Study HZA114971, A Multicentre Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Effects of a One-Year Regimen of Orally Inhaled Fluticasone Furoate 50 mcg Once Daily on Growth Velocity in Prepubertal, Paediatric Subjects With Asthma
Phase: PHASE4
Conditions: Asthma
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
HZA114971
1
TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
Study HZA114971, A Multicentre Randomised, Double-Blind, 
Placebo-Controlled, Parallel-Group Study to Evaluate the Effects 
of a One-Year Regimen of Orally Inhaled Fluticasone Furoate 50 
mcg once daily on Growth Velocity in Prepubertal, Paediatric 
Subjects with Asthma
Compound Number:
GW685698
Development Phase
IV
Effective Date:
06-MAR-2019
Author(s):
 
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD

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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2016N269987_00
2016-JUN-28
Original
2016N269987_01
2016-NOV-04
Amendment No. 1
This amendment was implemented:

Remove the term local growth charts and replace with US CDC charts for inclusion 
criteria 4 and 5.

Amend the text for inclusion criterion 7 to provide clarity on the time window used 
for re-scheduling the spirometry assessment at screening (Visit 1).

Remove the term WHO growth charts and replace with North America Longitudinal 
Standard Growth Velocity Charts for randomization criterion 1c.

Amended typographical error in Section 5.5.4 and to clarify that the subject will be 
withdrawn from study treatment (for consistency with Section 5.5.1).

Amend the text and provide clarity on the procedure around oropharyngeal exams in 
Section 7.3.5.

Amend the time and events table to show an ‘x’ for body weight at Visit 3 as this was 
missing.

Remove word “continuously” in Section 9.1

Add a supportive completers’ analysis of growth velocity over the 1-year double-
blind treatment period, based on subjects who completed the double-blind treatment 
period while remaining on study treatment, in Section 9.4.1.1.

Add a summary of change in height standard deviation scores (SDS) from baseline to 
endpoint in Section 9.4.2.1.
2016N269987_02
2019-MAR-06
Amendment No. 2
This amendment incorporates the following changes:
•
Removal of the upper limit of the FEV1 from inclusion criterion 7 (Section 5.1).

Justification for change: FEV1 is often close to or above 100% in young 
children with controlled asthma. This is due to the variability of asthma with 
normal spirometry lung function tests (LFT) values between asthma attacks in 
this young population (5-9 years) with controlled asthma. For this reason, an 
upper limit of 95% has not been used in previous similar studies (e.g. 

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Ciclesonide growth study. (2008) (paediatrics Vol 121 (1) e1-e14).
•
Removal of calcitriol from exclusion criteria 3 (Section 5.2) and from the 
prohibited medications Table 3 (Section 6.10.2).

Justification for change:  Children living in regions with low sun exposure 
(especially in winter) can be advised to take Calcitriol (synthetic version of 
Vitamin D3) at prophylactic doses (e.g. 400 IU in Caucasians, 800 IU in 
black children) to prevent Vitamin deficiency and rickets. Excluding children 
taking calcitriol at prophylactic doses may remove unnecessarily subjects 
likely to benefit from the study drug treatment.
•
Update of text in Section 5.3 (Screening/Baseline/Run-in Failures) to allow re-
screening of subjects who have failed screening.  

PPD
PPD
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone Number
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
MD
Discovery 
Medicine,
GlaxoSmithKline,
Gunnels wood 
Road,
Stevenage, SG1 
2NY, UK. 
Stevenage, UK
Secondary 
Medical 
Monitor
GSK, Stockley 
Park West 1-3 
Ironbridge Road, 
Middlesex, UB11 
1BT, UK
SAE 
contact  
information
 MD  (see above for contact information)
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): IND No: 070297
PPD
PPD
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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure that site staff receives the appropriate information throughout the 
study.
Investigator Name:  ______________________________
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY HZA114971...............................................10
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVES AND ENDPOINTS...........................................................................16
4.
STUDY DESIGN ....................................................................................................17
4.1.
Overall Design ............................................................................................17
4.2.
Treatment Arms and Duration.....................................................................17
4.3.
Type and Number of Subjects.....................................................................18
4.4.
Design Justification.....................................................................................19
4.5.
Dose Justification........................................................................................19
4.6.
Benefit:Risk Assessment ............................................................................20
4.6.1.
Risk Assessment .........................................................................21
4.6.2.
Risk Assessment for Montelukast ................................................25
4.6.3.
Benefit Assessment.....................................................................27
4.6.3.1.
Fluticasone Furoate....................................................27
4.6.3.2.
Leukotriene receptor antagonists................................27
4.6.4.
Overall Benefit:Risk Conclusion...................................................27
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............28
5.1.
Inclusion Criteria.........................................................................................28
5.2.
Exclusion Criteria........................................................................................29
5.3.
Screening/Baseline/Run-in Failures............................................................31
5.4.
Randomisation Criteria ...............................................................................31
5.5.
Withdrawal/Stopping Criteria.......................................................................32
5.5.1.
Subject Withdrawal by Investigator or Self-withdrawal .................32
5.5.2.
Subjects Lost to Follow-up...........................................................34
5.5.3.
Liver Chemistry Stopping Criteria ................................................34
5.5.3.1.
Study Treatment Restart or Rechallenge....................36
5.5.4.
QTc Stopping Criteria ..................................................................36
5.6.
Subject and Study Completion....................................................................36
6.
STUDY TREATMENT ............................................................................................37
6.1.
Investigational Product and Other Study Treatment....................................37
6.2.
Medical Devices..........................................................................................38
6.3.
Treatment Assignment................................................................................38
6.4.
Blinding.......................................................................................................38
6.5.
Packaging and Labelling.............................................................................39
6.6.
Preparation/Handling/Storage/Accountability..............................................39
6.7.
Compliance with Study Treatment Administration.......................................39
6.8.
Treatment of Study Treatment Overdose....................................................40
6.9.
Treatment after the End of the Study ..........................................................40
6.10.
Concomitant Medications and Non-Drug Therapies....................................40
6.10.1.
Permitted Medications and Non-Drug Therapies..........................40
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................40

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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................42
7.1.
Time and Events Table...............................................................................43
7.2.
Screening and Critical Baseline Assessments ............................................46
7.3.
Safety .........................................................................................................46
7.3.1.
Height (Stadiometry) Measurement .............................................46
7.3.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........47
7.3.2.1.
Time period and Frequency for collecting AE 
and SAE information...................................................47
7.3.2.2.
Method of Detecting AEs and SAEs ...........................47
7.3.2.3.
Follow-up of AEs and SAEs........................................48
7.3.2.4.
Regulatory Reporting Requirements for SAEs............48
7.3.3.
Asthma Exacerbations.................................................................48
7.3.4.
Physical Exams ...........................................................................49
7.3.5.
Oropharyngeal Examination.........................................................49
7.4.
Efficacy (as a Measure of Compliance).......................................................49
7.4.1.
Daily Diaries ................................................................................49
7.4.1.1.
Daily Asthma Symptom Scores ..................................50
7.4.1.2.
Daily PEF ...................................................................50
7.4.2.
Childhood Asthma Control Test ...................................................51
7.5.
Genetics .....................................................................................................51
8.
DATA MANAGEMENT ...........................................................................................51
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................52
9.1.
Hypotheses.................................................................................................52
9.2.
Sample Size Considerations.......................................................................52
9.2.1.
Sample Size Assumptions ...........................................................52
9.2.2.
Sample Size Sensitivity................................................................53
9.2.3.
Sample Size Re-estimation or Adjustment...................................53
9.3.
Data Analysis Considerations .....................................................................53
9.3.1.
Analysis Populations....................................................................53
9.3.2.
Interim Analysis ...........................................................................54
9.4.
Key Elements of Analysis Plan ...................................................................54
9.4.1.
Primary Safety Analyses..............................................................54
9.4.1.1.
Growth Velocity ..........................................................54
9.4.2.
Secondary Safety Analyses .........................................................55
9.4.2.1.
Growth........................................................................55
9.4.2.2.
Adverse Events ..........................................................56
9.4.2.3.
Asthma Exacerbations................................................57
9.4.3.
Other Analyses ............................................................................57
10. STUDY GOVERNANCE CONSIDERATIONS........................................................57
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............57
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................57
10.3.
Quality Control (Study Monitoring) ..............................................................58
10.4.
Quality Assurance.......................................................................................58
10.5.
Study and Site Closure ...............................................................................59
10.6.
Records Retention......................................................................................59
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................60

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11. REFERENCES.......................................................................................................61
12. APPENDICES........................................................................................................63
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................63
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................65
12.3.
Appendix 3- Genetic Research ...................................................................68
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................71
12.4.1.
Definition of Adverse Events........................................................71
12.4.2.
Definition of Serious Adverse Events...........................................72
12.4.3.
Recording of AEs and SAEs ........................................................73
12.4.4.
Evaluating AEs and SAEs............................................................74
12.4.5.
Reporting of SAEs to GSK...........................................................75
12.5.
Appendix 5- Country Specific Requirements...............................................77
12.6.
Appendix 6 – Protocol Changes..................................................................78

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1.
PROTOCOL SYNOPSIS FOR STUDY HZA114971
Rationale
Growth impairment is a well-established adverse effect of glucocorticosteroids in 
children. Due to significantly reduced systemic exposure the potential impact of inhaled 
corticosteroids (ICS) on growth is small when compared with the effect observed with 
the use of oral corticosteroid treatments. Evidence derived from a Cochrane meta-
analysis of randomised trials shows that regular use of ICS at low or medium daily doses 
is associated with a mean reduction of 0.48 cm per year in linear growth velocity and 
0.61 cm in change from baseline in height during a one-year treatment in children with 
mild to moderate persistent asthma. The effect size of ICS on linear growth velocity 
appears to be associated more strongly with the ICS molecule than device or dose (low to 
medium dose range). ICS-induced growth suppression seems to be maximal in the first 
year of therapy and less pronounced in the subsequent years of treatment (Zhang, 2014).  
Hence it is useful to assess the magnitude of growth reduction when developing a novel 
inhaled corticosteroid.   There is a regulatory requirement to evaluate the extent of 
reduction (if any) of growth velocity associated with ICS containing products that are to 
be administered to children, and to this end there is FDA regulatory guidance [Guidance 
for Industry Orally Inhaled and Intranasal Corticosteroids: Evaluation of the Effects on 
Growth in Children, 2007]. One year is considered the minimum duration to assess 
growth in a robust fashion. The one-year duration minimises some confounding factors 
such as seasonal variations and measurement errors.
The purpose of the study is to evaluate the magnitude of effect (with a level of precision) 
on growth velocity of prepubertal asthmatic paediatric subjects (aged 5 to <9 years) 
following administration of once daily (OD) inhaled fluticasone furoate (FF) 50 mcg for 
one year. This study fulfils EU and US regulatory requirements for the evaluation of 
potential growth suppression in children. 

