A Randomised, Double-blind, Parallel Group, Multicentre, Stratified, Study Evaluating the Efficacy and Safety of Once Daily Fluticasone Furoate/Vilanterol Inhalation Powder Compared to Once Daily Fluticasone Furoate Inhalation Powder in the Treatment of Asthma in Participants Aged 5 to 17 Years Old (Inclusive) Currently Uncontrolled on Inhaled Corticosteroids
Phase: PHASE3
Conditions: Asthma
Sponsor: GlaxoSmithKline

 
 
 
 
Protocol 
 
Study ID: 107116 
 
Official Title of Study: A randomised, double-blind, parallel group, multicentre, stratified, study 
evaluating the efficacy and safety of once daily fluticasone furoate/vilanterol inhalation powder 
compared to once daily fluticasone furoate inhalation powder in the treatment of asthma in 
participants aged 5 to 17 years old (inclusive) currently uncontrolled on inhaled corticosteroids 
 
EudraCT Identifier: 2016-004086-87 
 
IND Identifier: 077855   
 
Approval Date of Document: 24-AUG-2020 
 
 

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GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: A randomised, double-blind, parallel group, multicentre, stratified, study 
evaluating the efficacy and safety of once daily fluticasone furoate/vilanterol inhalation 
powder compared to once daily fluticasone furoate inhalation powder in the treatment of 
asthma in participants aged 5 to 17 years old (inclusive) currently uncontrolled on inhaled 
corticosteroids
Protocol Number: HZA107116/04
Short Title: A double-blind, parallel group study to evaluate the safety and efficacy of 
fluticasone furoate/vilanterol combination compared to fluticasone furoate in the 
treatment of asthma in participants (aged 5 to 17 years old inclusive)
Compound 
Number:
GW685698+GW642444
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information:  
, MD.  Details 
provided in SRM.
Regulatory Agency Identifying Number(s): IND No: 077855; EudraCT No: 2016-
004086-87
Approval Date: 24-AUG-2020
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

PPD
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 04
24-AUG-2020
Amendment 03
31-JAN-2020
Amendment 02
10-DEC-2019
This amendment was not implemented at clinical 
sites. 
Amendment 01
19-JUN-2019
This amendment was not implemented at clinical 
sites. 
Original Protocol
22-JUN-2017
Amendment 04: 24-AUG-2020
Overall Rationale for the Amendment: The main purpose of this amendment is to 
allow the option for certain visits to either be conducted at home by a qualified nurse or 
replaced by video-calls with the site, when appropriate and if permitted by local 
regulations. The screening, randomisation and Visit 6 (serial spirometry) will continue to 
be done in the clinic.  
Challenges resulting from the COVID-19 pandemic have the potential to impact the 
conduct and delivery of the study due to quarantines, site closures and travel limitations.  
The addition of these flexible visit options will address some of the challenges faced by 
sites impacted by the pandemic and aid study recruitment and retention by easing the 
burden on site staff, subjects and parents. 
This amendment also includes other minor edits including clarifications to some of the 
Inclusion/ Exclusion criteria and details for detecting and reporting device deficiencies 
have been added to Section 11.2.8 and Appendix 7. 
Appendix 9 provides details of home nursing and video-calling options are outlined in 
detail in Appendix 9 (COVID-19 Measures) and the table below summarises the changes 
made in this amendment. 

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Section # and Name
Description of Change
Brief Rationale
Protocol Amendment 
and Summary of 
Changes Table 
Document History updated to include 
Amendment 4.
Minor edits made to the document 
history table.
The rationale for amendment 3 
replaced by the rationale for 
Amendment 4
The table of changes for amendment 3 
moved to this Section (Appendix 10)
Updated to include 
Amendment 4
Table 1: Schedule of 
Activities 
A row added to the table to indicate 
type of visit e.g. clinic only, home or 
clinic, video-call or clinic etc 
Footnote 1 updated to clarify the run-in 
period for subjects that are re-screened 
and revise the screening window. 
Footnote 2 updated to include options 
of a video-call at Visit 5 and 7 and 
home visit (if spirometry is done) at 
Visits. Reference to direct to patient 
shipment of IP has been included. 
Footnote 12 corrected so that it applies 
to the current visit options available.
Footnote 15 added to clarify that the 
subject should be rescheduled, at the 
earliest opportunity, to collect serial 
spirometry, if it can not be done at the 
visit for any reason.  
Footnote 16 added to refer to the 
option of direct to patient shipment of 
IP that may be available to participants 
who will not be attending the clinic.
This Section has been 
updated to clarifying existing 
information and include the 
options of home visits and 
video-calls. 
Figure 1: Study 
Schematic
Text below the schematic updated to 
reflect the home nursing and 
telemedicine (video-calling options)
Updated to reflect the 
additional options of home 
visits and video-calling. 

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Section # and Name
Description of Change
Brief Rationale
Section 5.1 Overall 
Study Design
Text added to clarify that the run-in 
period is 4 weeks from screening and 
remains 4 weeks, if the spirometry is 
re-tested.
Text updated to include the home visit 
and telemedicine options. 
Text has been updated to 
added clarity with regards to 
the run-in period and to 
reflect additional options of 
home visits and video-
calling.
Section 8.1: Inclusion 
Criteria 
The note relating to criteria 3, updated 
for additional clarity 
Criteria 6 updated to include SAMA in 
the definition of stable asthma therapy 
Criteria 7 updated to include SAMA 
Some countries use SAMA 
instead of SABA as part of 
their stable asthma therapy 
regime.
Section 8.2: Exclusion 
Criteria
The unit measurement for fasting 
corrected for the fasting blood glucose 
in criteria 5 
Correction of typographical 
error
Section 8.3: Screen 
Failures 
Clarifying the timing of re-screens 
following a run-in or screen failure 
Updated for clarification 
Section 11.1.1: FEV1 
Section updated and added to reflect 
the home visit options. 
Updated to reflect the 
additional options of home 
visits
Section 11.1.1.1: 
Serial FEV1
Text added to clarify that the subject 
should be rescheduled, at the earliest 
opportunity, to collect serial spirometry, 
if it cannot be done at the visit for any 
reason.  
Updated for clarification 
Section 11.2.8: 
Medical Device 
Deficiencies 
Section added.  
To fulfil regulatory reporting 
obligations worldwide, this 
Section outlines the PI’s
responsibilities for the 
detection and documentation 
of events meeting the 
definitions of device 
deficiency that occur during 
the study. 
Appendix 1: 
Abbreviations and 
Trademarks
CRO added to the list of abbreviations 
and RELVAR added to the trademarks 
table. 
Updated to include an 
abbreviation and trademark 
product used in Appendix 9
Appendix 7: AEs, 
ADEs, SAEs, SADEs, 
Appendix added.
Definition and Procedures 
for Recording, Evaluating, 

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Section # and Name
Description of Change
Brief Rationale
USADEs and Device 
Deficiencies: 
Definition and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting in Medical 
Device Studies
Follow-up, and Reporting in 
AEs, ADEs, SAEs, SADEs, 
USADEs and Device 
Deficiencies in medical 
device studies added.
Appendix 9: COVID-
19 Measures
Appendix added.
This Appendix has been 
added to outline the changes 
that have been made in 
response to the COVID-19 
pandemic
Appendix 10: Protocol 
Amendment History 
This Section has been updated to 
include the changes made in 
Amendment 4
The Overall Rationale for Amendment 
3 (including the table with the 
description and rationale for the 
changes) moved from the Protocol 
Amendment and Summary of Changes 
Table at the front of the protocol to this 
Section (Appendix 8)
Changes made to Section 7.7.1 in 
Amendment 3 have been added to the 
table with the description and rationale 
in this Section (Appendix 10)
This Section includes 
changes made in 
amendment 4 
Details of amendment 3 
moved to this Section 
(Appendix 8) to maintain 
consistency in where 
changes to the protocol are 
being recorded 
In Amendment 3, changes 
made to Section 7.7.1 
inadvertently excluded from 
the table of changes has 
been added

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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................13
3.
INTRODUCTION....................................................................................................20
3.1.
Study Rationale ..........................................................................................20
3.2.
Background ................................................................................................20
3.3.
Benefit/Risk Assessment ............................................................................21
3.3.1.
Risk Assessment FF and FF/VI ...................................................21
3.3.2.
Benefit Assessment.....................................................................26
3.3.3.
Overall Benefit:Risk Conclusion...................................................26
4.
OBJECTIVES AND ENDPOINTS...........................................................................27
5.
STUDY DESIGN ....................................................................................................28
5.1.
Overall Design ............................................................................................28
6.
NUMBER OF PARTICIPANTS...............................................................................30
7.
PARTICIPANT AND STUDY COMPLETION..........................................................30
7.1.
Scientific Rationale for Study Design ..........................................................30
7.2.
Dose Justification........................................................................................31
8.
STUDY POPULATION...........................................................................................31
8.1.
Inclusion Criteria.........................................................................................31
8.2.
Exclusion Criteria........................................................................................33
8.3.
Screen Failures...........................................................................................35
8.4.
Randomisation Criteria ...............................................................................35
8.4.1.
Inclusion Criteria for Randomisation to Treatment .......................35
8.4.2.
Exclusion Criteria for Randomisation to Treatment ......................36
9.
TREATMENTS.......................................................................................................36
9.1.
Treatments Administered............................................................................36
9.1.1.
Medical Devices...........................................................................37
9.2.
Dose Modification .......................................................................................37
9.3.
Method of Treatment Assignment ...............................................................38
9.4.
Blinding.......................................................................................................38
9.5.
Preparation/Handling/Storage/Accountability..............................................38
9.6.
Treatment Compliance................................................................................39
9.7.
Concomitant Therapy..................................................................................39
9.7.1.
Prohibited Medications and Non-Drug Therapies.........................40
9.8.
Treatment after the End of the Study ..........................................................41
10. DISCONTINUATION CRITERIA.............................................................................41
10.1.
Discontinuation of Study Treatment ............................................................41
10.1.1.
Liver Chemistry Stopping Criteria ................................................42
10.1.2.
QTc Stopping Criteria ..................................................................44

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10.2.
Withdrawal from the Study..........................................................................45
10.3.
Lost to Follow Up........................................................................................45
11. STUDY ASSESSMENTS AND PROCEDURES .....................................................46
11.1.
Efficacy Assessments.................................................................................46
11.1.1.
FEV1 ............................................................................................46
11.1.1.1.
Serial FEV1.................................................................47
11.1.1.2.
Reversibility................................................................47
11.1.2.
Electronic Daily Diaries................................................................48
11.1.2.1.
Daily PEF ...................................................................48
11.1.2.2.
Asthma Symptom Scores ...........................................48
11.1.3.
Questionnaires ............................................................................49
11.1.3.1.
Childhood Asthma Control Test and Asthma 
Control Test................................................................49
11.1.3.2.
Asthma Control Questionnaire ACQ-5........................50
11.1.4.
Asthma exacerbation ...................................................................50
11.2.
Adverse Events...........................................................................................50
11.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................50
11.2.2.
Method of Detecting AEs and SAEs.............................................51
11.2.3.
Follow-up of AEs and SAEs.........................................................51
11.2.4.
Regulatory Reporting Requirements for SAEs .............................51
11.2.5.
Death Events...............................................................................52
11.2.6.
Pregnancy ...................................................................................52
11.2.7.
Treatment of Overdose................................................................52
11.2.8.
Medical Device Deficiencies ........................................................53
11.2.8.1.
Time Period for Detecting Medical Device 
Deficiencies................................................................53
11.2.8.2.
Follow-up of Medical Device Deficiencies...................53
11.2.8.3.
Prompt Reporting of Medical Device 
Deficiencies to Sponsor..............................................53
11.2.8.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................54
11.3.
Safety Assessments ...................................................................................54
11.3.1.
Physical Examination...................................................................54
11.3.2.
Oropharyngeal Examination.........................................................54
11.3.3.
Vital Signs....................................................................................54
11.3.4.
Electrocardiograms......................................................................55
11.3.5.
Clinical Safety Laboratory Assessments ......................................55
11.4.
Pharmacokinetics .......................................................................................55
11.5.
Pharmacodynamics ....................................................................................55
11.6.
Genetics .....................................................................................................55
11.7.
Biomarkers .................................................................................................56
11.8.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................56
12. STATISTICAL CONSIDERATIONS........................................................................56
12.1.
Sample Size Determination ........................................................................56
12.1.1.
Sample Size Assumptions ...........................................................56
12.1.1.1.
Sample Size Assumptions for 5-17 Years Old 
Population ..................................................................56

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12.1.1.2.
Sample Size Assumptions for 5-11 Years Old 
Population ..................................................................56
12.1.2.
Sample Size Sensitivity................................................................57
12.1.3.
Sample Size Re-estimation..........................................................58
12.2.
Populations for Analyses ............................................................................58
12.3.
Statistical Analyses.....................................................................................58
12.3.1.
Hypotheses..................................................................................58
12.3.2.
Treatment Comparisons ..............................................................60
12.3.2.1.
Primary Comparison of Interest ..................................60
12.3.2.2.
Other Comparisons of Interest....................................60
12.3.3.
Key Elements of Analysis Plan ....................................................61
12.3.3.1.
Primary Efficacy Analyses ..........................................62
12.3.3.1.1.
Primary Efficacy Analyses for 5-17 
Years Old Population..............................62
12.3.3.1.2.
Primary Efficacy Analyses for 5-11 
Years Old Population..............................62
12.3.3.2.
Secondary Efficacy Analyses .....................................63
12.3.3.3.
Other Analyses...........................................................65
12.3.4.
Interim Analyses ..........................................................................65
13. REFERENCES.......................................................................................................66
14. APPENDICES........................................................................................................68
14.1.
Appendix 1: Abbreviations and Trademarks................................................68
14.2.
Appendix 2: Study Governance Considerations..........................................70
14.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................74
14.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................80
14.5.
Appendix 5: Genetics..................................................................................83
14.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................84
14.7.
Appendix 7: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting in Medical Device Studies ..................................88
14.7.1.
Definition of Medical Device AE and ADE....................................88
14.7.2.
Definition of Medical Device SAE, SADE and USADE .................88
14.7.3.
Definition of Device Deficiency.....................................................89
14.7.4.
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies .................................................................................89
14.7.5.
Reporting of SAEs .......................................................................91
14.7.6.
Reporting of SADEs.....................................................................92
14.8.
Appendix 8: Country-specific requirements.................................................93
14.9.
Appendix 9: COVID-19 Measures...............................................................94
14.10. Appendix 10: Protocol Amendment History.................................................98

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1.
SYNOPSIS
Protocol Title: A randomised, double-blind, parallel group, multicentre, stratified, study 
evaluating the efficacy and safety of once daily fluticasone furoate/vilanterol inhalation 
powder compared to once daily fluticasone furoate inhalation powder in the treatment of 
asthma in participants aged 5 to 17 years old inclusive currently uncontrolled on inhaled 
corticosteroids
Short Title: A double-blind, parallel group study to evaluate the efficacy and safety of 
fluticasone furoate/vilanterol combination compared to fluticasone furoate in the 
treatment of asthma in participants (aged 5 to 17 years old inclusive)
Rationale:
A variety of asthma medications, generally targeting the inflammatory and/or obstructive 
components of the disease, may be selected for the treatment of asthma.  The 
evidence-based asthma treatment guidelines recommend a stepwise approach to treat 
asthma where medications are increased or decreased when appropriate to gain and 
maintain disease control.  For patients with persistent asthma symptoms, the preferred 
initiating controller medication (step 2 in the step-wise treatment paradigm) is low-dose 
inhaled corticosteroid (ICS) to target the inflammatory process in asthmatic airways.  For 
children ≥5 years of age and adolescents on low-dose ICS whose asthma is uncontrolled, 
low-dose ICS plus adjunctive therapy (e.g. long-acting beta agonist [LABA], leukotriene 
receptor antagonist [LTRA], theophylline) or monotherapy with medium-dose ICS, may 
all be considered as step 3 care. Due to the lack of comparative data for children ages 5 to 
11 years, the step 3 care options are considered equivalent. This study will evaluate the 
efficacy and safety of fluticasone furoate/vilanterol (FF/VI) compared to fluticasone 
furoate (FF) in the treatment of asthma in children aged 5 to 17 years old inclusive.
FF/VI has not been approved in the US in the adolescent population (12 to 17 years olds) 
and as a result, a cohort of adolescents is included in this study to further assess efficacy
and safety in this population.
Objectives and Endpoints:
Objective
Endpoint
Primary
Common to both 5-11 and 
5-17 years population

To compare the efficacy 
of once daily fluticasone 
FF/VI with once daily FF 
in participants with 
asthma.
The primary estimand is 
that of treatment policy 
Primary endpoint for  5-11 
years population

Change from baseline, 
averaged over weeks 1-
12 of the treatment 
period, in pre-dose (i.e. 
trough) morning peak 
expiratory flow (PEF), 
captured daily via 
electronic patient diary 
Primary endpoint for 5-17 
years population

Weighted mean FEV1
(0-4 hours) at week 12.
This is the primary 
endpoint for the 5-17y 
population [required by 
FDA]. This is a 
secondary endpoint for 

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Objective
Endpoint
(effectiveness-type 
estimand). The 
secondary efficacy-type 
estimand will be defined 
for the primary and 
powered secondary 
endpoints.
This is the primary 
endpoint for the 5-11y 
population [required by 
EMA]. This is a 
secondary endpoint for 
the 5-17 years 
population.   
the 5-11 years 
population.
Secondary endpoints common to both 5-11 and 5-17 years 
population:

Change from baseline in the percentage of rescue-free 24-
hour periods over weeks 1-12 of the treatment period 
(powered secondary endpoint for 5-11 years population) 
captured daily via electronic patient diary.

