A Randomized, Doubled-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily, Intranasal Administration of Fluticasone Furoate Nasal Spray 55 mcg and 110 mcg for 4 Weeks in Chinese Pediatric Subjects Ages 2 to 12 Years With Allergic Rhinitis
Phase: PHASE4
Conditions: Rhinitis, Allergic, Perennial and Seasonal, Rhinitis, Allergic
Sponsor: GlaxoSmithKline

2014N205225_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
201492
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Randomized, Doubled-Blind, Placebo-Controlled, Multicenter 
Study to Evaluate the Efficacy and Safety of Once-Daily, 
Intranasal Administration of Fluticasone Furoate Nasal Spray 55
µg and 110 µg for 4 Weeks in Chinese Pediatric Subjects Ages 2 
to 12 years with Allergic Rhinitis
Compound Number:
GW685698
Development Phase:
IV
Effective Date:
15-JAN-2016
Protocol Amendment Number:  02
Author (s):
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N205225_00
2015-MAR-09
Original
2014N205225_01
2015-JUL-13
Amendment No. 1
This protocol amendment is being implemented to update inclusion/exclusion criteria, 
screening/baseline/run-in failures clarified  and other minor protocol clarifications
2014N205225_02
2016-JAN-15
Amendment No. 2
Protocol defined positive Skin Prick Test (SPT) as diameter of wheal which is 
inconsistent with some of local laboratory tests. This was affecting patient recruitment.
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

PPD
PPD
PPD

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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 
Rm. 802, Tower A, 
Ocean 
International 
Center no. 56, Mid 
4th East Ring Rd. 
Beijing.100025
Secondary 
Medical 
Monitor
Rm. 802, Tower A, 
Ocean 
International 
Center no. 56, Mid 
4th East Ring Rd. 
Beijing.100025
SAE  
group
No.1, 917 Halei 
Road, Zhangjiang 
Hi-tech Park, 
Pudong, 
Shanghai.201203
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
United Kingdom (UK)
Regulatory Agency Identifying Number(s):  [2014B01855]
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 201492
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201492........................................................8
2.
INTRODUCTION....................................................................................................10
2.1.
Study Rationale ..........................................................................................10
2.2.
Brief Background ........................................................................................10
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................11
4.
STUDY DESIGN ....................................................................................................12
4.1.
Overall Design ............................................................................................12
4.2.
Type and Number of Subjects.....................................................................13
4.3.
Design Justification.....................................................................................13
4.4.
Dose Justification........................................................................................14
4.5.
Benefit:Risk Assessment ............................................................................14
4.5.1.
Risk Assessment .........................................................................15
4.5.2.
Benefit Assessment.....................................................................18
4.5.3.
Overall Benefit: Risk Conclusion..................................................18
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............18
5.1.
Inclusion Criteria.........................................................................................18
5.2.
Exclusion Criteria........................................................................................20
5.3.
Randomisation Criteria ...............................................................................23
5.4.
Screening/Baseline/Run-in Failures............................................................23
5.5.
Withdrawal/Stopping Criteria.......................................................................23
5.5.1.
Withdrawal criteria .......................................................................23
5.5.1.1.
Subject Withdrawal from the Investigational 
Product.......................................................................23
5.5.1.2.
Subject Withdrawal from the Study.............................24
5.5.2.
Liver Chemistry Stopping Criteria ................................................25
5.5.3.
QTc Stopping Criteria ..................................................................27
5.6.
Subject and Study Completion....................................................................27
6.
STUDY TREATMENT ............................................................................................27
6.1.
Investigational Product and Other Study Treatment....................................27
6.1.1.
Study Medication Review and Return ..........................................27
6.1.2.
Investigational Product Malfunction..............................................27
6.2.
Treatment Assignment................................................................................28
6.2.1.
Assignment of Subject Number....................................................29
6.2.2.
Assignment of Randomisation/Treatment Pack Numbers ............29
6.3.
Blinding.......................................................................................................30
6.4.
Packaging and Labeling..............................................................................30
6.5.
Preparation/Handling/Storage/Accountability..............................................31
6.6.
Compliance with Study Treatment Administration.......................................31
6.7.
Treatment of Study Treatment Overdose....................................................31
6.8.
Treatment after the End of the Study ..........................................................31
6.9.
Concomitant Medications and Non-Drug Therapies....................................32
6.9.1.
Permitted Medications and Non-Drug Therapies..........................32
6.9.2.
Prohibited Medications and Non-Drug Therapies.........................32

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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................33
7.1.
Time and Events Table...............................................................................34
7.2.
Diary Recorded Information ........................................................................36
7.3.
Screening and Critical Baseline Assessments ............................................36
7.4.
Efficacy.......................................................................................................36
7.4.1.
Nasal Symptoms of AR................................................................37
7.4.2.
Ocular Symptoms of AR ..............................................................38
7.4.3.
Anterior rhinoscopy findings of AR...............................................39
7.4.4.
Overall evaluation of Response to therapy by investigator...........40
7.4.5.
Primary Efficacy Endpoints ..........................................................40
7.4.6.
Secondary Efficacy Endpoints .....................................................40
7.5.
Safety .........................................................................................................41
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........41
7.5.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................41
7.5.1.2.
Method of Detecting AEs and SAEs ...........................42
7.5.1.3.
Follow-up of AEs and SAEs........................................42
7.5.1.4.
Regulatory Reporting Requirements for SAEs/ 
ADRs..........................................................................42
7.5.2.
Physical Exams ...........................................................................43
7.5.3.
Nasal Exams ...............................................................................43
7.5.4.
Vital Signs....................................................................................43
7.5.5.
Electrocardiogram (ECG).............................................................43
7.5.6.
Clinical Safety Laboratory Assessments ......................................43
8.
DATA MANAGEMENT ...........................................................................................45
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................45
9.1.
Hypotheses.................................................................................................45
9.2.
Sample Size Considerations.......................................................................46
9.2.1.
Sample Size Assumptions ...........................................................46
9.2.2.
Sample Size Sensitivity................................................................46
9.2.3.
Sample Size Re-estimation or Adjustment...................................47
9.3.
Data Analysis Considerations .....................................................................47
9.3.1.
Analysis Populations....................................................................47
9.3.2.
Interim Analysis ...........................................................................48
9.4.
Key Elements of Analysis Plan ...................................................................48
9.4.1.
Primary Analyses.........................................................................49
9.4.2.
Secondary Analyses ....................................................................50
9.4.3.
Other Analyses ............................................................................50
10. STUDY GOVERNANCE CONSIDERATIONS........................................................51
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............51
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................51
10.3.
Quality Control (Study Monitoring) ..............................................................51
10.4.
Quality Assurance.......................................................................................52
10.5.
Study and Site Closure ...............................................................................52
10.6.
Records Retention......................................................................................53
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................53

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11. REFERENCES.......................................................................................................55
12. APPENDICES........................................................................................................56
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................56
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................57
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................61
12.3.1.
Definition of Adverse Events........................................................61
12.3.2.
Definition of Serious Adverse Events...........................................62
12.3.3.
Recording of AEs and SAEs ........................................................64
12.3.4.
Evaluating AEs and SAEs............................................................65
12.3.5.
Reporting of SAEs to GSK...........................................................66
12.4.
Appendix 4: Protocol Amendment Changes................................................67
12.4.1.
Protocol Amendment 1 ................................................................67
12.4.2.
Protocol Amendment 2 ................................................................79

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1.
PROTOCOL SYNOPSIS FOR STUDY 201492
Rationale
Fluticasone Furoate is a corticosteroid with potent glucocorticoid activity. Intranasal 
corticosteroids are among the preferred treatments for allergic rhinitis (AR), and 
Fluticasone Furoate Nasal Spray has been proved as an excellent option in Chinese adult
patients with AR. This study is to evaluate the efficacy and safety of Fluticasone Furoate 
Nasal Spray (FFNS) 55 µg and 110 µg once daily for 4 weeks in Chinese pediatric 
subjects ages 2 to 12 years with AR.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To establish the efficacy of FFNS 55 µg and 110
µg QD  versus vehicle placebo nasal spray in 
pediatric subjects  (ages 2 to 12 years) with AR

Mean change from baseline over the first 2  weeks  
treatment period in daily, reflective total nasal symptom 
scores (rTNSS) in subjects ages 2 to 12 years
Secondary

To investigate the safety of FFNS 55 µg and 110µg 
QD versus vehicle placebo nasal spray in pediatric 
subjects (ages 2 to 12 years) with AR
Key secondary efficacy endpoints

Overall evaluation of response to therapy (evaluated on 
a 7-point categorical scale ) 

Mean change from baseline in intranasal finding score 
by anterior rhinoscopy 

Mean change from baseline in reflective total ocular 
symptoms score ( rTOSS)  

Rescue loratadine use (mean rescue-free days) 
Safety endpoints

Frequency and type of clinical adverse events

Results of clinical laboratory tests 

Results of physical and nasal examination

Vital signs (temperature, systolic and diastolic blood 
pressures, pulse rate, respiratory rate)
Overall Design

This phase Ⅳstudy will be a randomized, double-blind, placebo-controlled, 
multicenter parallel study. The study will be comprised of screen, run-in period (4
to 14 days), treatment period (28 days) and follow up period (3 to 7 days).

During the study period, all investigators, subjects and GlaxoSmithKline (GSK) 
personnel remain blinded.

Subjects will be assigned to randomised treatments in a 1:1:1 ratio, in accordance 
with a computer generated randomization schedule provided by GSK. 

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
The randomization will be centralized and stratified by age (≥2 to ≤6 years and >6 
to ≤12 years) and by classification of AR (intermittent vs. persistent) to ensure 
treatment balance in age groups and AR classification groups for both safety and 
efficacy assessments.  Subjects with 6 years old and less than 7 years old will be 
treated as 6 years of age; these subjects will be analysis in group of 2 to 6 years. 
Subjects with 12 years old and less than 13 years old will be treated as 12 years of 
age and will be analysis in group of 6 to 12 years.
Treatment Arms and Duration

Eligible subjects will participate in the study which begins with a 4 to 14-day run-in 
period with no treatment, then subjects meeting the randomisation criteria will be 
randomised in a 1:1:1 ratio to the following three treatment arms:

FFNS 110 µg once daily

FFNS 55 µg once daily

Vehicle placebo aqueous nasal spray

Following the 28-day treatment period, subjects will be followed up by telephone 
contact within 5±2 days after the last dose. 

Subjects entering the study will participate for maximum of 50 days, including five
clinical visits and a follow-up telephone contact.
Type and Number of Subjects

Subjects with AR ages 2 to 12 years. Approximately 360 subjects will be 
randomized (120 subjects per arm).

In each treatment group, there will be about 60 subjects with a diagnosis of IAR 
(intermittent allergy rhinitis) and about 60 subjects with a diagnosis of persistent 
allergy rhinitis (PER) .

As ≥2 to ≤6 years old pediatric subjects is a subgroup of interest in this study , there 
will be at least 60 subjects aged ≥2 to ≤6 years per arm.
Analysis
The study is designed to provide an estimated mean treatment difference between active 
drug groups and placebo group in change from baseline of daily rTNSS. This is a 
descriptive study and no formal inference is planned. All the results from analyses model 
are for descriptive purpose. 
The primary analysis  of the primary endpoint, mean change from baseline over the first 2 
weeks treatment period in daily rTNSS in subjects aged 2 to 12 years,  will be the 
pairwise comparison of treatment groups (active drug vs. placebo) using analysis of 
covariance (ANCOVA) adjusting for baseline daily rTNSS, classification of AR (IAR or 
PER),  age, gender and treatment.

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All the safety endpoints will be summarized using descriptive statistics. No modeling 
analysis will be done for safety endpoints. All the summary and analysis will be 
performed for the overall population and the ≥2 to ≤6 years population.
2.
INTRODUCTION
2.1.
Study Rationale
Fluticasone Furoate (FF) is a corticosteroid with potent glucocorticoid activity. Intranasal 
corticosteroids are considered to be the most effective pharmacology treatment for 
Allergic Rhinitis (AR) because their anti-inflammatory properties enable control of 
symptoms of AR in the majority of subjects treated.
Fluticasone Furoate Nasal Spray (FFNS) has been approved in China and many other 
countries for treatment of AR in adult, adolescent and pediatric subjects ≥2 year of age. 
FFNS development program had demonstrated FFNS is an effective treatment for the 
symptoms of IAR and PER in pediatric subjects aged 2 years and above (55 µg and 110 
µg once daily), although there is few data of FFNS for AR in Chinese pediatric subjects 
ages 2 to 12 years.
Accordance to requirement of CDE, this study will further establish the efficacy and 
safety of FFNS at dose of 55µg and 110 µg once daily in Chinese pediatric subjects (ages 
2 to 12 years) with AR. The dose selected in this study follows the label approved in 
China.
2.2.
Brief Background
Allergic Rhinitis (AR) in its seasonal and perennial form is a common allergic condition. 
It is clinically defined as a symptomatic disorder induced by immunoglobulin E (IgE)-
mediated inflammation after allergen exposure to mucous membranes of the nose.  
Allergen-bound IgE on the surface of mast cells induces mast cell degranulation and 
release of allergic and inflammatory mediators such as histamines, leukotrienes, 
prostaglandin D2, tryptase and kinins.
The majority of AR sufferers report nasal (congestion, sneezing, itching and rhinorrhea) 
and ocular (redness, watery eyes, itching and burning) symptoms which impact quality of 
life and can also be associated with substantial healthcare costs (e.g. exacerbations of 
sinusitis and asthma, nasal polyps, hearing impairment, etc) and other economic impacts 
(e.g. less work productivity) if not treated properly [Schoenwetter, 2004] 
Anti-inflammatory therapy is a well-accepted component of the management of AR. 
Intranasal corticosteroids are known to reduce vascular permeability and edema of the 
nasal mucosa through inhibiting activities of inflammatory cells and mediators, and are 
considered to be the most effective pharmacology treatment for AR [Wallace, 2008] 
because their anti-inflammatory properties enable efficacious control of symptoms of AR 
in the majority of patients treated. 