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Objectives/Endpoints
Objectives
Endpoints
Primary

To evaluate the magnitude of effect (with 
a level of precision) of inhaled FF 50 mcg 
versus inhaled placebo OD on growth 
velocity in prepubertal children over one 
year of treatment
Primary

Growth Velocity (cm/yr) over the double-
blind treatment period, as determined by 
stadiometry
Secondary 

Proportion of subjects below the 3rd
percentile of growth velocity

Change in growth velocity quartiles from 
baseline to endpoint

Growth velocity over the first 12 weeks of 
double-blind treatment period

Height standard deviation scores (SDS) 
at each visit
Secondary

To assess the safety of inhaled FF 50 
mcg OD 

Incidence of adverse events

Incidence of asthma exacerbations
Other

To assess the effect of inhaled FF 50 
mcg OD on efficacy endpoints, used as a 
measure of compliance to help identify 
non-adherence and/or poorly controlled 
asthma

Change from baseline in the percentage 
of rescue-free 24 hour periods over the 
double-blind treatment period

Change from baseline in the percentage 
of symptom-free 24 hour periods over 
the double-blind treatment period

Change from baseline in AM Peak 
Expiratory Flow (PEF) averaged over the 
double-blind treatment period 

Change from baseline in cACT score at 
the end of the double-blind treatment 
period

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Overall Design
This is a randomised, single-blind (run-in period)/double-blind (treatment period), 
parallel group, placebo controlled, multicentre study to assess the effect of once daily 
(OD) inhaled FF 50 mcg on growth velocity in prepubertal asthmatic children on a 
background therapy of open-label montelukast.  Study randomisation will be stratified by 
country. 
Treatment Arms and Duration
This study will be conducted over a total duration of approximately 76 weeks: 16-week 
run-in period, 52-week double-blind treatment period and 8-week follow-up period.  
Eligible subjects will receive a single-blind placebo inhaler during the 16-week run-in 
period.  After completing the run-in period, eligible subjects will be randomly allocated 
to one of two treatment regimens: 

inhaled FF 50 mcg administered OD in the morning for 52 weeks 
or

inhaled placebo administered OD in the morning for 52 weeks 
Each treatment will be administered via the ELLIPTA™ dry powder inhaler [formerly 
referred to as a novel dry powder inhaler (NDPI)].
Subjects will also receive open-label montelukast (4 mg for subjects who are 5 years old 
and 5 mg for subjects who are ≥6 years old).   Subjects will take one tablet of 
montelukast each evening for the duration of the study (from the run-in period through to 
the end of the follow-up period). Note:  subjects who turn 6 years old during the study, 
will subsequently receive 5 mg of open-label montelukast.
In addition, each subject 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.
Subjects (i.e., the child) must attend the clinic on the following visits for stadiometry and 
other key assessments:

Visits 1 and 3 (Screening visit and run-in period):
o
Visit 1, subjects will attend the clinic for screening procedures.  Subjects 
meeting the eligibility criteria will enter the 16-week run-in period.  
o
Visit 3, subjects will attend the clinic for stadiometry assessment and any 
other assessments as indicated in the Time and Events Table (Section 7.1).    

Visit 5 (Randomisation): 
o
Eligible subjects will be randomised to one of two treatment groups. 

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o
Subjects will attend the clinic for stadiometry assessments and any other 
assessments as indicated in the Time and Events Table (Section 7.1).    

Visits 6, 7, 8, 9, 12, 15 and 18 (Double-blind treatment period)
o
Subjects will attend the clinic for stadiometry assessments and any other 
assessments as indicated in the Time and Events Table (Section 7.1).    

Visit 20 (Follow-up period)
o
Subjects will attend the clinic for stadiometry assessments and any other 
assessments as indicated in the Time and Events Table (Section 7.1).    
NOTE:  While the subject (ie, the child) only has to attend the clinic on the scheduled 
visits for stadiometry assessments (as indicated above), their parents/guardians must
attend the clinic every month to collect/return diaries and collect/return double-blind 
treatment.
Type and Number of Subjects
Approximately 900 asthmatic prepubertal subjects, aged 5 to <8 years (girls) or 5 to <9 
years (boys), will be screened to achieve at least 450 randomised and 406 evaluable 
subjects (approximately 203 evaluable subjects per treatment group).  
Analysis
The primary analysis will be the comparison of the growth velocities between inhaled FF 
50 mcg once daily (OD) (plus montelukast open-label) and inhaled placebo (plus 
montelukast open-label) over the 52-week treatment period. An analysis of covariance 
(ANCOVA) will be performed to estimate the mean treatment difference in growth 
velocity over the double-blind treatment period, adjusting for baseline growth velocity, 
age at Visit 1, gender and country. A 95% confidence interval will also be provided for 
the estimated mean treatment difference in growth velocity over the double-blind 
treatment period.

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2.
INTRODUCTION
2.1.
Study Rationale
Growth impairment is a well-established adverse effect of glucocorticosteroids in 
children. Due to significantly reduced systemic exposure the potential impact of inhaled 
corticosteroids (ICS) on growth is small when compared with the effect observed with 
the use of oral corticosteroid treatments. Evidence derived from a Cochrane meta-
analysis of randomised trials shows that regular use of ICS at low or medium daily doses 
is associated with a mean reduction of 0.48 cm per year in linear growth velocity and 
0.61 cm in change from baseline in height during a one-year treatment in children with 
mild to moderate persistent asthma. The effect size of ICS on linear growth velocity 
appears to be associated more strongly with the ICS molecule than device or dose (low to 
medium dose range). ICS-induced growth suppression seems to be maximal in the first 
year of therapy and less pronounced in the subsequent years of treatment (Zhang, 2014).  
Hence it is useful to assess the magnitude of growth reduction when developing a novel 
inhaled corticosteroid. There is a regulatory requirement to evaluate the extent of 
reduction (if any) of growth velocity associated with ICS containing products that are to 
be administered to children, and to this end there is FDA regulatory guidance [Guidance 
for Industry Orally Inhaled and Intranasal Corticosteroids: Evaluation of the Effects on 
Growth in Children, 2007]. One year is considered the minimum duration to assess 
growth in a robust fashion. The one-year duration minimises some confounding factors 
such as seasonal variations and measurement errors.
The purpose of the study is to evaluate the magnitude of effect (with a level of precision) 
on growth velocity of prepubertal asthmatic paediatric subjects (aged 5 to <9 years) 
following administration of once daily (OD) inhaled fluticasone furoate (FF) 50 mcg for 
one year.
2.2.
Brief Background
Asthma is a chronic disease of the lungs characterised by airway inflammation, 
bronchoconstriction and increased airway responsiveness. Inhaled corticosteroids (ICS) 
are considered the most effective anti-inflammatory treatments for all severities of 
asthma [GINA, 2016; National Institutes of Health, 2007; British Guideline, 2008]. 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].
One of the well-recognised and specific adverse effects of glucocorticosteroids in 
children is potential growth impairment. The effects of glucocorticosteriods on the 
growth plate are complex. Local effects of glucocorticosteriods at the growth plate 
include reduction of IGF-I production, inducing IGF-I resistance and reducing production 
of C-type natriuretic peptide, which results in a reduction of chondrocyte proliferation, 
matrix synthesis and hypertrophy. These reductions in chondrocyte function result in 
decreased linear growth. 

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Although the use of inhaled corticosteroids results in lower systemic exposure than that 
with oral steroids, it does not completely exclude the risk of some mild degree of growth 
attenuation. It seems that the effect is more marked during the first year of treatment but 
is not sustained afterwards [Kelly, 2012]. A recent long term study has suggested that the 
initial decrease in attained height associated with the use of inhaled glucocorticoids in 
prepubertal children persisted as a reduction in adult height, although the decrease was 
not progressive or cumulative [Kelly, 2012]. 
Evidence derived from a Cochrane meta-analysis of randomised trials shows that regular 
use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm 
per year in linear growth velocity and 0.61 cm in change from baseline in height during a 
one-year treatment in children with mild to moderate persistent asthma. The effect size of 
ICS on linear growth velocity appears to be associated more strongly with the ICS 
molecule than device or dose (low to medium dose range). The ICS-induced growth 
suppression seems to be maximal in the first year of therapy and less pronounced in the 
subsequent years of treatment [Zhang, 2014].  Another Cohrane review of the literature 
concluded that in persistent asthma, a small but statistically significant group difference 
in growth velocity was observed between low doses of ICS and low to medium doses of 
HFA-beclomethasone equivalent, favouring the use of low-dose ICS [Pruteanu, 2014].   
In the four comparisons reporting linear growth over 12 months, a significant group 
difference was observed, clearly indicating lower growth velocity in the higher ICS dose 
group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged 
children; mean difference (MD) 0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39). 
The authors concluded that in view of prevailing parents’ and physicians’ concerns about 
the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity 
in more than 86% (19/22) of eligible paediatric trials including those using 
beclomethasone and budesonide, is a matter of concern. 
Therefore, there is good evidence to suggest that the first year of treatment with an 
inhaled corticosteroids is the most critical phase with respect to growth. In view of the 
seasonal variations in growth, one year is the minimum duration to reliably measure 
annual growth velocity [Tillmann, 2001].
Fluticasone furoate (FF) is a glucocorticoid approved in the United States of America for 
use as a once daily (OD) ICS for the maintenance treatment of asthma in patients aged 12 
years and over (ARNUITY™ ELLIPTA).  It is also the ICS component of a once daily 
ICS/Long Acting Beta Agonist (LABA) combination inhaler (fluticasone 
furoate/vilanterol) approved in over 50 countries for once daily treatment of asthma in 
patients aged 12 years of age and older (RELVAR™ ELLIPTA /BREO™ ELLIPTA).  
The fluticasone furoate/vilanterol inhalation powder, hereafter referred to as FF/VI 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. The FF 
and FF/VI paediatric asthma development programmes are currently ongoing.

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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the magnitude of effect (with 
a level of precision) of inhaled FF 50 mcg 
versus inhaled placebo OD on growth 
velocity in prepubertal children over one 
year of treatment
Primary

Growth Velocity (cm/yr) over the double-
blind treatment period, as determined by 
stadiometry
Secondary 

Proportion of subjects below the 3rd
percentile of growth velocity

Change in growth velocity quartiles from 
baseline to endpoint

Growth velocity over the first 12 weeks of 
double-blind treatment period

Height standard deviation scores 
(SDS) at each visit 
Secondary

To assess the safety of inhaled FF 50 
mcg OD 

Incidence of adverse events

Incidence of asthma exacerbations
Other

To assess the effect of inhaled FF 50 
mcg OD on efficacy endpoints, used as a 
measure of compliance to help identify 
non-adherence and/or poorly controlled 
asthma

Change from baseline in the percentage 
of rescue-free 24 hour periods over the 
double-blind treatment period

Change from baseline in the percentage 
of symptom-free 24 hour periods over 
the double-blind treatment period

Change from baseline in AM PEF 
averaged over the double-blind 
treatment period 

Change from baseline in cACT score at 
the end of the double-blind treatment 
period

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4.
STUDY DESIGN
4.1.
Overall Design
This is a randomised, single-blind (run-in period)/double-blind (treatment period), 
parallel group, placebo controlled, multicentre study to assess the effect of FF 50 mcg 
OD on growth velocity in prepubertal asthmatic children on a background therapy of 
open-label montelukast (Figure 1).  Study randomisation will be stratified by country.
Figure 1
Study Schematic
4.2.
Treatment Arms and Duration
This study will be conducted over a total duration of approximately 76 weeks: 16-week 
run-in period, 52-week double-blind treatment period and 8-week follow-up period.  The 
study randomisation will be stratified by country.
Eligible subjects will receive a single-blind placebo inhaler during the 16-week run-in 
period.  After completing the run-in period, eligible subjects will be randomly allocated 
to one of two treatment regimens: 

inhaled FF 50 mcg administered OD in the morning for 52 weeks 
or

inhaled placebo administered OD in the morning for 52 weeks 
Visit 1
Day -112
Visit 5
Day 0
Montelukast 4 mg or 
5 mg 
Visit 18
Day 365
Follow-Up Period
Double-Blind Treatment Period
Montelukast 4 mg or 
5 mg 
FF 50 mcg
Randomisation
Placebo
112 days
FF = Fluticasone Furoate Inhaled Powder.
*Montelukast 4mg will be provided to 5-year olds and montelukast 5 mg will be provided to 
children ≥ 6 years.
365 days
Visit 20
Day 421
56 days
Treatment End
Single-blind run-in 
period
Montelukast 4 mg or 
5 mg

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Each treatment will be administered via the ELLIPTA dry powder inhaler [formerly 
referred to as a novel dry powder inhaler (NDPI)].
Subjects will also receive open-label montelukast (4 mg for subjects who are 5 years old 
and 5 mg for subjects who are ≥6 years old).   Subjects will take one tablet of 
montelukast each evening for the duration of the study (from the run-in period through to 
the end of the follow-up period). Note:  subjects who turn 6 years old during the study, 
will subsequently receive 5 mg of open-label montelukast.
In addition, each subject 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.
Subjects (i.e., the child) must attend the clinic on the following visits for stadiometry and 
other key assessments:

Visits 1 and 3 (Screening visit and run-in period):
o
Visit 1, subjects will attend the clinic for screening procedures.  Subjects 
meeting the eligibility criteria will enter the 16-week run-in period.  
o
Visit 3, subjects will attend the clinic for stadiometry assessment and any 
other assessments as indicated in the Time and Events Table (Section 7.1).    