Change from baseline in the percentage of symptom-free 
24-hour periods over weeks 1-12 of the treatment period, 
captured daily via electronic patient diary.

Change from baseline in morning (AM) forced expiratory 
flow in 1 second (FEV1) in participants who can perform the 
manoeuvre at week 12.

Change from baseline in Asthma Control Questionnaire 
(ACQ-5) at week 24.

Incidence of exacerbations over the 24 week treatment 
period.
Other endpoints common to both 5-11 and 5-17 years 
population:

Change from baseline, averaged over weeks 1-12 of the 
treatment period in evening (PM) PEF, captured daily via 
electronic patient diary.
Secondary
Common to both 5-11 and 
5-17 years population

To assess the safety of 
FF/VI in participants with 
asthma 

Incidence of adverse events (AEs).

Evaluation of electrocardiogram (ECG) at screening and end 
of treatment.

Evaluation of fasting blood glucose pre- and post-treatment.

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Overall Design:
This is a randomised, double-blind, parallel group, multicentre, stratified, study designed 
to evaluate the efficacy and safety of once daily FF/VI inhalation powder compared to
once daily FF inhalation powder in the treatment of asthma in participants aged 5 to 17
years inclusive currently uncontrolled on inhaled corticosteroids.  The study will be 
conducted over approximately 29 weeks.
Number of Participants:
Approximately 2900 participants will be screened to achieve a total of 870 randomised
participants aged 5 to 17 years old inclusive.  Of this, 652 participants will be aged 5 to 
11 years (and at least 163 (25%) must be aged 5 to less than 8 years), and 218 
participants will be aged 12 to 17 years inclusive.
Treatment Groups and Duration:
After completing a 4-week open-label run-in period (during which all subjects will 
receive fluticasone propionate (FP) 100 mcg twice daily), eligible subjects, who meet
inclusion criteria for randomisation will be stratified by their age at the screening visit (5 
to 11 and 12 to 17) and randomised into a 24 week double-blind treatment period 
followed by a 1 week follow-up period.
Subjects aged 5-11 years of age will be randomised in a 1:1 ratio to one of the following 
two treatments:

FF 50 mcg once daily

FF/VI 50/25 mcg once daily 
Subjects aged 12-17 years of age inclusive will be randomised in a 1:1 ratio to one of the 
following two treatments:

FF 100 mcg once daily

FF/VI 100/25 mcg once daily

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2.
SCHEDULE OF ACTIVITIES (SOA)
The schedule of activities (SOA) in Table 1 details timing of procedures / assessments to 
be performed in this study.
The timing and number of planned study assessments may be altered during the course of 
the study based on newly available data to ensure appropriate monitoring. 
Any changes in the timing or addition of time points for any planned study assessments 
must be documented and approved by the relevant study team member and then archived 
in the sponsor and site study files, but will not constitute a protocol amendment.  The 
institutional review board (IRB)/independent ethics committee (IEC) will be informed of 
any safety issues that require alteration of the safety monitoring scheme or amendment of 
the informed consent form (ICF).

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Table 1
Schedule of Activities
Procedure
Screening
Pre-
randomisation
Randomisation
Treatment Period (Days, Weeks)
ETD
EW
FU TC
(7 days 
post-last 
visit)
Visit
V11
-4 to Day 
0
V2
V3
V4
V5
V615
V7
V8
V9
V10
Week
0
4
82
12
162
203
24
25
Day
(All visits except V2 
to occur within -5 to 
+2 days of specified 
day)
-28
-5 (-2 to +2)
0
28
56
84
112
140
168
175
Type of Visit
Clinic 
only
Home or 
Clinic
Clinic only
Home 
or 
Clinic
Home2, 
Video-
call or 
Clinic
Clinic 
only
Video-
call or 
clinic
Video-
call, 
Phone-
call or 
clinic
Home 
or 
Clinic
Home 
or 
Clinic
Home 
or 
Clinic
Video-call, 
Phone-call 
Informed consent and 
assent
X
Pharmacogenetics 
consent and assent
===========================
Inclusion and 
exclusion criteria
X13
Randomisation criteria
X
Demography
X
Medical history
X
Asthma history
X
Exacerbation history
X

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Procedure
Screening
Pre-
randomisation
Randomisation
Treatment Period (Days, Weeks)
ETD
EW
FU TC
(7 days 
post-last 
visit)
Visit
V11
-4 to Day 
0
V2
V3
V4
V5
V615
V7
V8
V9
V10
Week
0
4
82
12
162
203
24
25
Day
(All visits except V2 
to occur within -5 to 
+2 days of specified 
day)
-28
-5 (-2 to +2)
0
28
56
84
112
140
168
175
Type of Visit
Clinic 
only
Home or 
Clinic
Clinic only
Home 
or 
Clinic
Home2, 
Video-
call or 
Clinic
Clinic 
only
Video-
call or 
clinic
Video-
call, 
Phone-
call or 
clinic
Home 
or 
Clinic
Home 
or 
Clinic
Home 
or 
Clinic
Video-call, 
Phone-call 
Full physical exam 
including, height and 
weight
X
EFFICACY ASSESSMENTS
Electronic patient diary 
4
==================================
X
X
FEV1
X
X
X
X2
X
X
X5
FEV1 review of the 
overread only
X
Serial FEV1
X
Lung function (FEV1) 
reversibility testing6
X
cACT/ACT
X
X
ACQ
X
X
X

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Procedure
Screening
Pre-
randomisation
Randomisation
Treatment Period (Days, Weeks)
ETD
EW
FU TC
(7 days 
post-last 
visit)
Visit
V11
-4 to Day 
0
V2
V3
V4
V5
V615
V7
V8
V9
V10
Week
0
4
82
12
162
203
24
25
Day
(All visits except V2 
to occur within -5 to 
+2 days of specified 
day)
-28
-5 (-2 to +2)
0
28
56
84
112
140
168
175
Type of Visit
Clinic 
only
Home or 
Clinic
Clinic only
Home 
or 
Clinic
Home2, 
Video-
call or 
Clinic
Clinic 
only
Video-
call or 
clinic
Video-
call, 
Phone-
call or 
clinic
Home 
or 
Clinic
Home 
or 
Clinic
Home 
or 
Clinic
Video-call, 
Phone-call 
SAFETY ASSESSMENTS
Oropharyngeal 
examination
X
X
X
X
X7
Concomitant 
medication review2
X
========================
X
X
X
12-lead ECG14
X
X
X
X8
Vital signs
X
AE review2
========================
X
X
X
SAE review2
X
========================
X
X
X
Exacerbation review2
========================
X
X
X
LABORATORY ASSESSMENTS
Blood draw for fasting 
glucose9
X
X
X
X10
Pregnancy Test
X
X
X
X

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Procedure
Screening
Pre-
randomisation
Randomisation
Treatment Period (Days, Weeks)
ETD
EW
FU TC
(7 days 
post-last 
visit)
Visit
V11
-4 to Day 
0
V2
V3
V4
V5
V615
V7
V8
V9
V10
Week
0
4
82
12
162
203
24
25
Day
(All visits except V2 
to occur within -5 to 
+2 days of specified 
day)
-28
-5 (-2 to +2)
0
28
56
84
112
140
168
175
Type of Visit
Clinic 
only
Home or 
Clinic
Clinic only
Home 
or 
Clinic
Home2, 
Video-
call or 
Clinic
Clinic 
only
Video-
call or 
clinic
Video-
call, 
Phone-
call or 
clinic
Home 
or 
Clinic
Home 
or 
Clinic
Home 
or 
Clinic
Video-call, 
Phone-call 
Pharmacogenetic 
sample (saliva)11
X
STUDY TREATMENT
Dispense standardised 
FP run-in medication
X
Return FP run-in 
medication 
X
Dispense SABA 
rescue inhaler
X
Return SABA rescue 
inhaler
X
X

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Procedure
Screening
Pre-
randomisation
Randomisation
Treatment Period (Days, Weeks)
ETD
EW
FU TC
(7 days 
post-last 
visit)
Visit
V11
-4 to Day 
0
V2
V3
V4
V5
V615
V7
V8
V9
V10
Week
0
4
82
12
162
203
24
25
Day
(All visits except V2 
to occur within -5 to 
+2 days of specified 
day)
-28
-5 (-2 to +2)
0
28
56
84
112
140
168
175
Type of Visit
Clinic 
only
Home or 
Clinic
Clinic only
Home 
or 
Clinic
Home2, 
Video-
call or 
Clinic
Clinic 
only
Video-
call or 
clinic
Video-
call, 
Phone-
call or 
clinic
Home 
or 
Clinic
Home 
or 
Clinic
Home 
or 
Clinic
Video-call, 
Phone-call 
Treatment assignment 
(randomisation) via 
IVRS
X
Dispense double-blind 
study treatment via 
IVRS/IWRS16
X
X
X
X
X12
X
Return double-blind 
study treatment
X
X
X
X
X
X
X
X
Abbreviations: AE=adverse event; ACT=Asthma control test; cACT=Childhood asthma control test; ACQ=Asthma Control Questionnaire; ECG=electrocardiogram; ETD=early 
treatment discontinuation; EW=early withdrawal; FEV1=forced expiratory volume in 1 second; FP=fluticasone propionate; FU=follow-up; IVRS=interactive Voice Response 
System/Interactive Web Response System; SABA= short-acting beta agonist; SAE=serious adverse event; TC=telephone call; V=Visit.
1.
Prior to any study activities at Visit 1, including fasting for the blood glucose test, written informed consent should be obtained from at least one 1 parent/care giver (legal guardian) 
and accompanying informed assent from the participant (where the participant is able to provide assent).
Participants who are unable to perform the pre-bronchodilator FEV1 manoeuvre for any reason or  do not provide at least 2 acceptable pre or post bronchodilator measurements
[not necessarily repeatable] at Visit 1 can, at the discretion of the investigator, attend the clinic once more after Visit 1 to attempt to perform the pre-bronchodilator and post-

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bronchodilator FEV1 manoeuvres. This should be within 14 days of Visit 1. The 4 week run-in will start after eligibility is confirmed following the spirometry re-test. The window for 
Screening in this case will start at the re-test. 
2.
Week 8 (Visit 5) and Week 16 (Visit 7) can be parent only visit or video-calls.  For these visits, parents may need to come to the site to collect and return any study medication if 
direct to patient IP shipment is not available for any reason..  Parents should bring the diary to allow for review of concomitant medications, AEs, SAEs and exacerbations.    Note:  
If the participant does attend Visit 5 with the parent (or has a home-visit) and the visit occurs during the morning (6.00am to 11.00am) then the spirometry measure should be
performed.  If only the parent attends the clinic, then the visit can be at any time of day.     
3.
Week 20 (Visit 8) can be a telephone call if there are no problems with compliance.
4.
Asthma symptom scores, peak expiratory flow (PEF), rescue albuterol/salbutamol usage will be recorded on the electronic patient diary.  To be completed every day in the 
morning and evening from Visit 1 through to Visit 6 only.  
5.
FEV1 is not required at the Early Withdrawal Visit or Early Treatment Discontinuation Visit if these visits occurred after Visit 6.
6.
Following administration of 2 to 4 inhalations of albuterol/salbutamol.  Reversibility testing includes a baseline spirometry and repeat spirometry within 15 to 40 minutes after 
inhalation of 400 µg of salbutamol/albuterol.  The reversibility test will be considered positive if participants show improvement of FEV1 ≥12% after administration of 
salbutamol/albuterol.
7.
Oropharygneal examination is not required at the Early Withdrawal Visit if examination was performed at Early Treatment Discontinuation Visit.
8.
A 12-lead ECG is not required at the Early Withdrawal Visit if it was measured at the Early Treatment Discontinuation Visit.
9.
A blood draw is not required at the Early Withdrawal Visit if it was collected at the Early Treatment Discontinuation Visit.
10. A central laboratory will be used.
11. Informed consent for optional substudies, e.g. genetics consent must be obtained before collecting a sample.  Sample to be obtained post-randomisation.
12. Two inhalers to be dispensed at Visit 7 as Visit 8 does not need to be in the clinic if there are no problems with compliance.
13. Participants who provide an acceptable spirometry measure at screening but who do not meet the spirometry related inclusion criteria at this visit can be re-screened (see Section 
8.3).
14. Single or averaged QTc values of triplicate electrocardiograms to be obtained over a brief (e.g. 5 to 10 minute) recording period – see Section 10.1.2. 
15. If the participant is unable to attend the clinic at V6 for any reason, every attempt should be made to bring the participant back to the clinic to collect serial spirometry as soon as 
possible between Week 12 (Visit 6) and Week 24 (Visit 9). 
16. Study medication may be delivered directly to the participant, if the participant is not attending the clinic.

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3.
INTRODUCTION
3.1.
Study Rationale
A variety of asthma medications, generally targeting the inflammatory and/or obstructive 
components of the disease, may be selected for the treatment of asthma.  The 
evidence-based asthma treatment guidelines recommend a stepwise approach to treat 
asthma where medications are increased or decreased when appropriate to gain and 
maintain disease control.  For patients with persistent asthma symptoms, the preferred 
initiating controller medication (step 2 in the step-wise treatment paradigm) is low-dose 
ICS to target the inflammatory process in asthmatic airways.  For children ≥5 years of 
age and adolescents on low-dose ICS whose asthma is uncontrolled, low-dose ICS plus 
adjunctive therapy (e.g. long-acting beta agonist [LABA], leukotriene receptor antagonist 
[LTRA], theophylline) or monotherapy with medium-dose ICS, may all be considered as 
step 3 care (Global Initiative for Asthma [GINA, 2016; National Institutes of Health NIH, 
2007).  Due to the lack of comparative data for children ages 5 to 11 years, the step 3 care 
options are considered equivalent. Fluticasone furoate/vilanterol (FF/VI) has not been 
approved in the US in the adolescent population (12 to less than 18 years old) and as a 
result, a cohort of adolescents was included in this study to assess further efficacy and 
safety in this population.
This study will evaluate the efficacy and safety of fluticasone furoate/vilanterol (FF/VI) 
compared to fluticasone furoate (FF) in the treatment of asthma.   These objectives are 
common to the two study populations of interest:  the 5-11 years (inclusive) population 
and the 5-17 years (inclusive) population.
The rationale for the study design is provided in Section 7.1.
3.2.
Background
Asthma is a chronic disease of the lungs characterized by airway inflammation, 
bronchoconstriction and increased airway responsiveness.  Corticosteroids are the 
cornerstone of anti-inflammatory therapy for persistent asthma.  The goal of asthma 
treatment is to achieve and maintain asthma control and to reduce the future risk of 
exacerbations.  ICS are considered the most effective anti-inflammatory treatments for all 
severities of persistent asthma [GINA, 2016; NIH, 2007].  The benefits of ICS include 
control of asthma symptoms, improvement in lung function, decrease in airway hyper-
responsiveness and possibly, prevention of airway wall remodelling [Pedersen, 1997; 
Fanta, 2009].
FF (GW685698) as the ICS component and vilanterol (VI; GW642444) as the LABA 
component of the ICS/LABA combination, hereafter referred to as FF/VI, has been 
approved at the 100/25 mcg and 200/25 mcg dose in over 60 countries for once daily 
treatment of asthma.  FF/VI 100/25 mcg is also indicated for the maintenance treatment 
of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) 
including chronic bronchitis and/or emphysema and to reduce exacerbations of COPD in 
patients with a history of exacerbation.