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Fluticasone Furoate Nasal Spray has demonstrated substantial efficacy on treatment of 
AR in adult subjects.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To establish the efficacy of FFNS 55 µg 
and 110 µg QD versus vehicle placebo 
nasal spray over a period of 2 weeks in 
pediatric subjects (ages 2 to 12 years) with 
AR

Mean change from baseline over the first 2 
weeks treatment period in daily, reflective 
total nasal symptom scores (rTNSS) in 
subjects aged 2 to 12 years
Secondary

To investigate the safety of FFNS 55 µg 
and 110 µg QD  versus vehicle placebo 
nasal spray over a period of 4 weeks in 
pediatric subjects (ages 2 to 12 years) 
with AR
Secondary efficacy endpoints

Overall evaluation of response to therapy (evaluated 
on a 7-point categorical scale) after the first 2 weeks 
treatment (day15)

Mean change from baseline of intranasal finding 
score by anterior rhinoscopy at the first 2 weeks (day 
15)

Mean change from baseline over the first 2 weeks 
treatment period in the daily, reflective  total ocular 
symptoms score ( rTOSS)

Rescue loratadine use (mean rescue-free days) over 
the first 2 weeks treatment period

Mean change from baseline over the 4 weeks 
treatment period in daily rTNSS 

Overall evaluation of response to therapy after 4 
weeks treatment period (day 29)

The mean change from baseline of  intranasal 
finding score by anterior rhinoscopy at the end of 
treatment(day 29)

Mean change from baseline over the 4 weeks 
treatment period in the daily rTOSS

Rescue loratadine use (mean rescue-free days) over 
the entire 4 weeks treatment period 
Safety endpoints

Frequency and type of clinical adverse events

Results of clinical laboratory tests (Hematology and 
chemistry)

Results of physical and nasal examination

Vital signs ( temperature, systolic and diastolic blood 
pressures, pulse rate, respiratory rate )

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4.
STUDY DESIGN
4.1.
Overall Design
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 (Table 2), Section 7.1, are essential and required 
for study conduct. 

This phase Ⅳstudy will be a randomized, double-blind, placebo-controlled, 
multicenter parallel study.

Eligible subjects will participate in the study which begins with a 4 to 14-day run-in 
period with no treatment (Visit 1).

After a minimum 4-day run-in period, subjects meeting the randomisation criteria 
will be randomised in a 1:1:1 ratio to the following three treatment arms (Visit 2):, in 
accordance with a computer generated randomization schedule provided by 
GlaxoSmithKline (GSK), via an Interactive Voice Response System (IVRS) called 
Registration and Medication Ordering System (RAMOS). 

FFNS 110 µg once daily

FFNS 55 µg once daily

Vehicle placebo aqueous nasal spray

The randomization will be centralized and stratified by age (≥2 to ≤6 years and> 6 to 
≤12 years) and by classification of AR (intermittent vs. persistent) to ensure 
treatment balance in age groups and AR classification groups for both safety and 
efficacy assessments. Subjects with 6 years old and less than 7 years old will be 
treated as 6 years of age; these subjects will be analysis in group of 2 to 6 years.
Subjects with 12 years old and less than 13 years old will be treated as 12 years of 
age and will be analysis in group of 6 to 12 years.

Following the 28-day treatment period, subjects will be followed up by telephone 
contact within 5±2 days after the last dose. The following procedures will be 
performed: Adverse Event (AE)/ Serious Adverse Event (SAE) assessment. Subjects 
will be discharged from the study upon completion of the follow-up phone call.
In summary, this study is comprised of screen, run-in period (4 to14 days), double-
blind treatment period (28 days) and follows up period (3 to7 days). Subjects entering 
the study will participate for maximum of 50 days, including five clinical visits and a 
follow-up telephone contact.

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Figure 1
Study Design
4.2.
Type and Number of Subjects

Approximately 360 subjects with a diagnosis of AR will be randomised and 300
evaluable subjects for a total of 100 evaluable subjects per treatment group.

In each treatment group, there will be about 60 subjects with diagnosis of 
Intermittent Allergic Rhinitis (IAR) and about 60 subjects with diagnosis of PER.

There will enrolled at least 60 subjects ages ≥2 to ≤6 years per arm, and subjects
ages ≥2 to ≤6 years will be defined as a subgroup of interest in this study.
4.3.
Design Justification

This is a Phase Ⅳ, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of FFNS 55µg and 110 µg compared with 
placebo Chinese pediatric subjects with AR. The approach is consistent with the 
requirement of China regulatory. 

Treatment duration of 2 weeks is considered adequate for assessment of symptom 
and intranasal score in response to intranasal FF for both IAR and PER. 

The additional 2-week treatment (D15-D28) is to evaluate the safety, meanwhile 
keep consistent with [Chinese Guideline for Diagnosis and Treatment of AR in 
Pediatrics, 2011] .

A placebo arm is included in this study to allow for an absolute assessment of 
effect and safety of FFNS 55µg and 110 µg.

Rescue loratadine will be provided for use of relief medication only as needed 
throughout the treatment period. 

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
The main analysis will be done on the overall population. As ≥2 to ≤6 years old 
pediatric subjects is a subgroup of interest in this study, all the summary and 
analysis will also be done on ≥2 to ≤6 years population.
4.4.
Dose Justification
The doses evaluated for this study, 55µg and 110µg QD, follow the label for pediatric 
subjects age 2 to 12 years with AR, and are based on the data from phase III trials in 
pediatrics.
The efficacy of FFNS was evaluated in 1,112 children (633 boys and 479 girls), mean 
age of 8 years with IAR or PER in two controlled clinical trials (FFR10010 and 
FFR30008). The pediatric subjects received FFNS 55 or 110 µg once-daily for 2 to 12 
weeks (n = 369 for each dose). Children treated with FFNS in these studies generally 
exhibited greater decreases in nasal symptoms than placebo treated patients. Efficacy 
results demonstrated that once daily treatment with FFNS is an effective treatment for the 
symptoms of IAR and PER in pediatric subjects aged 2 years and above (55 µg and 110 
µg once daily).
Four clinical studies involved pediatric subjects with IAR or PER have been completed 
with FFNS. Based on a comprehensive assessment of safety data from the clinical 
development program, FFNS was well-tolerated in pediatric subjects two years of age 
and older with IAR and/or PER. 
Across all global paediatric studies , AE incidence was similar between the FF and 
placebo groups and the AE profile was similar to that in adults and adolescents. Most 
AEs were mild or moderate in intensity. 
Results involving adults, adolescents and pediatric subjects showed that FFNS 110 µg 
once-daily were not associated with HPA axis suppression as assessed by 24-h serum 
cortisol concentration and/or urinary cortisol excretion [GSK Document Number 
RM2004/00130/05].
4.5.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
intranasal GSK685698 can be found in the Investigator’s Brochure and product label.  
The following section outlines the risk assessment and mitigation strategy for this 
protocol:  

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4.5.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [i.e., GW685698] 
Systemic effects of 
corticosteroids: 
cortisol suppression
Systemic effects with nasal corticosteroids including cortisol suppression 
have been reported, particularly at high doses prescribed for prolonged 
periods. These effects are much less likely to occur than with oral 
corticosteroids and may vary in individual subjects and between different 
corticosteroid preparations. Detailed characterisation of the effect of 
intranasal FF on urine and serum cortisol has been performed, including 
a formal HPA axis study. The proposed doses of intranasal FF in this 
study are unlikely to lead to any clinically significant changes.
This risk has already been characterised during 
the intranasal FF development programme.
Review of AEs/SAEs reports.
Optimised treatment duration. 
It’s not common that HPA axis would be inhibited
in 4-week treatment.
Systemic effects of 
corticosteroids: growth 
retardation
A reduction in growth velocity has been observed in children treated with 
fluticasone furoate 110 micrograms daily for one year. A randomised, 
double-blind, parallel-group, multicentre, one-year placebo-controlled
clinical growth study evaluated the effect of FFNS 110 micrograms daily 
on growth velocity in 474 prepubescent children (5 to 7.5 years of age for 
girls and 5 to 8.5 years of age for boys) with stadiometry. Mean growth 
velocity over the 52-week treatment period was lower in the subjects 
receiving fluticasone furoate (5.19 cm/year) compared to placebo (5.46 
cm/year). The mean treatment difference was -0.27 cm per year [95% CI 
-0.48 to -0.06].
This risk has already been characterised during 
the intranasal FF development programme.
This risk had been disclosed in the label, with 
caution for long-term usage of intranasal FF. 
It’s not common that administration of FFNS for 4 
weeks would lead to growth retardation.
Systemic ocular effects 
of corticosteroids: 
As with other intranasal corticosteroids, physicians should be alert to 
potential systemic steroid effects including ocular changes. In a two-year 
This risk has already been characterised during 
the intranasal FF development programme.

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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [i.e., GW685698] 
glaucoma, cataract, 
raised intra-ocular 
pressure
study designed to assess the ocular safety of fluticasone furoate (110 
micrograms once daily intranasal spray), adults and adolescents with 
perennial AR received either fluticasone furoate (n=367) or placebo 
(n=181). The primary outcomes [time to increase in posterior 
subcapsular opacity (0.3 from baseline in Lens Opacities Classification 
System, Version III (LOCS III grade)) and time to increase in intraocular 
pressure (IOP; 7 mmHg from baseline)] were not statistically significant 
between the two groups. Increases in posterior subcapsular opacity 
(0.3 from baseline) were more frequent in subjects treated with 
fluticasone furoate 110 micrograms [14 (4%)] versus placebo [4 (2%)] 
and were transient in nature for ten subjects in the fluticasone furoate 
group and two subjects in the placebo group. Increases in IOP (7
mmHg from baseline) were more frequent in subjects treated with 
fluticasone furoate 110 micrograms: 7 (2%) for fluticasone furoate 110 
micrograms once daily and 1 (<1%) for placebo. These events were 
transient in nature for six subjects in the fluticasone furoate group and 
one placebo subject. At weeks 52 and 104, 95% of subjects in both 
treatment groups had posterior subcapsular opacity values within ± 0.1 
of baseline values for each eye and, at week 104, ≤1% of subjects in 
both treatment groups had 0.3 increases from baseline in posterior 
subcapsular opacity.  At weeks 52 and 104, the majority of subjects 
(>95%) had IOP values of within ± 5mmHg of the baseline value.  
Increases in posterior subcapsular opacity or IOP were not accompanied 
by any adverse events of cataracts or glaucoma
Review of AEs/SAEs reports. 

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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [i.e., GW685698] 
Nasal events 
A review of nasal events concluded that there was a reasonable 
possibility that rhinalgia, nasal discomfort (nasal burning, nasal irritation, 
nasal soreness) and nasal dryness were associated with the use of 
FFNS.  Epistaxis and nasal ulceration are known class effects of 
intranasal corticosteroids.  To complement the adverse event and nasal 
examination data and to characterise further effect on the nasal mucosa, 
GSK initiated a nasal biopsy study FFR104503. This study did not 
identify any new safety concerns for FFNS.
Focused nasal examinations will be conducted 
with grading system.
Nasal examination will be one of the safety 
endpoints.
Review AE and SAE reports.

