Post-Marketing Observational Study to Evaluate Safety Profile of Flixotide 50 μg pMDI Treatment in Chinese Subjects With Asthma Aged 1-<4 Years
Conditions: Asthma
Sponsor: GlaxoSmithKline

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TITLE PAGE
Division:  China Medicines Development
Information Type: Post Marketing Safety Study Protocol
Title:
Post-Marketing Observational Study to Evaluate Safety Profile 
of Flixotide 50 μg pMDI Treatment in Chinese Subjects with 
Asthma aged 1-<4 years
Compound 
Number:
CCI18781
Effective Date:
20-JUN-2017
Subject:
Drug safety
Author(s):
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

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TABLE OF CONTENTS
PAGE
1.
LIST OF ABBREVIATIONS......................................................................................4
2.
RESPONSIBLE PARTIES........................................................................................5
3.
ABSTRACT..............................................................................................................9
4.
AMENDMENTS AND UPDATES............................................................................11
5.
MILESTONES........................................................................................................11
6.
RATIONALE AND BACKGROUND........................................................................11
6.1.
Background ................................................................................................11
6.2.
Rationale ....................................................................................................12
7.
RESEARCH QUESTION AND OBJECTIVE(S)......................................................13
8.
RESEARCH METHODS.........................................................................................13
8.1.
Study Design ..............................................................................................13
8.2.
Monitoring Populations and Collaborative Hospitals ...................................15
8.2.1.
Subject selection..........................................................................15
8.2.2.
Subject Withdrawal......................................................................16
8.2.3.
Collaborative Hospitals ................................................................16
8.3.
Study size...................................................................................................16
8.4.
Data collection ............................................................................................16
8.5.
Data management ......................................................................................16
8.5.1.
Data handling conventions...........................................................16
8.5.2.
Timings of Assessment during follow-up......................................17
8.6.
Statistical analysis ......................................................................................17
8.6.1.
Hypotheses..................................................................................17
8.6.2.
Sample Size Consideration..........................................................17
8.6.3.
Data Analysis Consideration........................................................17
8.6.4.
Key Elements of Analysis Plan ....................................................17
8.7.
Quality control and Quality Assurance ........................................................18
8.8.
Limitations of the research methods ...........................................................18
8.8.1.
Study closure/uninterpretability of results.....................................18
8.9.
Other aspects .............................................................................................19
9.
PROTECTION OF HUMAN SUBJECTS ................................................................19
9.1.
Ethical approval and subject consent..........................................................19
9.2.
Subject confidentiality .................................................................................20
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ..........................................................................................................20
10.1.
Adverse Events (AE) and Serious Adverse Events (SAEs).........................20
10.1.1.
Time Period and Frequency for Collecting AE and SAE 
information...................................................................................21
10.1.1.1.
Method of Detecting AEs and SAEs ...........................21
10.1.1.2.
Follow-up of AEs and SAEs........................................21

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11. REFERENCES.......................................................................................................22
12. APPENDICES........................................................................................................23
12.1.
Appendix 1 Non-Serious Adverse Events/Adverse Drug Reaction 
(AE/ADR) Pages.........................................................................................23
12.2.
Appendix 2 Serious Adverse Events Pages................................................33

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1.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
bd
Two times a day
CFDA
China Food and Drug Administration
eCRF
Electronic Case Record Form
FP
Futicasone propionate
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HFA
Hydrofluoroalkane
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
pMDI
Pressurized Metered-Dose Inhaler
qds
Four times a day
SAE
Serious Adverse Event
SADR
Serious Adverse Drug Reaction
SCG
Sodium Cromoglycate
WHO 
World Health Organisation
μg
Microgram
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
FLIXOTIDE
None

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2.
RESPONSIBLE PARTIES
Clinical Study Identifier: 207734
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
United Kingdom (UK)
Sponsor Contact Address:
GlaxoSmithKline R&D Shanghai (China) Co., Ltd.
Building 1, 917  Halei Road, Zhangjiang Hi-tech Park, Pudong District
Shanghai, 201203, China.