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FF is approved in the United States of America and 10 other countries (Canada, 
Australia, Chile, Philippines, Switzerland, Singapore, New Zealand, South Korea, 
Mexico and Japan) for use as a once daily ICS for the maintenance treatment of asthma in 
patients aged 12 years and over. 
The FF and FF/VI paediatric asthma development programmes are currently ongoing.
3.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
fluticasone furoate (FF) and fluticasone furoate/vilanterol (FF/VI) can be found in the FF 
and FF/VI Investigator’s Brochures (GlaxoSmithKline Document Number: 
GM2004/00283/11, GlaxoSmithKline Document Number: RM2008/00012/09).
The following Section outlines the risk assessment and mitigation strategy for this 
protocol
3.3.1.
Risk Assessment FF and FF/VI
For FF and FF/VI, the risks associated with inhaled corticosteroids (ICS) and long-acting 
beta2 agonists (LABA) as well as the mitigation strategy applicable to adults and 
adolescent asthma patients are also considered applicable to paediatric patients with 
asthma.
The risks are referenced in the summary of safety concerns in the most recently approved 
European Union Risk Management Plan (EU-RMP) for FF/VI. 
The summary of data/rationale for the risks are referenced from the most currently 
available development safety update report (DSUR reporting period 03 July 2015 to 02 
July 2016) (doc ref number: 2016N278503) and from completed clinical studies since 
July 2016.
Only those risks considered of clinical significance with respect to the participants
included in this study are provided.
Potential risk of Clinical 
significance
Investigational product
Summary of data/ 
Rationale for the risk
Mitigation strategy
Pneumonia
FF and FF/VI
Pneumonia is a risk 
carried by the inhaled 
corticosteroids class of 
compounds. An increase 
incidence of pneumonia 
with higher doses of ICS 
cannot be ruled out; 
however, the absolute risk 
of pneumonia with FF
appears to be very small 
and consistent with other 
ICS.
The risk of pneumonia in 
asthma patients is very 
low and is consistent with 
the risk of other ICS. 
Subjects are alerted to the 
potential risk of 
pneumonia in the informed 
consent. Investigators are 
informed of the risk in 
Section 6 Warnings and 
Precautions Section of the 
IB. Subjects with 
concurrent respiratory 

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Potential risk of Clinical 
significance
Investigational product
Summary of data/ 
Rationale for the risk
Mitigation strategy
For FF; in an integrated 
analysis of 10 studies in 
asthma (6219 patients) 
the incidence of 
pneumonia seen with FF 
100 (8.5/1000 patient 
years) was similar to 
placebo (10.8/1000 
patient years) and slightly 
higher with FF 200 
(23.6/1000 patient years).  
Few of the pneumonia 
events were serious and a 
similar incidence was 
observed across all 
treatment groups.  
An increase incidence of 
pneumonia with higher 
doses of ICS cannot be 
ruled out; however, the 
absolute risk of 
pneumonia with FF 
appears to be very small 
and consistent with other 
ICS.
For FF/VI:
In an integrated analysis 
of 18 studies in asthma 
(10,322 patients), the 
incidence of pneumonia 
(adjusted for exposure, 
due to low numbers and 
limited number of patients 
on placebo) seen with 
FF/VI 100/25 mcg 
strength (8.5/1000 patient 
years) was similar to 
placebo (9.3/1000 patient 
years). There was a 
higher incidence of 
pneumonia in the FF/VI 
200/25 mcg strength 
(18.3/1000 patient years) 
compared to the FF/VI 
100/25 microgram 
strength. Few of the 
pneumonia events led to 
hospitalisation with either 
strength, and there were 
no observed differences in 
the incidence of serious 
disease are excluded from 
the study.

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Potential risk of Clinical 
significance
Investigational product
Summary of data/ 
Rationale for the risk
Mitigation strategy
events between the two 
treatment strengths.
Hypersensitivity
FF and FF/VI
For FF and FF/VI there 
were few events reported 
in the asthma studies.  As 
there was limited, short, 
exposure to placebo, any 
comparison is not reliable.
Spontaneous reports 
consistent with 
hypersensitivity reactions 
to inhaled FF/VI were 
identified on the GSK 
safety database.
Subjects and their 
parents/guardians will be 
informed about the risk of 
hypersensitivity in the 
informed consent. They 
will be advised to seek 
medical treatment if any 
signs/symptoms of 
hypersensitivity occur. 
Subjects with milk protein 
allergy or known 
hypersensitivity to FF, the 
class of ICS or any 
ingredient of the IP 
preparation will be 
excluded from 
participating in the study. 
Investigators are informed 
of this in Section 6 (contra-
indications) of the IB.
Systemic corticosteroid 
effects (adrenal 
suppression, effects on 
the eye, growth 
retardation)
FF and FF/VI
These are class risks
carried by all inhaled 
corticosteroid products.
Adrenal suppression
No studies have shown a 
clinically relevant effect of 
FF/VI on the hypothalamic 
pituitary axis (HPA). This 
includes a formal HPA 
study (HZA106851), using 
24 hour serum cortisol 
measurements, and 
multiple studies with 
COPD and asthma 
subjects which monitored 
urinary cortisol.
A completed 6-week HPA 
axis study in children aged 
5 to 11 years old did not 
show a clinically relevant 
effect of FF 50 mcg OD on 
adrenal function assessed 
by 24-hour serum cortisol 
profiles (HZA107118).
Subjects and their parents/ 
guardians will be informed 
about the risks in the 
informed consent. 
Investigators are made 
aware of the potential for 
these class effects in 
Section 6 (warnings and 
precautions) of the IB. 

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Potential risk of Clinical 
significance
Investigational product
Summary of data/ 
Rationale for the risk
Mitigation strategy
Corticosteroid-associated 
ocular effects
In study HZA106839 
(FF/VI and FP in subjects 
with asthma), formal 
Ophthalmic assessments 
were conducted (including 
lens opacities 
classification system 
[LOCS] III evaluations for 
ocular opacities) 
throughout the study. This 
study showed no apparent 
effects on lens 
opacification, compared to 
baseline. 
During studies in both 
subjects with asthma and 
COPD, no associated 
effect on ocular disorders 
was observed.
Growth retardation
Children with asthma may 
experience growth 
retardation, which has 
been attributed to the 
delayed onset of puberty 
seen in asthmatics relative 
to non-asthmatics [GINA, 
2016).  A systematic 
review of 25 trials 
involving 8471 (5128 ICS-
treated and 3343 control) 
children with mild to 
moderate persistent 
asthma showed that 
regular use of ICS at low 
or medium daily doses 
was associated with a 
statistically significant 
reduction in linear growth 
velocity (14 trials including 
5717 participants; MD -
0.48 cm/y, 95% 
confidence interval (CI) -
0.65 to -0.30, P value 
<0.0001) and in change 
from baseline in height (15 
trials including 3275 
participants; MD-0.61 

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Potential risk of Clinical 
significance
Investigational product
Summary of data/ 
Rationale for the risk
Mitigation strategy
cm/y, 95% CI -0.83 to 
-0.38, p value <0.00001) 
during a one-year 
treatment period. The 
effect size of ICS on linear 
growth velocity appeared 
to be associated more 
strongly with the ICS 
molecule than with the 
device or dose.  ICS-
induced growth 
suppression seemed to be 
maximal during the first 
year of therapy and less 
pronounced during 
subsequent years of 
treatment. This review did 
not find an overall effect of 
ICS during the first three 
months of treatment 
[Zhang, 2014].  A recent 
study demonstrated a 
reduced mean adult 
height of 1.2cm (95% CI: -
1.9 to 
-0.5) in subjects who 
received inhaled 
budesonide compared to 
placebo, after use of 4 to 
6 years [Kelly, 2012].
A completed knemometry 
study did not show a 
clinically significant effect 
of FF on short term leg 
growth compared with 
placebo (HZA107112).
Serious asthma related 
events
FF/VI
This is a risk carried by 
the class of LABA 
compounds.
During the FF/VI studies 
for the asthma composite 
endpoint (asthma 
exacerbations leading to 
hospitalization, intubation 
and/or death), there was 
no significant difference 
between the FF/VI group 
and the ICS group or non-
LABA group, 
demonstrating no 
increased risk when 
adding a LABA to an ICS.
Subjects with history of 
life-threatening asthma are 
excluded from the study. 
Inclusion criteria for the 
study require a subject to 
have their asthma disease 
controlled by current 
therapy. Subjects 
complete daily electronic 
diary entries for the 
symptoms of asthma, 
peak expiratory flow (PEF)
and rescue medication 
use. Subjects will be 
advised to contact the 

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Potential risk of Clinical 
significance
Investigational product
Summary of data/ 
Rationale for the risk
Mitigation strategy
Three large completed 
studies with ICS/LABA 
compounds (one in 
paediatric subjects) have 
shown no increased risk 
of serious asthma related 
events compared with ICS 
alone [Stempel, 2016a; 
Stempel, 2016b; Peters, 
2016].
investigator or their 
physician immediately.
3.3.2.
Benefit Assessment
Inhaled corticosteroids (ICS)
The use of ICS is well established in international treatment guidelines for paediatric 
asthma patients [GINA, 2016]. The benefits of an ICS include control of asthma 
symptoms, improvement in lung function and a decrease in airway hyperresponsiveness. 
In addition subjects will receive SABA for use as needed for relief of asthma symptoms. 
Addition of LABA to ICS
Combined treatment with ICS and LABA has been shown to be more effective than the 
individual components in asthma, leading to the development of fixed dose combination 
inhalers. The use of ICS/LABA is now well established in international treatment 
guidelines for patients for whom treatment with an ICS alone is no longer sufficient.
Improved compliance with once-daily treatment regimen
Data with marketed products suggests that compliance improves with less frequent 
administration and, therefore, it is expected that a once-daily treatment will improve 
compliance, which may lead to improvements in disease control and reductions in 
healthcare resource utilisation costs [Price, 2010; Toy, 2011; Wells, 2013].
3.3.3.
Overall Benefit:Risk Conclusion
GSK has assessed this study for any potential risks that a subject may experience. The 
investigational products (FF and FF/VI) have acceptable safety profiles for clinical use. 
The risks documented for FF and FF/VI belong to the class of products to which FF and 
FF/VI belong. The data support a positive benefit risk balance for the product. This 
conclusion is supported by the results of previously conducted clinical studies with the 
products in healthy volunteers and subjects with asthma and COPD. A safety criterion 
outlining details for subject discontinuation from IP or early withdrawal is included in the 
protocol (Section 10). Routine safety analyses of adverse events (AEs) and serious 
adverse events (SAEs) from this study will be conducted by GSK.

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Taking into account the measures to minimise risk to subjects participating in this study, 
the potential risks identified in association with FF and FF/VI are justified by the 
anticipated benefits that may be afforded to paediatric patients with asthma.
For the FP/Salmeterol section, information is taken from the current approved product 
information of Advair. Since Advair contains an ICS and LABA, the risk mitigation 
strategies for FF (ICS) and VI (LABA) component will be applicable.
4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary
Common to both 5-11 and 
5-17 years population

To compare the efficacy 
of once daily fluticasone 
FF/VI with once daily FF 
in participants with 
asthma.
The primary estimand is 
that of treatment policy 
(effectiveness-type 
estimand).  The 
secondary efficacy-type 
estimand will be defined 
for the primary and 
powered secondary 
endpoints
Primary endpoint for  5-11 
years population

Change from baseline, 
averaged over weeks 1-
12 of the treatment 
period, in pre-dose (i.e. 
trough) morning peak 
expiratory flow (PEF), 
captured daily via 
electronic patient diary. 
This is the primary 
endpoint for the 5-11y 
population [required by 
EMA]. This is a 
secondary endpoint for 
the 5-17 years 
population.   
Primary endpoint for 5-17 
years population

Weighted mean FEV1 
(0-4 hours) at week 12.  
This is the primary 
endpoint for the 5-17y 
population [required by 
FDA]. This is a 
secondary endpoint for 
the 5-11 years 
population.
Secondary endpoints common to both 5-11 and 5-17 years 
population:

Change from baseline in the percentage of rescue-free 24-
hour periods over weeks 1-12 of the treatment period 
(powered secondary endpoint for 5-11 years population) 
captured daily via electronic patient diary.

Change from baseline in the percentage of symptom-free 
24-hour periods over weeks 1-12 of the treatment period, 
captured daily via electronic patient diary.

Change from baseline in morning (AM) forced expiratory 
flow in 1 second (FEV1) in participants who can perform the 
manoeuvre at week 12.

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Objective
Endpoint

Change from baseline in ACQ-5 at week 24.

Incidence of exacerbations over the 24 week treatment 
period.
Other endpoints common to both 5-11 and 5-17 years 
population:

Change from baseline, averaged over weeks 1-12 of the 
treatment period in evening (PM) PEF, captured daily via 
electronic patient diary. 
Secondary
Common to both 5-11 and 
5-17 years population

To assess the safety of 
FF/VI in participants with 
asthma 

Incidence of adverse events (AEs).

Evaluation of fasting blood glucose pre- and post-treatment.
5.
STUDY DESIGN
5.1.
Overall Design
This is a randomised, double-blind, stratified, parallel group, multicentre study evaluating 
the efficacy and safety of once daily FF/VI inhalation powder compared to once daily FF
inhalation powder in the treatment of asthma in participants aged 5 to 17 years old 
inclusive currently uncontrolled on inhaled corticosteroids. The overall study design is 
shown in Figure 1.

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Figure 1
Study Schematic
This study will be conducted over a total duration of approximately 29 weeks: 4 week 
run-in period, 24-week double-blind treatment period and 1-week follow-up period.  
Participants who meet the eligibility criteria at Visit 1 (or after spirometry re-test) will 
enter a 4 week open-label run-in period.  During the 4 week run-in period, all subjects 
will receive fluticasone propionate (FP) 100mcg twice daily.   
After completing the run-in period, eligible participants will be stratified by age (5 to 11 
and 12 to 17) and randomised into a 24 week double-blind treatment period, as follows:

Participants aged 5 to11 years of age will be randomised in a 1:1 ratio to one of the 
following two treatments:

FF 50 mcg once daily in the morning

FF/VI 50/25 mcg once daily in the morning

Participants aged 12 to 17 years of age will be randomised in a 1:1 ratio to one of the 
following two treatments:

FF 100 mcg once daily in the morning

FF/VI 100/25 mcg once daily in the morning
Each treatment will be administered via the ELLIPTA dry powder inhaler (formerly 
referred to as a Novel Dry Powder Inhaler [NDPI]).
Visit 1
-4 Wk
4 week run-in 
on FP
R
FF 50 OD
(n = 326)
FF/VI 50/25 OD
(n = 326)
FF/VI 100/25 OD
(n = 109)
Visit 3 
Day 0
FF 100 OD
(n = 109)
adolescents
paediatrics
Visit 6
Week 12
Visit 9
Week 24
Visit 4 
Week 4
Visit 5 
Week 8
Visit 7 
Week 16
Visit 8
Week 20
FU TC
Week 25
Visit 2 
Visit 1 and 3 must be done in the clinic. Spirometry for V6 must be done in the clinic. Visit 2 is for spirometry only and 
can be at home or clinic. Visit 5 and Visit 7 can be parent only visits or video-calls. If spirometry is done at Visit it 5, it 
can be done at home or clinic. Visit 4, 9, ETD and EW can be done in the home or clinic. Visit 8 can be a video-call, 
phone-call or clinic visit. The FU TC can be a phone-call or video-call.  
–
;
-

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In addition, each participant will receive a short acting beta 2 agonist (SABA) (i.e., 
albuterol/salbutamol [inhalation aerosol or nebuliser]) to be used as needed throughout 
the entire study period as rescue medication for symptomatic relief of asthma symptoms.
Participants are required to attend the clinic at Visits 1, 3 and 6.. . Visit 2 is for 
spirometry only and can be at home or in the clinic. Visit 5 and Visit 7 can be parent only 
visits or video-calls. If spirometry is done at Visit it 5, it can be done at home or in the 
clinic. Visit 4, Visit 9, ETD and EW can be done in the home or clinic. Visit 8 can be a 
video-call, phone-call or clinic visit. The FU TC can be a phone-call or video-call. All 
spirometry (in the clinic or at home) must be started between 6am and 11am. 
6.
NUMBER OF PARTICIPANTS
Approximately 2900 participants will be screened to achieve a total of 870 randomised
participants aged 5 to 17 years, inclusive.  Of this, 652 participants will be aged 5 to 11 
years (and at least 163 (25%) must be aged 5 to less than 8 years), and 218 participants 
will be aged 12 to 17 years inclusive.
A 70% screening failure rate is expected.
7.
PARTICIPANT AND STUDY COMPLETION
A participant is considered to have completed the study if he/she has completed all visits 
of the study including the follow-up phone contact as shown in the SOA (Section 2).
A subject will be considered discontinued from study treatment if the subject was 
randomised, but intentionally and permanently stopped taking study treatment during the 
treatment period.
A subject will be considered withdrawn from the study if the subject left the study prior 
to completing all required visits and the follow-up phone contact.
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SOA.
7.1.
Scientific Rationale for Study Design
The design of this study has been developed based on advice received from the Food and 
Drugs Administration (FDA) and the European Medicines Agency (EMA) Scientific 
Advice Working Party (SAWP) and subsequently agreed with the Paediatric Committee 
(PDCO) via a modification to the paediatric investigational plan (PIP).
This study is designed to evaluate the efficacy and safety of FF/VI in participants aged 5 
to 11 years old with asthma currently uncontrolled on ICS.  In addition, the study is 
designed to evaluate the efficacy and safety of FF/VI in participants aged 5 to 17 years 
old with asthma that are uncontrolled on ICS.  The dose will be FF/VI 50/25 mcg for 
participants aged 5 to 11 years old and FF/VI 100/25 mcg for participants aged 12 to 17 