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4.5.2.
Benefit Assessment
Fluticasone Furoate is an intranasal corticosteroids with potent glucocorticoid activity. It 
has been shown to activate the glucocorticoid response element and inhibit pro-
inflammatory transcription factors. Because of the anti-inflammatory properties its 
efficacious control of symptoms of AR in the majority of patients treated. Anti-
inflammatory therapy is a well-accepted component of the management of pediatrict AR 
in china. The benefit of FFNS on pediatrict with AR is control symptoms effective at 
relieving nasal discharge, itch, postnasal drip and watery eyes. In addition, Patients of 
participating in this trial will benefit from regular medical assessments and
characterization of their AR, even if they are not receiving active treatment.
4.5.3.
Overall Benefit: Risk Conclusion
Taking into account the measures to minimize risk to subject participating in this study, 
the potential risks identified in association with FFNS are justified by the anticipated 
benefits that may be afforded to patients with AR.
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 Investigator Brochure (IB) 
and product label.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
[1] Informed Consent
1. Subject’s parent/guardian has provided with an appropriately signed and dated 
informed consent.
[2] Outpatient 
2. Chinese subject is treatable on an outpatient basis
[3] Gender
3. Both Male and Female

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[4] Age
4. Subjects must be ≥2 to ≤12 years of age at Visit 2.
Only premenarchal female subjects (of non-child bearing potential) are eligible to 
participate in this study.
[5] Diagnosis of AR
5. Subjects were diagnosed as IAR or PER according to the criteria for the diagnosis and 
classification of [Chinese Guideline for Diagnosis and Treatment of AR in Pediatrics, 
2011].
Criteria for the diagnosis of AR:
1. Symptoms: subjects must have 2 or more symptoms of AR (watery rhinorrhea, 
nasal obstruction, nasal itching and sneezing), which are also present 
consecutively or accumulatively more than 1 hour on each day prior to Visit 1, 
or/and concomitant ocular symptoms: ocular itching, red eyes, watery eyes etc. .
2. Physical signs: nasal mucosa pale, oedema, nasal secretion. Allergic shiner and 
allergic crease in severity pediatric
3. Laboratory test:
I.
Skin Prick Test (SPT)*: must represent a positive response using 
standardized allergen extract.
II.
Serum-specific IgE test*: represent a positive response using 
standardized allergen extract.
(*allergen must be aeroallergen)
Diagnosis: subjects have nasal symptoms described above or/and associated with 
ocular symptoms, as well as the nasal signs and one of laboratory test positive or 
documents.
Documents: that demonstrate SPT represented a positive response OR serum-
specific IgE testing represented a positive response within 12 months prior to 
Visit 1. 
Criteria for classification of AR:

Intermittent AR, IAR: the symptoms are present <4 days a week, OR for <4 
weeks.

Persistent AR, PER: the symptoms are present ≥4 days a week, OR for ≥4 
weeks.
[6] Exposure
6. Subject must be willing to maintain the same environment throughout the study
[7] Ability to Comply with Procedures
7. Subject and/or subject’s parent/guardian understands and is willing, able and likely to 

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comply with study procedures and restrictions as well as manage study drug 
administration
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1]  Concomitant Medical Conditions
1. Significant concomitant medical conditions, defined as:
a. Historical or current evidence of clinically significant uncontrolled disease of any 
body system. Significant is defined as any disease that, in the opinion of the 
investigator or which would confound the interpretation of the study results if the 
disease/condition exacerbated during the study.
Significant renal impairment, which based on the opinion of the 
investigator, would preclude the subjects’ participation in the study.
Current active liver or biliary disease (with the exception of Gilbert’s 
syndrome or asymptomatic gallstones or otherwise stable chronic liver 
disease per investigator assessment). 
NOTES: 
o
Stable chronic liver disease should generally be defined by the absence 
of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, 
oesophageal or gastric varices, or persistent jaundice, or cirrhosis.
o
Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface 
antigen (HBsAg) or positive hepatitis C antibody test result at 
screening or within 3 months prior to first dose of study treatment) are 
acceptable if subject otherwise meets entry criteria.
b. A severe physical obstruction of the nose(e.g., deviated septum ，nasal polyp or 
frequent bleeding of the nose that could affect the deposition of double blind 
intranasal study drug
c. Current or history of a Candida infection of the nose or oropharynx, shingles, 
chickenpox, measles, ocular herpes simplex.
d. Known hypersensitivity to corticosteroids or any excipients in the product.
e. Recent nasal septal surgery or nasal septal perforation 
f. Subjects start, discontinue or change desensitization treatment within 30 days 
prior to Visit 1.
g. Bacterial or viral infection of the eyes or upper respiratory tract within two weeks 
of Visit 1 or during the screening period.
h. Asthma, with the exception of mild intermittent asthma [Ruchi, 2009] 
i. Diagnosis of rhinitis medicamentosa, vasomotor AR or eosinophil rhinitis
2. Abnormal Laboratory Findings: A clinically significant laboratory abnormality 

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[1]  Concomitant Medical Conditions
including Liver Function Tests at Visit 1 meeting the following criteria (as below and 
further defined in the study procedure manual): 

ALT >2 x upper limit of normal (ULN) and bilirubin >1.5xULN (isolated 
bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct 
bilirubin <35%)
3. Abnormal ECG: Clinically significant abnormal ECG finding at Visit 1. Significant is 
defined as: QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch 
Block. 
NOTES: 
o
The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, 
machine-read or manually over-read.
o
The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to 
initiation of the study. In other words, several different formulae cannot be 
used to calculate the QTc for an individual subject and then the lowest 
QTc value used to include or discontinue the subject from the trail.
o
For purposes of data analysis, QTcB, QTcF, another QT correction 
formula, or a composite of available values of QTc will be used as 
specified in the Reporting and Analysis Plan (RAP). 
[2] Concomitant Medication
1.Use of prescription or over-the-counter medication that would significantly affect the 
course of AR, or interact with study drug （refer to Table 1）, such as:

Chronic use of concomitant medications such as tricyclic antidepressants, that 
would affect assessment of the effectiveness of the study drug

Chronic use of long– acting beta2-agonists (e.g., salmeterol) 

Potent Cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole, 
itraconazole, clarithromycin, etc)

Allergen immunotherapy for the treatment of allergies
2. Please refer to Section 6.9 for the list of concomitant medications permitted and 
prohibited during the study.

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Table 1
Prohibited concomitant medications
Medications
Timeframe indicated relative 
to Visit 1
1. Short-acting antihistamines, including ocular 
preparations and antihistamines contained in anti-cold 
medicine, insomnia or antalgic.
2. Oral or inhaled anticholinergics
3. Oral or intranasal decongestants
4. Oral or intranasal antileukotrienes
5. Oral or inhaled long-acting beta2 agonists
6. Chinese traditional medicines that have potential 
effect to AR
7. Liquorice preparation 
8. Medications that significantly inhibit the cytochrome 
P450 subfamily enzyme CYP3A4,including ritonavir 
and ketoconazole
5 Days
tricyclic antidepressants
9 Days
long-acting 
antihistamines( eg.desloratadine,fexofenadine, cetirizine 
and loratadine[ taken as rescue medication])
10 Days
Intranasal antihistamines; or Intranasal or ocular 
cromolyh
16 Days
Intranasal corticosteroids
30 Days
1. Inhaled, oral, intramuscular, intravenous, ocular 
and/or dermatological corticosteroid (with the 
exception of hydrocortisone cream/ointment, 1% or 
less)
2. Immunosuppressive medications
60 Days
Subcutaneous omalizumab
5 months
[3] Subjects Will Travel More Than 48 Hours During the Study may Cause the Change 
of Allergen
[4]  Investigators or Sub-investigators Consider that a Subject is Not Eligible

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5.3.
Randomisation Criteria
[1] At Visit 2, the Subject must continue to meet the inclusion/exclusion criteria above. In 
addition the subject must meet the following criteria:
a.
On the morning of Visit 2, subjects must have nasal or/and ocular symptoms.
b. Average of the last 8 rTNSS assessments (4 AM assessments, 4 PM assessments) 
over the consecutive four 24-hours periods prior to randomization must be ≥6. 
This includes the AM assessment on the morning of Visit 2.
c.
Average of the 8 reflective nasal symptom assessments for congestion (4 AM 
assessments, 4 PM assessments) over the consecutive four 24-hour periods prior 
to randomization must be ≥2. This includes the AM assessment on the morning of 
Visit 2.
5.4.
Screening/Baseline/Run-in Failures
Subjects who fail to meet the eligibility requirements at Visit 1 are considered a screen 
failure. Subjects who fail to meet the eligibility requirements at Visit 2 are considered a 
run-in failure. Subjects who are screen or run-in failures should not be re-screened.
Data for screening/Run-in failures will be collected in source documentation at the site 
and will be transmitted to GSK. The following information will be collected in the case 
report form (CRF) for subjects who are screen/Run-in failures:

Date of screening Visit

Subject number

Date of ICF signature

Demographic information including race, age and gender

Reason for screen/run-in failure 

SAE information
5.5.
Withdrawal/Stopping Criteria
5.5.1.
Withdrawal criteria
5.5.1.1.
Subject Withdrawal from the Investigational Product
Premature discontinuation of the study drug will be defined as discontinuation of the 
study drug for more than or equal 2 consecutive days before the end of the treatment 
period. Subjects who discontinue administration of study drug prematurely will be 
withdrawn from the study.

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5.5.1.2.
Subject Withdrawal from the Study
A subject who takes double-blinded study drug but withdraws prior to Visit 5 will be 
defined as withdrawn early. Subjects who withdrew early will not be replaced.
Subject withdrew from the study was required and Early Withdrawal procedures must be 
performed, when:

A subject is significantly non-compliant with the requirements of the protocol.

A subject has an adverse event that would, in the investigator’s judgment, make 
continued participation in the study an unacceptable risk.

Lost to follow-up

The treatment blind is broken for a subject (by other than GSK GCSP personnel), 
or

GSK discontinues the study.

Female subjects experience menarchal during study.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject (or subject parents/guardian) and re-
schedule the missed visit as soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator must 
make every effort to regain contact with the subject (where possible, 3 telephone 
calls and if necessary a certified letter to the subject’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records:

Review all information recorded on diary cards, including rTNSS, rTOSS, study 
medication administration，rescue medication use., any medical conditions or 
concomitant medications

Investigators must complete subjects’ nasal examination by anterior rhinoscopy 
and these examined results must be recorded on patient notes.

Conduct adverse event assessment 

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
Physical examination, vital signs and nasal examination

12-lead Electrocardiogram

Double-blind study drug collection

Clinical laboratory tests
These data should be recorded in the CRF, as appropriate, as they comprised an essential 
evaluation that should be done prior to discharging any subject from the study.
Subjects who have discontinued IP in the study should be encouraged to return to the 
clinic as soon as possible to complete the IP Discontinuation Visit assessments and to 
complete the safety follow-up contact 3 to 7 days following the subject’s last dose. If a 
subject is prematurely discontinued during a regularly scheduled visit, that visit will 
become the Early Withdrawal visit.
Any clinically significant adverse event, laboratory test, nasal examination, 
Electrocardiogram (ECG) finding, or clinically significant unfavorable change observed 
during the Early Withdrawal Visit necessitated that the subject be followed or treated 
until satisfactory resolution occurred.
In the event that a subject was prematurely discontinued from the study at any time due to 
an AE or SAE, the procedures stated in protocol must be followed.
5.5.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf

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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 Chemistry Increased Monitoring Algorithm with Continued Therapy for 
Alanine aminotransferase (ALT) 3x (Upper limit of normal ) ULN 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*

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Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2  
5.5.3.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception.  

The QTc should be based on single electrocardiograms obtained over a brief (e.g., 5-
10 minute) recording period.  
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTc > 450 msec 

QTc > 480 msec in subjects with Bundle Branch Block
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study throughout the 
screening and treatment period to Visit 5 and completes the procedures for Visit 5. Any 
subject who withdraws prior to the completion of Visit 5 will be considered an early 
withdrawal. The end of the study is defined as the last subject’s last visit.
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.
6.1.1.
Study Medication Review and Return
All supplies must be returned at the end of the study and returned to GSK for destruction
6.1.2.
Investigational Product Malfunction
An investigational product nasal spray that fails to function properly must be identified to 
GSK personnel for return to GSK for testing. Details of the failure will be documented in 

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the CRF. The subject should return the nasal spray to the clinic as soon as possible to 
avoid missing any doses. The site will then call the Registration and Medication Ordering 
System Interactive Voice Response System (RAMOS) and obtain a new treatment pack 
number for this subject and dispense a new study medication kit from the site’s product 
supply, as instructed by the RAMOS.
Treatment Products
Product name:
Fluticasone furoate
Placebo
Formulation 
description:
0.05% w/w Fluticasone furoate 
in an aqueous suspension 
preserved with EDTA (0.015% 
w/w) and Benzalkonium 
Chloride (0.015% w/w).
An aqueous suspension to match 
the other study treatments minus 
the active component(s).
Dosage form:
Intranasal aqueous 
microsuspension
Intranasal aqueous 
microsuspension
Unit dose 
strength(s)/Dosage 
level(s):
Each spray=27.5 µg
N/A
Route of Administration
Intranasal
intranasal
Dosing instructions:
Inhale one spray in each nostril 
from each device in the 
morning 
Inhale one spray in each nostril 
from each device in the morning 
Physical description:
An amber glass bottle encased 
within a light grey plastic casing 
fitted with a white plastic side 
lever and white plastic cap.  
The device is a side actuated 
metering atomising spray pump 
filled with a uniform white 
suspension
An amber glass bottle encased 
within a light grey plastic casing 
fitted with a white plastic side lever 
and white plastic cap.  The device 
is a side actuated metering 
atomising spray pump filled with a 
uniform white suspension
Device:
Only use this when a 
medical device is used. 
Note that in most cases, 
an inhaler (e.g. Diskus, 
Ellipta) is not a device
Mistpro device with VP7 pump, 
white cap and white side 
actuating lever
Mistpro device with VP7 pump, 
white cap and white side actuating 
lever
Method for 
individualizing dosage:
Metered atomising spray pump
Metered atomising spray pump
6.2.
Treatment Assignment
Subjects will be assigned to treatments for parallel group studies in accordance with the 
randomization schedule generated by Clinical Statistics, prior to the start of the study, 
using validated internal software.