Visit 5 (Randomisation): 
o
Eligible subjects will be randomised to one of two treatment groups. 
o
Subjects will attend the clinic for stadiometry assessments and any other 
assessments as indicated in the Time and Events Table (Section 7.1).   

Visits 6, 7, 8, 9, 12, 15 and 18 (Double-blind treatment period)
o
Subjects will attend the clinic for stadiometry assessments and any other 
assessments as indicated in the Time and Events Table (Section 7.1).   

Visit 20 (Follow-up period)
o
Subjects will attend the clinic for stadiometry assessments and any other 
assessments as indicated in the Time and Events Table (Section 7.1).   
NOTE:  While the subject (i.e., the child) only has to attend the clinic on the scheduled 
visits for stadiometry assessments (as indicated above), their parents/guardians must
attend the clinic every month to collect/return diaries and collect/return double-blind 
treatment.
4.3.
Type and Number of Subjects
Approximately 900 asthmatic prepubertal subjects, aged 5 to <8 years (girls) or 5 to <9 
years (boys) will be screened to achieve at least 450 randomised and 406 evaluable 

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subjects (approximately 203 evaluable subjects per treatment group; see Section 9.2 for 
further details on Sample Size Considerations).  
4.4.
Design Justification
This study will use stadiometry to determine the effect of once daily treatment with 
inhaled FF 50 mcg on growth velocity in children aged 5 to <9 years of age.
All elements of study design are based on recommendations/guidelines from regulatory 
authorities for growth velocity studies and regulatory advice for this development 
programme [Guidance for Industry Orally Inhaled and Intranasal Corticosteroids: 
Evaluation of the Effects on Growth in Children, 2007].  
The duration of the double-blind treatment period (52 weeks) is considered sufficient to 
determine an effect of inhaled corticosteroids on growth velocity.  This duration is 
considered sufficient to minimise measurement errors and seasonal variations. 
In order to optimise the accuracy of growth assessments, repeated measurements will be 
taken approximately every 3 months with more frequent measurements at the start of 
therapy.  Previous studies have shown that the greatest effect tends to be within the first 
few months [Roizen, 2012; Price, 2002; Pruteanu, 2014]. 
All subjects will be on a background of open-label montelukast tablets to avoid a “no 
treatment” arm. This should reduce the risk of uncontrolled asthma in the placebo group, 
hence minimising the rate of drop-outs, the negative growth effect of poor asthma control 
and confounding of concomitant corticosteroid used to treat exacerbations.   
To ensure blinding throughout the study, subjects will receive single-blind inhaled 
placebo during the run-in period and all subjects will receive inhaled FF or inhaled 
placebo OD via the ELLIPTA dry powder inhaler during the double-blind treatment 
phase. 
Furthermore, all children will be pre-pubertal to avoid the pubertal growth spurt, which is 
an important confounding factor in the assessment of paediatric growth.
The randomisation will be stratified by country to account for possible differences in 
medical practices and growth velocity across the countries.
4.5.
Dose Justification
The 50 mcg is proposed as the FF dose for this study. In the phase 2b dose-ranging study 
HZA106855 statistically significant improvements in lung function (peak flow) and 
asthma control (rescue free days) were seen for the 50 mcg FF dose compared to placebo 
in children with asthma. Furthermore, there was no statistically significant reduction in 
urinary cortisol associated with FF when compared to placebo.  

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4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
fluticasone furoate (FF) can be found in the FF Investigator’s Brochure 
[GlaxoSmithKline Document Number GM2004/00283/10].  
For montelukast, information is taken from the label of SINGULAIR [SMPC, Summary 
of Product Characteristics, May 2016 (5 mg) and February 2016 (4 mg)].
The following section outlines the risk assessment and mitigation strategy for this 
protocol:  

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4.6.1.
Risk Assessment
For FF, the following risks related to inhaled corticosteroid use (ICS)  as applicable to adult and adolescent asthma patients were taken 
from the risk table for ongoing risks for FF in the development safety update report 2015; (GlaxoSmithKline Document Number 
2015N240433).  The data/ rationale for the risks were derived from the literature, 2015 Investigator’s Brochure [GlaxoSmithKline 
Document Number GM2004/00283/10] and from an integrated analysis of key FF studies as well as information for FF/VI. 
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [Fluticasone furoate (GW685698)] 
Pneumonia
For FF; in an integrated analysis of 10 studies in 
asthma (6219 patients) the rate 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 rate was observed across 
all treatment groups.  
An increased 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.
Subjects and their parents/guardians will be 
informed about the risk of pneumonia in the 
informed consent. Subjects and their 
parent/guardian will be advised to seek medical 
treatment if any signs of pneumonia occur. 
Investigators are informed of the risk in Section 6 
(Contraindications) of the Investigator Brochure 
(IB).
Hypersensitivity
For FF there were few events reported in the 
asthma studies.  As there was limited, short, 
exposure to placebo, any comparison is not
Subjects and their parents/guardians will be 
informed about the risk of hypersensitivity in the 
informed consent. Subjects and their 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
reliable.
There are post-marketing reports of 
hypersensitivity to FF/VI.  Adverse reactions may 
include anaphylaxis, angiodema, urticaria and 
rash.
parent/guardian will be advised to seek medical 
treatment if any signs 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 the risk in Section 6 
(Contraindications) of the Investigator Brochure 
(IB).
Adrenal suppression
This is considered a class effect of ICS.
Preclinical studies showed that FF effects are 
comparable with other corticosteroids. No 
studies have shown a clinically relevant effect of 
FF/VI on the hypothalamic-pituitary adrenal axis 
(HPA) at the 100/25 mcg strength. 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.
Subjects and their parents/guardians will be 
informed about the risk of adrenal suppression in 
the informed consent.  Investigators are made 
aware of the potential for this class effect in 
Section 6 (Warnings and Precautions) of the IB. 
If systemic symptoms appear, investigators 
should implement an appropriate treatment while 
observing the subject’s asthma symptoms.
Corticosteroid associated eye disorders
This is considered a class effect of ICS.  
Preclinical studies showed FF at high dose 
comparable to other high dose corticosteroids. In 
study HZA106839 (FF/VI, FF and FP in subjects 
with asthma), formal ophthalmic assessments 
were conducted (including LOCS III evaluations 
for ocular opacities) throughout the study. This 
study showed no apparent effects on lens 
Subjects and their parents/guardians will be 
informed about the risk of corticosteroid 
associated eye disorders in the informed 
consent. Subjects will be advised to seek 
medical treatment if any signs of eye disorder 
occur. Investigators are made aware of the 
potential for this class effect in Section 5.3.2.2. 
(Adverse Effects) of the IB.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
opacification, compared to baseline. During 
studies in both subjects with asthma and COPD, 
no associated effect on ocular disorders was 
observed.
Growth suppression
Preclinical studies have shown that the effects of 
FF at high doses are comparable with those of 
other corticosteroids. No clinical data is currently 
available in children.
Children with asthma may experience growth 
retardation (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% 
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 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 
The protocol will explore the potential risk of 
reduction in growth velocity.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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). 
Study Procedures
Spirometry procedures
Shortness of breath, coughing, light-headedness 
or fainting, and/or chest tightness
If any of these symptoms should occur 
spirometry will be stopped and the subject will 
receive medical treatment.

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4.6.2.
Risk Assessment for Montelukast
Montelukast is a marketed drug with two dose strengths for the paediatric population:

2 to 5 years old: 4 mg chewable tab

6 to 14 years old: 5 mg chewable tab
In this study, montelukast will be used in line with the recommendations provided in the 
product label. A summary of the risks associated with montelukast is as follows:
Table 1
Common adverse reactions (≥1/100 to <1/10) in paediatric patients 
treated with montelukast
Body System Class
Paediatric Patients
6 to 14 years old
(one 8-week study; n=201)
(two 56-week studies; n=615)
Paediatric Patients
2 to 5 years old
(one 12-week study; n=461)
(one 48-week study; n=278)
Nervous system disorders
Headache
-
Gastrointestinal disorders
-
Abdominal pain
General disorders and 
administration site conditions
-
Thirst
1.
Adapted from SINGULAIR Paediatric Granules SMPC, Summary of Product Characteristics, May 2016 (5 mg) 
and February 2016 (4 mg).
Table 2
Adverse reactions reported in post-marketing use of montelukast
System Organ Class
Adverse Experience Term
Frequency Category*
Infections and infestations
upper respiratory infection†
Very Common
Blood and lymphatic system 
disorders
increased bleeding tendency
Rare
Immune system disorder
hypersensitivity reactions including 
anaphylaxis
Uncommon
hepatic eosinophilic infiltration
Very Rare
Psychiatric disorders
dream abnormalities including 
nightmares, insomnia, 
somnambulism, anxiety, agitation 
including aggressive behaviour or 
hostility, depression, psychomotor 
hyperactivity (including irritability, 
restlessness, tremor§)
Uncommon
disturbance in attention, memory 
impairment
Rare
hallucinations, disorientation, suicidal Very Rare

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System Organ Class
Adverse Experience Term
Frequency Category*
thinking and behaviour (suicidality)
Nervous system disorder
dizziness, drowsiness, 
paraesthesia/hypoesthesia, seizure
Uncommon
Cardiac disorders
palpitations
Rare
Respiratory, thoracic and 
mediastinal disorders
epistaxis
Uncommon
Churg-Strauss Syndrome (CSS)
Very Rare
pulmonary eosinophilia
Very Rare
Gastrointestinal disorders
diarrhoea‡, nausea‡, vomiting‡
Common
dry mouth, dyspepsia
Uncommon
Hepatobiliary disorders
elevated levels of serum 
transaminases (ALT, AST)
Common
hepatitis (including cholestatic, 
hepatocellular, and mixed-pattern liver 
injury).
Very Rare
Skin and subcutaneous 
tissue disorders
rash
Common
bruising, urticaria, pruritus
Uncommon
angiooedema
Rare
erythema nodosum, erythema 
multiforme
Very Rare
Musculoskeletal, connective 
tissue and bone disorders
arthralgia, myalgia including muscle 
cramps
Uncommon
General disorders and 
administration site 
conditions
pyrexia
Common
asthenia/fatigue, malaise, oedema,
Uncommon
*Frequency Category: Defined for each Adverse Experience Term by the incidence reported in the clinical 
trials data base: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), 
Rare (≥1/10,000 to <1/1000), Very Rare (<1/10,000).
†This adverse experience, reported as Very Common in the patients who received montelukast, was also 
reported as Very Common in the patients who received placebo in clinical trials.
‡This adverse experience, reported as Common in the patients who received montelukast, was also 
reported as Common in the patients who received placebo in clinical trials.
§ Frequency Category: Rare
1.
Taken from SINGULAIR Paediatric Granules SMPC, Summary of Product Characteristics, May 2016 (5 mg) and 
February 2016 (4 mg).

