placebo 
across the five dose escalation phases will be investigated using RM-ANOVA model.  If there 
appears to be an effect of repeated AMP challenge on placebo (e.g. a linear trend through time, or 
evidence contradicting the assumption that each of the placebo responses in the five escalation 
phases are the same) then the dose response modelling may be performed on an adjusted version 
of the dataset.
If an adjustment is deemed necessary, then the difference in adjusted means (relative to escalation 
phase one) would be derived for escalation phases two to five (and back transformed if necessary). 
Then, each point estimate for a mean difference would be subtracted from the individual subject 
response values of the corresponding escalation phase. The resulting dataset would be used to 
arrive the initial value of E0 for the dose response modelling process.
The log transformed (base 2) AMP PC20 Placebo data (the data from both types of placebo device 
will be combined) across the five dose escalation phases will also be analyzed by fitting RM-
ANOVA model with AMP escalation phase as fixed categorical effect and subject fitted as a 
random effect and escalation phase as repeated with the CS covariance structure. Visual 
examination of the data in conjunction with the Type III p-value for the main effect of AMP 
escalation phase (testing the underlying global hypothesis that the set of mean responses from all 
escalation phases are the same) will be used to determine whether the data provide evidence that 
an adjustment to the dataset is necessary before performing the dose response modelling. As a 
non-binding rule of thumb p-value < 0.1 would be considered potentially relevant but a clinically 
relevant change/trends could also be sufficient justification for an adjustment. 
A separate model will be constructed considering summary of screening values as E0 with all the 
parameters are same to dose response model above. Doubling dose difference will be calculated 
based on the model and will be reported as separate summary.
Plasma Cortisol
A similar dose response Emax model as mentioned for the AMP PC20 data will be
constructed to characterize the dose response of FF, FP and BUD on cortisol suppression 0-24 
hours weighted mean (ng/mL) after Day 6 dose with the pre-dose measurement on day 1 values as 
an extra covariate in the analysis to adjust for baseline variability. The cortisol 0-24 hours weighted 
mean will be log-transformed using natural logs (i.e. base e).
Therapeutic Index(TI)
Emax model as described above will also be used to obtain the ED20 (0-24 hr.) weighted mean 
cortisol suppression and the ED80 for AMP PC20. The TI is then calculated as ratio of ED20 cortisol 
suppression / ED80 for AMP PC20.
ED20 will be estimated for FF, FP and BUD loge (cortisol suppression) by using estimated ED50 of 
respective ICS.
 
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Primary Statistical Analyses
ED20= ED50*(0.2/0.8)
ED80 will be estimated for FF, FP and BUD log2(AMP PC20) by using estimated ED50 of respective 
ICS.
ED80= ED50*(0.8/0.2)
As an additional exploratory analysis, the therapeutic index will be computed as the ratio of ED50 
cortisol suppression / ED50 AMP PC20.
Model Checking & Diagnostics
The model fit will be explored graphically, including a scatter plot of the log2 AMP PC20/cortisol 
Suppression values (y-axis) against dose (x-axis), with the predicted value for each dose from the 
model superimposed on the plot.
Model Results Presentation
The predicted value for each of the doses will be calculated and back transformed to the original 
scale. The 95% confidence interval for each of the predicted values of each of the doses will also 
be calculated and back transformed. Both the predicted values and the 95% confidence intervals 
will be produced using the ESTIMATE statement in the SAS procedure NLMIXED.
The predicted value for the 3 parameters of interest (E0, Emax and ED50) for each of the treatments 
will be calculated and back transformed to the original scale.  The 95% confidence interval for 
predicted values of each of the parameters will also be calculated and back transformed.
Estimates and 95% confidence intervals for the doubling dose differences from placebo (i.e. 
treatment difference on the log (base 2) scale) from the model will also be presented for each 
active dose in original scale.
Predicted AMP PC20 values and 95% confidence intervals will be plotted against dose for each of 
the active treatments. The potency of FF and BUD relative to FP will be assessed by comparing 
the estimates for ED50.
For the placebo data RM-ANOVA model, the point estimates and the 95% CI will be produced at 
each escalation phases in original scale. 
The cortisol 0-24 hours weighted mean will be log-transformed using natural logs (i.e. base e). 
Similar model as that for AMP PC20 will be used for this cortisol suppression as well. The back 
transformed Predicted Estimates and 95% confidence intervals will be plotted against dose for 
each of the active treatments. 
The estimates of ED20 (0-24 hr.) weighted mean cortisol suppression and the ED80 for AMP PC20
and corresponding Therapeutic Index(TI) will be presented for each of the ICS.
For each of the AMP challenges, the concentrations of AMP (including saline) and corresponding 
FEV1 measurements after each of the AMP inhalations will be listed. The inhalation time and value 
of the FEV1 measurements and the percentage fall of the maximum of the two FEV1 
measurements from the latest highest saline FEV1 will also be included in the listing.
 
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Primary Statistical Analyses
A separate listing will be produced containing the latest highest pre-saline of first diluent and the
latest highest post saline FEV1 measurements at each challenge. The percentage change 
between post-saline and pre-saline will be presented (with the pre-saline measurement as the 
denominator) and a column will be included in the listing detailing if there is a fall of greater than 
10%.
Lung function data collected for assessment of inclusion/exclusion criteria (i.e. Screening), pre-
dose on Day 1 and at follow up, including any unscheduled assessments, will be listed.
Individual subject plots of the AMP dose response curve will be generated. In these plots, the 
percentage change in FEV1 (y-axis) will be plotted against the dose of AMP (x-axis). One set of 
plots will contain one graph per subject, per treatment. On each of these graphs, data points from 
the same treatment group will be joined. 
For each of the AMP challenges, the AMP PC20 will be calculated as described in Section 10.6.3.
This calculated PC20 will be listed alongside the date and start time of the challenge. The time 
deviation between the start time of AMP challenge in screening and actual start time of each AMP 
challenge during the treatment phase of the study will be calculated (post screening AMP 
challenge start time – Screening AMP challenge start time) and presented in this listing. Imputed 
PC20 values (e.g. when the FEV1 did not fall by 20% when the highest AMP concentration (320 
mg/mL) was administered) will be flagged.
The following summary statistics will be presented for the calculated PC20 for each treatment group 
and challenge: median, minimum, maximum, arithmetic mean, standard deviation, coefficient of 
variation, geometric mean, 95% confidence interval for the geometric mean and standard deviation 
of the logarithmically transformed data. 
7.2.
Exploratory Pharmacodynamic and Biomarker Analyses
7.2.1.
Endpoint / Variables
Exploratory Endpoints:

AMP PC20

Suppression of 24 hour weighted mean plasma cortisol compared to placebo.

Metabolic profiling of plasma samples collected pre-dose and 12 hours after the last dose 
on Day 7 compared to placebo
7.2.2.
Summary Measure

Predicted dose of FF and BUD for AMP PC20.

Predicted dose of FF and BUD for 24 hour weighted mean plasma cortisol.

Metabolic profiling sample analysis, data and statistical analysis and reporting will be 
conducted according to a separate analysis plan written and executed by Metabolon Inc, 
617 Davis Drive, Suite 100, Morrisville, NC  27560.
 
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7.2.3.
Population of Interest 
The exploratory efficacy analyses will be based on the PD population and actual treatment, unless 
otherwise specified.
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
The intercurrent event is treatment discontinuation. The dose response to be predicted will be the
hypothetical effect with the assumption that if all subjects who withdraw would have behaved the 
same as those who completed. Missing data due to any intercurrent events will not be imputed; all 
data will be analyzed as collected.
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays
As described in the Section 7.1.5.1 the Emax model will also be used to address the exploratory 
endpoint to assess the dose of FF and BUD that gives the same AMP/Cortisol suppression 
response as the FP doses administered in the study. 
The FF and BUD doses which can give the same predicted responses as the FP doses will be 
estimated from the model by using estimated E0, ED50, Emax, and predicted response of FP doses
based on the below formula
The estimates for the predicted values will be presented as a separate summary in log scale.
8.
SAFETY ANALYSES
The safety analyses will be based on the All subjects’ population and actual treatment, unless 
otherwise specified.
8.1.
Adverse Events Analyses
On-treatment Adverse event analyses including the analysis of adverse events (AEs), Serious 
adverse events (SAEs) will be based on templates provided for the study. Pre- treatment and post-
treatment AEs will be listed as per the GSK IDSL core standards. The details of the planned 
displays are provided in Appendix 9: List of Data Displays.
8.2.
Adverse Events of Special Interest Analyses
A comprehensive list of MedDRA terms based on clinical review will be used to identify each type 
of adverse event of special interest (AESI) event for FF, FP and BUD as per the details are 
provided in Section 10.6.4. The details of the planned displays are provided in Appendix 9: List of 
Data Displays.
 
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8.3.
Clinical Laboratory 
Laboratory evaluations of Chemistry laboratory tests and Hematology laboratory tests will be listed 
based on IDSL core standards. The details of the planned displays are provided in Appendix 9: 
List of Data Displays.
8.4.
Other Safety Analyses
The non-laboratory safety test results such as Peak Expiratory Flow rate (PEFR) will be 
summarized and listed. Vital signs and ECG values will only be listed based on templates provided 
for the study. The details of the planned displays are presented in Appendix 9: List of Data 
Displays.
 