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Subjects (and subject’s parent/guardian) will be educated at randomization prior to the 
first dose of IP regarding the use of the nasal sprays devices using a placebo 
demonstration device. Each subject will then be dispensed two treatment kits. Each kit 
will contain a nasal sprays device. One nasal spray device will be  labelled Device A and 
the other Device B. Subjects (on their own or with assistance from parent/guardian) 
should administer one spray from Nasal Spray Device A into each nostril followed by 
one spray from Nasal Spray Device B into each nostril once a day in the AM. The first 
dose of study drug will be administered before 10 AM in the clinic on Visit 2.
Treatment Arm
Device A
Device A Dosing 
Instructions
Device B
Device B Dosing 
Instructions
FF 55µg QD
FFNS
Inhale one spray in 
each nostril from 
Device A in the 
morning 
Placebo Nasal 
Spray
Inhale one spray in 
each nostril from 
Device B in the 
morning 
FF 110µg QD
FFNS
Inhale one spray in 
each nostril from 
Device A in the 
morning 
FFNS
Inhale one spray in 
each nostril from 
Device B in the 
morning 
Placebo QD
Placebo Nasal 
Spray
Inhale one spray in 
each nostril from 
Device A in the 
morning 
Placebo Nasal 
Spray
Inhale one spray in 
each nostril from 
Device B in the 
morning 
Daily doses should be administered in the morning following pre-dose symptom 
assessment, the last dose will be administered on the morning of Visit 5. . Administration 
of the spray should be conducted according to the Patient Instruction Leaflet that will be 
provided to the sites by GSK. The subject Instruction Leaflets should be reviewed with 
the subjects (and /or subject’s parent/guardian) and distributed to the subjects to take with 
them.
6.2.1.
Assignment of Subject Number
At Visit 1, a unique Subject Number (CRF number) will be assigned by the site to any 
subject who has at least one Visit 1 procedure performed (other than informed consent) 
from a list of unique numbers provided by GSK. The unique subject number will be used 
to identify individual subjects during the course of the study.
6.2.2.
Assignment of Randomisation/Treatment Pack Numbers
At Visit 2, subjects meeting the randomisation eligibility criteria will be assigned to study 
treatment via a telephone call to the RAMOS. During the call, the site will confirm the 
subject’s Subject Number and the RAMOS will then assign two additional numbers:

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1.
Treatment Kit Numbers that identifies the double-blind medication to be dispensed 
to the subject from the investigators inventory; and
2.
A Randomisation Number from the study randomisation schedule created by GSK. 
Once assigned, this number must not be reassigned.
6.3.
Blinding
This will be a double blind study and the following will apply. 

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor 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 
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.

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6.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment.  All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment are 
provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

A document describing occupational hazards and recommended handling 
precautions either will be provided to the investigator, where this is required by local 
laws, or is available upon request from GSK.
6.6.
Compliance with Study Treatment Administration
Subject compliance with double blind study medication will be assessed at Visit 3, 4 and 
Visit 5, other clinic visits as specified in the Time and Events during treatment and Early 
Withdrawal by assessment of subject reported use on the e-diary. To ensure protocol 
adherence, a subject may be re-education from the study if their compliance with study 
treatment is <80%. And this no-compliance will be reported as protocol deviation.  
6.7.
Treatment of Study Treatment Overdose
An overdose is defined as a dose greater than the total doses described above which 
results in clinical sign or symptoms.GSK does not recommend specific treatment for an 
overdose.  The investigator or physician in charge of the subject at the time will use 
clinical judgment to treat any overdose.
6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and/or other treatment options are available

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The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.9.
Concomitant Medications and Non-Drug Therapies
The concomitant medications related to Allergy Rhinitis diseases within 30 days prior to 
Visit 1 will be recorded in the CRF. All concomitant medications taken during the study 
will be recorded in the CRF. The minimum requirement is for the reporting of the generic 
drug name and dates of administration. 
6.9.1.
Permitted Medications and Non-Drug Therapies
Loratadine syrup, an on-the-count antihistamine, will be provided as rescue medication
on only an as needed basis during the treatment period of the study. At Visit 2 after 
randomization, subjects will be dispensed rescue medication. The subject (and/or 
subject’s parent/guardian) will record their daily use of allergy rescue medication, not to 
exceed 1 teaspoon (5 mL) with weight ≤30 kg or 2 teaspoon (10 mL) with weight >30 
kg a day. The use of rescue medication should be in accordance with the instructions 
provided with the medication.
6.9.2.
Prohibited Medications and Non-Drug Therapies
Use of prescription or over-the-counter medication would significantly affect the course 
of AR, or interact with study drug are prohibited. Any non-drug therapies including nasal 
irrigation solutions are prohibited during the screening and treatment periods. All 
medications of the below are prohibited throughout the study from Visit 1 to Visit 5 or 
withdrawal Visit.
Medications
Short-acting antihistamines, including ocular preparations and antihistamines contained 
in anti-cold medicine, insomnia or antalgic.
Oral or inhaled anticholinergics
Oral or intranasal decongestants
Oral or antileukotrienes
Oral or inhaled long-acting beta2 agonists
Chinese traditional medicines that have potential effect to AR
Liquorice preparation 
Medications that significantly inhibit the cytochrome P450 subfamily enzyme 
CYP3A4,including ritonavir and ketoconazole
long-acting antihistamines( eg.desloratadine,fexofenadine, cetirizine and loratadine[ 
taken as rescue medication])
Intranasal antihistamines; or Intranasal or ocular cromolyh
Intranasal corticosteroids

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Medications
Inhaled, oral, intramuscular, intravenous, ocular and/or dermatological corticosteroid 
(with the exception of hydrocortisone cream/ointment, 1% or less)
Immunosuppressive medications
Subcutaneous omalizumab
Chronic use of concomitant medications such as tricyclic antidepressants
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
Table 2
Time and Events Table1
Procedure
Visit Number
Early 
withdraw
Follow up
1
2
3
4
5
Study Day
Visit window (of days)
-4 to -14
1
8±2
15±2
29±2
5±2 days after
subject’s last 
dose 
Informed consent2
X
Subject number assignment
X
Medical history
X
Verification of inclusion/exclusion criteria
X
X
Skin testing / serum-specific IgE test (if not done 
within 12 months of visit 1)
X
Clinical laboratory tests[Randomisation if applicable]
X
X
X
12-Lead electrocardiogram
X
X
X
Verification of randomized criteria
X
Randomization number assignment
X
Dispense double-blind study drug
X
Dispense rescue loratadine
X
X3
X3
Nasal spray technique education
X
X
X
Collect study drug
X
X
Review screening diary4
X
Review medical problem/medication diary5
X
X
X
X
X
Compliance assessment
X
X
X
X
Review treatment diary4
X
X
X
X
Anterior rhinoscopy
X
X
X
X
X
Investigator assess overall response to therapy
X
X
X
Vital Signs
X
X
X
Nasal examination
X
X
X
X
X
X
Physical examination
X
X
X

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Procedure
Visit Number
Early 
withdraw
Follow up
1
2
3
4
5
Study Day
Visit window (of days)
-4 to -14
1
8±2
15±2
29±2
5±2 days after
subject’s last 
dose 
AE/SAE review
X6
   ==========================================
X
X
Concomitant medication review
X
==========================================
X
X
1.
Parent/ guardian will record the symptom diary instead of subjects for all ages. The involvement of the parent/guardian in assessing and rating rhinitis 
symptoms may vary per subject. While it may not always be possible, the preference is for a consistent level of parent/guardian involvement throughout the 
study.
2.
Informed Consent must be obtained prior to performing any Visit 1 procedures
3.
The dispense will depends on as needed
4.
The diary collects rTNSS, rTOSS, rescue usage and study medication usage
5.
The diary collect any medical problem (other than AR) and any medications used
6.
Serious AEs will be recorded from the time the consent form is signed until the follow-up visit.  All AEs will be recorded from the start of study treatment 
until the follow-up visit.

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7.2.
Diary Recorded Information
Subjects (and/or subject’s parent/guardian) will be provided with 3 diaries to record their 
allergy symptoms:

A screening diary will be used during the screening phase (from Visit 1 to Visit 
2) to capture the subjects’ baseline symptom scores.

A daily treatment diary will be used beginning on the first day of study 
medication administration (approximately 12 hours after the first dose at Visit 2) 
and throughout the remainder of the study.

Medical problem/medication dairy will be used during the study (from Visit 1 
to Visit 5)
Screening diary and daily treatment diary will be used e-dairy , both of them use the same 
4-point, categorical scale of 0 to 3 to assess symptoms. Throughout the study, subjects 
(and/or subject’s parent/guardian) will rate their nasal symptoms of AR and record them 
on a symptom diary. Parent/ guardian will record the symptom diary instead of subjects 
for all ages. E-dairy will be record approximately 12 hours after dose, include morning 
dairy and evening dairy, record time will be on every 6 to 10 morning and evening 
separately.  The involvement of the parent/guardian in assessing and rating rhinitis 
symptoms may vary per subject. While it may not always be possible, the preference is 
for a consistent level of parent/guardian involvement throughout the study.
Subjects (and/or subject’s parent/guardian) will also document study drug compliance 
and loratadine rescue medication use on the daily treatment diary. Additionally, subjects 
(and/or subject’s parent/guardian) will record any medical problem (other than AR) they 
experience and any medications used on medical problem/medication diary.
7.3.
Screening and Critical Baseline Assessments
All demographic and baseline assessments will be completed according to the Time and 
Events schedule in Section 7.1. Safety parameters physical exams, vital signs, 
electrocardiogram (ECG) and clinical safety laboratory assessments will be define as 
baseline at Visit 1. Nasal exams baseline will be assessed at Visit 2.  
Medical/medication history will be assessed as related to the eligibility criteria listed in 
Section 5. Height, weight, medical conditions will also be assessed at baseline. SAE 
information (see Section 12.3.2), if applicable, will also be assessed at baseline.
7.4.
Efficacy
Electronic diary card will be used in this study to collect subjects (and /or subject’s 
parent/guardian) rating efficacy endpoints, including rTNSS, rTOSS and rescue 
loratadine use.

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7.4.1.
Nasal Symptoms of AR
The nasal symptom endpoints for efficacy will be calculated from the daily subject-rated 
nasal scores. The four individual nasal symptoms that each subject will be assessed
throughout the study are:

Nasal Congestion

Nasal Itching

Rhinorrhea

Sneezing
The total nasal symptom score (TNSS) is a composite score of the above four 
components with a maximum score of 12. 
Rating
Subjects will use the following scale to assess the severity of each of the four symptoms 
above:
Rating Period
Using the 0 to 3 rating scale above, subjects will be instructed to score and document 
their symptoms in a reflective manner (rTNSS) using their diary.

The reflective rating represents how the subject has been feeling over the preceding 
12 hours. This assessment provides information on how effective the treatment is 
throughout the day and will be performed TWICE daily (AM and PM). 

The AM reflective assessment must be performed prior to administering the morning 
dose and assesses how the subject felt through the night. 

The PM reflective rating must be done approximately 12 hours after dosing but 
before bedtime and assesses how the subject felt during the day. 

The daily rTNSS is the average of the AM rTNSS and PM rTNSS assessments.

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Table 3
Scoring of nasal symptoms
Severity (score)
/symptom
None (0)
Mild (1)
Moderate (2)
Severe (3)
sneezing
Symptom is 
not present
sign/symptom is 
clearly present but 
minimal 
awareness; easily 
tolerated
definite 
awareness of 
sign/symptom 
that is 
bothersome but
tolerable
sign/symptom is 
hard to tolerate; 
causes interference 
with activities of
daily living and/or 
sleeping
rhinorrhea
Nasal congestion
Nasal itching
7.4.2.
Ocular Symptoms of AR
The ocular symptom endpoints for efficacy will be calculated from the daily subject-rated 
ocular symptom scores. The three individual ocular symptoms that each subject will 
assess throughout the study are:

Eye Itching and Burning

Eye Watering

Eye Redness
The total ocular symptom score (TOSS) is a composite score of the above three 
components with a maximum score of 9.
Rating
Subjects will use the following scale to assess the severity of each of the three symptoms 
above:
Similar to the nasal symptom assessments, the subjects will be instructed to score and 
document their ocular symptoms in the diary in a reflective manner (rTOSS) TWICE 
daily at the same time as assessing their reflective nasal symptoms.