PPD
PPD
PPD
PPD

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SPONSOR INFORMATION PAGE
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
United Kingdom (UK)
Sponsor Contact Address
GlaxoSmithKline (China) R&D Co., Ltd.
917 Halei Road, Pudong District
Shanghai, China
Sponsor Medical Monitor Contact Information:  
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
No. 1 building, 
917 Halei road, 
Pudong, 
Shanghai 
201203, China
Secondar
y Medical 
Monitor
9F, Tower A, 
Ocean 
International 
Center No. 56, 
Mid 4th East 
Ring Rd. 
Beijing.100025
China 
ADR/ 
SADR 
reporting 
group
No.1, 917 Halei 
Road, 
Zhangjiang Hi-
tech Park, 
Pudong, 
Shanghai.20120
3
Regulatory Agency Identifying Number(s): 2016B02085
PPD

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

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3.
ABSTRACT
Rationale
Flixotide administered via a pressurized metered-dose inhaler (pMDI) formulated with 
the propellant hydrofluoroalkane (HFA) was approved in China in 2002 with the strength 
of 50, 125 and 250 μg of fluticasone propionate per actuation. It was indicated for 
prophylactic treatment of asthma, including adults, adolescents older than 16 years of age 
and children aged 4 to 16 years and has demonstrated a positive benefit/risk profile in
Chinese patients.
In Nov 2016, China Food and Drug Administration (CFDA) approved the therapeutic use 
of Flixotide 50 μg (recommended dosing 50 to100 μg twice daily inhaled via a paediatric 
spacer device with a face mask) in children aged 1 to<4 years, with a requirement for 
GlaxoSmithKline (GSK) to conduct proactive safety monitoring in this population. To 
meet CFDA requirement, GSK will initiate this post-marketing safety monitoring 
program to evaluate the safety of Chinese patients aged 1 to <4 years when using 
Flixotide 50 μg via a paediatric spacer device with a face mask in clinical practice. It is 
anticipated that the obtained data from this post-marketing program will further enhance 
and supplement the currently available safety data from clinical trials as well as provide 
more detailed information than that obtained typically available through routine 
spontaneous adverse event reporting.
Objective
The objective of this program is to evaluate the post-marketing safety profile of Flixotide
50 μg inhaled via a paediatric spacer device with a face mask in patients aged 1 to <4 
years. The adverse drug reactions and predictors of these adverse reactions among 
patients will be observed.
Study Design
This is an observational study with no medical interventions. Subjects (children aged 1
to<4 years) information that is pre-defined in the protocol will be collected in the 
electronic case record form (eCRF). The decision to prescribe Flixotide 50 µg will not be 
influenced by whether or not to participate in this observational program.
The observational program will include subjects who have been prescribed Flixotide 
50 µg (recommended dosing 50 to100 μg twice daily inhaled via a paediatric spacer 
device with a face mask) for appropriate medical use for the first time. The subjects who
have been exposed to Flixotide 50 µg, 125 μg and 250 μg previously will not be included.
The maximum program duration will be 12 weeks with 3 visits. Visit1 (Day 1) is the start 
of the observational program. The follow-up visits will be scheduled at 4 weeks (Visit 2), 
and 12 weeks (Visit 3). Unless subjects discontinue Flixotide 50 μg treatment or 
withdraw their consent for continued data collection, subjects will remain in the program
until Visit 3. 

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This post-marketing program is planned to recruit paediatric subjects from 3 to5 hospitals 
(may be adjusted as per recruitment progress) in China. It is planned to include 150 
asthmatic subjects, aged 1 to<4 years who have been prescribed Flixotide 50 μg treatment
for appropriate medical use for the first time in China.