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9.
REFERENCES
GlaxoSmithKline Document Number 2016N281231_03 Study ID 203162. An escalating dose, 
randomized, placebo-controlled, incomplete block, 2 period cross-over study to assess the dose 
response for topical efficacy via airway responsiveness to adenosine-5' monophosphate (AMP) 
challenge and the dose response for systemic activity via 24 h plasma cortisol suppression and 
thereby the relative therapeutic index for fluticasone furoate (FF), fluticasone propionate (FP) and 
budesonide (BUD) in asthmatic subjects. Report date (26-APR-2018).
 
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10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with PAREXEL’s Protocol Deviation Specification, as outlined in the 
study Data 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.
A Per Protocol Population is not being defined for this study but exclusions to PD 
population as follows 
1. If any escalated dose given prior to AMP collection of previous escalation phase 
then, previous escalation phase information will be excluded from the analysis.
2. If dose was not escalated as planned for the complete duration of each of 
escalation phase then, that corresponding escalation phase information should be 
excluded from the analysis.
 
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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
Table 5
Screening and Follow-up Visit
Procedure
Screening Visit 1
Screening Visit 2
Treatment Period 1
Washoutd
Treatment Period 2d FU
Day
Day -42 to Day -4b
Day -14 to Day -4c
Assessments during 
treatment period are 
detailed in Table 6
Washout will be a 
minimum of 25 days
to maximum of 42 
days
Assessments during 
treatment period are 
detailed in Table 6
7 to 14 daysg
Outpatient visit
X
X
X
Informed consenta
X
Inclusion and exclusion criteria
X
X
Demography
X
Full physical examination including height and weight
X
Urine drugs of abuse and alcohol breath test
X
Brief physical
X
Medical history (includes substance usage)
X
Urine pregnancy test (all female subjects)
X
X
HIV, Hep B and Hep C screen
X
Safety labs: chemistry, hematology and urinalysis
X
X
12-lead ECG
X
Vital signs
X
Peak expiratory flow rate
Xb
Xb
AMP challenge
Xf
Spirometry (FEV1 and FVC)
X
X
X
AE/SAEe
X
X
X
Concomitant medication
X
X
X
AE – Adverse event; AMP- Adenosine 5 monophosphate; ECG – Electrocardiogram; FEV1 – Forced expiratory volume in 1 second; FVC – Forced vital capacity; FU – Follow-up; HIV-
Human immunodeficiency virus; Hep B –Hepatitis B; Hep C – Hepatitis C; SAE – Serious adverseevent;
a Informed consent may be obtained on a separate visit prior to screening visit 1.
b Subjects who are receiving low-dose ICS may take part after a 4-week washout.  For these subjects, screening visit 2 will be at least 28 days after screening visit 1.  Duringthe
4-week ICS washout subjects will keep a diary (from screening visit 1 to randomization) to record twice daily peak expiratory flow (subject to contact site if there is a 20% decrease) and
SABA use (subject to contact site if SABA intake is increased).  Salbutamol will be dispensed for rescueuse.
c Subjects who do not require an ICS washout may have only one screening visit, these procedures may then be done at screening visit 1. Screening visit 1 procedures maybe repeated
 
 
 
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at screening visit 2 as deemed necessary by the Investigator ordelegate.
d Subjects who consent to only 1 treatment period will not undergo the washout period or treatment period 2.
e AEs and concomitant medication will be documented on all days throughout the study, but review will only occur when the subject is in theunit.
f The screening visit 2 AMP challenge can be repeated only once; at least 72h after the first attempt.
g 7 to 14 days after the last dose of study treatment.
Table 6
Time and Events Treatment Period 1 and 2
Treatment period 1 and 2
Day 1, pre- Day 1
Days 2, 9,
Days 3, 10,
Days 4, 11,
Days 5, 12,
Days 6, 13,
Days 7, 14,
Day 36b
Dosea
dosing and
16, 23, 30
17, 24, 31
18, 25, 32
19, 26, 33
20, 27, 34
21, 28, 35
post-dose,
Days 8, 15,
22, 29
Study treatment dispensing
X
X
X
Outpatient visitd
X
X
Confinemente
X
X
Randomizationf
X
Urine pregnancy test (all female subjects)
X
X
X
Vital signsg
X
X
Use of inhaler trainingh
X
Peak expiratory flow ratei
X
X
X
X
X
X
X
Study Treatmentj
X
X
X
X
X
X
X
Patient diaryk
X
X
X
X
X
X
X
AMP challengel
X
X
Spirometry (FEV1 and FVC)
X
Blood sampling for plasma cortisolm
X
X
X
Metabolomics samplen
X
X
X
AE/SAEo
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
 
 
 
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AE – Adverse event; AMP- Adenosine monophosphate; FEV1 – Forced expiratory volume in 1 second; FVC – Forced vital capacity; SAE – Serious adverseevent.
   a Day 1 pre-dose completed at start of treatment period 1 and 2, respectively. Urine pregnancy test (where applicable), Vital signs, Spirometry (FEV1 and FVC), blood sampling for plasma
cortisol,metabolomics sample, AE/SAEreview, restriction checks and concomitant medication reviewwill be performed on the morning of Day 1 (Pre-dose) of each treatment period. 
Use of inhaler training, randomization (treatment period 1 only), AE/SAE review, restriction checks, concomitant medication review and study treatment dispensing will be performed in 
the evening of Day 1, prior to study treatmentadministration.
  b Day 36 completed following completion of treatment period 1 and 2, respectively.
c Subjects are dispensed study treatments for the first dose level on Day 1 prior to evening dose. Study treatments for the subsequent 4 dose levels are dispensed prior to release after
completion of the AMP challenge on Days 8, 15, 22, and 29.
d Subjects receive first dose for treatment Period 1 and 2 during the outpatient visit.
e Subject will be admitted to unit prior to evening dose on Days 6, 13, 20, 27 and 34 of each treatment period. Subjects will be confined in the unit until they have recovered from the AMP
challenge on Days 8, 15, 22, 29, and 36, but may leave the unit on the evenings of Days 7, 14, 21, 28, and 35 after their last plasma cortisol sample and return the following morning, if 
they prefer.
f Prior to first dose of treatment period 1 only.
g Performed on Days 1 and36.
h Reinforcement by the investigator on the proper use of theinhaler.
i Peak expiratory flow reading must be taken before each dose of study treatment at home. Three PEFR manoeuvres should be performed in each session. The highest PEFR of the3
efforts from any session will be the one that will be recorded in a paperdiary.
j Subjects will take doses of study treatment in the evening only (for all ELLIPTA FF/placebo doses, and the first escalation phase for FP [50 mcg dose] and BUD [100 mcg dose]) orin the 
morning and evening, 12 hours apart (for all other dose regimens). There will be no dosing in the mornings of Days 1, 8, 15, 22 and 29. When subjects are not at the unit, they will take 
their study treatments at home.
kOn Days 1, 8, 15, 22, and 29, subjects will receive a patient diary to document day and time of each dose, the peak expiratory flow rate (PEFR) recording and any AEs or concomitant
medication including the number of SABA doses.  The subject will enter their data in a paperdiary.
l The AMP challenges will be done in the morning of Days 8, 15, 22, 29, 36 and 12 hours after the preceding evening dose. If subjects cannot perform the AMP challenge, this may be
rescheduled 1-3 days later, in this case; the subjects will continue dosing at the same level until the rescheduled AMP challenge and the study schedule will be shifted.
m Blood samples for plasma cortisol will be taken on Day 1 pre-dose (baseline) and at the following time points related to evening study drug administration on Days 6, 13, 20, 27,34:
pre-dose and at 1, 2, 3, 5, 10, 12 (before morning dose), 14, 16, 18 and 24 hourspost-dose.
nThe plasma metabolomics will be taken on Day 1 pre-dose (baseline) and on Days 8, 15, 22, 29 and 36, at the end of each dose escalation phase, at 12 hour after the last evening dose 
(before AMP challenge procedure).
oAEs and concomitant medication will be documented on all days throughout the study, but review will only occur when the subject is in the unit.
 
 
 
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10.3.
Appendix 3: Assessment Windows
10.3.1.
Definitions of Assessment Windows for Analyses
In general, data collected at unscheduled time points will not be used to calculate any of the 
derived parameters. The exception to this is 
1.
In the assessment of the highest post-saline FEV1 to be used in the calculation of AMP 
PC20. Where the saline control has been inhaled more than once yielding unscheduled 
baseline assessments, the FEV1 measurements at 60 and 180 seconds after the last 
administration of the saline control will be used to ascertain the highest post-saline FEV1.
2.
If AMP PC20 collection gets postponed and it is captured as an unscheduled visit, then the 
unscheduled visit will be considered instead of the planned visit only for that Escalation
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10.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
10.4.1.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the start 
and/or stop date of the study treatment.
10.4.2.
Treatment States for AE Data
Treatment 
State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
AE onset date is on or after treatment start date & on or before treatment stop 
date plus 7 days.
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date +7 
days
Post-
Treatment
AE onset date is after the treatment stop date plus 7 days.
AE Start Date > Study Treatment Stop Date +7 days
Onset Time 
Since 1st Dose 
(Days)
Treatment Start Date ˃ AE Onset Date = AE Onset Date - Treatment Start Date
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 On-Treatment.
10.4.2.1.
Study Phases for Concomitant Medication
NOTES: 
• Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and 
partial dates for concomitant medication. Use the rules in this table if concomitant medication date 
is completely missing.
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to 
screening visit
Concomitant
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10.4.3.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment 
stop date plus 7 days 

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date 
+7 days.