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4.6.3.
Benefit Assessment
4.6.3.1.
Fluticasone Furoate
The use of ICS is now well established in international treatment guidelines for paediatric 
asthma patients.  The benefits of an ICS include control of asthma symptoms, 
improvement in lung function and a decrease in airway hyper-responsiveness. In addition 
subjects will receive short-acting beta2 agonists (SABA) for use ‘as needed’ for relief of 
asthma symptoms.
All subjects will undergo medical assessment at screening and over the treatment period.  
Subjects will have frequent clinic visits for the evaluation of their asthma during the 
study period.  Subjects will have an assessment of FEV1 at screening and there will be a 
review of a daily diary during the study.  The diary will contain PEF measurements, 
rescue albuterol/salbutamol usage, daily symptom scores, and any medical problems 
experienced and if any medication was required.
4.6.3.2.
Leukotriene receptor antagonists
Leukotriene receptor antagonists are established in international treatment guidelines for 
paediatric asthma patients [GINA, 2016]. Montelukast is an orally active compound 
which binds with high affinity and selectivity to the cysteinyl leukotriene 
(CysLT1) receptor. In children under 5 years of age, montelukast improved parameters of 
asthma control compared with placebo irrespective of concomitant controller therapy 
(inhaled/nebulized corticosteroids or inhaled/nebulized sodium cromoglycate) [SMPC, 
2016]. Benefits of treatment in children 6-14 years of age include an improvement in 
lung function and decreased "as-needed" β-agonist use [SMPC, 2016]. GINA guidance 
2014 states than LTRA are less effective than ICS but may be appropriate for initial 
controller treatment for patients unwilling or unable to use ICS, or for patients with 
intolerable side effects to ICS or for patients with concomitant allergic rhinitis.
4.6.4.
Overall Benefit:Risk Conclusion
GlaxoSmithKline (GSK) has assessed this study for any potential risks that a subject may 
experience. The investigational product (IP) FF has an acceptable safety profile for 
clinical use and there are no significant associated risks. This conclusion is supported by 
the results of previous clinical studies with the products in healthy volunteers and 
subjects with Asthma and COPD that can be found within the FF IB GlaxoSmithKline
Document Number GM2004/00283/10] and the FF/VI IB [GlaxoSmithKline Document 
Number RM2008/00012/07. Safety criteria outlining details for subject withdrawal is 
included in the protocol (Section 5.5, Withdrawal Criteria). A thorough summary and 
evaluation of the available pre-clinical data can be found in the IB [GlaxoSmithKline
Document Number GM2004/00283/10].
Montelukast is an authorised product for the treatment of paediatric asthma and as such it 
is generally accepted that the benefits of treatment outweigh the risks. It has been 
included in this study to ensure all subjects have at least one asthma controller medication 

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throughout the study, therefore reducing the risk of worsening asthma symptoms for 
subjects randomised to the placebo inhaler treatment arm.
Taking into account the measures to minimise risk to subjects participating in this study, 
the potential risks identified in association with FF are justified by the anticipated 
benefits that may be afforded to paediatric patients with asthma.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB/IB supplement(s) and 
product label.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardise the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply at screening:
DEMOGRAPHICS
1. Male or female subjects.
2. Age:  
a.
Males between 5 and <9 years old
b. Females between 5 and <8 years old
3. Subjects must be pre-pubertal (Tanner Stage 1).
4. Height centile between 3% and 97% based on US CDC charts.
5. Subjects with body weight and body mass index that is between 3rd and 97th centile 
based on the US CDC charts (provided in the Study Reference Manual [SRM]).
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
6. A documented history of symptoms consistent with a diagnosis of asthma for at least 
6 months prior to Visit 1.
7. A pre-bronchodilatory FEV1 at Visit 1 (Screening) of ≥60%. There should be no 
SABA use within 4 hours of this measurement.  
NOTE:  Only subjects who are unable to perform the FEV1 manoeuvre at their Visit 
1 can, at the discretion of the investigator, attend the clinic to perform the manoeuvre 
once more on another day before Visit 2.  This repeat FEV1 manoeuvre must be 
acceptable (as defined in the SRM) and must meet the FEV1 inclusion limits to be 
eligible for the study.
8. Able to replace their current SABA treatment with study supplied rescue 

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albuterol/salbutamol provided at Visit 1 for use as needed for the duration of the 
study.  
9. A cACT score of >19.
10. Patients should have required at least one course of corticosteroid for their asthma 
(inhaled or oral) in the past year. 

There must be no ICS use within 6 weeks of Visit 1 (Screening).

There must be no oral corticosteroids use within 12 weeks of Visit 1 (Screening)
11. Using one or more of the following asthma therapies prior to entry into the study:

Short acting beta-agonist (SABA) inhaler alone (e.g. salbutamol) on an as 
needed basis and/or

Regular non-ICS controller medications for asthma (e.g. cromones or 
leukotriene receptor antagonists).
INFORMED CONSENT
12. Written informed consent from at least one parent/care giver (legal guardian) and 
accompanying informed assent from the subject (where the subject is able to provide 
assent) prior to admission to the study.

If applicable, subject must be able and willing to give assent to take part in the 
study according to local requirement. The study investigator is accountable for 
determining a child's capacity to assent for participation in a research study, 
taking into consideration any standards set by the responsible IEC.

Subject and their legal guardian(s) understand that they must comply with study 
medication administration regimens and study assessments including recording 
of symptom scores and rescue albuterol/salbutamol use, attending all study 
visits, and being accessible by telephone.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply at screening:
CONCURRENT CONDITIONS/MEDICAL HISTORY 
1. Growth Criteria: 
a.
Any previous or current condition that affects growth, including sleep disorders, 
endocrine disorders, skeletal dysplasia, Turner and Noonan syndromes, Marfan, 
Beckwith–Wiedeman and Sotos syndromes, Klinefelter’s syndrome, coeliac 
disease, inflammatory bowel diseases and renal failure or any significant 
abnormality or medical condition that is identified at the screening medical 
assessment (including serious psychological disorder) that is likely to interfere 

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with the conduct of the study.
b. Subjects with premature adrenarche (further details will be provided in the SRM).
c.
A child who is unable to stand, or who finds standing difficult due to illness or 
physical disabilities should be excluded.
2. Disease Criteria:
a.
Subjects with a history of asthma exacerbation requiring the use of systemic 
corticosteroids (tablets, suspension, or injection) for at least 3 days or use of a 
depot corticosteroid injection within 3 months or those requiring 
hospitalisation for asthma (within 6 months) prior to screening.
b. Culture-documented or suspected bacterial or viral infection of the upper or 
lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks 
of Visit 1 and led to a change in asthma management or, in the opinion of the 
Investigator, is expected to affect the subject’s asthma status or the subject’s 
ability to participate in the study.
c.
Clinical visual evidence of candidiasis at Visit 1 (Screening).
d. Any significant abnormality or medical condition identified at the screening 
medical assessment that in the Investigator’s opinion, preclude entry into the 
study due to risk to the subject or that may interfere with the outcome of the 
study.
CONCOMITANT MEDICATIONS
3. General: 
a.
Prior use of any medication or treatment that might affect growth including, 
but not limited to: amphetamines, anticonvulsants, biphosphonates, calcitonin,  
erythropoietin, growth hormone, methylphenidate, phosphate binders, 
antithyroid drugs (e.g.,  Methimazole) or thyroid hormone.
4. Use of any of the prohibited medications listed in Section 6.10.2.
CONTRAINDICATIONS 
5. Hypersensitivity: Known hypersensitivity to corticosteroids, leukotrienes, or any 
excipients in the ELLIPTA inhaler and study tablets.  
6. Milk Protein Allergy: History of severe milk protein allergy.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).

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8. Exposure to more than 4 investigational medicinal products within 12 months prior to 
the first dosing day.
9. Children who are an immediate family member of the participating Investigator, sub-
Investigator, study coordinator, or employee of the participating Investigator.
10. The Parent or Guardian has a history of known or suspected 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 subject during the study

compliance of subject with study medication and study procedures 
(e.g.completion of daily diary, attending scheduled clinic visits)

subject safety and well-being
11. Children in care: Children who are wards of the government or state are not eligible 
for participation in this study.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial, are 
assigned a subject number, and complete at least one study procedure but are not 
subsequently entered into the run-in period.  Subjects who enter the run-in period but are 
not randomised are considered run-in failures. In order to ensure transparent reporting of 
screen failure subjects, meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements, and respond to queries from Regulatory 
authorities, a minimal set of screen failure information is required which may include 
Demography, Screen Failure details, Eligibility Criteria, and any Serious Adverse Events 
relating to study participation.
Re-screening of screen failures is permitted.  Individuals who do not meet the criteria for 
participation in this study (i.e., are a screen failure) may be re-screened up to one 
additional time if the investigator judges the subject can meet the eligibility criteria. 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.
Re-screening of run-in failures is not permitted.
5.4.
Randomisation Criteria
Subjects must meet the following criteria to be eligible for randomisation:
1. Growth 
a.
Prepubertal: Subjects must be pre-pubertal (Tanner Stage 1).

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b. Body weight and body mass index: Between the 3rd and 97th percentile based on 
the US CDC standard statistics or any local standards outside the US. The US 
CDC standards are provided in the SRM.
c.
Baseline growth velocity: Between the 3rd and 97th percentile based on North 
America Longitudinal Standard Growth Velocity charts.
d. Bone age: Within 2 years of subject’s chronological age as determined by 
hand/wrist x-ray during the baseline period.
2. Disease Changes
a.
Prohibited Diseases: No new medical conditions that would have been 
exclusionary at Visit 1. 
3. Medications
a.
Corticosteroid Use: No corticosteroid use during the baseline period that would 
likely have a systemic effect.
b. Prohibited Medications: No use of any medications during the baseline period 
that are detailed in the inclusion/exclusion criteria during the baseline period for 
worsening asthma symptoms. 
4. Study Compliance:
a. Responsibility: Subject/parent/guardian has demonstrated the ability to comply 
with all study procedures during the run-in study period, including proper study 
drug administration during the randomisation visit. 
b. Single-blind treatment: Compliance with single-blind placebo treatment as 
recorded in the daily diary and based on the dose counter. Subjects who have not 
taken their inhaler at least 80% of the time during the last 30 days of the run-in 
period will not be eligible for randomisation.
5. Assessments: Able to use the ELLIPTA inhaler correctly. 
5.5.
Withdrawal/Stopping Criteria
5.5.1.
Subject Withdrawal by Investigator or Self-withdrawal
The following criteria will cause a subject to be discontinued from study treatment but 
every effort should be made to keep the subject in the study:
1. Non-Compliance: A subject is significantly non-compliant with the requirements of 
the protocol (see Section 6.7).
2. Adverse Event: A subject has an adverse event that, in the investigator’s judgement, 
makes continued study treatment an unacceptable risk.

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3. Study Blinding Revealed: The treatment blind is broken for any subject other than 
by GSK GCSP personnel.
4. If during the study the subject has a blood sample taken and the results meet the liver 
chemistry stopping criteria (see Section 5.5.3).
5. If during the study the subject has an ECG and the results meet the QTc stopping 
criteria (see Section 5.5.4).
In addition to the reasons above, a subject may be discontinued from study treatment at 
any time at the discretion of the investigator for safety, behavioural or administrative 
reasons.
If a subject discontinues study treatment, the subject will not automatically be considered 
as being withdrawn from the study but will be encouraged to stay in the study. An Early 
Treatment Discontinuation Visit should be conducted within approximately 24 hours of 
the subject stopping study medication (Section 7.1). In the event a subject 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 Treatment 
Discontinuation Visit must be performed at this visit instead. These subjects will not be 
allowed to restart study treatment, however, will be asked to continue to follow the 
regular visit schedule (Section 7.1). Reasons for treatment discontinuation will be 
collected and, where possible, every effort will be made to collect growth measurements 
throughout the intended study period (with particular focus on obtaining the end of the 
52-week treatment period height measurement) and recorded in the CRF as planned. 
After the Early Treatment Discontinuation Visit the subjects will no longer be required to 
complete the e-diary. The investigator should prescribe appropriate asthma medication to 
subjects who discontinue study treatment and elect to continue in the study. After 
treatment discontinuation, the prohibited medications listed in Section 6.10.2 are no 
longer applicable. 
A subject may withdraw from the study at any time at his/her own request (or at the 
request of his/her parents/guardians). In this case, all study-related medications and other 
study related materials should be returned to the site by the subject. An Early Withdrawal 
Visit should also be scheduled within approximately 24 hours of the subject withdrawing 
from the study (Section 7.1). In the event a subject withdraws at or during a scheduled 
visit, an Early Withdrawal Visit is not required; however, all study procedures scheduled 
at an Early Withdrawal Visit must be performed at this visit instead. The primary reason 
of withdrawal from the study will be recorded in the CRF.  If a subject withdraws from 
the study, he/she may request destruction of any samples taken, and the investigator must 
document this in the study records.  
The only reasons for study withdrawal are patient withdrawal of consent to contribute 
additional outcome information and loss to follow-up.  

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5.5.2.
Subjects Lost to Follow-up
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the parent/subject and re-schedule the missed visit 
as soon as possible. 