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years old.  For each population (5-11 years and 5-17 years), the study is designed to show 
a statistically significant difference between FF/VI (ICS/ LABA combination therapy) 
and FF alone (ICS monotherapy), thereby demonstrating the contribution of the LABA 
(VI).  
The treatment duration of the study is 24 weeks, which is considered to be sufficient to 
evaluate safety.  Twelve weeks of treatment is considered to be sufficient to demonstrate 
efficacy in the proposed study population.
7.2.
Dose Justification
The safety and efficacy of a fixed-dose combination of FF 50 mcg and VI 25 mcg in 
asthmatic children aged 5 to 11 years of age (inclusive) will be evaluated in this study. 
This will be compared to a dose of FF 50 mcg alone. The doses of each of the 
components of FF/VI were selected from the results of two Phase IIb studies dose 
ranging studies HZA106853 for VI and HZA106855 for FF in asthmatic participants 
aged 5 to 11 years of age (inclusive).
HZA106853 was a dose-ranging study that evaluated 3 doses of VI (6.25 to 25 mcg on a 
background of ICS) over a 4-week treatment period in children aged 5 to 11 years, who 
were symptomatic on a low-dose ICS. Taking the totality of the data, lung function and 
symptoms, into consideration, a 25 mcg dose of VI was considered the most appropriate 
to take forward into combination with FF in this study.
HZA106855 was a dose ranging study that evaluated 3 doses of FF (25 to 100 mcg) over 
12 weeks of treatment in children aged 5 to 11 years with asthma who were symptomatic 
on a SABA, LTRA or low-dose ICS.  Taking the totality of data into consideration, 
50 mcg has been selected as the appropriate dose to take forward into combination with 
VI in this study.
In subjects aged 12 to 17 years of age FF 100mcg has been selected for this study as this 
is the starting dose currently approved for FF in subjects aged 12 years of age and older.  
FF/VI 100/25 mcg has been selected as the appropriate dose in this study for this age 
group based on the data generated from the FF and VI Phase IIb and FF/VI Phase III 
studies in subjects aged 12 years and older.  FF/VI 100/25 is the approved starting dose in 
over 60 countries for the once daily treatment of asthma.
8.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
8.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply at Visit 1:

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Age
1. Between 5 and 17 years of age inclusive, at the time of screening.
Type of Participant and Disease Characteristics
2. A history of symptoms consistent with a diagnosis of asthma for at least 6 months.
3. Pre-bronchodilator FEV1 >50% to ≤100% predicted normal. A minimum of 2 efforts 
that are considered acceptable (not necessarily repeatable) are required to be eligible 
(see Section 11.1.1).
NOTE:  These FEV1 measurements must be acceptable and must meet the FEV1
inclusion limits (as stated above) and the reversibility requirements (below) to be 
eligible for the study. Participants who are unable to perform the pre-bronchodilator 
FEV1 manoeuvre for any reason or do not provide at least 2 acceptable pre or post 
bronchodilator measurements [not necessarily repeatable] at Visit 1 can, at the 
discretion of the investigator, attend the clinic once more after Visit 1 to attempt to 
perform the pre-bronchodilator and post-bronchodilator FEV1 manoeuvres. This 
should be within 14 days of Visit 1 Patients who provide an acceptable 
spirometry measure, but who do not meet the spirometry related criteria 
(Inclusion criteria 3 and 4) are considered screen failures but can be re-screened 
(see Section 8.3).  
4. Lung function reversibility defined as an increase of ≥12% in FEV1 within 15 to 
40 minutes following 2 to 4 inhalations of albuterol/salbutamol inhalation aerosol (or 
1 nebulised treatment with albuterol/salbutamol solution).  Use of a spacer is 
permitted.
NOTE:  Participants who meet inclusion criteria 3 with a technically acceptable pre-
bronchodilator FEV1 manoeuvre at Visit 1, but are then unable to perform the 
technically acceptable post-bronchodilator FEV1 needed for reversibility can, at the 
discretion of the investigator, attend the clinic once more after Visit 1 to attempt to 
perform both the pre-bronchodilator and post-bronchodilator FEV1 manoeuvres 
again.  This should be within 14 days of Visit 1. These FEV1 measurements must be 
acceptable and must meet the FEV1 inclusion limits and the reversibility requirements 
to be eligible for the study.  Patients who provide an acceptable spirometry 
measure, but who do not meet the spirometry related criteria (3 and 4) can be 
re-screened (see Section 8.3).  
5. Uncontrolled asthma, with a cACT/ACT score ≤19.
6. Receiving stable asthma therapy (SABA or SAMA inhaler plus ICS [total daily dose 
≤FP 250 mcg or equivalent])for at least 4 weeks prior to Visit 1 (i.e., screening).
7. Able to replace their current SABA/SAMA treatment with salbutamol/albuterol
aerosol inhaler at Visit 1 for use as needed for the duration of the study. 
Salbutamol/albuterol metered dose inhaler (MDI) will be administered with or 
without a spacer, to be used as determined by the investigator. The use or non-use of 
the spacer should be consistent for an individual participant throughout the study.

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Sex
8. Male or female participants
Females of reproductive potential must agree to follow 1 of the options listed (which 
include abstinence) in the Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) (see Section 14.4) from 
30 days prior to the first dose of study medication and until at least five terminal 
half-lives OR until any continuing pharmacologic effect has ended, whichever is 
longer after the last dose of study medication and completion of the follow-up call. 
The investigator is responsible for ensuring that participants understand how to 
properly use these methods of contraception.
Note:  Any female participant who is lactating (breastfeeding) will not be included 
in the study.
Informed Consent
9. Written informed consent from at least 1 parent/care giver (legal guardian) and 
accompanying informed assent from the participant (where the participant is able to 
provide assent) prior to admission to the study. 

If applicable, participant must be able and willing to give assent to take part 
in the study according to the local requirement. The study investigator is 
accountable for determining a child's capacity to assent to participation in a 
research study, taking into consideration any standards set by the responsible 
IEC.

Participant and their legal guardian(s) understand that the study requires them 
to be treated on an outpatient basis.

Participant and their legal guardian(s) understand that they must comply with 
study medication and study assessments including recording of PEF and 
rescue SABA use, attending scheduled study visits, and being accessible by a 
telephone call.
8.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. A history of life threatening asthma defined for this protocol as an asthma episode 
that required intubation and/or was associated with hypercapnea, respiratory arrest or 
hypoxic seizures.
2. Any asthma exacerbation requiring the use of oral steroids within 6 weeks of Visit 1, 
systemic or depot corticosteroids within 12 weeks of Visit 1, OR ER attendance 
within 3 months of Visit 1 OR hospitalisation within 6 months of Visit 1.   

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3. A culture documented or suspected bacterial or viral infection of the upper or lower 
respiratory tract, sinus or middle ear that has not resolved within 4 weeks of Visit 1 
and which led to a change in asthma management or, in the opinion of the 
investigator, is expected to affect the participant’s asthma status or the participant’s 
ability to participate in the study.
4. Clinical visual evidence of oropharyngeal candidiasis.
5. Fasting blood glucose at screening >100 mg/dl (5.6mmol/L).  NOTE:  Participants 
who have a value that is above >100 mg/dl can have a repeat test before Visit 2.  
6. Severe obesity (BMI above the 99th centile based on the CDC charts).
7. Any significant abnormality or medical condition identified at the screening medical 
assessment (including serious psychological disorder) that in the investigator’s 
opinion, preclude entry into the study due to risk to the participant or that may 
interfere with the conduct and/or outcome of the study.
8. QT interval corrected using Fridericia’s formula (QTcF) >450 msec or QTcF >480 
msec in participants with bundle branch block or any other clinically significant 
abnormality in the Screening 12-lead ECG.
Notes: 

For purposes of data analysis, QT interval corrected for heart rate according to 
Bazett’s formula (QTcB), Fridericia’s formula (QTcF), another QT correction 
formula, or a composite of available values of QTc will be used as specified in the 
Reporting and Analysis Plan (RAP).
Prior/Concomitant Therapy
9. Use of any prohibited medications listed in Section 9.7.1.
Relevant Habits
10. Present use of any tobacco products including e-cigarettes and vaping.
Contraindications
11. Drug allergies: any adverse reaction including immediate or delayed hypersensitivity 
to any beta 2-agonists, sympathomimetic drug or any intranasal, inhaled, or systemic 
corticosteroid therapy. Known or suspected sensitivity to the constituents of the 
ELLIPTA Inhaler (i.e. lactose or magnesium stearate).
12. Milk Protein Allergy: history of severe milk protein allergy.
Diagnostic Assessments and Other Criteria
13. Participated in a clinical trial and has received an investigational product within the 
following time period prior to the first dosing day in the current study: 30 days, five 
half-lives or twice the duration of the biological effect of the study treatment
(whichever is longer).
14. Exposure to more than 4 investigational medicinal products within 12 months prior to 
the first dosing day.

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15. An affiliation with the investigator site: the parents/guardians or child is an immediate 
family member of the participating investigator, sub-investigator, study coordinator, 
or employee of the participating investigator.
16. The parent or guardian has a history of psychiatric disease, intellectual deficiency, 
substance abuse or other condition (e.g. inability to read, comprehend or write) which 
may affect:
validity of consent to participate in the study
adequate supervision of the participant during the study
compliance of participant with study medication and study procedures 
(e.g. completion of daily diary, attending scheduled clinic visits)
participant safety and well-being
17. Children in care:  children who are wards of the government or state are not eligible 
for participation in this study.
8.3.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
events (SAEs).
Participants who fail any of the screening or run-in criteria for any reason may be re-
screened once after a period of at least 1 month from the date of screen failure or run-in 
failure.  
Any re-screened subject must satisfy all of the protocol specified inclusion/exclusion 
requirements at the re-screening visit. Re-screened subjects should be assigned a new 
subject number at the time of re-screening.
8.4.
Randomisation Criteria
Subjects must meet the following criteria to be eligible for randomisation:
8.4.1.
Inclusion Criteria for Randomisation to Treatment
1. Asthma control: uncontrolled asthma, with a cACT/ACT score ≤19.
2. A technically acceptable pre-bronchodilator FEV1 >50% to ≤100% predicted normal
at Visit 2.  A minimum of 2 efforts that are considered acceptable and repeatable
following the overread are required to be eligible (see Section 11.1.1).
3. Symptoms and rescue use: demonstrated and reported in a daily diary symptoms of 
asthma (a score of ≥1 on the day-time or night-time asthma symptom scores) and/or 

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daily albuterol/salbutamol on at least 3 of the last 7 consecutive days of the run-in 
period (not including the date of randomisation).
4. Compliance with run-in medication: compliance is defined as use of run-in 
medication on at least 4 of the last 7 consecutive days of the run-in period (not 
including the date of randomisation) recorded in the electronic patient diary.
5. Compliance with completion of the daily diary reporting: defined as completion 
of all questions on 4 out of the last 7 days during the run-in period (not including the 
date of randomisation).
8.4.2.
Exclusion Criteria for Randomisation to Treatment
1. Changes in asthma medication that occur after screening.
2. Occurrence of a culture-documented or suspected bacterial or viral infection of the 
upper or lower respiratory tract, sinus or middle ear during the run-in period that led 
to a change in asthma management or, in the opinion of the investigator, is expected 
to affect the participant’s asthma status or the participant’s ability to participate in the 
study.
3. Evidence of an exacerbation, defined as a: 

deterioration of asthma requiring the use of oral corticosteroids for at least 3 days, 
or 

a depot corticosteroid injection, or 

an in-patient hospitalisation due to asthma that required systemic corticosteroids
between screening and randomisation.
4. Clinical visual evidence of oropharyngeal candidiasis at the Randomisation Visit.
5. Unable to use the ELLIPTA inhaler correctly.
9.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
Investigational product will be supplied by the Clinical Trial Supply group. The 
frequency at which the investigational product will be supplied to each individual site 
will be adapted to the availability of investigational product, recruitment capacity of that 
site, and to the expiry date of the investigational product.
9.1.
Treatments Administered
Details of study treatments that will be administered in this study are detailed in Table 2.

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Table 2
Study Treatments
Study Treatment 
Name:
Fluticasone 
Furoate / 
Vilanterol 50/25 
mcg dry 
powder inhaler*
Fluticasone 
Furoate / 
Vilanterol 
100/25 mcg dry 
powder inhaler*
Fluticasone 
Furoate 50 mcg 
dry powder 
inhaler**
Fluticasone 
Furoate 100 
mcg dry powder 
inhaler**
Dosage 
formulation:
Dry powder 
inhaler 
Dry powder 
inhaler
Dry powder 
inhaler 
Dry powder 
inhaler 
Unit dose 
strength(s)/Dosage 
level(s):
FF 50 mcg & VI 
25 mcg per 
actuation
FF 100 mcg & 
VI 25 mcg per 
actuation
FF 50 mcg per 
actuation
FF 100 mcg per 
actuation
Route of 
Administration: 
Inhaled
Inhaled
Inhaled
Inhaled
Dosing 
instructions:
Inhale once in 
the morning
Inhale once in 
the morning
Inhale once in 
the morning
Inhale once in 
the morning
Device:
Ellipta
Ellipta
Ellipta
Ellipta
Method of 
individualizing 
dosage:
Inhalation (oral)
Inhalation (oral)
Inhalation (oral)
Inhalation (oral)
*Dual Strip; **Single Strip
Fluticasone propionate mulitdose powder inhaler (100 mcg twice daily) will be supplied 
by the Clinical Trial Supply group for use during the run-in period. 
SABA inhalation aerosol (albuterol/salbutamol) will be provided locally for symptomatic 
relief of asthma symptoms during the study.
9.1.1.
Medical Devices
Peak flow meters will be provided by GSK for use in this study; however these devices
are not manufactured by, or on behalf of GSK.
Any malfunctions with the Ellipta inhaler should be reported and defective inhalers 
should be returned (see SRM for further details).
9.2.
Dose Modification
Not applicable.

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9.3.
Method of Treatment Assignment
Participants are required to meet the inclusion criteria for randomisation to treatment 
detailed in Section 8.4. Participants meeting exclusion criteria for randomisation to 
treatment will not be randomised to treatment.
Participants will be randomised to 1 of 2 treatment arms using Interactive Voice/Web 
Response System (IVRS/IWRS).
Before the study is initiated, the telephone number and call-in directions for the IVRS 
and/or the log in information and directions for the IWRS will be provided to each site.  
Study treatment will be dispensed (according to treatment assigned using IVRS) at the 
study visits summarised in SOA.  Returned study treatment should not be re-dispensed to 
the participants.
9.4.
Blinding
This is a double-blind study and the following will apply:

The IVRS/IWRS will be programmed with blind-breaking instructions.  The blind 
may be broken if, in the opinion of the investigator, it is in the participant’s best 
interest for the investigator to know the study treatment assignment.  GSK must be 
notified before the blind is broken unless identification of the study treatment is 
required for a medical emergency in which the knowledge of the specific blinded 
study treatment will affect the immediate management of the participant’s condition 
(eg, antidote is available).  In this case, GSK must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded 
in the source documentation and case report form (CRF), as applicable.

The date and reason for the unblinding must be fully documented in the CRF and 
source documentation. 

A subject may continue in the study if that subject’s treatment assignment is 
unblinded by GSK Global Clinical Safety and Pharmacovigilance (GCSP) personnel. 
The primary reason for discontinuation (the event or condition which led to the 
unblinding) will be recorded in the CRF.

GSK’s GCSP staff may unblind the treatment assignment for any participant with an 
SAE. If the SAE requires that an expedited regulatory report be sent to 1 or more 
regulatory agencies, a copy of the report, identifying the subject’s treatment 
assignment, may be sent to investigators in accordance with local regulations and/or 
GSK policy.
9.5.
Preparation/Handling/Storage/Accountability

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 participants 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 the 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.
9.6.
Treatment Compliance
Subject compliance with double-blind study medication will be assessed from Visit 3
(Randomisation visit) through to Visit 9 (End of Treatment Period) by reviewing the 
following:
1.
ELLIPTA dose counter assessment at each visit.
Subjects whose compliance falls below 80% during the study should be re-trained on 
appropriate dosing of study drug, and may be required to attend the clinic for an 
unscheduled visit.  
9.7.
Concomitant Therapy
Any medication that is not prohibited in Inclusion/Exclusion criteria section (see Section
8.1 and Section 8.2) is allowed during the study, as long as the dose remains constant 
wherever possible and their use is not expected to affect the outcome of the study 
assessments.
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:

reason for use

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
dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
The study site will supply salbutamol/albuterol aerosol inhaler at Visit 1 for use as 
needed for the duration of the study.  Salbutamol/albuterol MDI will be administered 
with or without a spacer, to be used as determined by the investigator.  The use or non-
use of the spacer should be consistent for an individual participant throughout the study.
SABA (inhalation aerosol or nebuliser) use should be withheld for 4 hours prior to the 
FEV1 measurement at screening and at all future visits where FEV1 is measured.  
9.7.1.
Prohibited Medications and Non-Drug Therapies
Note:  Participants should be treated as appropriate for asthma exacerbations without 
requirement to withdraw the participant from the study. 
Steroids will be an exclusion from randomisation if administered during the run-in period 
(apart from FP). However, they should never be withheld if deemed necessary. 
Use of the following medications is prohibited according to the timeframes indicated
unless they are deemed necessary to treat an asthma exacerbation or another condition 
appropriately:

From screening visit (Visit 1) to Visit 9: LTRAs, ketotifen, nedocromil sodium, 
orally inhaled sodium cromoglycate, SABA/short-acting muscarinic antagonist 
(SAMA) combinations (e.g. Combivent), and inhaled corticosteroids (except for FP 
which is given during the run-in).  

Within 4 weeks of Visit 1: participants who have changed their asthma medication.