If AE onset is during first period and worsens during a second period, it 
would be counted in both periods. For the first period the logic would be as 
above. For the second period the logic would use the treatment dates 
associated with the second period:

Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop 
Date +7 days.
NOTES: 

If the study treatment stop date is missing and the AE onset date is on or after study treatment 
start date, then the AE will be considered as On-Treatment.
 
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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
10.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject listings. 
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Compound
: /arenv/arprod/gw685698/mid203162/final_05
Analysis Datasets 

Analysis datasets will be created according CDISC standards (SDTM IG Version 3.2 & ADaM 
IG Version 1.0). 
Generation of RTF Files

RTF files will be generated.
 
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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures unless there is no 
AMP PC20 and cortisol suppression postponement visit as scheduled unless it is captured as 
unscheduled visit.

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, %
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.
 
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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Analysis Time Point

For post-saline FEV1 and FEV1 measurement after the dose of AMP, the higher of the two 
measurements will be used for the summary.
Study Day

Calculated as the number of days from exposure date:

Ref Date = Missing             → Study Day = Missing 

Ref Date < Exposure Date   → Study Day = Ref Date – Exposure Date    

Ref Date ≥ Exposure Date  → Study Day = Ref Date – (Exposure Date) + 1    
10.6.2.
Study Population
Demographics
Age

GSK standard 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’.

Age will be calculated based on screening visit date.
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 = Escalation Phase Stop Date – (Escalation phase Start 
Date) + 1

Subjects who were randomized but did not report a treatment start date will be categorized as 
having zero days of exposure. 

Total daily dose will be based on the formula:
        Total daily dose = the cumulative actual dose divided by the duration of exposure F
For dose escalation phases with twice-daily dosing (AM and PM) but only a single dose (PM) 
on the first day (AMP collection day) of the phase, that day will count as only 0.5 days in the 
calculation of duration of exposure.

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of all Total Daily Dose during each Escalation Phase

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
 
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10.6.3.
Pharmacodynamic derivation
AMP PC20
For each concentration of AMP, the percentage change in FEV1 will be calculated using the 
following formula:
For each concentration of AMP, the percentage fall in FEV1 will be calculated using the following 
formula:
where:
i.
highest FEV1 (post saline) = the highest value of two FEV1 measurements at 60 and 180 secs 
after the saline control
ii.
highest FEV1 (post AMP) = the highest value of the two FEV1 measurements at 60 and 180 
secs after the dose of AMP
The PC20 is then obtained by linear interpolation (on the log 2 concentration scale) between the 
lowest concentration of AMP that caused ≥20% fall from baseline (C2) and the preceding 
concentration (C1).
The formula is:
where:
i.
C1 = preceding concentration to C2
ii.
C2 = lowest concentration of AMP that caused a fall of ≥20% from baseline
iii.
R1 = % fall in FEV1 after C1
iv.
R2 = % fall in FEV1 after C2
If a fall in FEV1 of at least 20% is observed after inhalation of the first AMP concentration, the PC20
cannot be calculated using interpolation on the log 2 scale. In this case, PC20 will be calculated by 
linear interpolation on the original scale between 0 and the first AMP concentration inhaled. The 
formula is:
 
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AMP PC20
where:
i.
C2 = first AMP concentration inhaled
ii.
R2 = % fall in FEV1 after C2
In some instances, the FEV1 may not fall by at least 20% from baseline for any of the AMP 
concentrations administered. This could occur when the maximum concentration of AMP (320 
mg/mL) does not lead to a fall of a least 20% (e.g. if treatment provides protection to AMP at the 
highest concentration), or if the challenge was halted prematurely (e.g. if the site incorrectly 
calculated the percentage fall during the challenge). If the FEV1 has not fallen by at least 20% the 
PC20 will be imputed by linear extrapolation (on the log 2 concentration scale) using the previous 
two AMP concentrations unless:
1.
The highest FEV1 at the last AMP concentration inhaled represents an increase or no change 
in FEV1 from the previous AMP concentration inhaled.
2.
The PC20 calculated by linear extrapolation is more than two times the last AMP concentration 
inhaled.
The formula for linear extrapolation is:
where:
i.
C3 = penultimate concentration of AMP inhaled
ii.
C4 = last concentration of AMP inhaled
iii. R3 = % fall in FEV1 after C3
iv. R4 = % fall in FEV1 after C4
In the case of condition 1 or 2, the following imputation of AMP PC20 will be made:

If the last AMP concentration inhaled is the highest AMP concentration (i.e. 320 mg/mL) then 
the PC20 will be set to 320 mg/mL.

If the last AMP concentration inhaled is not the highest AMP concentration (i.e. is less than 
320 mg/mL) and the corresponding percentage fall from baseline in FEV1 is <15% then the 
PC20 will be set to missing.

If the last AMP concentration inhaled is not the highest AMP concentration (i.e. is less than 
320 mg/mL) and the corresponding percentage fall from baseline in FEV1 is 15% then the 
PC20 will be set to the last AMP concentration inhaled.
 
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Calculation of Weighted Means
Weighted means (0-24h) will be derived for plasma cortisol
All available (planned) data at the actual relative times will be included in the derivation of the 
weighted mean. If a measurement value is available and the actual time has not been captured, 
the time will be replaced with planned time for that value only.  Pre-dose will be taken as the 0h 
timepoint, and all subsequent timepoints will be calculated relative to dosing in that escalation 
phase for each period.
The weighted means will be derived by calculating the area under the curve (AUC) over the 0-
24-hour period using the trapezoidal rule, and then dividing it by the actual time interval.  
where   
represents the value of the endpoint at the ith timepoint,
represents the actual relative time at the ith timepoint,
represents the actual relative time at the first timepoint (
= 0 as the pre-dose 
measurement is used),
represents the actual relative time at the last timepoint (for example, the 24h timepoint),
represent the number of timepoints used in the AUC calculation. 
For plasma cortisol there are 11 planned timepoints at pre-dose (0 hr.) and at 1, 2, 3, 5, 10, 12 
(before morning dose), 14, 16, 18 and 24 hours post dose, weighted mean will be calculated for 
plasma cortisol values between PM dose on Day 6 to pre-dose PM dose Day 7.
 
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10.6.4.
Safety
Adverse Events
AEs of Special Interest
AE groups of special interest have been defined as AEs which have specified areas of interest for 
FF, FP and BUD.
AESI Group
MedDRA Terms
Hypersensitivity
Hypersensitivity SMQ, Angioedema (SMQ), Anaphylactic 
reaction (SMQ)
Infective Pneumonia 
Infective Pneumonia SMQ
Corticosteroids associated eye 
disorders
Glaucoma SMQ
Adrenal Suppression
GSK defined PTs
If this reference data is updated between the RAP approval and the reporting of the study, then 
this list will be updated and re-reviewed. A listing of all preferred terms used to identify AESIs will 
be produced.
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, and 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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10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General
Subject study completion (i.e. as specified in the protocol) was defined as “A 
completed subject is one who has completed the number of treatment periods they 
consented to, including the follow-up visit”. Withdrawn 
subjects will be handled in the study as mentioned below:
Withdrawn Subjects may be replaced. Replacement Subjects will be assigned to the 
same treatment sequence as the subject they are replacing.
For Subjects completing two treatment periods:

Each subject will receive 2 different treatments, one in treatment period 1, 
and one in treatment period 2; the possible treatment sequences are pre-
defined in Table 3. Two Subjects will be randomized to each of the 12 
treatment sequences (Table 3).

If a subject withdraws during treatment period 1, the replacement subject 
will start from the beginning of period 1 of the same treatment sequence. 

If a subject withdraws after period 1 or during period 2, the replacement 
subject may start from period 2; a maximum of 2 Subjects can be replaced 
from the start of period 2. If more than 2 Subjects withdraw after period 1 or 
during period 2, they will be replaced from the beginning of period 1.
For Subjects completing one treatment period:

Each Subject will receive one treatment, as defined in Table 4. Six 
Subjects will be randomized to each treatment, including placebo overall 
(Table 4). Replacements for withdrawn Subjects will start from the 
beginning of period 1 of the same treatment.
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.
.
10.7.2.
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 using 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”, “Not Done” 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.
Weighted 
Mean 
If missing values are present in data required for the calculation of the weighted 
 
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Element
Reporting Detail
Calculations
means, the following approach will be employed:

If more than a third of the observations are missing, then the weighted mean will 
be set to missing for that escalation phase of the subject. 

If missing values occur at the first or last time-point and the number of missing 
observations is less than a third, then the missing values will be imputed using 
the first non-missing observation carried backwards or the last non-missing 
observation carried forwards respectively.