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Table 4
Table scoring of ocular symptoms
severity (score) 
/symptom 
None (0) 
Mild (1) 
Moderate (2) 
Severe (3) 
Eye itching/ 
Burning
Symptom 
is not 
present 
sign/symptom is 
clearly present but 
minimal awareness; 
easily tolerated
definite awareness 
of sign/symptom 
that is bothersome 
but tolerable
sign/symptom is 
hard to tolerate; 
causes 
interference with 
activities of daily 
living and/or 
sleeping
Tearing/watering
Eye redness
7.4.3.
Anterior rhinoscopy findings of AR
The anterior rhinoscopy change will be calculated from the subject nasal concha mucosa 
symptoms score. The 4 individual score that each subject will assess throughout the study 
are:

swelling of inferior nasal concha mucosa

color of inferior nasal concha mucosa

watery secretion volume

description of rhinorrhea
Rating
Investigator will use the following scale to assess the severity of each of the three 
symptoms above:
The investigator used the following 0 to 3 scale to assess the severity of each item at 
baseline (Visit 2) and every visit of study (Visits 3, 4, 5/Early Withdrawal).
Table 5
Table scoring of anterior rhinoscopy findings
Items
None (0)
Mild (1)
Moderate (2)
Severe (3)
Swelling of 
inferior nasal 
concha
None
To center 
turbinate
Between 1 and 3
Cannot 
observe 
center 
turbinate

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Items
None (0)
Mild (1)
Moderate (2)
Severe (3)
Color of inferior 
nasal concha 
mucosa
Normal
Light red
red
pale
Watery secretion 
volume
None
Adhesion level
Between 1 and 3
Fullness
Description of 
rhinorrhea
None
purulent
Viscous
Aqueous 
7.4.4.
Overall evaluation of Response to therapy by investigator
The investigator will evaluate subject’s overall response to therapy (improvement in the 
symptoms of AR) compared with Visit 2, in accordance with the Time and Event Table, 
using 7 point categorical scale below and record it in the CRF.
1.
Significantly Improved
2.
Moderately Improved
3.
Mildly Improved
4.
No Change
5.
Mildly worse
6.
Moderately worse
7.
Significantly worse
7.4.5.
Primary Efficacy Endpoints
The primary efficacy endpoint will be the mean change from baseline over the first 2 
weeks treatment period in daily reflective total nasal symptom scores (rTNSS) in subjects 
ages 2 to 12 years.  
7.4.6.
Secondary Efficacy Endpoints
The secondary endpoints for the study will consist of the following measures:

Overall evaluation of response to therapy (evaluated on a 7-point categorical 
scale) after the first 2 weeks treatment (day 15)

The mean change from baseline of study intranasal finding score by anterior 
rhinoscopy at the first 2 weeks treatment (day 15)

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
Mean change from baseline over the first 2 weeks treatment period in the daily, 
reflective  total ocular symptoms score (rTOSS)

Rescue loratadine use (mean rescue-free days) over the first 2 weeks treatment 
period

Mean change from baseline over the 4 weeks treatment period in daily rTNSS 

Overall evaluation of response to therapy after 4  weeks treatment period (day 29)

The mean change from baseline of intranasal finding score by anterior rhinoscopy
at the end of treatment (day 29)

Mean change from baseline over the 4 weeks treatment period in the daily rTOSS

Rescue loratatine use (mean rescue-free days) over the entire 4 weeks
7.5.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (including but not limited to vital 
signs, physical exams and laboratory safety tests) may be added during the course of the 
study based on newly available data to ensure appropriate safety monitoring.
The safety endpoints for the study will consist of the following assessments. More 
detailed information is provided in Study Assessments and Procedures (Section 7.1)

Frequency and type of clinical adverse events

Results of clinical laboratory test (hematology and chemistry)

Results of physical and nasal examinations

Vital signs (temperature, systolic and diastolic blood pressures, pulse rate, 
respiratory rate)
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3.
7.5.1.1.
Time period and Frequency for collecting AE and SAE information

The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.

Serious AEs will be recorded from the time the consent form is signed until the 
follow-up contact. All AEs will be recorded from the start of study treatment until 
the follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 3. Investigators will assess causality and tick the box on SAE Form in 
eCRF within 72 hours. If not completed in 72 hours, protocol deviation will to be 
entered.

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
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 3
7.5.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” or “How does your child seem to feel?”

“Have you had any (other) medical problems since your last visit/contact?” or “Has 
your child had any (other) medical problems or seem to act differently in any way 
since his/her last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” or “Has your child needed to take any medicines, other than 
those provided in this study, since his/her last visit/contact?”
7.5.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.5.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up. 
Further information on follow-up procedures is given in Appendix 3.
7.5.1.4.
Regulatory Reporting Requirements for SAEs/ ADRs
SAEs shall be reported to CFDA as required per regulation of Provision for Drug 
Registration and Good Clinical Practice of Pharmaceutical Products, ADRS shall be 
reported to Adverse Drug Monitoring Center as required by regulation of Provision for 
Adverse Drug Reaction Reporting and Monitoring (Order 81. Of the Ministry of Health).
Prompt notification by the investigator to GSK of SAEs 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.

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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.
7.5.2.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded. 

Investigators should pay special attention to clinical signs related to previous serious 
illnesses

Physical examination results will be documented in the source documents only.
7.5.3.
Nasal Exams
A detailed nasal examination of the mucosa, septum,  secretions, nasal patency, size of 
any polyps and ulcers will be performed by the investigator at all visits (Visits 1 – 5 or 
Early Withdrawal) and the findings recorded on the nasal examination CRF page. Any 
unfavorable changes that are not reflective of the symptoms of AR from the Visit 1 
assessment will be recorded as an adverse event, documenting the start and stop dates of 
the adverse event. A diagnosis of nasal candidacies should be reported as an adverse 
event.
7.5.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse rate and 
respiratory rate. 
7.5.5.
Electrocardiogram (ECG)

Single 12-lead ECGs will be obtained at each time point during the study using an 
ECG machine that automatically calculates the heart rate (HR) and measures PR, 
QRS, QT, and QTc intervals.  Refer to Section 5.5 for QTc withdrawal criteria and 
additional QTc readings that may be necessary.

Continuous cardiac telemetry will be performed.  Full disclosures will be reviewed in 
detail and the review maintained as part of the subject’s source documents
7.5.6.
Clinical Safety Laboratory Assessments
This study will use local laboratory except for liver event. All protocol required 
laboratory assessments, as defined in Table 6, must be conducted in accordance with 
Protocol Time and Events Schedule. Reference ranges for all safety parameters will be 
provided by the local laboratory responsible for the assessments.

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If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 6. 
Table 6
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet 
Count 
Red blood cells 
(RBC) Indices:
White Blood Cells (WBC) 
count with Differential :
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry1
Blood urea 
nitrogen 
(BUN/UREA)
Potassium
AST (Serum 
glutamic-
oxaloacetic 
transaminase 
(SGOT))
Total and 
direct 
bilirubin
Creatinine
Sodium
ALT (Serum 
glutamic pyruvic 
transaminase 
(SGPT))
Total 
Protein
Glucose 
Calcium
Alkaline 
phosphatise
Albumin
Routine 
Urinalysis2

Specific gravity

pH, glucose, protein, blood and ketones 

Microscopic examination (if blood or protein is abnormal)
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.5.2 and 
Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.

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All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 4 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology
should be identified and the sponsor notified.
8.
DATA MANAGEMENT

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSK Drug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.

For this study subject data will be collected using GSK defined case report forms and 
combined with data provided from other sources in a validated data system.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The study is designed to provide an estimated mean treatment difference between active 
drug groups and placebo group in primary efficacy endpoint, change from baseline of 
daily rTNSS over the first 2 weeks treatment period. This is a descriptive study and no 
formal inference is planned.
The primary comparisons of interest between treatment groups are: 
FF 55 µg vs Placebo 
FF 110 µg vs Placebo
As a supportive comparison, the pooled active drug groups (low and high-dose) will be 
compared with placebo. 
Although no formal inference is planned, statistical models will be used to estimate mean 
differences between interest comparisons. Point estimates and corresponding 95% 
confidence intervals (CIs) will be presented for each treatment comparison. All the 
results from analyses model are descriptive and no statistical conclusion will be claimed. 

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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
This is a descriptive study and no formal inference is planned. The planned sample size is 
mainly based on the feasibility and regulatory requirement (100 evaluable subjects per 
arm). 
The study is planned for a total of 360 randomized subjects (120 subjects per each 
treatment group). It is assumed that 17% subjects will not be evaluable for the primary 
analysis. Therefore, the total of 360 randomized subjects should provide 100 evaluable 
subjects per arm. Among 100 evaluable subjects per arm, at least 50 subjects are ≥2 to ≤6 
years old. 
With a common standard deviation (SD) of 2.6 for the primary endpoint, based on 
previous global FF pediatric studies [FFR30008, FFR100010], a sample size of 100 
subjects per treatment group ensures that the half-width of 95% CI of the treatment 
difference between active drug and placebo is no larger than 0.725 for the age groups ≥2 
to≤12 years old and a sample size of 50 subjects per treatment group ensures the half-
width of 95% CI no larger than 1.032.
It is assumed that the treatment difference between active drug and placebo in change 
from baseline of daily rTNSS over the first two weeks treatment period for FF 110 µg is 
0.5 and FF 55 µg is 0.3 based on the pooled analysis of previous global FF pediatric
studies [FFR30008, FFR100010].  With 100 subjects per treatment group for ≥2 to≤12 
years old and 50 subjects per group for ≥2 to≤6 years old, the probabilities of observing a 
positive trend, i.e. at least one active drug is numerically superior to placebo, is calculated
by means of simulation. As shown in below table, the probability of observing a positive
trend in subjects aged ≥2 to≤12 years and subjects aged ≥2 to≤6 years is 95% and 90% 
respectively. The probability of observing a positive trend in both age groups is 88%.
Subjects aged ≥2 to≤12 years 
old (100 subjects per arm)
Subjects aged ≥2 to≤6 years old 
(50 subjects per arm)
In both age groups
95%
90%
88%
9.2.2.
Sample Size Sensitivity
The assumption of a standard deviation of 2.6 for primary endpoint, change from baseline 
in diary rTNSS over the first two weeks treatment period, is based on the estimated from 
previous studies. However, the actual standard deviation in this study may deviate from 
2.6. The following table presents the precision of the two sided 95% CI based on 
different standard deviations for a sample size of 100 subjects per treatment group aged 
≥2 to≤12 years and 50 subjects per treatment group aged ≥2 to≤6

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Common 
standard 
deviation
Distance from mean to limit
(1/2 of the width of the 95% confidence interval)
Subjects aged ≥2 to≤12 years old 
(100 subjects per arm)
Subjects aged ≥2 to≤6 years old 
(50 subjects per arm)
2.4
0.669
0.953
2.5
0.697
0.992
2.6
0.725
1.032
2.7
0.753
1.072
2.8
0.781
1.111
If the assumed the treatment difference between active drugs and placebo is not exactly   
0.3 for low dose and 0.5 for high dose, the probabilities of observing a positive trend 
calculated in Section 9.2.1 will not hold. Based on historical data, it is assumed that the 
treatment difference between high dose and placebo follows a normal distribution N(0.5, 
0.5),  and the treatment difference  between low dose and placebo follows a normal 
distribution N(0.3, 0.5). The common SD is assumed to be 2.6. Based on the above 
assumptions, the probability of observing a positive trend is re-calculated as following
In ≥2 to≤12 years old subjects
(100 subjects per arm)
In ≥2 to≤6 years old subjects
(50 subjects per arm)
In both age groups
91%
88%
85%
9.2.3.
Sample Size Re-estimation or Adjustment
Due to the uncertainties about standard deviation, the pooled SD will be monitored in 
blinded way. The pooled SD will be adjusted according to the assumed treatment effect.  
If the adjusted SD is much larger than 2.6, team will determine whether to increase 
sample size based on feasibility and the re-calculated probability of observing a positive
trend.   
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The intent-to-treat (ITT) population is defined as all randomized subjects who received at 
least one dose of study drug.  Subjects will be assessed according to the treatment they 
are randomised to. This population will be the primary analysis population for efficacy 
analysis.  Additional output(s) may be provided if subjects are mistakenly treated but not
randomized to support safety tables.
The Subset ITT population (2 to 6 years old) is defined as a subset of ITT population 
comprising subjects aged ≥2 to ≤6 years old. 
The per protocol (PP) population is defined as all randomized subjects in ITT population 
who do not have any full protocol deviations. This population will be used for supportive 
analysis of the primary efficacy endpoint only. These detailed criteria of full protocol 