Within 4 weeks of Visit 1, or any time between Visit 1 to 9: theophyllines, oral 
long-acting beta 2-agonists (e.g. bambuterol), inhaled long-acting beta 2-agonists 
(e.g. salmeterol, formoterol), combination products containing inhaled long-acting 
beta 2-agonists (e.g. Seretide, Symbicort, Dulera) and inhaled long-acting 
anticholinergics (e.g. tiotropium).  Potent cytochrome P450 3A4 (CYP3A4) inhibitors 
(e.g. clarithromycin).  Prescription or over-the-counter medication that would 
significantly affect the course of asthma or change in asthma medication, or interact 
with study drug including (but not limited to): anticonvulsants (barbiturates, 
hydantoins, carbamazepine); polycyclic anti-depressants; oral, systemic or 
transdermal beta-adrenergic blocking agents; phenothiazines and monoamine oxidase 
inhibitors.

Within 6 weeks of Visit 1 or any time between Visit 1 to 9: Oral corticosteroids.
NOTE:  During the double-blind treatment period subjects who require limited 
courses of oral corticosteroids should remain on study treatment.

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
Within 12 weeks of Visit 1 or any time between Visit 1 to 9: systemic or depot 
corticosteroids, anti-immunoglobulin E (IgE) (e.g. Xolair), anti-interleukin (IL)5 (e.g. 
Nucala) immunosuppressive medications (immunotherapy for the treatment of 
allergies is allowed during the study provided it was initiated at least 4 weeks prior to 
Visit 1 and the participant remains in the maintenance phase throughout the study).

Other:  a participant must not have used any inhaled SABA within 4 hours of Visit 1.
9.8.
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.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
10.
DISCONTINUATION CRITERIA
10.1.
Discontinuation of Study Treatment
Participants that permanently stop study treatment are encouraged to remain in the 
study.  Participants have the right to discontinue study treatment before the end of the 
study.  Participants who discontinue from study treatment prematurely (for any reason) 
should continue to be followed-up as per protocol until the completion of the follow-up 
assessments. The investigator must make every effort to keep the participant in the study 
to collect efficacy and safety data.
Participants may be discontinued from study treatment at any time by the investigator if it 
is considered to be detrimental for them to continue on study treatment. Specifically, a 
participant will be discontinued from study treatment if he/she meets any of the following 
criteria outlined below:

A participant becomes pregnant.

Female participants who reach menarche after Visit 1 and who do not agree to 
follow one of the options listed in the Modified List of Highly Effective Methods 
for Avoiding Pregnancy in FRP (which includes abstinence) as outlined in 
Section 14.4.

A participant meets the liver stopping criteria (see Section 10.1.1).

A participant meets the QTc stopping criteria (see Section 10.1.2).
A participant may discontinue study treatment at any time at his/her own request.  An 
Early Treatment Discontinuation Visit should be conducted within approximately 
24 hours of the participant stopping study medication. In the event a participant 
discontinues study treatment at or during a scheduled visit, an Early Treatment 
Discontinuation Visit is not required; however, all study procedures scheduled at an Early 

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Treatment Discontinuation Visit must be performed at this visit instead and reasons for 
treatment discontinuation should be collected. These participants will not be allowed to 
restart study treatment; however, participants will be asked to continue to follow the 
regular visit schedule, including the completion of the daily electronic patient diary (until 
Visit 6), and attending the clinic at Visit 6 to obtain serial FEV1 measurements. The 
investigator should prescribe appropriate asthma medication to participants who 
discontinue study treatment and elect to continue in the study. After treatment 
discontinuation, the prohibited medications listed in exclusion criterion 7 are no longer 
applicable. Every effort will be made to contact participants who do not attend the End 
of Treatment Visit to collect information on any AEs, SAEs and exacerbations, and to 
collect the e-diary.
10.1.1.
Liver Chemistry Stopping Criteria
There are no scheduled blood tests in this study, apart from the collection of a fasting 
glucose blood sample.  If however the participant has a routine blood test during the 
study and the results suggest abnormal liver function, then the liver stopping criteria will 
apply.
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the Food 
and Drug Administration [FDA] premarketing clinical liver safety guidance). These 
protocol guidelines are in alignment with FDA premarketing clinical liver safety 
guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm or if 
the investigator believes that it is in the best interest of the participant. 

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Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.

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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
10.1.2.
QTc Stopping Criteria
ECGs will be performed as outlined in the SOA (Table 1).  QTcF will be used for each 
individual participant to determine eligibility for and discontinuation from the study.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g. 5 to 10 minute) recording period.  
A participant who meets the bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from study treatment:

QTcF > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTcF > 60 msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:

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Baseline QTcF with Bundle Branch 
Block
Discontinuation QTcF with Bundle 
Branch Block
<450 msec
>500 msec
450–480 msec
≥530 msec
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
10.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or 
at the request of his/her legal guardian(s),or may be withdrawn at any time at the 
discretion of the investigator for safety, behavioural, or administrative reasons.

If the participant withdraws assent or if his/her legal guardian(s) withdraw 
consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples (e.g. saliva) taken and not tested, and the investigator must document 
this in the site study records.

Refer to the SOA (Table 1) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed.
If the participant chooses to withdraw from the study, all study-related medications and 
other study related materials should be returned to the site by the participant.  An Early 
Withdrawal Visit should be conducted within approximately 24 hours of the participant 
stopping study medication.  In the event a participant withdraws at or during a scheduled 
visit, an Early Withdrawal Visit is not required; however, all study procedures scheduled 
at an Early Withdrawal Visit must be performed at this visit instead.  A follow-up phone 
contact or video-call should be made 7 days after the Early Withdrawal Visit.  The 
primary reason for study treatment discontinuation or study withdrawal will be recorded 
in the electronic case report form (eCRF) and any data collected up until the point of 
withdrawal will be used in the data analyses.
10.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 

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the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant or legal guardian(s)
(where possible, 3 telephone calls and, if necessary, a certified letter to the 
participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
11.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SOA (Table 1). 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SOA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SOA.

A 2mL blood sample will be collected for the assessment of fasting blood glucose
from each participant at Visits 1 and 9 (and ETD/DW, and if repeat test is required at 
Visit 1).
11.1.
Efficacy Assessments
The timing of all efficacy assessments is provided in the SOA.
11.1.1.
FEV1
Spirometry at Visit 2, Visit 4, Visit 5 (if applicable), ETD and EW may be collected at 
home or in the clinic. At-home spirometry must be done using a Masterscope provided by 
the spirometry vendor, ERT (with central over-read). Home nurses will be experienced in 
spirometry and will be trained by ERT. 
Spirometry at Visit 1 and Visit 6 must be done in the clinic. 

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Spirometry will be performed to assess FEV1. It will be measured using a standardised 
calibrated spirometer.  At least 3 spirometry manoeuvres (from a maximum of 8 
attempts) should be achieved on each occasion that spirometry assessments are 
performed. For all spirometry data collected, best spirometry effort will be selected from 
a measurement that meets the American Thoracic Society (ATS)/ European Respiratory 
Society (ERS) guidelines. 
For both the pre-bronchodilator and post-bronchodilator time points at screening (Visit 
1), there must be a minimum of 2 spirometry efforts that are considered acceptable (not
necessarily repeatable) to be eligible for the study.  
At the pre-randomisation visit (Visit 2), there must be a minimum of 2 spirometry efforts 
that are considered acceptable and repeatable (available and reviewed at Visit 3) in order 
to be eligible for randomisation.
For all data (including both pre-dose and serial FEV1) collected during the treatment 
period (Visits 4 and 6, and where collected at Visit 5) and ETD/EW, there must be a 
minimum of 2 efforts that are considered acceptable (not necessarily repeatable).
Predicted FEV1 values will be based on Quanjer (GLI2012) [Quanjer, 2012].
For all visits and time points, spirometry will be subject to a central overread. The final 
value after the overread is the value that will be databased and analysed. This is also the 
value that will be used to determine eligibility for the spirometry at Visits 1 and 2.
Participants must withhold from using salbutamol/albuterol (inhalation aerosol or 
nebuliser) for 4 hours prior to FEV1 measurements. In addition, participants must not
take their study drug (if applicable) prior to the visit and performing their pre-dose FEV1
measurement. 
Pre-dose FEV1 will be measured in the morning between 6.00am and 11.00am.  
11.1.1.1.
Serial FEV1
Serial FEV1 measurements at Visit 6 will occur at 15 minutes pre-dose and 30, 60, 
120,180, and 240 minutes post dose.
If the participant is unable to attend the clinic at Visit 6 for any reason, every attempt 
should be made to bring the participant back to the clinic to collect serial spirometry as 
soon as possible between Visit 6 (Week 12) and Visit 9 (Week 24). 
Any serial measurements that are collected after week 12 will be used in the primary 
analysis, which is considered acceptable as the drug effect is expected to have reached a 
plateau by 3 months post-randomisation, and should not significantly change afterwards.
11.1.1.2.
Reversibility
At Visit 1, to check eligibility, reversibility in FEV1 will be assessed.  

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FEV1 will be measured within 15 to 40 minutes following 2 to 4 inhalations of 
albuterol/salbutamol (a spacer device may be used if required) or one nebulised treatment 
with albuterol/salbutamol solution. Subjects who fail to demonstrate a 12% increase in 
FEV1 will not be eligible to take part in the study (see Section 8.1. for further 
information).
Percent reversibility will be calculated as follows:
(Post-bronchodilator FEV1 – Pre-bronchodilator FEV1 ) X 100
Pre-bronchodilator FEV1
11.1.2.
Electronic Daily Diaries
Participants will be issued with an electronic patient diary and instructed on how to 
complete it.  The following parameters will be recorded in the electronic patient diary
from Visits 1 to 6 only: 

Daily PEF (morning and evening) (see Section 11.1.2.1 for further details)

Daily asthma symptom scores (morning and evening) (see Section 11.1.2.2 for 
further details)

Number of inhalations of rescue albuterol/salbutamol inhalation aerosol used during 
the day and night.  Note:  Rescue medication taken as preventative treatment before 
exercise will be excluded from this count and should not be entered into the daily 
eDiary.
11.1.2.1.
Daily PEF
PEF will be measured in the morning and evening using a peak flow meter that will be 
issued to participants at Visit 1. The best of three attempts will be recorded in the 
electronic patient diary. 
PEF will be measured prior to any study medication and any rescue albuterol/salbutamol 
inhalation aerosol use.
11.1.2.2.
Asthma Symptom Scores
The following should be recorded in the electronic patient diary in the evening at bedtime 
(PM) before taking any rescue or study medication and before PEF measurements:

Day-time Symptom Score:
o
o
o
o
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.

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o
o
The following will be recorded every day in the eDiary in the morning (AM) upon rising 
before taking any rescue medication and before PEF measurement:

Night-time Symptom Score:
o
o
o
o
o
11.1.3.
Questionnaires
Questionnaires should be completed before any procedures are performed on the 
participant to avoid influencing the participant’s response. To avoid biasing responses, 
the participants should not be told the results of diagnostic tests prior to completing the 
questionnaires and it is recommended that the questionnaires be administered at the same 
time of day during each visit (as applicable).  Adequate time must be allowed to complete 
all items on the questionnaires; the questionnaires must be reviewed for completeness 
and, if necessary, the participant must be encouraged to complete any missing 
assessments or items.
11.1.3.1.
Childhood Asthma Control Test and Asthma Control Test
The Childhood Asthma Control Test (cACT) or Asthma Control Test (ACT) will be 
completed at Visit 1 and Visit 3 only as part of the eligibility and randomisation criteria.  
The cACT will be completed by participants aged 5 to 11 years old and the ACT will be 
completed by participants 12 to 17 years old.  
The cACT is a 7-item questionnaire to measure asthma control in children.  It is designed 
for completion by the participant and by the participant’s parent/legal guardian.  The 
child should complete questions 1-4 as independently as possible; however, if a child has 
difficulty with completion, the parent/legal guardian can provide assistance.  The 
parent/legal guardian should complete questions 5-7 without letting their child’s 
responses influence their answers.  The investigator or designated study site personnel 
should encourage the child not to skip questions on the cACT or take breaks during the 
completion of the paper questionnaire.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
which are protected by third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.

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The ACT is a five-item questionnaire, which has been developed as a measure of 
subjects’ asthma control that can be quickly and easily completed in clinical practice. The 
questions are designed to be self-completed by the subject. To avoid biasing responses, 
the subjects should not be told the results of diagnostic tests prior to completing the 
questionnaire and should be completed before any procedures are performed on the 
subject to avoid influencing the subject’s response. Adequate time should be allowed to 
complete all items on the ACT.
11.1.3.2.
Asthma Control Questionnaire ACQ-5
The ACQ-5 is a five-item questionnaire, which has been developed as a measure of 
participants’ asthma control that can be quickly and easily completed [Juniper, 2005a].  
The questions are designed to be self-completed by the participant.  
Participants will complete the ACQ-5 at Visits 3, 6 and 9.  The ACQ 5 includes five 
questions (concerning nocturnal awakening, waking in the morning, activity limitation, 
shortness of breath and wheeze) which enquire about the frequency and/or severity of 
symptoms over the previous week.  The response options for all these questions consist 
of a zero 
 to six 
) scale. A score of 
<0.75 indicates well-controlled asthma and a score 1.5 indicates poorly controlled 
asthma [Juniper, 2006]. A change of 0.5 in score suggests a clinically important change 
in score [Juniper, 2005b].
11.1.4.
Asthma exacerbation
An exacerbation is defined as deterioration of asthma requiring the use of systemic 
corticosteroids (tablets, suspension, or injection) for at least 3 days or a single depot 
corticosteroid injection or an in-patient hospitalisation or emergency department visit due 
to asthma that required systemic corticosteroids.  Investigators should follow current 
asthma management guidelines in the evaluation of patients with worsening of asthma 
and in the management of acute exacerbations.  Asthma exacerbations should not be 
recorded as an AE, unless they meet the definition of an SAE.  For the purposes of this 
study, asthma exacerbations will be collected and recorded on the exacerbations log in 
the eCRF.  The treatment details must also be recorded in the eCRF.
11.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment study (see Section 10). 
11.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from signing of the ICF until the follow-up call at the
time points specified in the SOA (Section 2).
CCI
CCI

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
All AEs will be collected from the start of treatment until the follow-up call at 
the time points specified in the SOA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 
24 hours, as indicated in Appendix 3. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.
11.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
11.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, [and non serious AEs of special 
interest (as defined in Section 3.3)], will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 10.3). Further information on follow-up procedures is given in Appendix 3.
11.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRBs/IECs, and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

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
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g. summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
11.2.5.
Death Events
For all deaths, whether or not they are considered SAEs, specific Death sections of the 
CRF will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported.
11.2.6.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until the last follow-up visit.

If a pregnancy is reported, the investigator should inform the CRO within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.

Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
11.2.7.
Treatment of Overdose
For this study, any dose of FF/VI combination or FF that is more than that permitted by 
the protocol within a 24-hour time period that results in clinical signs or symptoms will 
be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities including a 
morning cortisol (to be assessed based on the duration and magnitude of the 
overdose) until FF and / or VI (depending on treatment group) can no longer be 
detected systemically (at least 5 days from last dose administered).
3. Obtain a plasma sample for PK analysis within 1 to 5 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a case-
by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.

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Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
11.2.8.
Medical Device Deficiencies
Medical devices are being provided for use in this study. To fulfil regulatory reporting 
obligations worldwide, the investigator is responsible for the detection and 
documentation of events meeting the definitions of device deficiency that occur during 
the study with such devices.
The definition of a Medical Device Deficiency can be found in Section 14.7 Appendix 7.
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Appendix 7 of the protocol. 
11.2.8.1.
Time Period for Detecting Medical Device Deficiencies

Medical device deficiencies that result in an incident will be detected, 
documented, and reported during all periods of the study in which the medical 
device is used. 

If the investigator learns of any device deficiency at any time after a participant 
has been discharged from the study, and such device deficiency is considered 
reasonably related to a medical device provided for the study, the investigator will 
promptly notify the sponsor.

The method of documenting Medical Device Incidents is provided in Appendix 7.
11.2.8.2.
Follow-up of Medical Device Deficiencies

Follow-up applies to all participants, including those who discontinue study 
intervention or the study.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.
11.2.8.3.
Prompt Reporting of Medical Device Deficiencies to Sponsor

Device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a device 
deficiency.

The Medical Device Deficiency Report Form will be sent to the CRO by the 
electronic data collection tool. If the electronic data collection tool is unavailable, 
then the paper SAE data collection tool should be utilized.

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
The CRO will be the contact for the receipt of device deficiency reports.
11.2.8.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (e.g., the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC.
11.3.
Safety Assessments
Planned time points for all safety assessments are provided in the SOA.
11.3.1.
Physical Examination

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be recorded.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
11.3.2.
Oropharyngeal Examination
Oropharyngeal examination for visual evidence of oral candidiasis will be carried out at 
as outlined in the SOA. If the visual oropharyngeal examination is abnormal prior to 
randomisation the participant must not be randomised.  
If there is any visual clinical evidence of oral candidiasis during the double-blind 
treatment period of the study, subjects may continue in the study and appropriate anti-
infective therapy should be instituted at the discretion of the investigator. If the subject 
requires therapy with a medication prohibited by the protocol, the subject should be 
treated appropriately and discontinued from study treatment. All visual clinical evidence 
of candidiasis must be reported as an AE.
The results of the oropharyngeal examinations and any relevant pharmacotherapy will be 
recorded in the subject’s clinic notes and eCRF.
11.3.3.
Vital Signs
Vital signs (systolic and diastolic blood pressure and heart rate) will be measured at 
Screening only. The measurement will be taken after 5 minutes rest prior to spirometry.  
One reading of blood pressure and pulse will be taken and will only be repeated if out of 
the normal range.    