If missing values occur at a time-point between non-missing values, the value 
will be interpolated using the two non-missing values based on the below 
formula:
Where 
= missing value at timepoint
           
= first available non-missing value after the missing timepoint
           
= first available non-missing value before the missing timepoint
             
, where a is the distance from 
to 
and b is the distance 
from  
to 

If it is considered that a non-negligible amount of missing data is present, a 
sensitivity analysis to assess the effect of the imputation described above may 
also be carried out and reported in CSR.
 
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10.7.2.1.
Handling of Missing and Partial 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
or only 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:
Partially Missing Dates:
o
Missing Start Day: First of the month will be used as the Day (i.e. 01) 
unless the first of the month 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: 
Study Phases and Treatment Emergent Adverse Events
o
Missing Start Month: January will be used as the Month unless this is 
before the Month of start of the study treatment; in that case the 
Month of study treatment start, will be used.
o
Missing Stop Day: Last day of the month will be used as the Day (i.e. 
28/29/30/31 dependent on the month and year) unless the last day of 
the month is after the stop date of study treatment; in this case the 
study treatment stop date will be used as the Day
o
Missing Stop Month: December will be used as the Month unless this 
is after the Month of stop of the study treatment; in that case the 
Month of study treatment stop will be used.
Fully Missing Dates:

Completely missing start or end dates (i.e. no year specified) will remain 
missing, with no imputation applied. Consequently, time to onset and duration 
of such events will be reported as missing.  The same approach will be 
adopted for all AEs regardless of whether the AE is assumed to have 
occurred during treatment or not
Concomitant 
Medications/M
edical History

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.
 
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10.8.
Appendix 8: Abbreviations & Trade Marks
10.8.1.
Abbreviations
AE
Adverse Event
AMP
Adenosine-5-monophosphate
AMP PC20
Provocative concentration of AMP causing a 20% fall in 
forced expiratory volume in 1 second
ANOVA
Analysis of variance
BMI
Body mass index
BUD
Budesonide
CI
Confidence interval
CS
Compound Symmetry
CRF
Case report form
ECG
Electrocardiogram
eCRF
Electronic case report form
E0
Response at dose 0
ED20
Dose at which 20% of the maximum effect is reached
ED50
Dose at which 50% of the maximum effect is reached
ED80
Dose at which 80% of the maximum effect is reached
Emax
Maximum effect
FF
Fluticasone furoate
FP
Fluticasone propionate
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FU
Follow-up
FVC
Forced vital capacity
GSK
GlaxoSmithKline
ICH
International Conference on Harmonization
ICS
Inhaled corticosteroids
ITT
Intention-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
Mcg
Microgram
PC
Provocative concentration
PD
Pharmacodynamic
PEFR
Peak expiratory flow rate
RAP
Reporting analysis plan
SAE
Serious adverse event
SD
Standard deviation
 
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10.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
DISKUS
SAS
ELLIPTA
Turbuhaler
 
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10.9.
Appendix 9: List of Data Displays
10.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.16
N/A
Pharmacodynamic
2.1 to 2.15
2.1 to 2.5
Safety
3.1 to 3.13
N/A
Section
Listings
ICH Listings
1 to 24
Other Listings
25 to 36
10.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated, and if required, example mock-up displays 
provided in Appendix 10: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Pharmacodynamic
PD_Fn
PD_Tn
PD_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /Example Shell’ or ‘Programming Notes’ 
column as ‘[Non-Standard] + Reference.’
10.9.3.
Deliverables
Delivery [Priority] 
Description
In-Stream Data Review
In-Stream Data Review will be conducted to assess the need for a 
sample size re-estimation or interim analysis
SAC 
Final Statistical Analysis Complete
 
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10.9.4.
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
Only total column is required
SAC
1.2.
All 
Subjects
ES4
Summary of Subject Disposition at Each Study Epoch
Summarize by escalation phase
SAC
1.3.
Screened
ES6
Summary of Screening Status and Reasons for Screen 
Failures
SAC
1.4.
Enrolled
NS1
Summary of Number of Subjects by Country and Site ID
Only total column is required
SAC
1.5.
Enrolled 
IE2
Summary of Inclusion and Exclusion Criteria Deviations
Only total column is required
SAC
Protocol Deviation
1.6.
All 
Subjects
DV1
Summary of Important Protocol Deviations
Only total column is required
SAC
Population Analyzed
1.7.
Screened 
SP1
Summary of Study Populations 
Only total column is required 
Add footnote to explain the population 
based on Section 4
SAC
1.8.
All 
Subjects
POP_T1
Summary of Subject Completion at Each Escalation 
Phase
Only total column is required
SAC
 
 
 
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No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
1.9.
All 
Subjects
DM3
Summary of Demographic Characteristics 
Only total column is required
Footnote: age is imputed as full date of birth 
is not collected
Footnote: Race collected as AFRICAN 
AMERICAN/AFRICAN HERITAGE is shown 
as BLACK OR AFRICAN AMERICAN
SAC
1.10.
Enrolled
DM11
Summary of Age Ranges 
Only total column is required
Age categories Adult (18-64 years), >=65-
84 years, >=85 years
Footnote: age is imputed as full date of birth 
is not collected
SAC
1.11.
All 
Subjects
DM5
Summary of Race and Racial Combinations 
Only total column is required
Footnote: Note: Race collected as 
AFRICAN AMERICAN/AFRICAN 
HERITAGE is shown as BLACK OR 
AFRICAN AMERICAN.
SAC
Prior and Concomitant Medications
1.12.
All 
Subjects
MH4
Summary of Current Medical Conditions 
Only total column is required
SAC
1.13.
All 
Subjects
MH4
Summary of Past Medical Conditions 
Only total column is required
SAC
 
 
 
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No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
1.14.
All 
Subjects
SU1
Summary of Smoking History at Screening
Only total column is required
Present only Smoking HistorySee IDSL for 
options related to ATC groupings and multi-
ingredient medications. 
SAC
1.15.
All 
Subjects
CM1
Summary of Concomitant Medications by Generic Term 
Only total column is required See IDSL for 
options related to ATC groupings and multi-
ingredient medications. 
SAC
Exposure and Treatment Compliance
1.16.
All 
Subjects
POP_T2
Summary of Exposure to Study Treatment 
Page by each treatment
SAC
 
 
 
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10.9.5.
Pharmacodynamic Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Endpoint – Dose Response Analysis
2.1
PD
PD_T1
Summary of AMP PC20 (mg/mL) Data
SAC
2.2
PD
PD_T2
Summary of Log Transformed AMP PC20 (mg/mL) Data
SAC
2.3
PD
PD_T3
Summary of Statistical Analysis of AMP PC20 (mg/mL) 
Placebo Data (ANOVA Model)
Footnote: The Repeated Measures 
ANOVA model was fitted for log 
transformed AMP PC20 with Dose 
escalation phase as fixed categorical 
effects, subject fitted as a random 
effect and Dose escalation phase as 
repeated with the CS covariance 
structure.
Note: SE = Standard Error. CI = 
Confidence Interval.
SAC
2.4
PD
PD_T4
Summary of Dose Response Analysis for Log Transformed 
AMP PC20 (mg/mL) Data
Footnote: Note: [1] E0 – Placebo 
response (log 2 scale). Emax -
Maximum effect. ED50 - Dose at 
which 50% of the maximum effect is 
reached (mcg).
SAC
2.5
PD
PD_T8
Summary of the Mean Doubling Dose Differences (95% CI) 
from Placebo for AMP PC20 (mg/mL)
SAC
2.6
PD
PD_T1
Summary of Cortisol Suppression 0-24 Hours Weighted Mean
(ng/mL)
SAC
 
 
 
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No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.7
PD
PD_T2
Summary of Log Transformed Cortisol Suppression 0-24 
Hours Weighted Mean (ng/mL)
SAC
2.8
PD
PD_T3
Summary of Statistical Analysis of Cortisol Suppression 
Placebo Data (ANOVA Model)
Footnote: The Repeated Measures 
ANOVA model was fitted for log 
transformed Cortisol Suppression
values with Dose escalation phase 
as fixed categorical effects, subject 
fitted as a random effect and Dose 
escalation phase as repeated with 
the CS covariance structure.
Note: SE = Standard Error. CI = 
Confidence Interval.
SAC
2.9
PD
PD_T5
Summary of the Dose Response Analysis for Log 
Transformed Cortisol Suppression 0-24 Hours Weighted 
Mean (ng/mL)
Footnote: Note: [1] E0 – Placebo 
response (log 2 scale). Emax -
Maximum effect. ED50 - Dose at 
which 50% of the maximum effect is 
reached (mcg).
SAC
Primary Endpoint - Therapeutic Index
2.10
PD
PD_T6
Summary of the Dose Response Analysis for ED20 Cortisol 
Suppression (ng/mL) /ED80 for AMP PC20 (mg/mL)
SAC
2.11
PD
PD_T10
Summary of the Dose Response Analysis for ED50 Cortisol 
Suppression (ng/mL) /ED50 for AMP PC20 (mg/mL)
SAC
 
 
 