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deviations will be defined in the Reporting and Analysis Plan (RAP). The PP population 
will not be analyzed if this population comprises more than 95% or less than 50% of the 
ITT population.  
All the summary and analysis will be performedfor both ITT population and Subset ITT 
population (2 to 6 years old). Both the ITT, Subset ITT and PP populations will be 
determined prior to unblinding of the study.
9.3.2.
Interim Analysis
There are no interim analyses planned for this study.
9.4.
Key Elements of Analysis Plan
Where possible, data from subjects who withdraw prematurely from the study will be 
included in any analyses. In general, the minimum data required will be a baseline 
evaluation (if baseline is needed for analysis) and at least one post-baseline evaluation. 
TNSS for each assessment time point is the sum of the 4 individual nasal symptom scores 
(rhinorrhea, nasal congestion, nasal itching and sneezing), ranging from 0 to 12, since 
each of the four individual symptoms will be scored on a four-point scale from 0 to 3. 
rTNSS is the symptom score which documented in a reflective manner (represents how 
the subjects has been feeling over the preceding 12 hours).
The daily rTNSS will be computed as the average of the PM rTNSS and the AM rTNSS 
of the next day, based on the assessments prior to dosing. For example, the Day 1 rTNSS 
will be computed as: [(PM rTNSS)Day1, first day of dosing + (AM rTNSS)Day 2, prior to second dosing]/2.
If for a given subject and at a given assessment time (i.e., AM or PM) any of the four 
symptoms are missing, then the rTNSS will be considered missing for that assessment 
time. If one (but not both) of the AM and PM rTNSS is missing for a given day (e.g., a 
dosing interval during the treatment period), the non-missing rTNSS for that day will be 
used as the rTNSS for the day. 
The baseline period for diary card endpoints is defined as 4 days prior to randomization, 
including the AM symptom assessment on the randomization (i.e., treatment initiation) 
date. Day 1 assessments include the PM assessment on the randomization (i.e., treatment 
initiation) date and the AM assessment of the day after treatment initiation. The first 2-
week treatment period is defined as the first 14 dosing (24-hour) days of the treatment 
period.  Baseline values for other endpoints will be those used as appropriate from either 
Visit 1 (Screening) or Visit 2 for clinic visit.
Endpoints relating to daily diary assessments will be calculated from all available data 
over the period of interest.  The mean value over the period refers to the mean of the non-
missing values of each endpoint during the period.  No imputations will be performed on 
missing daily diary data.

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Means, standard deviation, median, minimum, and maximum will be given for the 
summary of continuous variables and frequencies and percentages will be given for the 
summary of categorical variables. 
In each efficacy analysis table , sample size, least square mean, standard error of the least 
square mean, least square mean difference, 2-sided p-values and 2-sided 95% CIs 
(whenever appropriate) for all pair wise comparisons will be given but no inference will 
be drawn. All the results from analysis modeling are for descriptive purpose. 
No multiplicity adjustments are necessary since no formal hypothesis test will be done. 
Appropriate graphs will be reviewed as part of the model checking process to ensure that 
distributional assumptions hold. In all cases, if any assumptions of the proposed method 
of analyses are not met, alternative methods (i.e., nonparametric methods) of analyses 
will be used.
9.4.1.
Primary Analyses
The primary efficacy endpoint is the mean change from baseline over the first 2 weeks 
treatment period in daily rTNSS (rhinorrhea, nasal congestion, nasal itching and 
sneezing), as evaluated on a 4-point categorical scale. The minimum data required for the 
primary endpoint analysis will be 4 days daily rTNSS data in baseline period and at least 
4 days daily rTNSS data in the first 2 week treatment period after randomisation. 
The primary analysis method will be the pair wise comparison of treatment groups 
(active vs. placebo) using analysis of covariance (ANCOVA) adjusting for baseline daily 
rTNSS, classification of AR (IAR or PER),  age, gender and treatment.
Mean daily rTNSS and mean change from baseline in daily rTNSS will be summarized 
by week (over each week) as well as over the first 2 weeks (14 days) of treatment period 
and over the entire treatment period (28 days) by treatment group. 
The change from baseline in daily rTNSS over Week 1, Week 2, Week 3, and Week 4
will also be analyzed. The analysis results of changes over Week 1, Week 2 will be used 
to reinforce the robustness of the primary efficacy endpoint.
All graphs, summary and analysis tables will be provided for the ITT population (of 
primary interest), PP population (supportive if appropriate) and the subset ITT-≥2 to ≤6 
years population (supportive). 
For the modeling analysis on ITT-≥2 to ≤6 years population, if the statistical model does 
not converge for all the covariates, sex, age will be dropped from the model. If the model 
still does not converge, then classification of AR (IAR or PER) will be further dropped. 
The details will be included in the RAP. 
Some of summary tables will also be repeated for the subgroup by classification of AR 
and age category. 

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9.4.2.
Secondary Analyses
Regarding the secondary analyses for diary card endpoints (rTOSS and rTNSS over 4 
weeks), the analysis method will be the same as the primary efficacy analysis..
Overall evaluation of response to therapy for subjects who are in the ITT population  will 
be summarized, and analyzed using logistic regression adjusting for age, gender, 
classification of AR (IAR or PER),  and treatment.
ANCOVA model adjusting for baseline nasal finding score by anterior rhinoscopy, 
classification of AR (IAR or PER), age, gender and treatment will be used to analyze 
nasal finding score by anterior rhinoscopy. 
ANCOVA model adjusting for classification of AR (IAR or PER), age, gender and 
treatment will be used to analyze the mean rescue-free days over the first 2 weeks and 
over the 4 week treatment. 
9.4.3.
Other Analyses
Safety analysis
Safety data will be summarized and/or listed by treatment group for the ITT population.
Extent of Exposure
The extent of exposure to study drug will be summarized by treatment group.
Adverse Events (AEs)
AEs will be coded using the standard GSK dictionary, MedDRA, and grouped by body 
system. AEs occurring pre-treatment, during active treatment and post-treatment will be 
summarized separately. The number and percentage of subjects experiencing at least one 
AE of any type, AEs within each body system and AEs within each preferred term will 
be presented for each treatment group. Separate summaries will be provided for all AEs, 
drug related AEs, SAEs, and for AEs leading to withdrawal.
Clinical Laboratory Evaluations
Clinical laboratory evaluations, including hematological and clinical chemistry, will be 
summarized by treatment group for each visit. Further details will be provided in the 
RAP.
Nasal Examinations
Nasal examinations will be performed at each visit, and will include assessments of 
nostril patent, septum, mucosa, secretions, ulcers, and polyposis. Nasal examination 
results will be summarized by visit for each of the 6 examination parameters listed above. 
At all visits, frequencies of classifications (yes/no, absent/present) will be calculated. 
Shift from baseline (Visit 2) will be summarized for each individual nasal examination 
parameter. Abnormal nasal examination results will be listed.

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Vital Signs Assessments
Vital signs will be summarized for each clinic visit. Further details will be provided in the 
RAP.
Deaths and SAEs
All SAEs will be tabulated and listed by treatment group. Deaths and SAEs will be 
documented in case narrative format.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with International Conference on 
Harmonisation (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

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study
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.  

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
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.
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.  

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
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.

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.

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GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.

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11.
REFERENCES
Chinese Medical Association of Otorhinolaryngology, Head and Neck Surgery, Pediatric 
group. Chinese Guideline for Diagnosis and Treatment of AR in Pediatrics. Chin J 
Otorhinolaryngol Head Neck Surg. 2011;46:7-8. 
GSK Document Number RM2004/00130/05 Investigator's Brochure for Intranasal 
Fluticasone Furoate. 15-DEC-2011.
Ruchi, Gupta,  Kevin B. Weiss,. The 2007 National Asthma Education and Prevention
Program Asthma Guidelines: Accelerating Implementation and Facilitating Their Impact
Children With Asthma. Pediatrics. 2009;123:S193-198. 
Schoenwetter WF, Dupclay L, Appajosyula S, Botteman MF, Pashos CL. Economic 
impact and quality-of-life burden of allergic rhinitis. Curr Med Res Opin. 
2004;20(3):305-317. 
Wallace DV, Dykewicz MS, Bernstein DI, Blessing-Moore J, Cox L, Khan DA et al. The 
diagnosis and management of rhinitis: An updated practice parameter. J Allergy Clin 
Immunol. 2008;122:S1-84. 

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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase 
AR
Allergic Rhinitis
BUN
Blood urea nitrogen
CPK
Creatinine Phosphokinase
CRF
Case Report Form
ECG
Electrocardiogram
FF
Fluticasone furoate
GCSP
Global Clinical Safety and Pharmacovigilance
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
h/hr
Hour(s)
HBsAg
Hepatitis B surface antigen
HR
Heart rate
IAR
Intermittent Allergic Rhinitis
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgE
Immunoglobulin E
INR
International Normalised ratio
IRB
Institutional Review Board
µg
Microgram
mL
Millilitre
PAR
Persistent Allergic Rhinitis
RAP
Reporting and Analysis Plan
RBC
Red blood cells
SAE
Serious Adverse Event
SD
Standard deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
TOSS
Total Ocular Symptom Score
TNSS
Total Nasal Symptom Score
ULN
Upper limit of normal
UK
United Kingdom
WBC
White Blood Cells
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
MedDRA

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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
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) 
International 
Normalised 
ratio (INR)2 
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(HBsAg)) quantitative hepatitis B 
DNA and hepatitis delta antibody5.

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 72 hours after 
last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

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granted 
If restart/rechallenge not  allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessment
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

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)   

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4.
Includes: Hepatitis A IgM antibody; HBsAg and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for 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.  
Liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment   

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN to 
≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.

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References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW,Hinson JA, et al. 
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, Deny P,et al. Quantification of 
Hepatitis Delta Virus RNA in Serum by Consent 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: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific 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.
12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 

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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
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.  If fractionation is unavailable and ALT 3xULN and total 
bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 2 for the required liver chemistry follow-up instructions

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12.3.3.
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.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.

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12.3.4.
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.

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.

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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.
12.3.5.
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 Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data.

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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12.4.
Appendix 4: Protocol Amendment Changes
12.4.1.
Protocol Amendment 1
This amendment applies to all sites participating in 201492.
Rationale
This protocol amendment is being implemented to update inclusion/exclusion criteria, 
screening/baseline/run-in failures clarified and other minor protocol clarifications.
The following revisions were made:

Inclusion criteria updated: SPT laboratory test aeroallergen clarified

Screening/Baseline/Run-in failures: screening/run-in failures clarified

Time and Events Table: early withdraw added

Subject’s ages clarified

Cardiovascular Events(CV) Definition deleted

Editing errors or typo amended
List of Specific Changes
Section: Description
First: Section 1 Protocol Synopsis: Objectives and endpoints
Second: Original text:
Safety endpoints

Frequency and type of clinical adverse events

Results of clinical laboratory tests 

Results of physical and nasal examination

Vital signs ( systolic and diastolic blood pressures, pulse rate)
Third: Amendment text: 

Frequency and type of clinical adverse events

Results of clinical laboratory tests 

Results of physical and nasal examination
Vital signs (temperature, systolic and diastolic blood pressures, pulse rate, respiratory rate)

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First: Section 1 Protocol Synopsis: Overall design and Section 4.1 Overall design
Second: Original text:
The randomization will be centralized and stratified by age (≥2 to ≤6 years and >6 to ≤12 
years) and by classification of AR (intermittent vs. persistent) to ensure treatment balance 
in age groups and AR classification groups for both safety and efficacy assessments.  
Third: Amendment text: 

The randomization will be centralized and stratified by age (≥2 to ≤6 years and >6 
to ≤12 years) and by classification of AR (intermittent vs. persistent) to ensure 
treatment balance in age groups and AR classification groups for both safety and 
efficacy assessments.  Subjects with 6 years old and less than 7 years old will be 
treated as 6 years of age; these subjects will be analysis in group of 2 to 6 years.
Subjects with 12 years old and less than 13 years old will be treated as 12 years of 
age and will be analysis in group of 6 to 12 years.
First: Section 4.1 Overall design
Second: Original text:
Following the 28-day treatment period, subjects will be followed up by telephone contact 
within 5±2 days after the last dose. The following procedures will be performed: Adverse 
Event (AE)/ Serious Adverse Event (SAE) assessment and register visit in RAMOS. 
Subjects will be discharged from the study upon completion of the follow-up phone call.
Third: Amendment text: 
Following the 28-day treatment period, subjects will be followed up by telephone contact 
within 5±2 days after the last dose. The following procedures will be performed: Adverse 
Event (AE)/ Serious Adverse Event (SAE) assessment. Subjects will be discharged from 
the study upon completion of the follow-up phone call.
First: Section 4.4 Dose Justification
Second: Original text:
For pediatric subjects, the most commonly reported AEs with an incidence of >3% and 
more common than placebo included headache, nasopharyngitis, epistaxis, pyrexia, 
pharyngolaryngeal pain and cough. Across all studies however, AE incidence was similar 
between the FF and placebo groups and the AE profile was similar to that in adults and 
adolescents. Most AEs were mild or moderate in intensity. 
Third: Amendment text: 
Across all global paediatric studies, AE incidence was similar between the FF and 
placebo groups and the AE profile was similar to that in adults and adolescents. Most 
AEs were mild or moderate in intensity. 