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11.3.4.
Electrocardiograms
12-Lead electrocardiogram measurements will be performed at Visit 1, Visit 9, and the 
Early Treatment Discontinuation/Early Withdrawal Visit.  
The 12-lead ECG will be recorded at 25 mm/sec and will consist of a recording of leads I, 
II, III, aVR, aVL, aVF and V1 to V6 and 10 seconds recording of lead II (rhythm strip).  
At least 3 complete evaluable complexes per lead will be recorded. The following ECG 
parameters will be determined.  Single 12-lead ECG will be obtained as outlined in the 
SOA using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. Refer to Section 10.1.2 for QTc withdrawal criteria and 
additional QTc readings that may be necessary.  
Further details on ECG measurements will be provided in the SRM.
11.3.5.
Clinical Safety Laboratory Assessments
No clinical laboratory tests will be performed in this study, except for the collection of a 
2 ml fasting glucose blood sample at the Screening Visit (Visit 1) and Visit 9 (End of 
Treatment) or at the ETD/EW visit if applicable. A central laboratory will be used.
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the CRF.
11.4.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
11.5.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
11.6.
Genetics
A 2 mL saliva sample for deoxyribonucleic acid (DNA) isolation will be collected from 
participants who have consented to participate in the genetics analysis component of the 
study. Participation is optional. Participants who do not wish to participate in the genetic 
research may still participate in the study.
In the event of DNA extraction failure, a replacement genetic sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement 
sample unless it was included in the original consent.
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM.

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11.7.
Biomarkers
Biomarkers are not evaluated in this study.
11.8.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
12.
STATISTICAL CONSIDERATIONS
12.1.
Sample Size Determination
12.1.1.
Sample Size Assumptions
Approximately 870 participants will be randomised in this study in a ratio of 1:1 giving 
435 randomised participants per arm in the 5-17 years old population. There will be 652 
randomised participants who will be 11 years old or less at screening, giving 326 
randomised participants per arm in the 5-11 years old population.
12.1.1.1.
Sample Size Assumptions for 5-17 Years Old Population
The sample size calculation for the 5-17 years old population is based on the primary 
efficacy endpoint of weighted mean FEV1 (0-4 hours). The sample size allows for up to 
20% of participants to not contribute to the primary endpoint giving a total of 348 
evaluable participants per arm.
The standard deviation is assumed to be 280mL for 5-11 year olds and 500mL for 12-17 
year olds based on previous studies. Using the assumed representation across the age 
ranges (652 and 218 randomized participants, respectively), a standard deviation of 
348mL has been assumed for the 5-17 years old population based on a weighted average 
of the variances (i.e. assuming equal means).
The sample size has 93% power, based on a true population difference of 90mL and 
significance declared at the two-sided 5% significance level. The smallest observed effect 
predicted to result in a statistically significant difference between treatment groups is 
52mL.
12.1.1.2.
Sample Size Assumptions for 5-11 Years Old Population
The sample size calculation for the 5-11 years old population is based on the primary 
efficacy endpoint of AM PEF and on the nominated powered secondary endpoint of 
change from baseline in rescue-free 24-hour periods. The sample size allows for up to 4% 
of participants to not contribute to either endpoint giving a total of 312 evaluable 
participants per arm.
For the primary endpoint of AM PEF, a standard deviation of 30 L/min is assumed, based 
on previous studies. The sample size has 91% power, based on a true population 

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difference of 8 L/min and significance declared at the two-sided 5% significance level. 
The smallest observed effect predicted to result in a statistically significant difference 
between treatment groups is 4.7 L/min.  
For the nominated powered secondary endpoint of change from baseline in rescue-free 
24-hour periods, a standard deviation of 30% is assumed, based on previous studies. The 
sample size has 99% power, based on a true population difference of 10% and 
significance declared at the two-sided 5% significance level. The smallest observed effect 
predicted to result in a statistically significant difference between treatment groups is 
4.7%.  
Assuming a correlation of 0.1 between the primary endpoint and the nominated powered 
secondary endpoint, the overall power for both endpoints in the 5-11 years old population 
is 90%.
12.1.2.
Sample Size Sensitivity
The standard deviation assumptions are based on estimates from previous studies. Table 
3 presents the power achieved for the FF/VI versus FF treatment comparison in the 5-17 
years old population with the proposed sample size, should the assumption around the 
standard deviation of the data change. Table 4 presents the power achieved for the FF/VI 
versus FF treatment comparison in the 5-11 years old population with the proposed 
sample, should the assumptions around the standard deviation of the data change. In each 
case, the actual assumptions used in the sample size calculations are shaded in grey.
Table 3
Impact of Standard Deviation on Power for 5-17 Years Old 
Population
Standard Deviation
Power (%)
Weighted Mean FEV1 (0-4 hours):
300mL
98
325mL
95
348mL
93
375mL
89
400mL
84
Table 4
Impact of Standard Deviation on Power for 5-11 Years Old 
Population
Standard 
Deviation
Power (%) for 
Individual 
Endpoints
Overall Power (%) 
Across Both 
Endpoints
AM PEF:
% Rescue-free 24 hr periods:
20 L/min
20%
>99
>99
>99
AM PEF:
% Rescue-free 24 hr periods:
25 L/min
25%
98
>99
98
AM PEF:
% Rescue-free 24 hr periods:
30 L/min
30%
91
99
90
AM PEF:
% Rescue-free 24 hr periods:
35 L/min
35%
82
95
77

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Standard 
Deviation
Power (%) for 
Individual 
Endpoints
Overall Power (%) 
Across Both 
Endpoints
AM PEF:
% Rescue-free 24 hr periods:
40 L/min
40%
70
88
62
12.1.3.
Sample Size Re-estimation
No sample size re-estimation is planned.
12.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Total Population
The Total Population will comprise all participants screened and for 
whom a record exists on the study database and will be used for the 
tabulation and listings of reasons for withdrawal before 
randomisation.
ITT (5-17 Years Old) 
Population
The ITT (5-17 Years Old) Population will comprise all participants 
randomised to treatment and who received at least 1 dose of study 
medication. Randomised participants will be assumed to have 
received study medication unless definitive evidence to the contrary 
exists. Outcomes will be reported according to the randomised
treatment allocation. This will constitute one of the two primary 
populations for all efficacy measures and safety measures.
ITT (5-11 Years Old) 
Population
The ITT (5-11 Years Old) Population will be a subset of the ITT (5-
17 Years Old) Population for subjects aged 11 years old or younger 
at screening. Outcomes will be reported according to the 
randomised treatment allocation. This will constitute one of the two 
primary populations for all efficacy measures and safety measures.
12.3.
Statistical Analyses
12.3.1.
Hypotheses
The primary efficacy endpoint for the 5-17 years old population is weighted mean FEV1
(0-4 hours). For the 5-11 years old population the primary efficacy endpoint is the change 
from baseline in AM PEF and the nominated powered secondary endpoint is the change 
from baseline in rescue-free 24-hour periods. For each of these endpoints there will be a 
single inequality comparison of FF/VI versus FF. Demonstration of efficacy for each of 
these inequality comparisons will be based on a hypothesis testing approach, whereby the 
null hypothesis is that there is no difference between treatment groups for the endpoint of 

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interest and the alternative hypothesis is that there is a difference between treatment 
groups.  
A 2-sided 5% risk associated with incorrectly rejecting any of the null hypotheses 
(significance level) is considered acceptable for this study. As the comparisons on the 5-
17 years old population and the 5-11 years old population are being made for different 
purposes they will each have distinct multiple testing strategies which will be assessed 
separately.  
For each of the two populations, in order to account for multiplicity across the key 
endpoints, a step-down closed testing procedure will be applied to the inequality 
comparison of FF/VI versus FP whereby this comparison will be required to be 
significant at the 0.05 level for the primary endpoint in order to infer on the secondary 
endpoints and inference for a test in the pre-defined hierarchy of secondary endpoints is 
dependent upon statistical significance having been achieved for the previous comparison 
in the hierarchy of secondary endpoints. If a given statistical test fails to reject the null 
hypothesis of no treatment difference at the significance level of 0.05, then all tests lower 
down in the hierarchy will be interpreted as descriptive only.
Figure 2
Statistical Testing Strategy for 5-17 Years Old Population
Testing of each endpoint is dependent on significance at the 0.05 level having been achieved 
on the previous endpoint in the hierarchy.
Primary Efficacy Endpoint
1) Weighted mean FEV1 (0-4 hours):
FF/VI vs. FF
Secondary Efficacy Endpoints
2) Rescue-free 24 hour periods:
FF/VI vs. FF
3) Symptom-free 24 hour periods:
FF/VI vs. FF
4) AM FEV1:
FF/VI vs. FF
5) AM PEF:
FF/VI vs. FF
6) ACQ:
FF/VI vs. FF

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Figure 3
Statistical Testing Strategy for 5-11 Years Old Population
The treatment comparisons defined as part of the multiple testing strategy will be limited 
to the specified key comparisons shown in Figure 2 and Figure 3. Analyses of other 
efficacy measures in either population for the FF/VI versus FF treatment comparison are 
nested under the secondary efficacy measures and no multiplicity adjustment is planned 
for these other efficacy endpoints.
In each population, if significance is achieved for the FF/VI versus FF treatment 
comparison on the primary efficacy endpoint, then the secondary endpoints will be tested 
in a closed-testing manner using the hierarchy of comparisons. If significance is also 
achieved for each of the secondary efficacy endpoints, then all other efficacy endpoints 
will be tested for the FF/VI versus FF treatment comparison without further multiplicity 
adjustment.
12.3.2.
Treatment Comparisons
12.3.2.1.
Primary Comparison of Interest
The primary treatment comparison for the 5-17 years old population will be FF/VI versus 
FF for the primary efficacy endpoint of weighted mean FEV1 (0-4 hours) at week 12.
The primary treatment comparison for the 5-11 years old population will be FF/VI versus 
FF for the primary efficacy endpoint of change from baseline in AM PEF averaged over 
weeks 1-12.
12.3.2.2.
Other Comparisons of Interest
The primary treatment comparison of FF/VI versus FF will also be performed for the 
secondary and other efficacy endpoints.
Testing of each endpoint is dependent on significance at the 0.05 level having been achieved 
on the previous endpoint in the hierarchy.
Primary Efficacy Endpoint
1) AM PEF:
FF/VI vs. FF
Secondary Efficacy Endpoints
2) Rescue-free 24 hour periods:
FF/VI vs. FF
3) Symptom-free 24 hour periods:
FF/VI vs. FF
4) AM FEV1:
FF/VI vs. FF
5) ACQ:
FF/VI vs. FF
6) Weighted mean FEV1 (0-4 hours):
FF/VI vs. FF

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12.3.3.
Key Elements of Analysis Plan
The FF/VI 50/25 mcg and FF/VI 100/25 mcg treatment groups will be combined into one 
FF/VI treatment group for the purpose of reporting. Similarly, the FF 50 mcg and FF 100 
mcg treatment groups will be combined into one FF treatment group for the purpose of 
reporting.
In this study, every effort will be made for participants who withdraw from study 
medication to remain in the study and continue with the normal visit schedule providing 
all of the expected data. The main analysis for all efficacy endpoints will evaluate the 
primary de facto estimand of treatment policy (effectiveness-type estimand): the mean 
difference between treatment groups for the time point of interest regardless of whether 
the participant remained on-treatment. This means that for any given endpoint, all 
available data for a participant will be used including any data that was collected after the 
participant was withdrawn from study medication. Specific details for inclusion will be 
detailed in the reporting and analysis plan (RAP), but in general the minimum data 
required will be a baseline evaluation and at least one post-baseline evaluation. For the 
powered endpoints only, a secondary de jure efficacy-type estimand will be evaluated by 
using only on-treatment data.
Endpoints relating to daily diary assessments will be calculated from all available data 
over the time period of interest. In addition to the weeks 1-12 time period, smaller time 
periods will also be defined in order to perform sensitivity analyses. However for any 
given time-period that is defined, no imputations will be performed on missing daily 
diary data within that time period. Any defined time period for a diary data endpoint will 
be considered missing if less than 2 days (i.e., 24-hr periods) are recorded in that time 
period.
For the derivation of the percentage of symptom-free 24-hour periods, a given 24-hour 
period will be considered as missing if both the day-time and night-time data are missing 
or if one is symptom-free but the other is missing. However, if either the daytime or the 
night-time has symptoms then the 24-hour period will be considered not symptom-free. 
The same principals will be applied to the derivation of the percentage of rescue-free 24-
hour periods. 
Any tests for interactions will be 2-sided at the 10% level of significance. In all cases, if 
any assumptions of the proposed method of analyses are not met, alternative methods of 
analyses will be used.
It is anticipated that a large number of centers will participate in the study. Therefore, it is 
likely that many centers will enroll very small number of participants. Consequently, all 
centers within the same country will be pooled. In addition, if there are any countries 
enrolling very small numbers in total (<12), these countries will be pooled with another 
country within a similar geographical region. All amalgamations will be finalized and 
documented prior to unblinding the treatment codes. These amalgamations will be used 
wherever region is incorporated into the analysis.

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Baseline values for each endpoint will be those used as appropriate from either Visit 2 or 
Visit 3 for clinic visit endpoints or derived from the last 7 days of the run-in daily diary 
prior to the randomisation of the patient.
12.3.3.1.
Primary Efficacy Analyses
12.3.3.1.1. Primary Efficacy Analyses for 5-17 Years Old Population
To address the primary effectiveness-type estimand, the primary analysis on the ITT (5-
17 Years Old) population will include data from all participants regardless of whether or 
not they were on-treatment at the time of their week 12 serial FEV1 measurements. 
To address the secondary efficacy-type estimand, the analysis will be repeated using only 
on-treatment data.
The primary endpoint of weighted mean FEV1 (0-4 hours) at week 12 will be derived 
using the post-dose assessments (after 30 minutes and 1, 2, 3, 4 hours) with their actual 
times and using the pre-dose assessment as the 0 hour measurement. The weighted mean 
will be calculated as the average area under the curve using the trapezoidal rule, and 
dividing by the relevant time interval (i.e. the time between the actual time of dose and 
the actual time of the last FEV1 measurement being used). 
The weighted mean will be analysed using an analysis of covariance (ANCOVA) model 
with effects due to baseline pre-dose FEV1, region, sex, age and treatment group. The 
adjusted means for each treatment and the estimated treatment differences for the 
treatment comparison will be presented together with 95% confidence intervals for the 
difference and a p-value for the treatment comparison.
12.3.3.1.2. Primary Efficacy Analyses for 5-11 Years Old Population
To address the primary effectiveness-type estimand, the primary analysis on the ITT (5-
11 Years Old) population will include all available AM PEF data from weeks 1-12, 
regardless of whether the participant was still on-treatment at the time of the 
measurement.
To address the secondary efficacy-type estimand, the analysis will be repeated using only 
on-treatment data.
The primary endpoint of change from baseline in AM PEF averaged over weeks 1-12 will 
be calculated for each participant using only data that are from the first 84 calendar days 
after randomisation.
The primary analysis will be performed using an ANCOVA model with effects due to 
baseline AM PEF, region, sex, age and treatment group. The adjusted means for each 
treatment and the estimated treatment differences for the treatment comparison will be 
presented together with 95% confidence intervals for the difference and a p-value for the 
treatment comparison.
A sensitivity analysis for the primary effectiveness-type estimand will be performed 
including all data from weeks 1-12 (regardless of treatment state). For this analysis, the 