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No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exploratory Endpoint
2.12
PD
PD_T7
Summary of Dose of FF and BUD that gives the same AMP 
PC20 (mg/mL) response as the FP doses administered
SAC
2.13
PD
PD_T9
Summary of Dose of FF and BUD that gives the same cortisol 
suppression (ng/mL) as the FP doses administered
SAC
Others
2.14
PD
PD_T4
Summary of Dose Response Analysis for Log Transformed 
AMP PC20 (mg/mL) Data - considering Screening values as E0
SAC
2.15
PD
PD_T8
Summary of the Mean Doubling Dose Differences from 
Screening/Pre-dose for AMP PC20 (mg/mL)
SAC
 
 
 
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10.9.6.
Pharmacodynamic and Biomarker Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Endpoint
2.1
PD
PD_F1
Plot of Individual AMP Dose Response Curves by Subject and 
Treatment 
SAC
2.2
PD
PD_F2
Plot of The Predicted AMP PC20 (95% CI) vs Dose by Treatment 
SAC
2.3
PD
PD_F3
Plot of the Mean Doubling Dose Differences (95% CI) from Placebo for 
AMP PC20 (mg/mL)
SAC
2.4
PD
PD_F4
Plot of Individual Plasma Cortisol Suppression values by Subject and 
Treatment 
SAC
2.5
PD
PD_F2
Plot of Predicted Cortisol Suppression 0-24 Hours Weighted Mean 
(ng/mL) (95% CI) vs Dose by Treatment
SAC
 
 
 
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10.9.7.
Safety Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1
All Subjects
AE13
Overview of Adverse Events
Summarize by PART
SAC
3.2
All Subjects
SAFE_T1
Summary of On-Treatment Adverse Events by System Organ Class and 
Preferred Term 
Summarize by PART
SAC
3.3
All Subjects
SAFE_T2
Summary of Common (>=3%) Adverse Events by Overall Frequency 
Summarize by PART 
Summarize by PART
SAC
3.4
All Subjects
SAFE_T1
Summary of Drug-Related Adverse Events by System Organ Class and 
Preferred Term 
SAC
3.5
All Subjects
SAFE_T3
Summary of Common (>=3%) Non-Serious Adverse Events by System 
Organ Class and Preferred Term (Subjects & No. of Occurrences)
Summarize by PART 
Summarize by PART 
Summarize by PART 
Summarize by PART 
Summarize by PART
SAC
3.6
All Subjects
SAFE_T4
Summary of Adverse Events of Special Interest by System Organ Class 
and Preferred Term
Summarize by PART 
Summarize by PART
SAC
Serious and Other Significant Adverse Events
3.7
All Subjects
SAFE_T2
Summary of Fatal Serious Adverse Events by System Organ Class and 
Preferred Term
SAC
3.8
All Subjects
SAFE_T2
Summary of Drug-Related Fatal Serious Adverse Events by System 
Organ Class and Preferred Term 
SAC
 
 
 
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No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.9
All Subjects
SAFE_T2
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term
SAC
3.10
All Subjects
SAFE_T2
Summary of Drug-Related Serious Adverse Events by System Organ 
Class and Preferred Term
SAC
3.11
All Subjects
SAFE_T5
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and Occurrences)
SAC
3.12
All Subjects
SAFE_T1
Summary of Adverse Events Leading to Permanent Discontinuation of 
Study Treatment or Withdrawal from Study by System Organ Class and 
Preferred Term 
SAC
Peak expiratory flow rate
3.13
All Subjects
SAFE_T6
Summary of Peak Expiratory Flow Rate Measurements 
SAC
 
 
 
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10.9.8.
ICH Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
1.
Screened 
population
ES7
Listing of Reasons for Screen Failure
SAC
2.
All Subjects
ES3
Listing of Reasons for Study Withdrawal
Include escalation phase in 
treatment column
SAC
3.
All Subjects
BL2
Listing of Subjects for Whom the Treatment Blind was Broken
Include escalation phase in 
treatment column
SAC
4.
All Subjects
TA2
Listing of Planned and Actual Treatments
Include escalation phase in 
treatment column
SAC
5.
All Subjects
DV2A
Listing of Important Protocol Deviations
Include escalation phase in 
treatment column
Population flag columns are 
not required
SAC
6.
Enrolled 
population
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
SAC
7.
All Subjects
DM2
Listing of Demographic Characteristics
SAC
8.
All Subjects
DM9
Listing of Race
SAC
9.
All Subjects
SU2
Listing of Smoking History at Screening
Present only Smoking History
SAC
 
 
 
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56
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
10.
All Subjects
CM4
Listing of Concomitant Medications by Generic Term
Include escalation phase in 
treatment column
SAC
11.
All Subjects
EX4
Listing of Exposure to Study Treatment
1.Include escalation phase in 
treatment column 
2.Page by treatment
3.Add a total daily dose 
column
SAC
Adverse Events
12.
All Subjects
AE9
Listing of All Adverse Events
Include escalation phase in 
treatment column 
SAC
13.
All Subjects
AE9
Listing of Pre-Treatment Adverse Events
SAC
14.
All Subjects
AE9
Listing of Post-Treatment Adverse Events
SAC
15.
All Subjects
AE9
Listing of All Adverse Events of Special Interest
Include escalation phase in 
treatment column
SAC
16.
All Subjects
AE7
Listing of Subject Numbers for Individual Adverse Events
Include escalation phase in 
treatment column
SAC
17.
All Subjects
AE9
Listing of Fatal Serious Adverse Events
Include escalation phase in 
treatment column
SAC
18.
All Subjects
AE9
Listing of Non-Fatal Serious Adverse Events
Include escalation phase in 
treatment column
SAC
19.
All Subjects
AE9
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
Include escalation phase in 
treatment column
SAC
 
 
 
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No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory Parameters
20.
All Subjects
LB6
Listing of Hematology Data
PCI ranges will not be reported
SAC
21.
All Subjects
LB6
Listing of Clinical Chemistry Data
PCI ranges will not be reported
SAC
22.
All Subjects
EG4
Listing of ECG Values
PCI ranges will not be reported
SAC
23.
All Subjects
EG6
Listing of ECG Findings
PCI ranges will not be reported
SAC
24.
All Subjects
VS5
Listing of Vital Signs
SAC
 
 
 
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58
10.9.9.
Non-ICH Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Event
25.
All Subjects
AE2
Listings of Relationship between System Organ Class and Verbatim 
Text
SAC
26.
All Subjects
SAFE_L3
AE Terms of Special Interest
SAC
Peak expiratory flow rate
27.
All Subjects
SAFE_L1
Listing of Peak Expiratory Flow Rate Measurements 
SAC
28.
All Subjects
SAFE_L2
Listing of Lung Function Test Data
SAC
Efficacy
29.
PD
PD_L1
Listing of AMP PC20 Data 
SAC
30.
PD
PD_L2
Listing of Lung Function Test Data by Part (During AMP Challenge)
SAC
31.
PD
PD_L3
Listing of Percentage Change Between Highest Pre-Saline & Post 
Saline FEV1 Measurements 
SAC
32.
PD
PD_L4
Listing of Log Transformed Cortisol Suppression 0-24 Hours 
Weighted Mean (ng/mL)
SAC
33.
PD
Raw SAS Output from the Dose Response Analysis for Log 
Transformed AMP PC20 Data 
SAC
34.
PD
Raw SAS Output from the Statistical Analysis of AMP PC20 Placebo 
Data (ANOVA Model)
SAC
 
 
 
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No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
35.
PD
Raw SAS Output from the Dose Response Analysis for Log 
Transformed Cortisol suppression 0-24 hours weighted mean
SAC
Patient Profile 
36.
Enrolled
CVD_DEATH
Listing of All Cause Deaths
SAC
 
 
 
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10.10.
Appendix 10: Example Mock Shells for Data Displays
POP_T1
Protocol: 203162                                                                   
Page 1 of x   
Population: All subjects
Table 1.x
Summary of Subject Completion at Each Escalation Phase
Visit
All Subjects Population
(N=XXX)
PD Population
(N=XXX)
Period 1
Period 2
Period 1
Period 2
Number of Subjects 
entering each period
XX
XX
XX
XX
Escalation Phase 1
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Escalation Phase 2
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Escalation Phase 3
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Escalation Phase 4
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Escalation Phase 5
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Footnote: Percentages were calculated for each escalation phases based on the number of subjects entering the period.
 
 
 
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POP_T2
Protocol: 203162                                                                   
                Page 1 of x   
Population: All subjects
Table X
Summary of Exposure to Study Treatment
                               FF 50 mcg
(N=100)
FF 100 mcg
(N=100)
FF 200 mcg
(N=100)
FF 400 mcg
(N=100)
FF 800 mcg
(N=100)
Time on Study Treatment (days) [1]
n
  xx
  xx
  xx
  xx
  xx
Mean
  xx.x
  xx.x
  xx.x
  xx.x
  xx.x
SD
  xx.xx
  xx.xx
  xx.xx
  xx.xx
  xx.xx
Median
  xx.x
  xx.x
  xx.x
  xx.x
  xx.x
Min.
  xx
  xx
  Xx
  xx
  xx
Max.
  xx
  xx
  Xx
  xx
  xx
Subject Daily Dose (mg) [2]
n
  xx
  xx
  xx
  xx
  xx
Mean
  xx.x
  xx.x
  xx.x
  xx.x
  xx.x
SD
  xx.xx
  xx.xx
  xx.xx
  xx.xx
  xx.xx
Median
  xx.x
  xx.x
  xx.x
  xx.x
  xx.x
Min.
  xx
  xx
  Xx
  xx
  xx
Max.
  xx
  xx
  Xx
  xx
  xx
Cumulative Actual Dose (mg)
n
  xx
  xx
  Xx
  xx
  xx
Mean
  xx.x
  xx.x
  xx.x
  xx.x
  xx.x
SD
  xx.xx
  xx.xx
  xx.xx
  xx.xx
  xx.xx
Median
  xx.x
  xx.x
  xx.x
  xx.x
  xx.x
Min.
  xx
  xx
  Xx
  xx
  xx
Max.
  xx
  xx
  Xx
  xx
  xx
[1] The time on study drug does not include dose interruptions.
[2] the subject daily dose (the cumulative actual dose divided by the duration of exposure) is calculated for each subject first and summary statistics are calculated based on the subject 
average daily dose.
For dose escalation phases with twice-daily dosing (AM and PM) but only a single dose (PM) on the first day of the phase, that day is counted as only 0.5 days in the calculation of time 
on study treatment.
 