The site must counsel the parent/subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
should continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the parent/subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the parent/subject continue to be unreachable, only then will the subject be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”. 
5.5.3.
Liver Chemistry Stopping Criteria
Clinical laboratory tests are not planned at Screening or during this study.  However, if a 
subject has a blood test taken during the study the following stopping criteria apply.
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf

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

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Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow-up Assessments Section can be found in 
Appendix 2.
5.5.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.5.4.
QTc Stopping Criteria
ECGs are not planned at Screening or during this study.  However, if during the study a 
subject has an ECG performed the following stopping criteria apply.
A subject who meets the bulleted criteria below will be withdrawn from the study 
treatment:

QTc > 500 msec OR Uncorrected QT > 600 msec
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.

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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
FF (GW685698) 50mcg 
Dry Powder Inhaler*
Placebo*
Montelukast (open label)
Formulation 
description:
Dry Powder Inhaler
Dry Powder 
Inhaler
4 mg chewable tablet (5 
year old subjects)
5 mg chewable tablet (≥6 
year old subjects)
Note:  subjects who turn 6 
years old during the study, 
will subsequently receive 5 
mg of open-label 
montelukast.
Dosage form:
Dry Powder Inhaler
Dry Powder 
Inhaler
Chewable tablet
Unit dose 
strength(s)/Dosage 
level(s):
50 mcg per blister
Lactose
4 mg or 5 mg
Route of 
Administration
Inhaled
Inhaled
Oral
Dosing 
instructions:
Inhale once daily in the 
MORNING
Inhale once 
daily  in the 
MORNING
Once daily in the EVENING
Physical 
description:
Dry White Powder
Dry White 
Powder
Chewable tablet
Storage conditions
Store up to 25°C (77°F)
Store up to 
25°C (77°F)
Per commercial Label:
59°F to 86°F (15°C to 
30°C). 
Device:
ELLIPTA
ELLIPTA
N/A
Method for 
individualizing 
dosage:
Inhalation (oral)
Inhalation 
(oral)
Chewable tablet
*Single Strip
During the run-in period, all eligible subjects will receive a single-blind placebo 
ELLIPTA inhaler. 

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Each subject will also receive an 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.  
6.2.
Medical Devices
Medical devices (peak flow meters and stadiometers) will be provided by GSK for use in 
this study. However, none of the devices provided are manufactured by, or on behalf of 
GSK.
6.3.
Treatment Assignment
All subjects will receive a single-blind placebo inhaler during the 16-week run-in period.
Subjects will be stratified by country and be assigned to double-blind treatment (either 
inhaled FF 50 mcg or inhaled placebo) in accordance with the randomisation schedule 
generated prior to the start of the study, using validated software.
6.4.
Blinding
This will be a double-blind study and the following will apply:

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the CRF and 
source documentation. 
A subject may continue in the study if that subject’s treatment assignment is unblinded by 
GSK GCSP Personnel. The primary reason for discontinuation (the event or condition 
which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.

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6.5.
Packaging and Labelling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability

Only subjects enrolled in the study may receive study treatment and only authorised 
site staff may supply or administer study treatment.  All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the 
investigator and authorised site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment are 
provided in the Study Reference Manual (SRM). 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
6.7.
Compliance with Study Treatment Administration
Subject compliance with single-blind treatment will be assessed during the run-in period 
(Visits 1 to 5) by reviewing the dose counter and daily e-diaries. 
Subject compliance with double-blind study medication will be assessed at Visit 5 
(Randomisation visit) through to Visit 20 (Follow-up visit/Early Withdrawal) by 
reviewing the following:
1. ELLIPTA dose counter assessment at each visit.
2. Daily e-diary recordings of treatment adherence.
Compliance with open-label montelukast will be assessed throughout the study (Visit 1 to 
Visit 20 [Follow-up visit/Early Withdrawal]) by reviewing the daily e-diaries. 
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.  In the instance of significant and repeated non-compliance, the subject 
may be withdrawn after discussion with the Medical Monitor.

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6.8.
Treatment of Study Treatment Overdose
For this study, any dose of 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.
1. Contact the Medical Monitor immediately
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until FF can no longer be detected systemically (at least 
5 days for FF from the date of the last dose of study treatment)
3. Obtain a plasma sample for pharmacokinetic (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.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.10.
Concomitant Medications and Non-Drug Therapies
6.10.1.
Permitted Medications and Non-Drug Therapies
Any medication that is not prohibited in the Inclusion/Exclusion criteria or in the 
Prohibited Medications section 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. In addition, the following guidelines apply for specific medications:

Immunotherapy:  Immunotherapy for the treatment of allergies is allowed during the 
study if it was initiated 30 days prior to Visit 1 and there are no significant changes 
in the dose, concentration or dilution during the study.
6.10.2.
Prohibited Medications and Non-Drug Therapies
Use of the following medications is prohibited according to the timeframes below:

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Table 3
Prohibited Medications
Within 2 weeks prior to Visit 1 and at any time during the study
Theophyllines
Administration of prescription or over-the-counter medication that would 
significantly affect the course of asthma, or interact with study drug.
Within 6 weeks prior to Visit 1 and at any time during the study
Intranasal, inhaled and high potency topical (dermatological) corticosteroids
NOTE:  During the double-blind treatment period subjects who require limited 
courses of inhaled and/or intranasal corticosteroids should remain on study 
treatment.
Oral long-acting beta2-agonists (e.g. bambuterol) and inhaled long-acting beta2-
agonists (e.g. salmeterol, formoterol) or combination products containing inhaled 
long–acting beta2-agonists (e.g. SERETIDE™, Symbicort, Dulera)
The following potent Cytochrome P450 3A4 (CYP3A4) inhibitors (Clarithromycin, 
atazanavir, indinavir, itraconazole, ketoconazole, nefazadone, nelfinavir; ritonavir; 
saquinavir; telithromycin, troleandomycin, voriconazole, mibefradil, cyclosporine)
Within 12 weeks prior to Visit 1 and at any time during the study
Systemic, oral, or depot corticosteroids
NOTE:  During the double-blind treatment period subjects who require limited 
courses of oral corticosteroids should remain on study treatment.
Anti-IgE (e.g. Xolair) and anti-IL 5
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 subject remains 
in the maintenance phase throughout the study)
General therapies not permitted prior to or during the study
Prior use of any medication or treatment that might affect growth including, but not 
limited to: amphetamines, anabolic steroids, anticonvulsants, biphosphonates, 
calcitonin, erythropoietin, estrogens, growth hormone, methylphenidate, phosphate 
binders, progestins, thyroid hormone, or testosterone.
In addition, albuterol/salbutamol (inhalation aerosol or nebuliser) use should be withheld 
for 4 hours prior to the FEV1 measurement at screening.

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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1.

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7.1.
Time and Events Table
Screening/Baseline
Double-blind Treatment
Follow Up
T/D
W/D
Visit Number 
(*Child Visits)
1*
2
3*
4
5*
6*
7*
8*
9*
10
11
12*
13
14
15*
16
17
18*
19
20*
*
*
Week Number
-16
-12
-8
-4
0
4
8
12
16
20
24
28
32
36
40
44
48
52
+4
+ 8
Day
(All visits to occur 
within -5 to +2 days 
of specified day)
-112
-84
-56
-28
1
29
57
85
113
141
169
197
225
253
281
309
337
365
+28
+56
Written Informed 
Consent1 for Study 
and PGx Sample
X
Assign Subject 
Number
X
Subject Demography
X
Medical (Including 
Asthma) History
X
Therapy History
X
Physical 
Examination 
X
Tanner Staging
X
X
X
X
X
X
X
Stadiometry2
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Weight 
Measurement
X
X
X
X
X
X
X
X
X
X
BMI Measurement
X
X
X
X
X
X
X
X
X
X
Inclusion/Exclusion 
Criteria Verified
X
Completion of daily 
e-diary (PEF,
asthma symptoms 
and compliance with 
study medication)3
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Screening/Baseline
Double-blind Treatment
Follow Up
T/D
W/D
Visit Number 
(*Child Visits)
1*
2
3*
4
5*
6*
7*
8*
9*
10
11
12*
13
14
15*
16
17
18*
19
20*
*
*
Week Number
-16
-12
-8
-4
0
4
8
12
16
20
24
28
32
36
40
44
48
52
+4
+ 8
Day
(All visits to occur 
within -5 to +2 days 
of specified day)
-112
-84
-56
-28
1
29
57
85
113
141
169
197
225
253
281
309
337
365
+28
+56
Assess e-diary and 
compliance3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Spirometry-
generated FEV1
X
cACT
X
X
X
X
X
Concomitant 
Medication 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacogenetic 
Sample5
X (One Sample Only)
Adverse Event 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Event Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oropharyngeal Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
Hand/Wrist X-Ray 
Scheduled
Bone Age Result
X
Assess 
Randomisation 
Criteria
X
Assign 
Randomisation 
Number 
X
Dispense Open-label 
Montelukast
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Screening/Baseline
Double-blind Treatment
Follow Up
T/D
W/D
Visit Number 
(*Child Visits)
1*
2
3*
4
5*
6*
7*
8*
9*
10
11
12*
13
14
15*
16
17
18*
19
20*
*
*
Week Number
-16
-12
-8
-4
0
4
8
12
16
20
24
28
32
36
40
44
48
52
+4
+ 8
Day
(All visits to occur 
within -5 to +2 days 
of specified day)
-112
-84
-56
-28
1
29
57
85
113
141
169
197
225
253
281
309
337
365
+28
+56
Dispense Single-
Blind Treatment
X
X
X
X
Dispense Double-
Blind Treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Rescue 
Med (PRN)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect All 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
          
1.
If applicable, subject 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/IRB. 
2.
Subjects must attend the clinic for scheduled visits when stadiometry will be assessed.  Subjects’ parents/guardians will need to attend the clinic every month to 
collect/return diaries and study medication.
3.
Subjects will be required to record compliance with study medication (single-blind run-in treatment, double-blind treatment and open label montelukast) each day in the e-
diary.  Daily salbutamol use, asthma symptom scores and PEF will be recorded in the e-diary each day and will be collected at each visit.   Note: After the Early Treatment 
Discontinuation Visit subjects will no longer be required to complete the e-diary.
4.
At Visit 1, e-diary will be dispensed only.
5.
Saliva (2mL) is spit into the DNA self-collection kit. This should ideally be taken as soon after randomisation (Visit 5) as possible, but may be taken at any other visit after 
randomisation, if necessary. Genetics consent must be obtained prior to PGx sampling.
*= Child Visit – these visits are where the child (subject) must attend the clinic.
NOTE:  W/D = Early Withdrawal Visit and T/D= Early Treatment Discontinuation Visit

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7.2.
Screening and Critical Baseline Assessments
The following demographic parameters will be captured: month and year of birth, sex, 
race and ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
A hand/wrist x-ray (left hand) will be performed in the period between Visit 2 and Visit 4 
so that the results are available prior to the randomisation visit (Visit 5).  If subjects are 
unable to use their left hand due to injury or deformity then the right hand can be used for 
the x-ray.
Spirometry-generated FEV1 will be measured at screening only. All sites will use 
standardized spirometry equipment provided by an external vendor.  At least two 
acceptable efforts (no more than 8) will be obtained, confirmed by central overread of 
spirometry results and the highest will be recorded in the eCRF.  Subjects must withhold 
from using albuterol/salbutamol (inhalation aerosol or nebuliser) for 4 hours prior to 
FEV1 measurements.  
General procedures conducted as part of the subject’s routine clinical management e.g. 
blood count and obtained prior to signing of informed consent may be utilised for 
screening or baseline purposes.  If liver function tests are abnormal then the subject 
should be excluded from participating in the study.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  
7.3.1.
Height (Stadiometry) Measurement
Height (stadiometry) measurements will be carried out as outlined in the Time and 
Events Table (Section 7.1).  Stadiometers will be provided by GSK.  Measurements will 
be conducted by site personnel who are trained in the study-specific stadiometry and 
calibration procedures.  Every effort should be made to ensure that the same site 
personnel take all the height measurements in the study at a given centre, and should be 
blinded to the study phase.
Three reproducible height measurements will be taken using a stadiometer and will be 
recorded in the CRF.  The measurements must be taken consistently at the same time of 
day (3 hours) for each subject at each visit.  Measurements will be recorded to the 
nearest 1/10th of a centimetre.  If the stadiometer has not been calibrated in the last 4 
hours before the subject’s height is measured, it must be calibrated immediately before 
use.  A calibration log must be kept.  All subjects’ heights will be measured without 
socks, shoes or hats in place.  