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First: Section 5.1 Inclusion Criteria
Second: Original text:
I.
Laboratory test:
Skin Prick Test (SPT): must represent a positive response using standardized 
allergen extract
II.
Serum-specific IgE test: represent a positive response using standardized 
allergen extract.
Third: Amendment text: 
I.
Skin Prick Test (SPT)*: must represent a positive response using 
standardized allergen extract).
A positive skin test is defined as an allergen wheal ≥3 mm, a histamine wheal
≥3mm and a negative control test represents negative for prick testing.
II.
Serum-specific IgE test*: represent a positive response using 
standardized allergen extract.
(*allergen must be aeroallergen)
First: Section 5.4 Screening/Baseline/Run-in Failures
Second: Original text:
Data for screening failures will be collected in source documentation at the site and will 
be transmitted to GSK. The following information will be collected in the case report 
form (CRF) for subjects who are screen failures:

Date of screening Visit

Subject number

Date of ICF signature

Demographic information including race, age and gender

Reason for screen failure 

SAE information, if applicable, only for any SAE considered as related to study 
participation (e.g. study treatment , protocol mandated procedures, invasive tests, 
or change in existing therapy) or related to GSK concomitant medication
Third: Amendment text: 
Data for screening/Run-in failures will be collected in source documentation at the site 
and will be transmitted to GSK. The following information will be collected in the case 
report form (CRF) for subjects who are screen/Run-in failures:

Date of screening Visit

Subject number

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
Date of ICF signature

Demographic information including race, age and gender

Reason for screen failure 

SAE information
First: Section 5.5.1.2 Subject Withdrawal from the Study
Second: Original text:
A subject who takes double-blinded study drug but withdraws prior to Visit 5 will be 
defined as withdrawn early. Subjects who withdrew early will not be replaced.
Subject withdrew from the study was required and Early Withdrawal procedures must be 
performed, when:

A subject is significantly non-compliant with the requirements of the protocol.

A subject has an adverse event that would, in the investigator’s judgment, make 
continued participation in the study an unacceptable risk.

The treatment blind is broken for a subject (by other than GSK GCSP personnel), 
or

GSK discontinues the study.

Female subjects experience menarchal during study.
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records:

Review all information recorded on diary card(s), including rTNSS, rTOSS, study 
medication administration.

Investigators must complete subjects’ nasal examination by anterior rhinoscopy 
and these examined results must be recorded on patient notes.

Conduct adverse event assessment 

Physical examination, vital signs and nasal examination

12-lead Electrocardiogram

Double-blind study drug collection

Clinical laboratory tests
These data should be recorded in the CRF, as appropriate, as they comprised an essential 
evaluation that should be done prior to discharging any subject from the study.

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Third: Amendment text: 
A subject who takes double-blinded study drug but withdraws prior to Visit 5 will be 
defined as withdrawn early. Subjects who withdrew early will not be replaced.
Subject withdrew from the study was required and Early Withdrawal procedures must be 
performed, when:

A subject is significantly non-compliant with the requirements of the protocol.

A subject has an adverse event that would, in the investigator’s judgment, make 
continued participation in the study an unacceptable risk.

Lost to follow-up

The treatment blind is broken for a subject (by other than GSK GCSP personnel), 
or

GSK discontinues the study.

The following actions must be taken in relation to a subject who fails to attend the 
clinic for a required study visit:

The site must attempt to contact the subject (or subject parents/guardian) and re-
schedule the missed visit as soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records:

Review all information recorded on diary card(s), including rTNSS, rTOSS, study 
medication administration，rescue medication use, any medical conditions or con

Investigators must complete subjects’ nasal examination by anterior rhinoscopy 
and these examined results must be recorded on patient notes.

Conduct adverse event assessment 

Physical examination, vital signs and nasal examination

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
12-lead Electrocardiogram

Double-blind study drug collection

Clinical laboratory tests
These data should be recorded in the CRF, as appropriate, as they comprised an essential 
evaluation that should be done prior to discharging any subject from the study.
Subjects who have discontinued IP in the study should be encouraged to return to the 
clinic as soon as possible to complete the IP Discontinuation Visit assessments and to 
complete the safety follow-up contact 3 to 5 days following the subject’s last dose. If a 
subject is prematurely discontinued during a regularly scheduled visit, that visit will 
become the Early Withdrawal visit.
First: Section 6.1.2 Investigation Product Malfunction
Second: Original text:
An investigational product nasal spray that fails to function properly must be identified to 
GSK personnel for return to GSK for testing. Details of the failure will be documented in 
the CRF. The subject should return the nasal spray to the clinic as soon as possible to 
avoid missing any doses. The site will then call the Registration and Medication Ordering 
System Interactive Voice Response System (RAMOS) and obtain a new treatment pack 
number for this subject and dispense a new study medication kit from the site’s product 
supply, as instructed by the IVRS.
Third: Amendment text: 
An investigational product nasal spray that fails to function properly must be identified to 
GSK personnel for return to GSK for testing. Details of the failure will be documented in 
the CRF. The subject should return the nasal spray to the clinic as soon as possible to 
avoid missing any doses. The site will then call the Registration and Medication Ordering 
System Interactive Voice Response System (RAMOS) and obtain a new treatment pack 
number for this subject and dispense a new study medication kit from the site’s product 
supply, as instructed by the RAMOS.
First: Section 6.6 Compliance with Study Treatment Administration
Second: Original text:
Subject compliance with double blind study medication will be assessed at Visit 3, 4 and 
Visit 5, other clinic visits as specified in the Time and Events during treatment and Early 
Withdrawal by assessment of subject reported use on the e-diary. To ensure protocol 
adherence, a subject may be re-education from the study if their compliance with study 
treatment is <80% or >120%.

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Third: Amendment text: 
Subject compliance with double blind study medication will be assessed at Visit 3, 4 and 
Visit 5, other clinic visits as specified in the Time and Events during treatment and Early 
Withdrawal by assessment of subject reported use on the e-diary. To ensure protocol 
adherence, a subject may be re-education from the study if their compliance with study 
treatment is <80% or >120%. And this no-compliance will be reported as protocol 
deviation.  
First: Section 7.1 Time and Events Table
Second: Original text:
Procedure
Visit Number
Early 
withdraw
Follow 
up
1
2
3
4
5
Study Day
Visit window (of days)
-4 
to -
14
1
8±2
15±2
29±2
32 to 
36
Informed consent2
X
Subject number 
assignment
X
Medical history
X
Verification of 
inclusion/exclusion 
criteria
X
Skin testing / serum-
specific IgE test (if not 
done within 12 months of 
visit 1)
X
Clinical laboratory 
tests[Randomisation] if 
applicable
X
X
X
12-Lead 
electrocardiogram
X
X
X
Verification of 
randomized criteria
X
Randomization number 
assignment
X
Dispense double-blind 
study drug
X
Dispense rescue 
loratadine
X
X
X
Nasal spray technique 
education
X
X
X
Collect study drug
X
X
Review screening diary3
X
Compliance assessment
X
X
X
X
Review treatment diary3
X
X
X
Anterior rhinoscopy
X
X
X
X
Investigator assess 
overall response to 
therapy
X
X

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Procedure
Visit Number
Early 
withdraw
Follow 
up
1
2
3
4
5
Study Day
Visit window (of days)
-4 
to -
14
1
8±2
15±2
29±2
32 to 
36
Vital Signs
X
X
X
Nasal examination
X
X
X
X
X
X
Physical examination
X
X
X
AE/SAE review
X4
   
==========================================
X
X
Concomitant medication 
review
==========================================
X
X
1.
Parent/ guardian will record the symptom diary instead of subjects for all ages. The involvement 
of the parent/guardian in assessing and rating rhinitis symptoms may vary per subject. While it 
may not always be possible, the preference is for a consistent level of parent/guardian involvement 
throughout the study.
2.
Informed Consent must be obtained prior to performing any Visit 1 procedures
3.
The diary collects rTNSS, rTOSS, rescue usage
4.
Serious AEs will be recorded from the time the consent form is signed until the follow-up visit.  
All AEs will be recorded from the start of study treatment until the follow-up visit.
Third: Amendment text: 
Procedure
Visit Number
Early 
withdraw
Follow 
up
1
2
3
4
5
Study Day
Visit window (of days)
-4 
to -
14
1
8±2
15±2
29±2
5±2 
days 
after 
V5 or 
EW
Informed consent2
X
Subject number 
assignment
X
Medical history
X
Verification of 
inclusion/exclusion 
criteria
X
X
Skin testing / serum-
specific IgE test (if not 
done within 12 months of 
visit 1)
X
Clinical laboratory 
tests[Randomisation if 
applicable]
X
X
X
12-Lead 
electrocardiogram
X
X
X
Verification of 
randomized criteria
X

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Procedure
Visit Number
Early 
withdraw
Follow 
up
1
2
3
4
5
Study Day
Visit window (of days)
-4 
to -
14
1
8±2
15±2
29±2
5±2 
days 
after 
V5 or 
EW
Randomization number 
assignment
X
Dispense double-blind 
study drug
X
Dispense rescue 
loratadine
X
X3
X3
Nasal spray technique 
education
X
X
X
Collect study drug
X
X
Review screening diary4
X
Review medical 
problem/medication 
diary5
X
X
X
X
X
Compliance assessment
X
X
X
X
Review treatment diary4
X
X
X
X
Anterior rhinoscopy
X
X
X
X
X
Investigator assess 
overall response to 
therapy
X
X
X
Vital Signs
X
X
X
Nasal examination
X
X
X
X
X
X
Physical examination
X
X
X
AE/SAE review
X6
   
==========================================
X
X
Concomitant medication 
review
X
==========================================
X
X
1.
Parent/ guardian will record the symptom diary instead of subjects for all ages. The involvement 
of the parent/guardian in assessing and rating rhinitis symptoms may vary per subject. While it 
may not always be possible, the preference is for a consistent level of parent/guardian involvement 
throughout the study.
2.
Informed Consent must be obtained prior to performing any Visit 1 procedures
3.
The dispense will depends on as needed
4.
The diary collects rTNSS, rTOSS, rescue usage and study medication usage
5.
The diary collect any medical problem (other than AR) and any medications used
6.
Serious AEs will be recorded from the time the consent form is signed until the follow-up visit.  
All AEs will be recorded from the start of study treatment until the follow-up visit.

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First: Section 7.2 Diary Recorded Information
Second: Original text:
Subjects (and/or subject’s parent/guardian) will be provided with 2 diaries to record their 
allergy symptoms:

A screening diary will be used during the screening phase (from Visit 1 to Visit 
2) to capture the subjects’ baseline symptom scores.

A daily treatment diary will be used beginning on the first day of study 
medication administration (approximately 12 hours after the first dose at Visit 2) 
and throughout the remainder of the study.
use the same 4-point, categorical scale of 0 to 3 to assess symptoms. Throughout the 
study, subjects (and/or subject’s parent/guardian) will rate their nasal symptoms of AR 
and record them on a symptom diary. Parent/ guardian will record the symptom diary 
instead of subjects for all ages. The involvement of the parent/guardian in assessing and 
rating rhinitis symptoms may vary per subject. While it may not always be possible, the 
preference is for a consistent level of parent/guardian involvement throughout the study.
Subjects (and/or subject’s parent/guardian) will also document study drug compliance 
and loratadine rescue medication use on the daily treatment diary. Additionally, subjects 
(and/or subject’s parent/guardian) will record any medical problem (other than AR) they 
experience and any medications used diary.
Third: Amendment text: 
Subjects (and/or subject’s parent/guardian) will be provided with 3 diaries to record their 
allergy symptoms:

A screening diary will be used during the screening phase (from Visit 1 to Visit 
2) to capture the subjects’ baseline symptom scores.

A daily treatment diary will be used beginning on the first day of study 
medication administration (approximately 12 hours after the first dose at Visit 2) 
and throughout the remainder of the study.