 
 
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Example PD_T1
Protocol: 203162                                                                          
   Page 1 of 1
Population: PD 
Table 2.x
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Treatment
N
n
Mean
95% CI 
      SE
Median
Min.
Max.
Placebo 
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x  
xxx.x
FF 25 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
FF 100 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
FF 200 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
FF 400 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
FF 800 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
FP 50 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
FP 200 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
FP 500 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
FP 1000 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
FP 2000 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
BUD 100 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
BUD 400 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
BUD 800 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
BUD 1600 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
BUD 3200 mcg
xx
xx
xx.xx   
(x.xx,  x.xx)
xx.xxx   
x.xx    
x.x   
xxx.x
Note: CI = Confidence Interval, SE = Standard Error, Min. = Minimum, Max. = Maximum.
Note: N = Number of subjects randomized to receive the treatment.
Note: n = number of patients entering each dose escalation phase.
Note: FF-Fluticasone Furoate, FP- Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_T2
Protocol: 203162                                                                           
  Page 1 of 1
Population: PD 
Table 2.x
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Treatment
N
n
Geo.
Mean
95% CI for
Geo. Mean
  CV%    
SD
Logs
Placebo 
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
FF 25 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
FF 100 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
FF 200 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
FF 400 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx   
FF 800 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
FP 50 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
FP 200 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
FP 500 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
FP 1000 mcg
xx
xx
x.xx    
(x.xx,  x.xx)
xxx.x
x.xxx    
FP 2000 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
BUD 100 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
BUD 400 mcg
xx
xx
x.xx     
(x.xx,  x.xx)
xxx.x
x.xxx    
BUD 800 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
BUD 1600 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
BUD 3200 mcg
xx
xx
x.xx  
(x.xx,  x.xx)
xxx.x
x.xxx    
Note: Covariance percentage (CV%) of geometric mean was calculated based the formula: CV%= Square root (exp(variance for log transformed data)-1)*100.
Note: Geo = Geometric, CI = Confidence Interval, CV = Coefficient of Variation, SD = Standard Deviation.
Note: N = Number of subjects randomized to receive the Particular treatment. 
Note: n = number of patients entering each dose escalation phase.
Note: FF-Fluticasone Furoate, FP- Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_T3
Protocol: 203162                                                                             
Page 1 of1
Population: PD 
Table 2.x
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Treatment
Adjusted 
Mean
SE
95% CI 
Placebo 1
xx.xx
xx.xxx
(xx.xx, xx.xx)
Placebo 2
xx.xx
xx.xxx
(xx.xx, xx.xx)
Placebo 3
xx.xx
xx.xxx
(xx.xx, xx.xx)
Placebo 4
xx.xx
xx.xxx
(xx.xx, xx.xx)
Placebo 5
xx.xx
xx.xxx
(xx.xx, xx.xx)
 
 
 
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65
Example PD_T4
Protocol: 203162                                                                
            Page 1 of 1
Population: PD 
Table 2.x
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
                                         
                             Predicted AMP PC20 Values (mg/mL)
                                                      Model Parameters
                 Dose                            Estimate                        95% CI                       Parameter [1]              Estimate            95% CI
              
                 FF 25 mcg
x.xx
            ( x.xx,  x.xx)
             E0
x.xx
( x.xx,  x.xx)
                  FF 100 mcg
x.xx
( x.xx,  x.xx)
Emax
x.xx
( x.xx,  x.xx)
                  FF 200 mcg
x.xx
( x.xx,  x.xx)
ED50
x.xx
( x.xx,  x.xx)
                 FF 400 mcg
x.xx
( x.xx,  x.xx)
                  FF 800 mcg
x.xx
( x.xx,  x.xx)
 
   FP 50 mcg
x.xx
( x.xx,  x.xx)
E0
x.xx
( x.xx,  x.xx)
                  FP 200 mcg
x.xx
( x.xx,  x.xx)
Emax
x.xx
( x.xx,  x.xx)
                 FP 500 mcg
x.xx
( x.xx,  x.xx)
ED50
x.xx
( x.xx,  x.xx)
                  FP 1000 mcg
x.xx
( x.xx,  x.xx)
                  FP 2000 mcg
x.xx
( x.xx,  x.xx)
 
   BUD 100 mcg
x.xx
( x.xx,  x.xx)
E0
x.xx
( x.xx,  x.xx)
                 BUD 400 mcg
x.xx
( x.xx,  x.xx)
Emax
x.xx
( x.xx,  x.xx)
                  BUD 800 mcg
x.xx
( x.xx,  x.xx)
ED50
x.xx
( x.xx,  x.xx)
                  BUD 1600 mcg
x.xx
       ( x.xx,  x.xx)
                 BUD 3200 mcg
x.xx
       ( x.xx,  x.xx)
  
             
Note: CI - Confidence Interval.
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_T5
Protocol: 203162                                                                          
   Page 1 of 1
Population: PD 
Table 2.x
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
                                           
                      Predicted Mean for Cortisol Suppression Values (ng/mL)
                               Model Parameters
                   Dose                                Estimate                          95% CI                         Parameter [1]               Estimate             95% CI
             
                  FF 25 mcg
x.xx
              ( x.xx,  x.xx)
             E0
x.xx
( x.xx,  x.xx)
                  FF 100 mcg
x.xx
( x.xx,  x.xx)
Emax
x.xx
( x.xx,  x.xx)
                  FF 200 mcg
x.xx
( x.xx,  x.xx)
ED50
x.xx
( x.xx, x.xx)
                  FF 400 mcg
x.xx
( x.xx,  x.xx)
                  FF 800 mcg
x.xx
( x.xx,  x.xx)
 
   FP 50 mcg
x.xx
( x.xx,  x.xx)
E0
x.xx
( x.xx,  x.xx)
                  FP 200 mcg
x.xx
( x.xx,  x.xx)
Emax
x.xx
( x.xx,  x.xx)
                  FP 500 mcg
x.xx
( x.xx,  x.xx)
ED50
x.xx
( x.xx,  x.xx)
                  FP 1000 mcg
x.xx
( x.xx,  x.xx)
                  FP 2000 mcg
x.xx
( x.xx,  x.xx)
 
   BUD 100 mcg
x.xx
( x.xx,  x.xx)
E0
x.xx
( x.xx,  x.xx)
                  BUD 400 mcg
x.xx
( x.xx,  x.xx)
Emax
x.xx
( x.xx,  x.xx)
                  BUD 800 mcg
x.xx
( x.xx,  x.xx)
ED50
x.xx
( x.xx,  x.xx)
                  BUD 1600 mcg
x.xx
       ( x.xx,  x.xx)
                  BUD 3200 mcg
x.xx
       ( x.xx,  x.xx)
  
             
Note: CI - Confidence Interval. 
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_T6
Protocol: 203162                                                                           
Page 1 of 1
Population: PD
Table 2.x
Summary of the Dose Response Analysis for ED20 Cortisol Suppression (ng/mL) /ED80 for AMP PC20 (mg/mL)
Treatment
Parameter
Estimate
FF
ED20 Cortisol Suppression
xx.x
ED80 for AMP
xx.x
ED20 / ED80
xx.x
FP
ED20 Cortisol Suppression
xx.x
ED80 for AMP
xx.x
ED20 / ED80
xx.x
BUD
ED20 Cortisol Suppression
xx.x
ED80 for AMP
xx.x
ED20 / ED80
xx.x
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
Example PD_T7
Protocol: 203162        
Page 1 of 1                                                                 
 
 
 