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weeks 1-12 time period will be split into 6 separate time periods: Weeks 1-2, Weeks 3-4, 
Weeks 5-6, Weeks 7-8, Weeks 9-10 and Weeks 11-12. The data will then be analysed 
using a mixed model repeated measures (MMRM) model, which will allow for effects 
due to baseline AM PEF, region, sex, age, time period and treatment group. This model 
will also contain a time period-by-baseline interaction term and a time period-by-
treatment interaction term. Missing data are not implicitly imputed in this analysis. 
However, all non-missing data for a participant will be used within the analysis to 
estimate the average treatment effect over Weeks 1-12.
12.3.3.2.
Secondary Efficacy Analyses
Change from Baseline in the Percentage of Rescue-free 24-Hour Periods for the 
ITT (5-11 Years Old) Population
To address the primary effectiveness-type estimand, the primary analysis on the ITT (5-
11 Years Old) population will include all available data from weeks 1-12, regardless of 
whether the participant was still on-treatment at the time of the question.
To address the secondary efficacy-type estimand, the analysis will be repeated using only 
on-treatment data.
The powered secondary endpoint of change from baseline in the percentage of rescue-
free 24 hour periods over weeks 1-12 will be calculated for each participant using only 
data that are from the first 84 calendar days after randomisation.
The primary analysis will be performed using an ANCOVA model with effects due to 
baseline, region, sex, age and treatment group. The adjusted means for each treatment 
and the estimated treatment differences for the treatment comparison will be presented 
together with 95% confidence intervals for the difference and a p-value for the treatment 
comparison.
A sensitivity analysis for the primary effectiveness-type estimand will be performed 
including all data from weeks 1-12 (regardless of treatment state). For this analysis, the 
weeks 1-12 time period will be split into 6 separate time periods: Weeks 1-2, Weeks 3-4, 
Weeks 5-6, Weeks 7-8, Weeks 9-10 and Weeks 11-12. The data will then be analysed 
using a mixed model repeated measures (MMRM) model, which will allow for effects 
due to baseline, region, sex, age, time period and treatment group. This model will also 
contain a time period-by-baseline interaction term and a time period-by-treatment 
interaction term. Missing data are not implicitly imputed in this analysis. However, all 
non-missing data for a participant will be used within the analysis to estimate the average 
treatment effect over Weeks 1-12.
Change from Baseline in the Percentage of Rescue-free 24-Hour Periods for the 
ITT (5-17 Years Old) Population
The change from baseline in the percentage of rescue-free 24 hour periods over weeks 1-
12 is a secondary endpoint for the 5-17 years old population and will be calculated for 
each participant using only data that are from the first 84 calendar days after 

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randomisation. The primary analysis will be performed using an ANCOVA model with 
effects due to baseline, region, sex, age and treatment group.
Change from Baseline in the Percentage of Symptom-free 24-Hour Periods
The change from baseline in the percentage of symptom-free 24 hour periods over weeks 
1-12 will be calculated for each participant using only data that are from the first 84 
calendar days after randomisation. The primary analysis will be performed using an 
ANCOVA model with effects due to baseline, region, sex, age and treatment group.
Change from Baseline in AM FEV1
Change from baseline in AM FEV1 at week 12 will be defined using the pre-dose FEV1
assessment at the Week 12 clinic visit. Analysis will be performed using an MMRM 
model, which will allow for effects due to baseline FEV1, region, sex, age, visit and 
treatment group. This model will also contain a visit-by-baseline interaction term and a 
visit-by-treatment interaction term. Missing data are not implicitly imputed in this 
analysis. However, all non-missing pre-dose data for a participant taken at scheduled 
visits 3, 4 and 5 (weeks 4, 8 and 12) will be used within the analysis to estimate the week 
12 treatment effects.
Change from Baseline in ACQ-5
Change from baseline in ACQ-5 at week 24 will be analysed using an MMRM model, 
which will allow for effects due to baseline, region, sex, age, visit and treatment group. 
This model will also contain a visit-by-baseline interaction term and a visit-by-treatment 
interaction term. Missing data are not implicitly imputed in this analysis. However, all 
non-missing data for a participant taken at scheduled visits 5 and 8 (weeks 12 and 24) 
will be used within the analysis to estimate the week 24 treatment effects.
Weighted Mean FEV1 (0-4 hours) for 5-11 Years Old Population
Weighted mean FEV1 (0-4 hours) at week 12 is a secondary endpoint for the 5-11 years 
old population. It will be analysed using an analysis of covariance (ANCOVA) model 
with effects due to baseline FEV1, region, sex, age and treatment group. 
Change from Baseline in AM PEF for 5-17 Years Old Population
The change from baseline in PM PEF over weeks 1-12 is a secondary endpoint for the 5-
17 years old population and will be calculated for each participant using only data that 
are from the first 84 calendar days after randomisation. The primary analysis will be 
performed using an ANCOVA model with effects due to baseline, region, sex, age and 
treatment group.
Change from Baseline in PM PEF
The change from baseline in PM PEF over weeks 1-12 will be calculated for each 
participant using only data that are from the first 84 calendar days after randomisation. 
The primary analysis will be performed using an ANCOVA model with effects due to 
baseline, region, sex, age and treatment group.

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12.3.3.3.
Other Analyses
The reporting and analysis of other endpoints as specified in the protocol will be provided 
in the RAP.
12.3.4.
Interim Analyses
There are no interim analyses planned during this study.

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13.
REFERENCES
Fanta CH.  Asthma.  N Engl J Med. 2009;360(1):1002-14.
Global Initiative for Asthma (GINA).  Global strategy for asthma management and 
prevention 2015. Available at: www.ginasthma.org.
Global Initiative for Asthma (GINA).  Global strategy for asthma management and 
prevention 2016. Available at: http://ginasthma.org/2016-gina-report-global-strategy-for-
asthma-management-and-prevention.
Investigator’s Brochure for FF, GlaxoSmithKline Document Number: 
GM2004/00283/11; August 2016.
Investigator’s Brochure for FF/VI, GlaxoSmithKline Document Number: 
RM2008/00012/09; September 2016.
Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying 'well-
controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. 
Respir Med 2006;100:616-621.
Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med 2005b;99:553-
558.
Juniper EF, Svensson K, Mörk AC, Ståhl E. Modification of the Asthma Quality of Life 
Questionnaire (standardised) in patients 12 years and older. Health and Quality of Life 
Outcomes 2005a;3:58.
Kelly HW, et al. Effects of inhaled corticosteroids in childhood on adult height. N Engl J 
Med 2012;367: 904-12.
National Institutes of Health (NIH).  Guidelines for the Diagnosis and Management of 
Asthma - Expert Panel Report 3, 2007.  U.S. Department of Health and Human Services, 
Bethesda, MD; 2007.  NIH Publication No. 07-4051.
Pedersen S, O'Byrne P.  A comparison of efficacy and safety of inhaled corticosteroids in 
asthma.  Allergy. 1997;52(39 Suppl):1-34.
Peters SP, Bleeker ER, Canonica GW, Park YB, Ramirez R, et al.  Serious asthma events 
with budesonide plus formoterol vs. budesonide alone.  N Engl J Med 2016;375:850-60.
Price D, Robertson A, Bullen K, Rand C, Horne R, Standinger H.  Improved adherence 
with once-daily versus twice-daily dosing of mometasone furoate administered via a dry 
powder inhaler:  a randomized open-label study. BMC Pulmonary Medicine. 2010;10:1-
9.

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Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J 2012; 40: 1324–1343.
Stempel DA, Raphiou I, Kral KM, Yeakey A, Emmett AH, et al. Serious asthma events 
with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med 2016a;374:1822-
30.
Stempel DA, Szefler S, Pedersen S, Zeiger, RS, Yeakey AM, et al.  Safety of adding 
salmeterol to fluticasone propionate in children with asthma.  N Engl J Med 
2016b;375:840-9.
Toy EL, Beaulieu NU, McHale JM, Welland TR, Plauschinat CA, Swensen A, Duh MS. 
Treatment of COPD: relationships between daily dosing frequency, adherence, resource 
use, and costs. Respir Med 2011;105:435-44.
Wells KE, Peterson EL, Ahmedani BK, et al. Real-world effects of once vs greater daily 
inhaled corticosteroid dosing on medication adherence. Ann Allergy Asthma Immunol. 
2013 Sep;111(3):216-20.
Zhang L, Prietsch SOM.  Effect of inhaled corticosteroids on linear growth in children 
with persistent asthma.  Paediatric Respir Rev. 2014;15(4):322–4.

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14.
APPENDICES
14.1.
Appendix 1: Abbreviations and Trademarks
ACQ
Asthma Control Questionnaire
AE
Adverse event
AM
Ante meridiem (morning)
ANCOVA
Analysis of covariance
ATS
American Thoracic Society
BID
Twice daily
BMI
Body Mass Index
cACT
Childhood asthma control test
CDC
Centers for Disease Control and Prevention
CI
Confidence interval
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
CRF
Case report form
CRO
Contract Research Organisation
CYP3A4
Cytochrome P450 3A4
dl
Decilitre
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
ERS
European Respiratory Society
ETD
Early treatment discontinuation
EW
Early withdrawal
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FF
Fluticasone furoate
FF/VI
Fluticasone furoate/vilanterol
FP
Fluticasone propionate
FRP
Females of reproductive potential
FU
Follow-up
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
HPA
Hypothalamic-pituitary adrenal axis
ICF
Informed consent document
ICS
Inhaled corticosteroid
IEC
Independent ethics committee
IgE
Immunoglobulin E
IL
Interleukin
IRB
Institutional review board
ITT
Intent-to-treat

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IVRS/IWRS
Interactive Voice Response System/Interactive Web Response 
System
L/Min
Litre per Minute
LABA
Long-acting beta agonist
LOCS
Lens opacities classification system
LTRA
Leukotriene receptor antagonist
mcg
Microgram
MDI
Metered dose inhaler
mol/L
Mole per Litre
MMRM
Mixed model repeated measures
MSDS
Material Safety Data Sheet
msec
Millisecond
NIH
National Institutes of Health
PDCO
Paediatric Committee
PEF
Peak expiratory flow
PIP
Paediatric investigational plan
PM
Post meridiem (evening)
QTcB
QT interval corrected for heart rate according to Bazett’s formula
QTcF
QT interval corrected for heart rate according to Fridericia’s formula
RAP
Reporting and Analysis Plan
SABA
Short-acting beta agonist
SDS
Standard Deviation Score
SAE
Serious adverse event
SAMA
Short-acting muscarinic antagonist
SAWP
Scientific Advice Working Party
SOA
Schedule of activities
SRM
Study reference manual
SUSAR
Suspected unexpected serious adverse reactions
TC
Telephone call
V
Visit
VI
Vilanterol
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELLIPTA
Combivent
NUCALA
Dulera
RELVAR
Symbicort
SERETIDE
Xolair

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14.2.
Appendix 2: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH)
Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Committees Structure
Not applicable.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicentre studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

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
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
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 randomisation 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.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 

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Source Documents

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 CRF or entered in the eCRF 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 source data 
agreement or source data verification form.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development

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14.3.
Appendix 3: Adverse Events: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study treatment, whether or not considered 
related to the study treatment.

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 study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g. ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (ie, not 
related to progression of underlying disease).

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 before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug 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 it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses 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. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of 
an AE or SAE.

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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’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 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which 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.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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 inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant 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 AE. 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 persistent disability/incapacity

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 (eg, sprained ankle) which may interfere with 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 SAE 
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 participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.
Examples of such events include 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.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records 
before submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.

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Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/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 underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in 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 in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any post-
mortem findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to t GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper SAE data collection tool (see next Section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next Section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

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
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames.

Contacts for SAE reporting can be found in the SRM.

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14.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal 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 before study enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 5. 

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Table 5
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed.  If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least X, corresponding to time needed to eliminate study treatment plus 30 days for 
study treatments with genotoxic potential  after the last dose of study treatment 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test 

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
Additional pregnancy testing is not required during the treatment period 
corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential  after the last dose of study treatment and as 
required locally 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 5, 10, 25 mIU/mL will be performed and 
assayed in a certified laboratory OR and assayed in the central laboratory OR using 
the test kit provided by the central laboratory / provided by the sponsor /approved by 
the sponsor and in accordance with instructions provided in its package insert  
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 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. 

Any female participant who becomes pregnant while participating will discontinue 
study treatment

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14.5.
Appendix 5: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a saliva sample will be collected for deoxyribonucleic acid (DNA)
analysis.

DNA samples will be used for research related to [FF/VI or FF] or [asthma] and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests) related to [FF/VI or FF] (or study treatments of this drug class), and [asthma]. 
Genetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome [or analysis of the entire genome] 
(as appropriate).

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on [FF/VI or FF] (or study treatments of 
this class) or [asthma] continues but no longer than [15] years or other period as per 
local requirements.

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14.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology (in alignment with 
FDA premarketing clinical liver safety guidance.  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf).
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within 
baseline (see MONITORING below)

Do not restart/rechallenge participant with 
study treatment unless allowed per protocol 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Only in those with underlying chronic 
Hepatitis B at study entry (identified by 
positive Hepatitis B surface antigen) 
quantitative Hepatitis B DNA and 
Hepatitis delta antibody5.

Obtain blood sample for pharmacokinetic 
(PK) analysis, within insert time interval 
recommended by clinical 

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Liver Chemistry Stopping Criteria 
and GSK Medical Governance approval is 
granted.

If restart/rechallenge not  allowed or not 
granted, permanently discontinue study 
treatment and continue participant 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 participants 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 participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
pharmacokinetics representative after 
last dose6

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 
formincluding acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page
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 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

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.

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1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant 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 participants 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 (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If Hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of Hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants 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 PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss 
participant safety. 

Participant can continue study treatment 

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline.

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References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 

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14.7.
Appendix 7: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device 
Studies

The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155 and European Medical Device Regulation (MDR) 2017/745 for 
clinical device research (if applicable). 

Both the investigator and the sponsor will comply with all local medical device 
reporting requirements for medical devices.

The detection and documentation procedures described in this protocol apply to 
all GSK medical devices provided for use in the study (see Section 9.1.1. for the 
list of GSK medical devices).
14.7.1.
Definition of Medical Device AE and ADE
Medical Device AE and ADE Definition 

An AE is any untoward medical occurrence, in a clinical study participant, users, 
or other persons, temporally associated with the use of study intervention whether 
or not considered related to the investigational medical device. 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 an investigational medical device. This definition 
includes events related to the investigational medical device or comparator and 
events related to the procedures involved.

An adverse device effect (ADE) is  an AE related to the use of an investigational 
medical device. This definition includes any AE resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device as well as any 
event resulting from use error or from intentional misuse of the investigational 
medical device.
14.7.2.
Definition of Medical Device SAE, SADE and USADE
A Medical Device SAE is any serious adverse event that:
g.
Led to death 
h.
Led to serious deterioration in the health of the participant, that either resulted in:

A life-threatening illness or injury. The term ‘life-threatening' in the definition 
of ‘serious' refers to an event in which the participant 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.

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
A permanent impairment of a body structure or a body function.

Inpatient or prolonged hospitalization. Planned hospitalization for a pre-
existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered an SAE.

Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function
i.
Led to fetal distress, fetal death or a congenital abnormality or birth defect
j.
Is a suspected transmission of any infectious agent via a medicinal product
SADE definition

A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.

Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate.
Unanticipated SADE (USADE) definition

An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a 
serious adverse device effect that by its nature, incidence, severity or outcome has 
not been identified in the current version of the risk analysis report (see Section
3.3).
14.7.3.
Definition of Device Deficiency
Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and information supplied by the manufacturer.
14.7.4.
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies
AE, SAE and Device Deficiency Recording

When an AE/SAE/device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/device deficiency 
information in the participant’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the appropriate form.

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
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the CRO in lieu of completion of the CRO/AE/SAE/device 
deficiency form.

There may be instances when copies of medical records for certain cases are 
requested by the CRO. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records 
before submission to the CRO.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency.
o
A remedial action is any action other than routine maintenance or servicing of 
a medical device where such action is necessary to prevent recurrence of a 
device deficiency. This includes any amendment to the device design to 
prevent recurrence.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following 
categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category used for rating 
the intensity of an event; both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, not when it is rated as severe.

Other measures to evaluate AEs and SAEs may be utilized (e.g., National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]).
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

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
The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) in his/her 
assessment.

For each AE/SAE/device deficiency, the investigator must document in the 
medical notes that he/she has reviewed the AE/SAE/device deficiency and has 
provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE/SAE/device deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide the CRO 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 the CRO within 24 hours of 
receipt of the information.
14.7.5.
Reporting of SAEs
SAE Reporting to GSK via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to the CRO will be the electronic 
data collection tool.

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
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next table) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken offline to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next Section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper Data CollectionTool

Facsimile transmission of the SAE data collection tool is the preferred method to 
transmit this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE paper data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE paper data collection tool within the designated 
reporting time frames.

Contacts for SAE reporting can be found in the SRM.
14.7.6.
Reporting of SADEs

SADE Reporting to GSK 

NOTE: There are additional reporting obligations for medical device deficiencies
that are potentially related to SAEs that must fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies. 

Any device deficiency that is associated with an SAE must be reported to the CRO
within 24 hours after the investigator determines that the event meets the definition 
of a device deficiency.

The CRO will review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These device deficiencies will be 
reported to the regulatory authorities and IRBs/IECs as required by national 
regulations.

Contacts for SAE reporting can be found in the SRM.

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14.8.
Appendix 8: Country-specific requirements
For Germany only exclusion criterion 8 will be as follows:
Exclusion of participants with QTc > 450 msec or those with any other significant 
abnormality in the screening 12-lead ECG.