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7.3.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.2.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.3.2.3), at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in  
Appendix 4.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.3.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 

“How does your child seem to feel?”

“Has your child had any (other) medical problems or seem to act differently in any 
way since his/her last visit/contact?”

“Has your child needed to take any medicines, other than those provided in this 
study, since his/her last visit/contact?”

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7.3.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.5.2). Further information on follow-up procedures is given in 
Appendix 4.
7.3.2.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs related to study 
treatment (even for non- interventional post-marketing studies) is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a 
product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.3.
Asthma Exacerbations
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 (ED) 
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 AEs, unless they meet the definition of 
an SAE (Appendix 4). 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.

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7.3.4.
Physical Exams

A complete physical examination will be done as indicated in the Time and Events 
Schedule.  It will include, at a minimum, assessment of the Cardiovascular, 
Respiratory, Gastrointestinal and Neurological systems.  

Body weight (including BMI) will be measured and recorded as as outlined in the 
Time and Events Schedule (see Table in Section 7.1).  

Tanner staging will be assessed as outlined in the Time and Events Schedule (see 
Table in Section 7.1).  Further details will be provided in the SRM.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.3.5.
Oropharyngeal Examination
Oropharyngeal examination for visual evidence of oral candidiasis will be carried out at 
as outlined in the Time and Events Table. If the visual oropharyngeal examination is 
abnormal prior to randomisation they 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.
7.4.
Efficacy (as a Measure of Compliance)
7.4.1.
Daily Diaries
Subjects/parents/guardians will be issued an eDiary for daily use throughout the study 
and will be instructed on how to complete the eDiary.  As well as recording compliance 
with study medication (single-blind treatment during the run-in period, double-blind 
treatment and open-label montelukast) in the eDiary, the following parameters will be 
recorded used as a measure of compliance to help identify non-adherence and/or poorly 
controlled asthma:

Daily asthma symptom scores 

Daily PEF (measured in the morning only)

Daily albuterol/salbutamol use. 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.

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If a subject discontinues study treatment, the subject should be encouraged to remain in 
the study and continue to follow the regular visit schedule.  However, the subject will no 
longer be required to complete the eDiary.
  
7.4.1.1.
Daily Asthma Symptom Scores
The following asthma symptom scores will be recorded once daily in the morning in the 
eDiary before taking any study treatment, before using any rescue medication, and before 
the daily PEF measurement:
Day-time Symptom Score for previous day:
Night-time Symptom Score:
7.4.1.2.
Daily PEF
PEF will be measured daily in the morning using an electronic Peak Flow Meter that will 
be issued to subjects at Visit 1.  The best of three attempts will be recorded by the 
subjects in the eDiary.
PEF will be measured and recorded daily throughout the study.  PEF measurements must 
be done: 

Each morning prior to taking any study treatment and before using any rescue 
medication.
For all randomised subjects, a PEF Stability Limit will be calculated as follows:

Mean PEF from the available 7 consecutive days preceding Visit 2 (during run-
in period) x 60%.
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 PEF from the morning of Visit 2 will be included in the calculation of the 
PEF stability limit.
Subjects will be alerted if their PEF has fallen below the PEF Stability Limit.
7.4.2.
Childhood Asthma Control Test
The Childhood Asthma Control Test (C-ACT) will be assessed at scheduled visits 
outlined in the Time and Events Table. 
The C-ACT is a 7-item questionnaire which has been developed as a measure of 
paediatric subjects’ (4-11 years old) asthma control [Liu, 2007], and which can be 
quickly and easily completed in clinical practice. It is designed for completion by the 
subject and by the subject’s parent/legal guardian. The subject (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 patient 
not to skip questions on the C-ACT or take breaks during the completion of the paper 
questionnaire. Responses to questions should not be changed or modified after collection. 
Upon completion of the C-ACT, the investigator or designated site personnel will collect 
the questionnaire and calculate the total score. The C-ACT responses will be 
administered and recorded in the CRF by the investigator or delegate.
7.5.
Genetics
Information regarding genetic research is included in Appendix 3.
8.
DATA MANAGEMENT

For this study subject data will be entered into electronic case report forms 
(eCRFs), transmitted electronically to GSK or designee and combined with data 
provided from other sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) or alternative, and a validated 
medication dictionary (e.g.  GSKDrug). 

CRFs (including queries and audit trails) will be retained by GSK or designee, and 
copies will be sent to the investigator to maintain as the investigator copy.  
Subject initials will not be collected or transmitted to GSK according to GSK 
policy.

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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective of this study is to characterise the estimated difference in 
prepubescent growth velocities between subjects treated for one year with inhaled FF 50 
mcg once daily (OD) (plus montelukast 4mg or 5mg open-label) and inhaled placebo 
(plus montelukast 4mg or 5mg open-label).
No formal statistical hypotheses are to be tested.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The proposed sample size for this study is based on FDA guidance [Guidance for 
Industry Orally Inhaled and Intranasal Corticosteroids: Evaluation of the Effects on 
Growth in Children, March 2007].     
The study is not powered to detect any treatment differences. The study is designed to 
provide the estimated mean treatment difference between inhaled FF 50 mcg once daily 
(OD) (plus montelukast open-label) and inhaled placebo (plus montelukast open-label) in 
prepubescent growth velocities, with a certain degree of precision on the 95% confidence 
interval.  The primary population for growth analyses will be the Growth Population 
(defined in Section 9.3.1). An analysis of covariance (ANCOVA) model will be used to 
estimate the mean treatment difference in growth velocities over the double-blind 
treatment period, adjusting for baseline growth velocity, age at Visit 1, gender, and 
country. A 95% confidence interval will also be provided for the estimated mean 
treatment difference in growth velocity over the double-blind treatment period (Section 
9.4.1).
Eligible subjects will be stratified by country and randomised in a 1:1 ratio to inhaled FF 
50 mcg OD (plus montelukast open-label) or inhaled placebo (plus montelukast open-
label). At least 450 subjects will be randomised (approximately 225 per treatment arm). 
Assuming a withdrawal rate from study medication of up to 10% within the first 12 
weeks, this would still ensure at least 406 eligible subjects (approximately 203 per 
treatment arm) for inclusion in the Growth Population (Section 9.3.1) analyses. Assuming 
a standard deviation for the growth velocities of 1.2 cm/year (based on study 
FFR101782), a sample size of 203 eligible subjects per treatment arm ensures the width 
of the confidence interval for the mean treatment difference is no greater than 0.5cm/year 
(Section 9.2.2).  

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9.2.2.
Sample Size Sensitivity
To demonstrate the sensitivity of the sample size calculation for this study, the following 
table presents the precision of the two-sided 95% confidence interval for the estimated 
mean treatment difference on growth velocities under different circumstances in terms of 
standard deviation and the number of subjects per treatment group for the growth 
analyses.
The shaded area represents the number of subjects per treatment group and the standard 
deviation that correspond to a 95% confidence interval with a width no greater than 
0.5cm/year, as recommended in the FDA guidance.
9.2.3.
Sample Size Re-estimation or Adjustment
Sample size re-estimation or adjustment is not planned.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Three subject populations will be defined:
Total Population: The Total Population will comprise all subjects screened and for 
whom a record exists on the study database and will be used for the tabulation and listing 
of reasons for withdrawal before randomisation.
Intent-to-Treat (ITT) Population: The ITT Population is defined as all randomised 
subjects who receive at least one dose of study drug. All safety and efficacy (compliance 
assessments) data analyses will use the Intent-to-Treat (ITT) population. 
Growth Population: The Growth Population is defined as all ITT subjects with height 
assessments via stadiometry from at least three post-randomisation, on-treatment clinic 
visits during the double-blind treatment period. This will be the primary population for 
analyses of growth data (Section 9.4.1).

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9.3.2.
Interim Analysis
No interim analyses are planned during this study.
9.4.
Key Elements of Analysis Plan
It is anticipated that approximately 70 sites from multiple countries in North America, 
South America, South Africa and Europe will participate in the study. Therefore it is 
likely that many centres will enrol very small numbers of subjects. Consequently, all 
centres 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 country is incorporated into the analysis.  
The detailed statistical methodology for the data analyses will be provided in the 
Reporting and Analysis Plan (RAP).
9.4.1.
Primary Safety Analyses
9.4.1.1.
Growth Velocity
Height assessments will be conducted at the following clinic visits: Visits 1, 3, and 5 
during the 16-week baseline period; Visits 6-9, 12, 15 and 18 during the 52-week double-
blind treatment period; and Visit 20 during the 8-week follow-up period. For each height 
assessment at a given clinic visit, triplicate stadiometry measurements will be collected 
for each subject. For the purposes of these analyses, each set of triplicate measurements 
will be averaged to derive one estimated height per subject per visit.
For each study period (baseline, double-blind treatment, and follow-up), growth velocity 
(cm/yr) will be calculated for each subject based on stadiometry data by fitting a 
regression line to all height measurements recorded for that subject during the period and 
determined by the slope of the fitted regression line. These will be calculated for the 
Growth population and for the ITT population and details of the calculations will be 
provided in the RAP.  Baseline, double-blind treatment and follow-up growth velocities 
will be summarised by treatment while statistical analysis will only be performed for the 
double-blind treatment period. 
The primary population for the primary growth analysis will be the Growth population 
(Section 9.3.1).  The primary analysis will evaluate the primary de facto estimand: the 
mean difference in growth velocities between treatment groups over the double-blind 
treatment period, regardless of whether or not the subject remained on-treatment after 
their third post-randomization visit. For subjects in the Growth population who 
discontinue study treatment early after their third post-randomization clinic visit, all 
available on- and off- study treatment height assessments available during the treatment 
period will be included in the primary analysis.  An ANCOVA model will be used to 
estimate the mean treatment difference in growth velocity over the double-blind 
treatment period, adjusting for baseline growth velocity, age at Visit 1, gender, and 

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country. A 95% confidence interval will also be provided for the mean treatment 
difference in growth velocity over the double-blind treatment period.
Given subjects who discontinue study treatment may be administered other medications 
that may affect growth, a supportive analysis will be performed to evaluate the following 
de jure estimand: the mean difference in growth velocities between treatment groups over 
the double-blind treatment period, based on data measured while subjects are taking 
study treatment.  This will be estimated using the Growth Population (Section 9.3.1) and 
using all on-treatment height measurements obtained up to the point of study treatment 
discontinuation. 
Additional supportive analyses will be provided for the following subsets of the Growth 
Population:
1. Excluding subjects who exhibit greater than or equal to Tanner Stage 2 
characteristics at any point during the treatment period or follow-up period
2.
Excluding subjects who have questionable height measurements (definition of 
questionable measurements will be provided in the RAP)
3. Excluding subjects who have height measurements taken after receiving rescue
systemic corticosteroids during the treatment period
4. Excluding subjects who have height measurements taken after receiving rescue
inhaled and/or intranasal and/or systemic corticosteroids during the treatment 
period
5. Excluding subjects who have any of the above
A supportive completers’ analysis of growth velocity over the 1-year double-blind 
treatment period, based on subjects in the Growth Population who completed the double-
blind treatment period and remained on study treatment during that period, will also be 
performed.
Additional supportive analyses evaluating the primary de facto estimand, including all 
subjects (using the ITT Population, Section 9.3.1) will be performed.  Further details will 
be provided in the RAP. 
9.4.2.
Secondary Safety Analyses
9.4.2.1.
Growth
Secondary analyses pertinent to growth will also include the following:
1. Summary of the proportion of children who are below the 3rd percentile of growth 
velocity 

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2.
Summary of change (shift) in growth velocity quartile for each child from 
baseline to endpoint (definition of baseline and endpoint will be provided in the 
RAP)
3. Analysis of the first 12 weeks (~10 to 13 weeks given visit windows, Section 7.1) 
of data
4. Summary of growth velocities during the baseline and follow-up periods
5. Analysis of growth velocities for the following region subgroups: USA and Non-
USA
6.
Descriptive comparison of the growth velocities based on gender and ethnicity
7. Summary by visit and by treatment group of standard deviation scores and 
summary of change  in height standard deviation scores from baseline to endpoint 
(definition of standard deviation scores, baseline and endpoint will be provided in 
the RAP)
8. Analysis of random coefficients
9.4.2.2.
Adverse Events
Regarding the safety assessment of inhaled FF 50 mcg, adverse events (incidence, type, 
severity) will be assessed throughout the study.
Adverse events (AEs) will be summarised for each study period (16-week single-blind 
baseline period, 52-week double-blind treatment period, and 8-week follow-up period) 
and displayed by treatment group. The onset date of the adverse events relative to the 
clinic visit dates will be used to determine in which period an adverse event occurs. 
Adverse events during the pre-treatment period include those with date of onset prior to 
study treatment initiation (first dose date). Adverse events during the on-treatment period 
include those with date of onset on or after the date of study treatment initiation and on or 
before the study treatment termination date. Adverse events during the post-treatment 
period include those with date of onset after the study treatment termination date.
The CRF text for AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be reported using the primary System Organ Class (SOC) 
and Prederred Term (PT). The number of subjects with one or more events of any type 
will be calculated. Results will be displayed in the order of decreasing frequency, both 
across SOC and within SOC. A SOC will not be presented when the overall incidence for 
any adverse event within the particular system is 0. If the total incidence for any two or 
more adverse events is equal, the events will be presented in alphabetical order. 
Adverse events during each study period (baseline, treatment and follow-up) will also be 
listed, with SOC, event (preferred term), treatment group, number of subjects with the 
event, and specific subject numbers. Demographic details (e.g. age, gender and race), as 
well as details of the individual adverse events, will be included in these listings. Listings 
will be sorted within subject by the date of onset of the AE.