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Population: PD 
Table 2.x
Summary of Dose of FF and BUD that gives the same AMP PC20 (mg/mL) response as the FP doses administered
FP Dose (mcg)
Estimated mean AMP 
PC20 (mg/mL) values
Predicted 
corresponding FF 
Doses (mcg)
Predicted 
corresponding BUD 
Doses (mcg)
50 
xxx.xx
xx.xx 
xx.xx 
200 
xxx.xx
xx.xx 
xx.xx 
500 
xxx.xx
xx.xx 
xx.xx 
1000 
xxx.xx
xx.xx 
xx.xx 
2000 
xxx.xx
xx.xx 
xx.xx 
Note: The estimated AMP PC20 reported in Log 2 scale.
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_T8
Protocol: 203162   
Page 1 of 1                                                                        
Population: PD 
Table x.xx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Treatment Comparison
Estimate
95% Confidence Interval
FF 25 mcg vs. Placebo 
x.xx
(x.xx,x.xx)
FF 100 mcg vs. Placebo
x.xx
(x.xx,x.xx)
FF 200 mcg vs. Placebo
x.xx
(x.xx,x.xx)
FF 400 mcg vs. Placebo
x.xx
(x.xx,x.xx)
FF 800 mcg vs. Placebo
x.xx
(x.xx,x.xx)
FP 50 mcg vs. Placebo
x.xx
(x.xx,x.xx)
FP 200 mcg vs. Placebo
x.xx
(x.xx,x.xx)
FP 500 mcg vs. Placebo
x.xx
(x.xx,x.xx)
FP 1000 mcg vs. Placebo
x.xx
(x.xx,x.xx)
FP 2000 mcg vs. Placebo
x.xx
(x.xx,x.xx)
BUD 100 mcg vs. Placebo
x.xx
(x.xx,x.xx)
BUD 400 mcg vs. Placebo
x.xx
(x.xx,x.xx)
BUD 800 mcg vs. Placebo
x.xx
(x.xx,x.xx)
BUD 1600 mcg vs. Placebo
x.xx
(x.xx,x.xx)
BUD 3200 mcg vs. Placebo
x.xx
(x.xx,x.xx)
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide. 
 
 
 
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Example PD_T9
Protocol: 203162        
Page 1 of 1                                                                 
Population: PD 
Table 2.x
Summary of Dose of FF and BUD that gives the Same Cortisol Suppression (ng/mL)
as the FP Doses administered
FP Dose (mcg)
Estimated weighted 
mean of Cortisol 
Suppression (ng/mL) 
values
Predicted 
corresponding FF 
Doses (mcg)
Predicted 
corresponding BUD 
Doses (mcg)
50 
xxx.xx
xx.xx 
xx.xx 
200 
xxx.xx
xx.xx 
xx.xx 
500 
xxx.xx
xx.xx 
xx.xx 
1000 
xxx.xx
xx.xx 
xx.xx 
2000 
xxx.xx
xx.xx 
xx.xx 
Note: The estimated Cortisol suppression (ng/mL) reported in loge scale.
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_T10
Protocol: 203162                                                                           
Page 1 of 1
Population: PD
Table 2.x
Summary of the Dose Response Analysis for ED50 Cortisol Suppression (ng/mL) /ED50 for AMP PC20 (mg/mL)
Treatment
Parameter
Estimate
FF
ED50 Cortisol Suppression
xx.x
ED50 for AMP
xx.x
ED50 / ED50
xx.x
FP
ED50 Cortisol Suppression
xx.x
ED50 for AMP
xx.x
ED50 / ED50
xx.x
BUD
ED50 Cortisol Suppression
xx.x
ED50 for AMP
xx.x
ED50 / ED50
xx.x
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example: SAFE_T1
Protocol: 203162                                                                      
      Page 1 of x
Population: All Subjects
Table 3.x
Summary of On-Treatment Adverse Events by System Organ Class and Preferred Term
    System Organ Class
Placebo
FF 25 mcg
FF 100 mcg
FF 200mcg 
FF 400 mcg     
      Preferred Term
(N=6)
(N=6)
(N=6)
(N=6)
(N=24)    
    ANY EVENT
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%) 
    Infections and infestations
      Any event
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
      Abscess
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
      Gastroenteritis viral
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
      Herpes simplex
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
      Lower respiratory tract
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
      Infection
      Rhinitis
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
      Sinusitis
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
      Subcutaneous abscess
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
      Tooth infection
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example: SAFE_T2
Protocol: 203162                                                                          
   Page 1 of x
Population: All Subjects
Table 3.x
Summary of Common (>=3%) Adverse Events by Overall Frequency
    System Organ Class
Placebo
FF 25 
mcg
FF 100 mcg
FF 200mcg 
FF 400 mcg     
      Preferred Term
(N=6)
(N=6)
(N=6)
(N=6)
(N=24)    
    ANY EVENT
xx (xx%)
x (xx%)
xx (xx%)
x (xx%)
x (xx%) 
      Abscess
x (x%)
x (x%)
x (x%)
x (x%)
x (x%)     
      Gastroenteritis viral
x (x%)
x (x%)
x (x%)
x (x%)
x (x%)     
      Herpes simplex
x (x%)
x (x%)
x (x%)
x (x%)
x (x%)     
      Lower respiratory tract
x (x%)
x (x%)
x (x%)
x (x%)
x (x%)     
      Infection
      Rhinitis
x (x%)
x (x%)
x (x%)
x (x%)
x (x%)     
      Sinusitis
x (x%)
x (x%)
x (x%)
x (x%)
x (x%)     
      Subcutaneous abscess
x (x%)
x (x%)
x (x%)
x (x%)
x (x%)     
      Tooth infection
x (x%)
x (x%)
x (x%)
x (x%)
x (x%)     
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example: SAFE_T3
Protocol: 203162                                                                             Page 1 of x
Population: All Subjects
Table 3.x
Summary of Common Non-Serious Adverse Events by System Organ Class and Preferred Term 
(Subjects & No. of Occurrences)
System Organ Class
  Preferred Term
Placebo 
(N=6)
FF 25 mcg 
(N=6)
FF 100 mcg (N=6)
FF 200 mcg (N=6)
ANY EVENT             
Number of Subject with AEs
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
  
Number of AEs
xx 
xx 
xx 
xx 
Nervous system disorders
 Dizziness
Number of Subject with AEs
xx (xx%)
xx (xx%)
x (<x%)
xx (xx%)
Number of AEs
xx 
xx 
x 
xx 
 Dyskinesia
Number of Subject with AEs
x (x%)
x (x%)
xx (xx%)
x (x%)
Number of AEs
x 
x 
xx 
x 
 Somnolence
Number of Subject with AEs
x (x%)
x (x%)
x
x (x%)
Number of AEs
x 
x 
x 
x 
Gastrointestinal disorders
Nausea
Number of Subject with AEs
xx (xx%)
xx (xx%)
x (<x%)
xx (xx%)
Number of AEs
xx 
xx 
x 
xx 
 Constipation
Number of Subject with AEs
x (<x%)
x (<x%)
xx (x%)
x (<x%)
Number of AEs
x 
x 
xx 
x 
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example: SAFE_T4
Protocol: 203162                                                                           
  Page 1 of x
Population: All Subjects
Table 2.x
Summary of Adverse Events of Special Interest by System Organ Class and Preferred Term
   
Special Interest Group/Subgroup                           
    Sub-SMQ                                     Placebo      FF 25 mcg     FF 100 mcg   FF 200 mcg   
     Preferred Term                             (N=xx)        (N=xx)       (N=xx)       (N=xx)
  
  
   Adrenal suppression
        Any event                                x (xx%)       x (xx%)      x (xx%)     x (xx%)
        Adrenal insufficiency                    x (xx%)       x (xx%)      x (xx%)     x (xx%)
   Anticholinergic syndrome (SMQ)
        Any event                               xx (x%)       xx (x%)      x (xx%)     x (xx%)
        Dizziness                                x (x%)        x (x%)      x (xx%)     x (xx%)
        Dry mouth                                x (x%)        x (x%)      x (xx%)     x (xx%)
        Pyrexia                                  x (<x%)       x (x%)      x (xx%)     x (xx%)
        Tachycardia                              x (<x%)       x (x%)      x (xx%)     x (xx%)
        Dry eye                                  x                               
        Dysphagia                                x (<x%)       x (x%)      x (xx%)     x (xx%)
        Vision blurred                           x (<x%)       x (x%)      x (xx%)     x (xx%)
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example:SAFE_T5
Protocol: 203162                                                                             
Page 1 of x
Population: All Subjects
Table 3.x
Summary of Serious Adverse Events by System Organ Class and Preferred Term 
(Subjects & No. of Occurrences)
System Organ Class
  Preferred Term
Placebo
(N=6)
FF 25 mcg
(N=6)
FF 100 mcg 
(N=6)
FF 200 mcg 
(N=6)
ANY EVENT             
Number of Subject with SAEs
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
  