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4.
AMENDMENTS AND UPDATES
None.
5.
MILESTONES
Milestone
Planned date
Start of data collection
31-Aug-2017
Study progress report 
30-Sep-2017
End of data collection
30-Aug-2018
Final report of study results
31-Oct-2018
6.
RATIONALE AND BACKGROUND
6.1.
Background
Fluticasone Propionate Inhaled Aerosol (Flixotide™) is the brand-name product of 
GlaxoSmithKline (GSK) Group. Flixotide is an established inhaled corticosteroid which 
has been approved worldwide for use in the prophylactic treatment of mild, moderate and 
severe asthma in adults (maximum daily dose of 2000 μg/day) and children aged 4 to16 
years (maximum daily dose of 400 μg/day). For children aged 1 to<4 years, Flixotide is 
currently registered for the treatment of asthma (100 to 200 μg/day) in East Asian 
markets including Hong Kong, Taiwan and Korea, as well as some countries in South 
East Asia and the West. Similar clinical pharmacology data was obtained for subjects 
aged 1 to<4 years compared to subjects aged 4 to11 years and adults for fluticasone 
propionate (FP) pMDI 100 μg bd [GlaxoSmithKline Document Number 
YM2002/00005/00, 2002].
Data presented in the [Module 2.5, Fluticasone propionate. 2013], from both clinical 
trials and the published literature have shown that the Flixotide 50 μg can provide similar 
benefits in terms of enhanced lung function, decreased symptoms and an acceptable 
safety profile [Module 2.5, Fluticasone propionate. 2013]. In the global development 
program, a total of 703 subjects aged 1 to<4 years from the four key studies FAS30007 
[GlaxoSmithKline Document Number GM2001/00151/00], FAS30009 
[GlaxoSmithKline Report Number GM2001/00103/00], FLTB3016 [GlaxoSmithKline 
Report Number GM1996/00034/00] and FLTB3017 [GlaxoSmithKline Report Number 
GM1996/00033/00] received FP pMDI 100 μg bd for up to 12 or 52 weeks; this is 
calculated to be equivalent to 469 subject-years [GlaxoSmithKline Document Number 
YM2002/00005/00, 2002]. The safety profile has been summarized as below:

The majority of adverse events (AEs) reported during the clinical programme were 
primarily from the ear, nose and throat and lower respiratory body systems; typical 
for this subject population.  No new or unexpected events were identified.

A higher percentage of subjects aged <2 years experienced AEs during treatment than 
did those aged 2 years.

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
In the 52-Week study (FAS30009), there was no apparent evidence of any important 
clinical differences in the AEs occurring before and after Day 175, nor any evidence 
to suggest increasing rates of AEs in either the FP 100 μg bd or sodium cromoglycate
(SCG) 5 mg qds treatment group after Day 175.

Drug-related AEs were uncommon and not of clinical concern.  The incidence of 
subjects withdrawing due to an AE was low.  The incidence of serious adverse events 
(SAEs) was low, none were attributable to FP treatment and there were no deaths.

A single incident of cataract was reported in subjects treated with FP 100 μg bd out of 
a total subject population of 703 and one further case was identified in a steroid naïve 
subject at Screening.

FP 100 μg bd treatment for 52 weeks in children aged 1 to<4 years had no negative 
effect on growth compared to SCG.

Serum/urinary cortisol levels generally reduced in subjects receiving FP 100 μg bd.  
Two subjects that received FP 100 μg bd in FAS30009 shifted from normal to low 
serum cortisol levels.  No cortisol changes were associated with symptoms of adrenal 
insufficiency.

No changes in clinical chemistry or haematology measurements examined were of 
clinical concern.  There was no apparent evidence that treatment with FP 100 μg bd 
had any effects on vital signs and physical examinations.  Incidence of oral 
candidiasis was uncommon.

The SAEs reported from the studies were consistent with the known safety profile of 
FP, as established in the original Marketing Authorisation Application and variations.  
No new safety concerns, specific to the use of FP in a 1 to<4 year-old subject 
population were identified.
Overall, FP 100 μg bd was at least as well tolerated as placebo and the active comparator 
(SCG) in children 1 to<4 years old [for details please refer to Module 2.5, Fluticasone
propionate. 2013].  The risk: benefit profile of FP 100 μg bd in the treatment of asthma in 
paediatrics aged 1 to<4 years old has been preferable.
In addition, GSK Global Clinical Safety and Pharmacovigilance (GCSP) regularly 
reviews the literature relating to matters of safety, and maintains a database of 
spontaneously reported AEs and literature references. In the recent [Periodic Benefit Risk 
Evaluation Report, 2016], it is concluded that benefit profile of FP in authorized 
indications continues to be positive; also there is no significant change to the risk profile.
6.2.
Rationale
Flixotide administered via a pressurized metered-dose inhaler (pMDI) formulated with 
the propellant hydrofluoroalkane (HFA) was approved in China in 2002 with the strength 
of 50, 125 and 250 μg of FP per actuation. It was indicated for prophylactic treatment of 
asthma, including adults, adolescents older than 16 years of age and children aged 4 to 16 
years and has demonstrated a positive benefit/risk profile in Chinese patients.
In Nov 2016, China Food and Drug Administration (CFDA) approved the therapeutic use 
of Flixotide 50 μg (recommended dosing 50 to100 μg twice daily inhaled via a paediatric 
spacer device with a face mask) in children aged 1 to <4 years, with a requirement for 