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Similar summaries and listings will be provided for drug-related adverse events, and
adverse events leading to withdrawal from study treatment.
Any deaths, pregnancies and serious adverse events (SAEs) reported during the study 
period will also be listed.
9.4.2.3.
Asthma Exacerbations
The number and percentage of subjects experiencing an exacerbation over the double-
blind treatment period and the follow-up period will be summarised for each treatment 
group alongside the primary causes of the exacerbation.
9.4.3.
Other Analyses
The reporting of other endpoints pertaining to efficacy as a measure of compliance as 
specified in the protocol will be described in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

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
Signed informed consent must be obtained for each subject prior to participation 
in the study.

Signed assent will be obtained where considered appropriate according to the 
subject’s age and comprehension, as determined by the Investigator.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the “CRF”
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.

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10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

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
GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the 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.

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11.
REFERENCES
British Guideline on the Management of Asthma: A national clinical guideline. Thorax 
2008 63: iv1-iv121.
GlaxoSmithKline Document Number: 2015N240433.  GlaxoSmithKline Development 
Safety Update Report for Fluticasone Furoate, 2015.
GlaxoSmithKline Investigator’s Brochure for Fluticasone furoate / GW685698, GSK 
document number GM2004/00283/10. Effective Date: 06 August 2015.
GlaxoSmithKline Investigator’s Brochure. Fluticasone Furoate + Vilanterol.  
GlaxoSmithKline Document Number for RM2008/00012/07.  Effective Date: 07 August 
2015.
Global Initiative for Asthma (GINA)). Pocket guide for the Global Strategy for Asthma 
Management and Prevention. GINA, www.ginasthma.org; 2016.  
Guidance for Industry Orally Inhaled and Intranasal Corticosteroids: Evaluation of the 
Effects on Growth in Children. U.S. Department of Health and Human Services, Food 
and Drug Administration, Center for Drug Evaluation and Research (CDER): March 
2007.
Kelly HW, et al. Effects of inhaled corticosteroids in childhood on adult height. N Engl J 
Med 2012;367: 904-12.
Liu AH, Zeiger R, Sorkness C, Mahr T, Ostrom N, Burgess S, et al. Development and 
cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin 
Immunol. 2007;119:817-25.
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):1-34.
Price J, Hindmarsh P, Hughes S, Efthimiou J. Evaluating the effects of asthma therapy on 
childhood growth: principles of study design. Eur Respir J  2002; 19: 1167–1178.
Pruteanu AI, Chauhan BF, Zhang L, Prietsch SOM, Ducharme FM Inhaled 
corticosteroids in children with persistent asthma: dose-response effects on growth 
(Review) EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW 
JOURNAL Evid.-Based Child Health 9:4: 931–1046 (2014).
Roizen J, Alter C, and Bamba V. Recent research on inhaled corticosteroids and growth 
Curr Opin Endocrinol Diabetes Obes 2012, 19: 53–56.

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Summary of Product Characteristics (SMPC) for SINGULAIR (Montelukast). Summary 
of Product Characteristics, May 2016 (5.mg) and February 2016 (4 mg).
Tillmann V, Clayton PE. Diurnal variation in height and the reliability of height 
measurements using stretched and unstretched techniques in the evaluation of short-term 
growth.  Annals of Human Biology 2001, 28 (2), 195-206.
Zhang L, Prietsch SOM, Ducharme FM. Inhaled corticosteroids in children with 
persistent asthma: effects on growth.Cochrane Database of Systematic Reviews 2014, 
Issue 7. Art. No.: CD009471. DOI: 10.1002/14651858.CD009471.pub2.

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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ANCOVA
Analysis of Covariance
BMI
Body mass index
cACT
Childhood Asthma Control Test
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CS
Corticosteriod
CRF
Case Record Form
CYP3A4
Cytochrome P450 3A4   
DPI
Dry Powder Inhaler
EU-RMP
European Union-Risk Management Plan
FDA
Food and Drug Administration
FEV1
Forced Expiratory Flow in 1 second
FF
Fluticasone furoate
FF/VI
Fluticasone furoate/vilanterol
FP
Fluticasone propionate
GCs
Glucocorticosteriods
GCSP
Global Clinical Safety and Pharmacovigilence
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
GSK Drug
GlaxoSmithKline Validated Medication Dictionary
IB
Investigator Brochure
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
ICS
Inhaled Corticosteroid
IEC
Independent Ethics Committee
IGF-1
Insulin-like growth factor-1
IgE
Immunoglobulin E
IL
Interleukin
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intention to Treat
LABA
Long Acting Beta Agonist
mcg
Microgram
MD
Mean difference

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MedDRA
Medical Dictionary for Regulatory Activities
MSDS
Material Safety Data Sheet
NDPI
Novel dry powder inhaler
OD
Once Daily
PEF
Peak Expiratory Flow
PK
Pharmacokinetics
prn
As required
PT
Preferred Term
SABA
Short Acting Beta 2 Agonist
SAE
Serious Adverse Event
SOC
System organ class
SRM
Study Reference Manual
WHO
World Health Organisation
US
United States
US CDC
United States Centers for Disease Control and Prevention
VI
Vilanterol trifenatate
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ARNUITY
Dulera
BREO ELLIPTA
Singulair
ELLIPTA
Symbicort
RELVAR ELLIPTA
Xolair
SERETIDE

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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 1-5days after last 
dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 

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granted

If restart/rechallenge is not allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). 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.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
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5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
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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12.3.
Appendix 3- Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including any treatment regimens under investigation in 
this study or any concomitant medicines;

Asthma susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.

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Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 2 ml saliva sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A Saliva sample is collected at the baseline visit, after the subject has been 
randomised and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the saliva sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The saliva sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any saliva being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 

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

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

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Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

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from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

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the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.4.4.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

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
The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.5.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the SAE coordinator

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 

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the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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12.5.
Appendix 5- Country Specific Requirements
No country-specific requirements exist.

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12.6.
Appendix 6 – Protocol Changes
Protocol Amendment 01
This amendment applies to all study centers participating in HZA114971.
Description
This amendment was implemented in order to make the following changes:

Remove the term local growth charts and replace with US CDC charts for inclusion 
criteria 4 and 5.

Amend the text for inclusion criterion 7 to provide clarity on the time window used 
for re-scheduling the spirometry assessment at screening (Visit 1).

Remove the term WHO growth charts and replace with North America Longitudinal 
Standard Growth Velocity Charts for randomization criterion 1c.

Amended typographical error in Section 5.5.4 and to clarify that the subject will be 
withdrawn from study treatment (for consistency with Section 5.5.1).

Amend the text and provide clarity on the procedure around oropharyngeal exams in 
Section 7.3.5.

Amend the time and events table to show an ‘x’ for body weight at Visit 3 as this was 
missing.

Remove word “continuously” in Section 9.1.

Add a supportive completers’ analysis of growth velocity over the 1-year double-
blind treatment period, based on subjects who completed the double-blind treatment 
period while remaining on study treatment, in Section 9.4.1.1.

Add a summary of change in height standard deviation scores (SDS) from baseline to 
endpoint in Section 9.4.2.1.
Method of Amendment
Original and amended text is presented below with the original text preceding the revised 
text contained in this Amendment No. 01 in the order of occurrence within the protocol. 
Amendment Details
Section 5.1- Inclusion Criteria – Inclusion Criterion 4 (Height Centiles)
This edit applies to inclusion criterion 4.
Original Text:  
Inclusion Criterion 4:  Height centile between 3% and 97% based on local growth charts.
Revised Text:  
Inclusion Criterion 4:  Height centile between 3% and 97% based on US CDC charts.

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Section 5.1- Inclusion Criteria – Inclusion Criterion 5 (Body Weight and Body Mass 
Index)
This edit applies to inclusion criterion 5.
Original Text:  
Inclusion Criterion 5:  Subjects with body weight and body mass index that is between 
3rd and 97th centile based on the US CDC standard statistics or any local standards 
outside the US. The US CDC standards are provided in the Study Reference Manual 
(SRM).
Revised Text:  
Inclusion Criterion 5:  Subjects with body weight and body mass index that is between 
3rd and 97th centile based on the US CDC charts (provided in the Study Reference 
Manual [SRM]).
Section 5.1- Inclusion Criteria – Inclusion Criterion 7 (Pre-bronchodilatory FEV1 at 
screening (Visit 1))
This edit applies to inclusion criterion 7.
Original Text:  
Inclusion Criterion 7:  A pre-bronchodilatory FEV1 at Visit 1 (Screening) of between 
≥60% to ≤95% predicted. There should be no SABA use within 4 hours of this 
measurement.  NOTE:  Only subjects who are unable to perform the FEV1 manoeuvre at 
their Visit 1 can, at the discretion of the investigator, attend the clinic to perform the 
manoeuvre once more on another day (within the time window specified in the Time and 
Events Table).  This repeat FEV1 manoeuvre must be acceptable (as defined in the SRM) 
and must meet the FEV1 inclusion limits to be eligible for the study.
Revised Text:  
Inclusion Criterion 7: A pre-bronchodilatory FEV1 at Visit 1 (Screening) of between 
≥60% to ≤95% predicted. There should be no SABA use within 4 hours of this 
measurement.  NOTE:  Only subjects who are unable to perform the FEV1 manoeuvre at 
their Visit 1 can, at the discretion of the investigator, attend the clinic to perform the 
manoeuvre once more on another day before Visit 2.  This repeat FEV1 manoeuvre must
be acceptable (as defined in the SRM) and must meet the FEV1 inclusion limits to be 
eligible for the study.

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Section 5.4- Randomisation Criteria – Randomisation Criterion 1c (Baseline 
Growth Velocity)
This edit applies to randomisation criterion 1c.
Original Text:  
Baseline growth velocity: Between the 3rd and 97th percentile based on World Health 
Organisation (WHO) charts.
Revised Text:  
Baseline growth velocity: Between the 3rd and 97th percentile based on North America 
Longitudinal Standard Growth Velocity charts.
Section 5.5.4 QTc Stopping Criteria
This edit applies to amend the typographical errors in the sentence before the bullet and 
to clarify that the subject will be withdrawn from study treatment (for consistency with 
Section 5.5.1)
Original Text:
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTc > 500 msec OR Uncorrected QT > 600 msec
Revised Text:
A subject who meets the bulleted criteria below will be withdrawn from study treatment:

QTc > 500 msec OR Uncorrected QT > 600 msec
Section 7 Study Assessments and Procedures –Time and Events Table 
This edit applies to addition of an ‘X’ at Visit 3 for body weight (Visit 3 only) on the 
Time and Events Table.  
Original Text:
There was no ‘X’ at Visit 3 for body weight on the Time and Events Table. This was 
missing in error.  
Revised Text:  
An ‘X’ was added at Visit 3 for body weight on the Time and Events Table. 