Medical problem/medication dairy will be used during the study (from Visit 1 
to Visit 5)
Screening diary and daily treatment diary will be used e-dairy , both of them use the same 
4-point, categorical scale of 0 to 3 to assess symptoms. Throughout the study, subjects 
(and/or subject’s parent/guardian) will rate their nasal symptoms of AR and record them 
on a symptom diary. Parent/ guardian will record the symptom diary instead of subjects 
for all ages. E-dairy will be record approximately 12 hours after dose, include morning 
dairy and evening dairy, record time will be on every 6 to 10 morning and evening 
separately.  The involvement of the parent/guardian in assessing and rating rhinitis 
symptoms may vary per subject. While it may not always be possible, the preference is 
for a consistent level of parent/guardian involvement throughout the study.
Subjects (and/or subject’s parent/guardian) will also document study drug compliance 
and loratadine rescue medication use on the daily treatment diary. Additionally, subjects 

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(and/or subject’s parent/guardian) will record any medical problem (other than AR) they 
experience and any medications used on medical problem/medication diary.
First: Section 7.3 Screening and Critical Baseline Assessments
Second: Original text:
All demographic and baseline assessments will be completed according to the Time and 
Events schedule in Section 7.1.Safety parameters will be assessed at Visit 1.
Medical/medication history will be assessed as related to the eligibility criteria listed in 
Section 5. Cardiovascular medical history/risk factors including height, weight, blood 
pressure, smoking history, medical conditions will also be assessed at baseline. SAE 
information (see Section 12.3.2), if applicable, will also be assessed at baseline
Third: Amendment text: 
All demographic and baseline assessments will be completed according to the Time and 
Events schedule in Section 7.1.Safety parameters physical exams, vital signs, 
electrocardiogram (ECG) and clinical safety laboratory assessments will be define as 
baseline at Visit 1. Nasal exams baseline will be assessed at Visit 2. 
Medical/medication history will be assessed as related to the eligibility criteria listed in 
Section 5. Height, weight, medical conditions will also be assessed at baseline. SAE 
information (see Section 12.3.2), if applicable, will also be assessed at baseline
First: 7.4.2 Ocular Symptoms of AR
Second: Original text:
The total ocular symptom score (TOSS) is a composite score of the above three 
components with a maximum score of 9.Scores for both eyes will be averaged.
Similar to the nasal symptom assessments, the subjects will be instructed to score and 
document their ocular symptoms in the diary in a reflective manner (rTOSS) TWICE 
daily at the same time as assessing their instantaneous and reflective nasal symptoms.
Third: Amendment text: 
Similar to the nasal symptom assessments, the subjects will be instructed to score and 
document their ocular symptoms in the diary in a reflective manner (rTOSS) TWICE 
daily at the same time as assessing their reflective nasal symptoms.
The total ocular symptom score (TOSS) is a composite score of the above three 
components with a maximum score of 9.

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First: Section 7.5.1.1 Time period and Frequency for collection AE and SAE information
Second: Original text:
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 3.
Third: Amendment text: 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 3. Investigators will assess causality and tick the box on SAE Form in 
eCRF within 72 hours. If not completed in 72 hours, protocol deviation will to be 
entered.
First: full protocol applicable
Second: Original text:
2 to ≤6 years, 6-≤12 years
Third: Amendment text: 
≥2 to ≤6 years, >6-≤12 years
First: Section 12.3.2 Definition of Cardiovascular Events
Second: Original text:
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization

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Third: Amendment text: 
Delete.
12.4.2.
Protocol Amendment 2
This amendment applies to all sites participating in 201492.
Rationale
This protocol amendment is being implemented to clarify SPT laboratory test, update 
safety laboratory assessment and other minor protocol clarifications.
The following revisions were made:

Inclusion criteria updated: SPT laboratory test 

Safety laboratory assessment table updated

Treatment assignment

Compliance with study treatment administration

Time and event table

Editing errors or typo amended
List of Specific Changes
Section: Description
First: Section 5.1: Inclusion Criteria
Second: Original text: Diagnosis of AR
I.
Skin Prick Test (SPT)*: must represent a positive response using 
standardized allergen extract). 
A positive skin test is defined as allergen wheal ≥3 mm, a histamine wheal 
≥3mm and a negative control test represents negative for prick testing.
Third: Amendment text:
I.
Skin Prick Test (SPT)*: must represent a positive response using 
standardized allergen extract. 

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First: Section 5.4: Screening/Baseline/Run-in Failures
Second: Original text:
Data for screening/Run-in failures will be collected in source documentation at the site 
and will be transmitted to GSK. The following information will be collected in the case 
report form (CRF) for subjects who are screen/Run-in failures:

Date of screening Visit

Subject number

Date of ICF signature

Demographic information including race, age and gender

Reason for screen failure 

SAE information
Third: Amendment text:
Data for screening/Run-in failures will be collected in source documentation at the site 
and will be transmitted to GSK. The following information will be collected in the case 
report form (CRF) for subjects who are screen/Run-in failures:

Date of screening Visit

Subject number

Date of ICF signature

Demographic information including race, age and gender

Reason for screen/run-in failure 

SAE information
First: Section 5.5.1.2: Subject Withdrawal from the Study
Second: Original text:
Subjects who have discontinued IP in the study should be encouraged to return to the 
clinic as soon as possible to complete the IP Discontinuation Visit assessments and to 
complete the safety follow-up contact 3 to 5 days following the subjects last dose. If a 
subject is prematurely discontinued during a regularly scheduled visit, that visit will 
become the Early Withdrawal visit.
Third: Amendment text:
Subjects who have discontinued IP in the study should be encouraged to return to the 
clinic as soon as possible to complete the IP Discontinuation Visit assessments and to 
complete the safety follow-up contact 3 to 7 days following the subjects last dose. If a 

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subject is prematurely discontinued during a regularly scheduled visit, that visit will 
become the Early Withdrawal visit.
First: Section 6.2: Treatment Assignment
Second: Original text:
Daily doses should be administered in the morning following pre-dose symptom 
assessment except on the morning of Visit 5, where the last dose will be administered 
in the clinic. Administration of the spray should be conducted according to the Patient 
Instruction Leaflet that will be provided to the sites by GSK. The subject Instruction 
Leaflets should be reviewed with the subjects (and /or subject’s parent/guardian) and 
distributed to the subjects to take with them.
Third: Amendment text:
Daily doses should be administered in the morning following pre-dose symptom 
assessment, the last dose will be administered on the morning of Visit 5. Administration 
of the spray should be conducted according to the Patient Instruction Leaflet that will be 
provided to the sites by GSK. The subject Instruction Leaflets should be reviewed with 
the subjects (and /or subject’s parent/guardian) and distributed to the subjects to take with 
them.
First: Section 6.2.2: Assignment of Randomisation/Treatment Pack Numbers
Second: Original text: 
At Visit 2, subjects meeting the randomisation eligibility criteria will be assigned to study 
treatment via a telephone call to the IVRS. During the call, the site will confirm the 
subject’s Subject Number and the IVRS will then assign two additional numbers:
Third: Amendment text:
At Visit 2, subjects meeting the randomisation eligibility criteria will be assigned to study 
treatment via a telephone call to the RAMOS. During the call, the site will confirm the 
subject’s Subject Number and the RAMOS will then assign two additional numbers:
First: Section 6.6: Compliance with Study Treatment Administration
Second: Original text:
To ensure protocol adherence, a subject may be re-education from the study if their 
compliance with study treatment is <80% or >120%. And this no-compliance will be 
reported as protocol deviation.  
Third: Amendment text:
To ensure protocol adherence, a subject may be re-education from the study if their 
compliance with study treatment is <80%. And this no-compliance will be reported as 
protocol deviation.  

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First: Section 6.9: Concomitant Medications and Non-Drug Therapies
Second: Original text:
All concomitant medications taken during the study will be recorded in the CRF. The 
minimum requirement is for the reporting of the generic drug name and dates of 
administration.
Third: Amendment text:
The concomitant medications related to Allergy Rhinitis diseases within 30 days prior to 
Visit 1 will be recorded in the CRF. All concomitant medications taken during the study 
will be recorded in the CRF. The minimum requirement is for the reporting of the generic 
drug name and dates of administration. 
First: Section 7.1 Time and Events Table
Second: Original text
Procedure
Visit Number
Early 
withdraw
Follow 
up
1
2
3
4
5
Study Day
Visit window (of days)
-4 
to -
14
1
8±2
15±2
29±2
5±2 
days 
after 
V5 or 
EW  
Informed consent2
X
Subject number 
assignment
X
Medical history
X
Verification of 
inclusion/exclusion 
criteria
X
X
Skin testing / serum-
specific IgE test (if not 
done within 12 months of 
visit 1)
X
Clinical laboratory 
tests[Randomisation] if 
applicable
X
X
X
12-Lead 
electrocardiogram
X
X
X
Verification of 
randomized criteria
X
Randomization number 
assignment
X
Dispense double-blind 
study drug
X
Dispense rescue 
loratadine
X
X3
X3
Nasal spray technique 
education
X
X
X
Collect study drug
X
X
Review screening diary4
X

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Procedure
Visit Number
Early 
withdraw
Follow 
up
1
2
3
4
5
Study Day
Visit window (of days)
-4 
to -
14
1
8±2
15±2
29±2
5±2 
days 
after 
V5 or 
EW  
Review medical 
problem/medication 
dairy5
X
X
X
X
X
Compliance assessment
X
X
X
X
Review treatment diary4
X
X
X
X
Anterior rhinoscopy
X
X
X
X
X
Investigator assess 
overall response to 
therapy
X
X
X
Vital Signs
X
X
X
Nasal examination
X
X
X
X
X
X
Physical examination
X
X
X
AE/SAE review
X6
   
==========================================
X
X
Concomitant medication 
review
X
==========================================
X
X
Third: Amendment text:
Procedure
Visit Number
Early 
withdraw
Follow 
up
1
2
3
4
5
Study Day
Visit window (of days)
-4 
to 
-
14
1
8±2
15±2
29±2
5±2 
days 
after 
subjects 
last 
dose 
Informed consent2
X
Subject number 
assignment
X
Medical history
X
Verification of 
inclusion/exclusion 
criteria
X
X
Skin testing / serum-
specific IgE test (if not 
done within 12 months 
of visit 1)
X
Clinical laboratory 
tests[Randomisation] if 
applicable
X
X
X
12-Lead 
electrocardiogram
X
X
X

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Procedure
Visit Number
Early 
withdraw
Follow 
up
1
2
3
4
5
Study Day
Visit window (of days)
-4 
to 
-
14
1
8±2
15±2
29±2
5±2 
days 
after 
subjects 
last 
dose 
Verification of 
randomized criteria
X
Randomization number 
assignment
X
Dispense double-blind 
study drug
X
Dispense rescue 
loratadine
X
X3
X3
Nasal spray technique 
education
X
X
X
Collect study drug
X
X
Review screening diary4
X
Review medical 
problem/medication
dairy5
X
X
X
X
X
Compliance 
assessment
X
X
X
X
Review treatment diary4
X
X
X
X
Anterior rhinoscopy
X
X
X
X
X
Investigator assess 
overall response to 
therapy
X
X
X
Vital Signs
X
X
X
Nasal examination
X
X
X
X
X
X
Physical examination
X
X
X
AE/SAE review
X6
   
==========================================
X
X
Concomitant medication 
review
X
==========================================
X
X
First: Section 7.5.6: Clinical Safety Laboratory Assessments
Second: Original text: 
Laboratory 
Assessments
Parameters
Haematology
Platelet 
Count 
Red blood cells 
(RBC) Indices:
White Blood Cells (WBC) 
count with Differential :
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils

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Laboratory 
Assessments
Parameters
Basophils
Clinical 
Chemistry 1
Blood urea 
nitrogen 
(BUN)
Potassium
AST (Serum 
glutamic-
oxaloacetic 
transaminase 
(SGOT))
Total and 
direct 
bilirubin
Creatinine
Sodium
ALT (Serum 
glutamic pyruvic 
transaminase 
(SGPT))
Total 
Protein
Glucose 
Calcium
Alkaline 
phosphatise
Albumin
Routine 
Urinalysis2

Specific gravity

pH, glucose, protein, blood and ketones 

Microscopic examination (if blood or protein is abnormal)
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.5.2 and 
Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
Third: Amendment text:
Laboratory 
Assessments
Parameters
Haematology
Platelet 
Count 
Red blood cells 
(RBC) Indices:
White Blood Cells (WBC) 
count with Differential :
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry1
Blood urea 
nitrogen 
(BUN/UREA)
Potassium
AST (Serum 
glutamic-
oxaloacetic 
transaminase 
(SGOT))
Total and 
direct 
bilirubin

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Laboratory 
Assessments
Parameters
Creatinine
Sodium
ALT (Serum 
glutamic pyruvic 
transaminase 
(SGPT))
Total 
Protein
Glucose 
Calcium
Alkaline 
phosphatise
Albumin
Routine 
Urinalysis2

Specific gravity

pH, glucose, protein, blood and ketones 

Microscopic examination (if blood or protein is abnormal)
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.5.2 and 
Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.