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GSK to conduct proactive safety monitoring in this population. To meet CFDA
requirement, GSK initiates this post-marketing safety monitoring program to evaluate the 
safety of Chinese patients aged 1 to <4 years when using Flixotide 50 μg via a paediatric 
spacer device with a face mask in clinical practice.
7.
RESEARCH QUESTION AND OBJECTIVE(S)
The data obtained from this post-marketing program will further enhance and supplement 
the currently available safety data from clinical trials as well as provide more detailed 
information than that obtained typically available through routine spontaneous adverse 
event reporting, thus justify the safety use of Flixotide 50 μg inhaled via a paediatric 
spacer device with a face mask in Chinese children aged 1 to <4 years old. 
The objective of this program is to evaluate the post-marketing safety profile of Flixotide
50 μg in patients aged 1 to <4 years. The adverse drug reactions and predictors of these 
adverse reactions among patients will be observed. The primary goals of this program are 
listed below:
1. To observe the incidence of known adverse reactions in children aged 1 to <4
years.
2. To observe the occurrence of unexpected adverse reactions in children aged 1 to 
<4 years.
8.
RESEARCH METHODS
8.1.
Study Design
This is a single arm observational study with no medical interventions. Subjects (children
aged 1 to <4 years) information that is pre-defined in the protocol will be collected in the 
electronic case record form (eCRF). The decision to prescribe Flixotide 50 μg 
(recommended dosing 50 to 100 μg twice daily inhaled via a paediatric spacer device 
with a face mask) will not be influenced by whether or not to participate in this 
observational program.
The observational program will include subjects who have been prescribed Flixotide 50
μg (recommended dosing 50 to 100 μg twice daily inhaled via a paediatric spacer device 
with a face mask) for appropriate medical use for the first time. The subjects who have 
been exposed to Flixotide 50 μg, 125 μg and 250 μg previously will not be included.
The maximum program duration will be 12 weeks with 3 visits. Visit1 (Day 1) is the start 
of the observational program. The follow-up visits will be scheduled at 4 weeks (Visit 2), 
and 12 weeks (Visit 3). Unless subjects discontinue Flixotide 50 μg treatment or 
withdraw their consent for continued data collection, subjects will remain in the program
until Visit 3. 
Visit1 is an on-site visit where subjects have been prescribed Flixotide 50 µg for 
appropriate medical use. The following procedures/assessments will be performed and 
recorded during Visit1: 

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
Obtain written informed consent

Verification of inclusion criteria

Obtain the demographic information

Obtain the medical history
-
Disease history: asthma disease history and other systemic severe
disease assessed by investigator.

Collect concomitant medication use
-
Asthma treatment medication within 30 days prior to Visit 1. 
-
Other important medications for severe disease treatment in the past 1
month.

AEs and SAEs 
Visit 2 and Visit 3 are follow-up visit. The follow-up can be conducted on site or by 
telephone based on the decision made by qualified medical staff. The following 
assessments will be performed at Visit 2 and Visit3:

AEs and SAEs

Collect Flixotide 50 μg treatment information 

Review concomitant medication use
Time and Events Table (Table 1) provides an outline of the information that will be 
collected on subjects who have provided consent for data collection according to local
ethical guidelines for observational program. Visit 1 is an on-site visit; Visit 2 and Visit 3 
are follow-up visits which can be conducted on site or by telephone.
Table 1
Time and Events Table
Procedure
Visit Number
Visit
(Visit Window)
11
Day1
2
4Ws ±3d
3
12Ws±3d
Early 
Withdrawal
Informed consent
×
Demographic data 
×
Medical history 
×
Flixotide 50 μg therapy2
×
×
×
×