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Section 7.3 Safety – Sub-Section 7.3.5 Oropharyngeal Exams
This edit applies to Section 7.3.5 second sentence of the first paragraph.  
Original Text:
If the visual oropharyngeal examination is abnormal at Visits 1 and 3 (screening and run-
in period), the subject must be excluded from entering the randomisation period.  If the 
visual oropharyngeal examination is abnormal at Visit 5 (randomisation), the subject 
must not be randomised.
Revised Text:  
If the visual oropharyngeal examination is abnormal prior to randomisation they must not 
be randomised.  
Section 9.1. Hypotheses  
This edit applies to Section 9.1.
Original Text:
The primary objective of this study is to characterise the estimated difference in 
prepubescent growth velocities between subjects continuously treated  for one year with 
inhaled FF 50 mcg once daily (OD) (plus montelukast 4mg or 5mg open-label) and 
inhaled placebo (plus montelukast 4mg or 5mg open-label).
Revised Text:  
The primary objective of this study is to characterise the estimated difference in 
prepubescent growth velocities between subjects treated for one year with inhaled FF 50 
mcg once daily (OD) (plus montelukast 4mg or 5mg open-label) and inhaled placebo 
(plus montelukast 4mg or 5mg open-label).
Section 9.4.1 Primary Safety Analysis – Sub-Section 9.4.1.1 Growth Velocity
This edit applies to the end of Section 9.4.1.1: 
Original Text:
Additional supportive analyses evaluating the primary de facto estimand, including all 
subjects (using the ITT Population, Section 9.3.1) will be performed.  Further details will 
be provided in the RAP. 
Revised Text:  
A supportive completers’ analysis of growth velocity over the 1-year double-blind 
treatment period, based on subjects in the Growth Population who completed the double-

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blind treatment period and remained on study treatment during that period, will also be 
performed.
Additional supportive analyses evaluating the primary de facto estimand, including all 
subjects (using the ITT Population, Section 9.3.1) will be performed.  Further details will 
be provided in the RAP. 
Section 9.4.2 Secondary Safety Analysis – Sub-Section 9.4.1.2 Growth 
This edit applies to Section 9.4.1.2: 
Original Text:
Secondary analyses pertinent to growth will also include the following:
1. Summary of the proportion of children who are below the 3rd percentile of growth 
velocity 
2.
Summary of change (shift) in growth velocity quartile for each child from 
baseline to endpoint (definition of baseline and endpoint will be provided in the 
RAP)
3. Analysis of the first 12 weeks (~10 to 13 weeks given visit windows, Section 7.1) 
of data
4. Summary of growth velocities during the baseline and follow-up periods
5. Analysis of growth velocities for the following region subgroups: USA and Non-
USA
6.
Descriptive comparison of the growth velocities based on gender and ethnicity
7. Summary by visit and by treatment group of standard deviation scores (definition 
of standard deviation scores will be provided in the RAP)
8. Analysis of random coefficients
Revised Text:  
Secondary analyses pertinent to growth will also include the following:
1. Summary of the proportion of children who are below the 3rd percentile of growth 
velocity 
2.
Summary of change (shift) in growth velocity quartile for each child from 
baseline to endpoint (definition of baseline and endpoint will be provided in the 
RAP)

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3. Analysis of the first 12 weeks (~10 to 13 weeks given visit windows, Section 7.1) 
of data
4. Summary of growth velocities during the baseline and follow-up periods
5. Analysis of growth velocities for the following region subgroups: USA and Non-
USA
6.
Descriptive comparison of the growth velocities based on gender and ethnicity
7. Summary by visit and by treatment group of standard deviation scores and 
summary of change in height standard deviation scores from baseline to endpoint 
(definition of standard deviation scores, baseline and endpoint  will be provided in 
the RAP)
8. Analysis of random coefficients
Protocol Amendment 02
This amendment applies to all study centers participating in Study HZA114971.
Description
This amendment was implemented in order to make the following changes:

Removal of the upper limit of the FEV1 from inclusion criterion 7 (Section 5.1).

Removal of calcitriol from exclusion criterion 3 (Section 5.2) and from the prohibited 
medications Table 3 (Section 6.10.2).

Update of text in Section 5.3 Screening/Baseline/Run-in Failures to allow re-
screening of screen failures.
Method of Amendment
Original and amended text is presented below with the original text preceding the revised 
text contained in this Amendment No. 01 in the order of occurrence within the protocol. 
Amendment Details
Section 5.1- Inclusion Criteria – Inclusion Criterion 7 (Pre-bronchodilatory FEV1)
This edit applies to inclusion criterion 7.
Original Text:  
Inclusion Criterion 7:  A pre-bronchodilatory FEV1 at Visit 1 (Screening) of between 
≥60% to ≤95% predicted. There should be no SABA use within 4 hours of this 
measurement.  

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NOTE:  Only subjects who are unable to perform the FEV1 manoeuvre at their Visit 1 
can, at the discretion of the investigator, attend the clinic to perform the manoeuvre once 
more on another day before Visit 2.  This repeat FEV1 manoeuvre must be acceptable (as 
defined in the SRM) and must meet the FEV1 inclusion limits to be eligible for the study.
Revised Text:  
Inclusion Criterion 7:  A pre-bronchodilatory FEV1 at Visit 1 (Screening) of  ≥60%.  
There should be no SABA use within 4 hours of this measurement.  
NOTE:  Only subjects who are unable to perform the FEV1 manoeuvre at their Visit 1 
can, at the discretion of the investigator, attend the clinic to perform the manoeuvre once 
more on another day before Visit 2.  This repeat FEV1 manoeuvre must be acceptable (as 
defined in the SRM) and must meet the FEV1 inclusion limits to be eligible for the study.
Section 5.2- Exclusion Criterion 3 a ( Concomitant Medications - General)
This edit applies to inclusion criterion 3 (a).
Original Text:  
Exclusion Criterion 3 (as): Prior use of any medication or treatment that might affect 
growth including, but not limited to: amphetamines, anticonvulsants, biphosphonates, 
calcitonin, calcitriol, erythropoietin, growth hormone, methylphenidate, phosphate 
binders, antithyroid drugs (e.g., Methimazole) or thyroid hormone.
Revised Text:
Exclusion Criterion 3 (as): Prior use of any medication or treatment that might affect 
growth including, but not limited to: amphetamines, anticonvulsants, biphosphonates, 
calcitonin, erythropoietin, growth hormone, methylphenidate, phosphate binders, 
antithyroid drugs (e.g., Methimazole) or thyroid hormone.
Section 6.10.2 – Prohibited Medications and Non-drug Therapies (Table 3 Row 
Related to General)
This edit applies to the last row in Table 3 within Section 6.10.2.
Original Table:
Table 3
Prohibited Medications
Within 2 weeks prior to Visit 1 and at any time during the study
Theophyllines
Administration of prescription or over-the-counter medication that would 
significantly affect the course of asthma, or interact with study drug.
Within 6 weeks prior to Visit 1 and at any time during the study
Intranasal, inhaled and high potency topical (dermatological) corticosteroids

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NOTE:  During the double-blind treatment period subjects who require limited 
courses of inhaled and/or intranasal corticosteroids should remain on study 
treatment.
Oral long-acting beta2-agonists (e.g. bambuterol) and inhaled long-acting beta2-
agonists (e.g. salmeterol, formoterol) or combination products containing inhaled 
long–acting beta2-agonists (e.g. SERETIDE™, Symbicort, Dulera)
The following potent Cytochrome P450 3A4 (CYP3A4) inhibitors (Clarithromycin, 
atazanavir, indinavir, itraconazole, ketoconazole, nefazadone, nelfinavir; ritonavir; 
saquinavir; telithromycin, troleandomycin, voriconazole, mibefradil, cyclosporine)
Within 12 weeks prior to Visit 1 and at any time during the study
Systemic, oral, or depot corticosteroids
NOTE:  During the double-blind treatment period subjects who require limited 
courses of oral corticosteroids should remain on study treatment.
Anti-IgE (e.g. Xolair) and anti-IL 5
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 subject remains 
in the maintenance phase throughout the study)
General therapies not permitted prior to or during the study
Prior use of any medication or treatment that might affect growth including, but not 
limited to: amphetamines, anabolic steroids, anticonvulsants, biphosphonates, 
calcitonin, calcitriol erythropoietin, estrogens, growth hormone, methylphenidate, 
phosphate binders, progestins, thyroid hormone, or testosterone.
Revised Table:
Table 3
Prohibited Medications
Within 2 weeks prior to Visit 1 and at any time during the study
Theophyllines
Administration of prescription or over-the-counter medication that would 
significantly affect the course of asthma, or interact with study drug.
Within 6 weeks prior to Visit 1 and at any time during the study
Intranasal, inhaled and high potency topical (dermatological) corticosteroids
NOTE:  During the double-blind treatment period subjects who require limited 
courses of inhaled and/or intranasal corticosteroids should remain on study 
treatment.
Oral long-acting beta2-agonists (e.g. bambuterol) and inhaled long-acting beta2-

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agonists (e.g. salmeterol, formoterol) or combination products containing inhaled 
long–acting beta2-agonists (e.g. SERETIDE™, Symbicort, Dulera)
The following potent Cytochrome P450 3A4 (CYP3A4) inhibitors (Clarithromycin, 
atazanavir, indinavir, itraconazole, ketoconazole, nefazadone, nelfinavir; ritonavir; 
saquinavir; telithromycin, troleandomycin, voriconazole, mibefradil, cyclosporine)
Within 12 weeks prior to Visit 1 and at any time during the study
Systemic, oral, or depot corticosteroids
NOTE:  During the double-blind treatment period subjects who require limited 
courses of oral corticosteroids should remain on study treatment.
Anti-IgE (e.g. Xolair) and anti-IL 5
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 subject remains 
in the maintenance phase throughout the study)
General therapies not permitted prior to or during the study
Prior use of any medication or treatment that might affect growth including, but not 
limited to: amphetamines, anabolic steroids, anticonvulsants, biphosphonates, 
calcitonin, erythropoietin, estrogens, growth hormone, methylphenidate, phosphate 
binders, progestins, thyroid hormone, or testosterone.
Section 5.3. Screening/Baseline/Run-in Failures
This edit applies to the screening failure text:
Original Text:
Screen failures are defined as subjects who consent to participate in the clinical trial, are 
assigned a subject number, and complete at least one study procedure but are not 
subsequently randomised.  Subjects who enter the run-in period but are not randomised 
are considered run-in failures. In order to ensure transparent reporting of screen failure 
subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, and respond to queries from Regulatory authorities, a minimal set of screen 
failure information is required which may include Demography, Screen Failure details, 
Eligibility Criteria, and any Serious Adverse Events relating to study participation.
Re-screening of screen failures and run-in failures is not permitted.
Revised Text:
Screen failures are defined as subjects who consent to participate in the clinical trial, are 
assigned a subject number, and complete at least one study procedure but are not 
subsequently entered into the run-in period.  Subjects who enter the run-in period but are 

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not randomised are considered run-in failures. In order to ensure transparent reporting of 
screen failure subjects, meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements, and respond to queries from Regulatory 
authorities, a minimal set of screen failure information is required which may include 
Demography, Screen Failure details, Eligibility Criteria, and any Serious Adverse Events 
relating to study participation.
Re-screening of screen failures is permitted.   Individuals who do not meet the criteria for 
participation in this study (i.e., are a screen failure) may be re-screened up to one 
additional time if the investigator judges the subject can meet the eligibility criteria. Any 
re-screened subject must satisfy all of the protocol specified inclusion/exclusion 
requirements at the re-screening visit. Re-screened subject should be assigned a new 
subject number at the time of re-screening.
Re-screening of run-in failures is not permitted.