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14.9.
Appendix 9: COVID-19 Measures
Protocol Title: A randomised, double-blind, parallel group, multicentre, stratified, study 
evaluating the efficacy and safety of once daily fluticasone furoate/vilanterol inhalation 
powder compared to once daily fluticasone furoate inhalation powder in the treatment of 
asthma in participants aged 5 to 17 years old (inclusive) currently uncontrolled on inhaled 
corticosteroids
Protocol Number: HZA107116/04 Amendment 4
Compound Number 
or Name:
GW685698+GW642444
Brief Title: A double-blind, parallel group study to evaluate the safety and efficacy of 
fluticasone furoate/vilanterol combination compared to fluticasone furoate in the 
treatment of asthma in participants (aged 5 to 17 years old inclusive)
Study Phase: IIIA
Approval Date: 24-AUG-2020
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF 
PROTOCOL HZA107116
Overall Rationale for this Appendix 
COVID-19 pandemic may impact the conduct and delivery of clinical studies. Challenges 
may arise from quarantines, site closures, travel limitations and/or interruptions to the 
supply chain for the investigational product. These challenges may lead to difficulties in 
meeting protocol-specified procedures, 
including administering 
or 
using 
the 
investigational product, adhering to protocol-mandated visits, laboratory/diagnostic testing
and study timelines. 
HZA107116 is included in the Paediatric Investigation Plan (PIP) for Relvar™ Ellipta™, 
with a commitment to deliver to agreed European Medicines Agency (EMA) timelines. 
The COVID-19 pandemic may delay study timelines due to low recruitment rates as a 
result of site closures and travel limitations and may lead to a greater number of early 
withdrawals.

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This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic and to ease the burden on site staff, subjects and parents by 
allowing flexibility in the way the visits are conducted in an attempt to counter the impact 
of COVID-19 pandemic on recruitment and retention. The purpose of the appendix is to 
provide information on the measures to be taken to protect participants’ safety, welfare and 
rights, promote data integrity and deliver the study within the agreed timelines of the PIP. 
These measures will remain in place until study completion.
Study Procedures During COVID-19 Pandemic
During the special circumstances caused by the current COVID-19 pandemic, sites should 
consider specific public health guidance, the impact of any travel restrictions implemented 
by local/regional health authorities and local institutions, and individual benefit /risk when 
making enrollment and treatment decisions for trial participants.
Clinical investigators should document in site files and in source data, how COVID related 
restrictions or challenges may have impacted study conduct for any participants. Missing 
or delayed protocol required data/visits due to COVID-19 should be noted in participant 
notes and recorded as a COVID-19 protocol deviation. 
Protocol Defined Procedures/Visits:
Where applicable country and local regulations and infrastructure for home healthcare 
allow, home healthcare may take place at a location other than the clinical trial site to 
perform study assessments, which may include collection of blood and urine samples, 
measurement of vital signs, weight, spirometry and dispensation and collection of study 
drug (at the discretion of the Investigator). It is the responsibility of the investigator to 
inform the CRO when this occurs and to document in source notes.

Remote visits may be performed at the participant’s home by qualified study 
personnel, unless the Investigator deems that a site visit is necessary.

Additional unscheduled safety assessments such as routine blood sampling may be 
performed at the discretion of the Investigator including in the participant’s home, 
if deemed necessary. Biological samples may be collected at a different location, 
other than the study site (e.g., at participant’s home) by qualified study personnel 
or at a local medical facility according to standard operating procedures and 
applicable regulations (see note). Biological samples should not be collected if they 
cannot be processed in a timely manner or appropriately stored until the intended 
use. 

Spirometry may be collected by a home health nurse, at visits indicated in the SOA, 
to alleviate the burden on subjects of frequent visits to the study site. The spirometry 
must be done using a Masterscope provided by the spirometry vendor, ERT (with 
central over-read).  Nurses will be experienced in spirometry and will be trained by 
ERT. 
NOTE: Serial spirometry at Visit 6 must be done in the clinic.

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
If visits to a site/home are not feasible, then the medical evaluation of asthma may 
take place by telemedicine which will use secure video conferences, phone calls, 
and a web portal and/or mobile application as a way of communicating with and 
monitoring the participant’s progress. The CRO will be accountable for working 
with Science 37 (the vendor) to ensure the site has the required equipment, training 
and support for this model and should be notified as soon as possible by the 
investigator that the service is required.

As part of this model, study visits are completed using the Science 37 platform, 
which is a software interface that connects participants to their investigators and 
study teams through either a study-issued smartphone or participant’s own device 
(BYOD) model in addition to providing a data collection platform. This technology 
may be used in combination with visits from mobile study personnel (e.g. mobile 
nurses) to participants’ homes for various lab collections and designated study 
procedures. 

The study investigator is responsible for ensuring that the identification, 
management, and reporting of AEs and SAEs are completed in accordance with the 
protocol and applicable regulations. AEs are first reported by participants to the 
investigator/study team or may be identified by the study team during interactions 
with the participants via telemedicine encounters. In addition, mobile nurses may 
identify AEs as well and report them to the investigator for evaluation. 
Additionally, AEs may be identified from lab reports, imaging or ECG reports, and 
other records. As determined by the investigator, the appropriate medical 
intervention, therapeutic intervention, and/or support measures are instituted, as 
necessary. Provision of a study-issued smartphone or the Science 37 app on a 
participant’s own device allows for study participants to report AEs at any time. 
Participants can also request a timely secure videoconference with the investigator 
and/or site staff.

The participant should be informed of the plan and any potential risks associated 
with the virtual medium and sign a revised Informed Consent Form if required. 
IRB/Ethics committee should be informed and/or approve of this change in 
approach and the process documented in study files.

The schedule of study activities is provided in Table 1.
Study Intervention(s)
If allowed by country regulation/ethics, then study intervention (including rescue study 
medication and ancillary supplies related to IMP administration) can be shipped direct-to-
patient (DTP) from the investigational site to the participant’s home address. The process 
for this shipment must be agreed with the CRO who will provide the relevant 
documentation and links to courier sites required to ensure shipments are adequately 
temperature controlled (if required) throughout transportation.
The Principal Investigator assumes Good Clinical Practice (GCP) responsibilities for IMP 
handling and the medical control for dispensing to patients. Site Staff should document the 

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dispensing in the Dispensing/Accountability Logs adding a comment that this was a DTP 
dispensing. 
Compliance with provisioning and collection of study drug will be verified through 
observation by study staff or trained home healthcare professionals.
In some cases, trial participants who no longer have access to investigational product or 
the investigational site may need additional safety monitoring (e.g., on withdrawal of an 
active investigational treatment).
Data Management/Monitoring
The eDiary device provided to the participant may be returned to the home nurse after Visit 
9)/ETD/EW or the participant should be instructed to maintain the device and to return 
them to the site when a visit to the site will be allowed.] 
If on-site monitoring is no longer permitted, the CRO will consider remote Source Data 
Verification/Source Document Review (SDV/SDR) where permitted by the clinical 
site/institution. Remote SDV/SDR will be proposed to study sites to meet a patient and/or 
critical quality need, e.g., to assess participant safety or to ensure data integrity. In case of 
remote SDV/SDR, the CRO will work with the site to ensure subject privacy. 
eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) is responsible 
for ensuring that the data within the eCRF casebook and any other data sources utilized 
during the study for each study participant is complete and consistent with source 
documents throughout the study (ICH GCP 4.9.1 4.9.2). The PI may sign/re-sign the eCRF 
from any computer/location by accessing the eDC platform using his/her unique eCRF log-
in credentials. The PI may delegate this activity to another medically qualified and trained 
sub-investigator and this must be documented on the Delegation of Responsibilities (DoR) 
Log. It is recommended that the PI identifies a sub-investigator as a back-up for eCRF 
signatures. The sub-investigator must be appropriately trained on the protocol and eCRF 
requirements (with training documented), and the DoR log updated accordingly. 
Essential Document Sign Off Process: If an investigator is unable to print and sign essential 
documents such as Protocol /Amendment signature page then Email approval can be 
accepted by replying to the relevant email that is sent by the CRO.

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14.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
The Protocol Amendment Summary of Changes for the previous amendments 
(Amendment 01 and Amendment 02) is provided below.  
Amendment 01 19-JUN-2019
Overall Rationale for the Amendment: The aim of this amendment is to aid in the 
recruitment of participants in this study. The changes will allow flexibility to perform 
spirometry manoeuvres are screening especially in the younger participants.  
Section # and Name
Description of Change
Brief Rationale
Sponsor Signature 
Page
Amended to indicate new sponsor 
signatory
Amended as there is a 
change in sponsor signatory.
Synopsis and Section 
4 Objectives and 
Endpoints
Added clarity around the primary 
endpoint to indicate which was required 
by the FDA and EMA.
To provide clarity based on 
regulatory feedback.
Section 6.1 Inclusion 
criteria
Inclusion criterion 3 –
Prebronchodilator FEV1.  
The note to this criterion has been 
amended to allow participants who are 
unable to perform their 
prebronchodilator FEV1 at Visit 1 
another attempt that can be within 7 
days of this visit.   
This was amended to allow 
flexibility to the younger 
participants in this study, 
who may find it challenging 
to perform spirometry for the 
first time at the screening 
visit.  
Section 6.1 Inclusion 
criteria
Inclusion criterion 4: Reversibility 
This criterion has been amended to 
reflect that the waiting time after SABA 
will be within 15 and 40 minutes 
instead of 10 and 40 minutes as in the 
original protocol.  
This was amended to allow 
more time for the SABA to 
take effect and allow 
participants a better chance 
of demonstrating 
reversibility.
Section 6.1 Inclusion 
criteria
Inclusion criterion 8:  Male and Female 
participants
A note has been added to clarify that 
females who are lactating are not to be 
included.  
Added based on feedback 
that was received when the 
original protocol was issued.  
An administrative letter was 
produced for sites at the 
time.  
Section 6.2 Exclusion 
criteria
Exclusion criterion 6: Obesity 
This criterion has been amended to 
ensure that severely obese participants 
(ie, participants who have a BMI above 
the 99th) are excluded rather than 
Amended to ensure that 
severely obese participants 
were excluded as severe 
obesity has an impact on 
respiratory function.

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Section # and Name
Description of Change
Brief Rationale
those who classed as obese (ie, had a 
BMI at the 97th centile as in the original 
protocol).
Section 6.2 Exclusion 
criteria
Exclusion criterion 8: QTc  
This criterion has been amended to 
indicate that only QTc(F) will be used 
for eligibility purpose.  
Amended to provide clarity 
and to ensure that sites are 
consistently using one QTc 
formula when assessing a 
participant’s eligibility.
Section 6.2 Exclusion 
criteria
Exclusion criterion 10: Relevant habits 
(Tobacco use) 
This criterion has been amended to 
indicate that participants using e-
cigarettes and who are vaping are also 
excluded. 
Amended to ensure that all 
tobacco or smoking-related 
use was not allowed.
Section 6.3 
Screen Failures
This was amended to allow for re-
screening of screen failures up to one 
additional time.  
Amended to help with 
recruitment of a difficult to 
recruit population.
Section 9.1.1 Efficacy 
Assessments - FEV1
Added that predicted FEV1 values are 
based on ERT standards for 
spirometry.
Added for clarity
Section 10.1.1.1.
Sample Size 
Assumptions for 5-17 
Year Old Population
Corrected an error and added more 
detail regarding the standard deviation 
assumed for the primary endpoint for 
the 5-17 years old population.
Added following a regulatory 
request from the FDA for 
more information.
Section 12.7 Appendix 
related to country-
specific changes
Added a change in exclusion criterion 8 
that is applicable to participants in 
Germany only.
Added based on feedback 
that was received when the 
original protocol was issued.  
An administrative letter was 
produced for sites at the 
time.  
Amendment 02 10-DEC-2019
Overall Rationale for the Amendment: Asthma is a variable condition especially in 
children.  Additionally, spirometry is a procedure that is often challenging to perform in 
this population and children may have symptomatic asthma even when they appear to 
have normal lung function.  The changes in this amendment take into account the 
variability in asthma by allowing re-screening, and also by increasing the maximum 
permitted FEV1 at screening and randomisation to 100% predicted normal.   These 
changes are expected to help with recruitment of this population.

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Section # and Name
Description of Change
Brief Rationale
Schedule of Activities 
(SOA)
Visit 4 and Visit 5 will become optional 
parent only visits, and as a result FEV1
measure will only need to be done if 
the participant attends the clinic.   
A footnote is added to indicate this.  
Also, the footnote states if the 
participant does come to the clinic with 
the parent, and the visit occurs in the 
morning (6.00am to 11.00am) then the 
spirometry measurement should be 
performed. If only the parent attends, 
then this can be at any time of day.     
This was amended to give 
participants the option of not 
attending to reduce burden 
on younger participants 
having to miss more school 
days and come to the site.  
Parents will need to come to 
collect study treatment.
Section 5.1, Overall 
Study Design
Figure 1 – Study Schematic updated to 
add footnotes relating to Visits 4 and 5
Last paragraph in Section updated with 
details around Visits 4 and 5. And 
amended wording to indicate which 
visits need to be morning visits.
Changes made for 
consistency and clarity.
Section 6.1 Inclusion 
criteria
Inclusion criterion 1 – Age
Changed ‘at the time of signing the 
informed consent’ to ‘at the time of 
screening’.
This was amended for 
consistency as participants 
are stratified by age at 
screening.
Section 6.1 Inclusion 
criteria
Inclusion criterion 3 –
Prebronchodilator FEV1.  
The upper limit of the range has been 
changed from ≤90% to ≤100%  
This was amended to reflect 
that the younger population 
often have a pre-
bronchodilator FEV1
predicted that is normal but 
they may still have 
symptomatic asthma. This 
change was therefore to aid 
recruitment of symptomatic 
asthma participants who 
demonstrate reversibility but 
who may have normal lung 
function.  
Section 6.1 Inclusion 
criteria
Inclusion criterion 3 –
Prebronchodilator FEV1.  
The note to this criterion has been 
amended to allow participants who are 
unable to perform their FEV1 at Visit 1 
another attempt that can be within 14 
days of this visit. This is extended from 
the 7 days that was allowed in 
amendment 1. 
This was amended to allow 
flexibility to the younger 
participants in this study, 
who may be unfamiliar with 
the procedure and may find 
it challenging to perform 
spirometry for the first time 
at the screening visit.  

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Section # and Name
Description of Change
Brief Rationale
Section 6.1 Inclusion 
criteria
Inclusion criterion 3 – Reversibility.  
The note to this criterion has been 
amended to allow participants who are 
unable to attempt to perform their FEV1
at Visit 1 another attempt that can be 
within 14 days of this visit.   
This was amended to allow 
flexibility to the younger 
participants in this study, 
who may be unfamiliar with 
the procedure and find it 
challenging to perform 
spirometry for the first time 
at the screening visit.  
Section 6.3 
Screen Failures
This was amended to allow for re-
screening of screen failures. 
Asthma is a variable 
condition especially in 
children, thus participants 
who have screen-failed 
could be re-screened at a 
later date if the severity of 
their asthma has changed. 
This will help recruitment of 
younger participants. 
Section 8.1.2 
Amended text to indicate that only 
QTcF is used for the ECG.  
A footnote was added to the SOA to 
indicate that the QTc should be based 
on a single or averaged QTc values of 
triplicate ECGs.
Amended for clarity.
Section 9.1.1

Amended the visits in 4th
paragraph.

Removed reference to ERT in 5th
paragraph. 

Standardise wording

Added Quanjar (2012) 
for calculation of 
predicted normal FEV1. 
General throughout
Added Albuterol.  
Standardise wording to 
reflect the fact that 
salbutamol is known as 
albuterol in USA and some 
other countries.
Amendment 03 31-JAN-2020
Overall Rationale for the Amendment: As Visit 4 is the first visit after randomisation 
to study treatment, it is considered an important visit at which to collect clinical data.
Section # and Name
Description of Change
Brief Rationale
Sponsor Signatory
Change to the sponsor signatory 
department details
Revision made due to 
organisational changes.
Schedule of Activities 
(SOA)
Visit 4 will no longer be an optional 
parent only visit.  
As Visit 4 is the first visit 
after randomization to study
treatment, it was considered 

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Section # and Name
Description of Change
Brief Rationale
The participant will need to attend this 
visit where clinical assessments as 
indicated in the schedule of activities 
will need to be assessed. 
Thus ‘Footnote 2’ has been amended 
to remove Visit 4.
by the regulators to be an
important visit at which to 
collect clinical data.   
Section 5.1, Overall 
Study Design
Figure 1 – Study Schematic updated to 
remove reference to Visit 4 being an 
optional parent only visit.
Last paragraph in this Section 
amended to correctly reference Visit 4.
Changes made for 
consistency and clarity.
Section 7.7.1, 
Prohibited 
Medications and Non-
Drug Therapies
The changes made to Section 7.7.1 
included the addition of the following 
note and new text (red text denotes 
new text):
•Note:  Participants should be treated 
as appropriate for asthma 
exacerbations without requirement to 
withdraw the participant from the study. 
Steroids will be an exclusion from 
randomisation if administered during 
the run-in period (apart from FP). 
However, they should never be 
withheld if deemed necessary. 
•Use of the following medications is 
prohibited according to the timeframes 
indicated unless they are deemed 
necessary to treat an asthma 
exacerbation or another condition 
appropriately:
•From screening visit (Visit 1) to Visit 9: 
LTRAs, ketotifen, nedocromil sodium, 
orally inhaled sodium cromoglycate, 
SABA/short-acting muscarinic 
antagonist (SAMA) combinations (e.g. 
Combivent), and inhaled corticosteroids 
(except for FP which is given during the 
run-in).    
To provide further clarity on 
the use of steroids.
Section 9.1.1 FEV1
Fourth paragraph amended text to 
correctly reference Visit 4.
Changes made for 
consistency and clarity.