Number of SAEs
xx 
xx 
xx 
xx 
Number of Drug-related SAEs
xx 
xx 
xx 
xx
Number of Fatal SAEs
xx 
xx 
xx 
xx 
Number of Drug-related Fatal SAEs
x 
x 
x 
x 
Infections and 
infestations
 Diabetic Gangrene 
Number of Subject with SAEs
xx (xx%)
xx (xx%)
x (<x%)
x (<x%)
Number of SAEs
xx 
xx 
x 
x 
Number of Drug-related SAEs
x
x
x
x
Number of Fatal SAEs
x 
x 
x
x
Number of Drug-related Fatal SAEs
x 
x 
x 
x 
 Erysipelas
Number of Subject with SAEs
x (<x%)
x (<x%)
xx (x%)
xx (x%)
Number of SAEs
x 
x 
xx 
xx 
Number of Drug-related SAEs
x
x
x
x
Number of Fatal SAEs
x
x
x 
x 
Number of Drug-related Fatal SAEs
x 
x 
x 
x 
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example SAFE_T6
Protocol: 203162                                                                        
Page 1 of x
Population: All Subjects
Table 3.x
Summary of Peak Expiratory Flow Rate Measurements
Period/
Escalation Phase/
Dose
Time point
Placebo
(N=XX)
FF
(N=XX)
FP
(N=XX)
BUD
(N=XX)
Period 1/
Escalation Phase 1
Day 1 AM
n
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
(95% CI)
(xx.x,xx.x)
(xx.x,xx.x)
(xx.x,xx.x)
(xx.x,xx.x)
SD
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
Min, Max
xx, xx
xx, xx
xx, xx
xx, xx
Day 2 AM
n
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
(95% CI)
(xx.x,xx.x)
(xx.x,xx.x)
(xx.x,xx.x)
(xx.x,xx.x)
SD
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
Min, Max
xx, xx
xx, xx
xx, xx
xx, xx
…
…
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
Programming note: repeat for all time points
 
 
 
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Example PD_F1
Protocol: 203162                                                                          
Page 1 of x 
Population: PD
Figure 2.x
Plot of Individual AMP Dose Response Curves by Subject and Treatment
    
Subject= Treatment=FF
 
 
 
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Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_F2
Protocol: 203162                                                                         
Page 1 of x 
Population: PD
Figure 3.x
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
                      
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
Note: CI = Confidence Interval.
Programming note: Y-axis label = “Cortisol suppression”
 
 
 
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Example PD_F3
Protocol: 203162                                                                       
Page 1 of x 
Population: PD
Figure 3.x
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
Note: CI = Confidence Interval.
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_F4
Protocol: 203162                                                                          
Page 1 of x 
Population: PD
Figure 2.x
Plot of Individual Plasma Cortisol Suppression values by Subject and Treatment
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_L1
Protocol: 203162                                                                         
   Page 1 of x
Population: PD
Listing xx
Listing of AMP PC20(mg/mL)Data
      
Site Id./
Unique
                                                                                Time
Subject Id./
Period/Escalation 
phase/
                              Start
           Deviation
     PC20
Seq.
Visit
Treatment
Date Time
              (mins)[1]
                   (mg/mL)
SCREENING
xxxxxxxxx  xx:xx
               x.xx
A/B
Period 1/ Escalation 
phase1/Day 8
FF 25 mcg
xxxxxxxxx  xx:xx
x
x.xx
Period 1/ Escalation 
phase 2/Day 14
FF 100 mcg
xxxxxxxxx  xx:xx
x
x.xx
Period 1/ Escalation 
phase 3/Day 22
FF 200 mcg
xxxxxxxxx  xx:xx
x
x.xx
Period 1/ Escalation 
phase 4/Day 29
FF 400 mcg
xxxxxxxxx  xx:xx
x
x.xx
Period 1/ Escalation 
phase 5/Day 36
FF 800 mcg
xxxxxxxxx  xx:xx
               x.xx
Note: * Indicates imputed PC20 value as the FEV1 did not fall by 20% for any AMP concentration administered.
[1] Time Deviation is calculated as start time for AMP challenge at that visit minus start time for Screening AMP challenge. 
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_L2
Protocol: 203162                                                                         
   Page 1 of x
Population: PD
Listing xx
Listing of Lung Function Test Data (During AMP Challenge)
Planned
Highest
Site Id./
Unique
Relative
Actual
FEV1
FEV1
%Change
Subject ID/
Seq.
Period/ Escalation 
Phase/
Treatment/
Visit 
DateTIme      
AMP Conc.
(mg/mL)
Time
Time
(L)
[1]
[2]
Period 1/
Escalation Phase 1/
FF 100 mcg/
Day 1
xxxxxxxxx
DILUENT
60S
xx:xx
x.xx
x.xx
180S
xx:xx
x.xx
0.04
60S
xx:xx
x.xx
x.xx
x.xx
180S
xx:xx
x.xx
0.08
60S
xx:xx
x.xx
x.xx
x.xx
180S
xx:xx
x.xx
0.16
60S
xx:xx
x.xx
x.xx
x.xx
180S
xx:xx
x.xx
x.xx
60S
xx:xx
x.xx
x.xx
x.xx
180S
xx:xx
x.xx
320.00
60S
xx:xx
x.xx
x.xx
x.xx
180S
xx:xx
x.xx
[1] Highest FEV1 is maximum of FEV1 collected at 60s and 180 seconds.
[2] Percentage change is calculated by ((Highest FEV1 post saline – Highest DIUENT FEV1)/ Highest DIUENT FEV1) * 100.
 
 
 
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Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
Example PD_L3
Protocol: 203162                                                                         
  Page x of x
Population: PD
Listing 30
Listing of Percentage Change Between Highest Pre-Saline and Post Saline FEV1 Measurements
Site Id./
Unique
Highest
Subject Id./
Pre-saline
Post-saline
%
>10%
Seq.
Treatment
Period/
Escalation
Phase/
Visit
Date
FEV1 (L)
FEV1 (L)
Change
Fall?
SCREENING2
Screening
xxxxxxxxx
x.xx
x.xx
x.xx
FF 25 mcg
Period 1/ 
Escalation phase 
1/Day 8
xxxxxxxxx
x.xx
x.xx
x.xx
Yes    
A
FF 100 mcg
Period 1/ 
Escalation phase 
2/Day 14
xxxxxxxxx
x.xx
x.xx
x.xx
FF 200 mcg
Period 1/ 
Escalation phase 
3/Day 22
xxxxxxxxx
x.xx
x.xx
x.xx
FF 400 mcg
Period 1/ 
Escalation phase 
4/Day 29
xxxxxxxxx
x.xx
x.xx
x.xx
FF 800 mcg
Period 1/ 
Escalation phase 
5/Day 36
xxxxxxxxx
x.xx
x.xx
x.xx
                          
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example PD_L4
Protocol: 203162                                                                            Page 1 of n
Population: PD
Listing 31
Listing of Log-transformed Cortisol Suppression 0-24 Hours Weighted Mean (ng/mL)
      
        
       Site Id./
       Unique
Cortisol 0-24 Hours
       Subject Id./
Weighted
       Seq.
Period/ Escalation
Phase/
Visit
Date
Mean (mL)     
       
        
Screening
xxxxxxxxx
x.xx
        
Period 1/ Escalation 
phase 1/Day 8
xxxxxxxxx
x.xx
       B
Period 1/ Escalation 
phase 2/Day 14
xxxxxxxxx
x.xx
Period 1/ Escalation 
phase 3/Day 22
xxxxxxxxx
x.xx
Period 1/ Escalation 
phase 4/Day 29
xxxxxxxxx
x.xx                   
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example SAFE_L1
Protocol: 203162                                                                         
Page 1 of x 
Population: All Subjects
Listing xx
Listing of Peak Expiratory Flow Rate Measurements 
Site Id./
Unique Subject Id./
Seq.
Age
(Years)/
Sex/
Race Detail
Visit/   
Period/Escalatio
n Phase
Planned Time
DateTime
Study Day
Peak Expiratory 
Flow Rate
L/min.
B
57/
M/
ASIAN -
JAPANESE 
HERITAGE
Screening1
XXXXXXXXXTXX:XX
X
  xx
Day 1/
Period 1/ 
Escalation 
Phase 1
PM dose
XXXXXXXXXTXX:XX
X
  xx
Day 2/
Period 1/ 
Escalation 
Phase 1
AM dose
PM dose
XXXXXXXXXTXX:XX
XXXXXXXXXTXX:XX
X
                 x
xx
xx
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example :SAFE_L2
Protocol: 203162                                                                          
  Page 1 of n
Population: PD
Listing xx
Listing of Lung Function Test Data
Site Id./
Unique 
Subject Id./
Seq.
  
Period/
Visit
Planned 
Time
DateTime
Study Day
FEV1 (L)  
% Predicted
FEV1 
FVC (L)  
B
Screening1
SCREENING
XXXXXXXXXTXX:XX
     XX
X.XX
XX.XX
X.XX
Day 1/
Period 1
PRE-DOSE  
XXXXXXXXXTXX:XX
    XX
X.XX
XX.XX
X.XX
Note: FF-Fluticasone Furoate, FP-Fluticasone Propionate, BUD-Budesonide.
 
 
 
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Example: SAFE_L3
Protocol: 203162
Page 1 of n
Population: All subjects
Listing xx
AE Terms of Special Interest
Special Interest Term
Subgroup
Preferred Term
xxxxx xxxxx xxxxxx
Xxxxxxx
Xxxxxxx
xxxxxxx xxxxxxx
Xxxx
xxxxxxx xxx
xxxxxxx xxxxxxxxxx
Xxxxxxxxxxxxxxx
xxxxxxx xxxxxx
xxxxxxx xxxx xxxxx
Xxxx
Xxxxxxxxxxx
Xxxxxxx
Xxxxxxx
xxxx xxxxxx xxxxxxx
xxxxxx xxxxxxx
Xxxxxxxxx
xxxxx xxxxxx xxxxxxx xxxxxx
Note: All the pre-specified preferred terms that were assigned to special interest terms are shown, regardless of whether they occurred in the study.
 
 
 
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