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Procedure
Visit Number
Visit
(Visit Window)
11
Day1
2
4Ws ±3d
3
12Ws±3d
Early 
Withdrawal
Concomitant medication
×
×
×
×
Adverse Event3
×
×
×
×
Serious Adverse event3
×
×
×
×
Diary card dispense4
×
1.
Visit 1 marks the start of the observational period.
2.
Change in drug dosage, discontinuation or resumption and reasons for these changes, and compliance of 
Flixotide 50 μg therapy.
3.
SAEs will be recorded from the time the consent form is signed through Visit 3; AEs will be recorded from the start 
of Flixotide 50 μg treatment through Visit 3.
4.
Paper diary cards will be dispensed at Visit 1 for the parent/guardian of the subject to record Flixotide 50 μg 
therapy, concomitant medication, AEs and SAEs. The investigator will record the source information in the 
medical records by asking the parent/guardian of the subject during the follow-up on site or telephone visits. 
8.2.
Monitoring Populations and Collaborative Hospitals
8.2.1.
Subject selection
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
I.
Informed consent
An appropriately signed and dated assent must be obtained from the 
parent/guardian of the subject.
II.
Age
1 to<4 years of age at Visit 1.
III.
Flixotide 50 μg treatment
Subjects who have been prescribed Flixotide 50 µg for a medically appropriate 
use for the first time will be included in this observational program. Flixotide
50 μg therapy should be in line with the approved dosing: 50 to100 µg twice daily. 
Subjects should have the ability to inhale the doses via a paediatric spacer with a 
face mask appropriately. Subjects who have been exposed to Flixotide 50 μg, 125
μg and 250 μg treatment previously will not be included.
IV.
The parent/guardian of the subject must provide reliable contact information
which includes home phone or cell phone for the follow up visits.

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V.
The parent/guardian of the subject must have the ability to comply study 
procedures. 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on Flixotide 50 μg that may impact subject eligibility is 
provided in the approved product label.
8.2.2.
Subject Withdrawal
A subject and their parent/guardian may withdraw consent to have their data collected in 
the program at any time. If this occurs, they must be withdrawn from this study. Data 
collected until the point of consent withdrawal will be used.
8.2.3.
Collaborative Hospitals
This post-marketing program is planned to recruit paediatric subjects from 3 to5 hospitals 
(may be adjusted as per recruitment progress) in China. 
8.3.
Study size
It is planned to include 150 asthmatic subjects, aged 1 to 4 years who have been 
prescribed Flixotide 50 μg treatment for appropriate medical use for the first time in 
China.
8.4.
Data collection
The information of the subjects’ demographic factors, medical history, Flixotide 50 μg
therapy, concomitant medications, AEs and SAEs, will be collected. Paper diary cards
will be dispensed at Visit 1 for the parent/guardian of the subject to record Flixotide 50
μg therapy, concomitant medication, AEs and SAEs. The investigator will record the 
source information in the medical records by asking the parent/guardian of the subject 
during the follow-up on site or telephone visits.
Subjects’ data will be entered into GSK defined eCRFs.
No data will be collected on subjects until consent for data collection has been obtained 
in line with local ethical standards for observational program.
8.5.
Data management
8.5.1.
Data handling conventions
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data. Adverse events 
and concomitant medications terms will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) and, World Health Organisation (WHO)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.

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8.5.2.
Timings of Assessment during follow-up
Visit 1 will be defined as baseline. Follow-up visits will be performed at 4 weeks and 12 
weeks since baseline visit. There is ±3 day window period for every follow up visit.
8.6.
Statistical analysis
8.6.1.
Hypotheses 
This is a post-marketing observational study. A descriptive approach will be used and no 
formal inference is planned in this study. Some justification is provided as follows.  
8.6.2.
Sample Size Consideration
Considering that Flixotide is an established brand, which has been in the China market 
for more than 10 years, it is more sensible to consider drug related AE (adverse drug 
reaction, ADR) instead of any specific rare case.
Based on global phase III studies FAS30007 [GlaxoSmithKline Document Number
GM2001/00151/00], FAS30030 [GlaxoSmithKline Document Number 
RM2004/0187/00] and FAS30009 [GlaxoSmithKline Report Number 
GM2001/00103/00] on 1 to<4 years old, the smallest incidence rate of ADR in a given 
study was 3%. The Japanese post market safety survey reported the ADR rate as 1.68%. 
Taken the lowest estimate between two approaches, assuming the ADR rate in Chinese 1
to<4 year old children patients is not lower than 1.5%, it is calculated that a study with 
150 subjects will have approximately 90% probability to observe at least one ADR.
8.6.3.
Data Analysis Consideration
The safety population is defined as all included subjects who received at least one dose of 
Flixotide 50 μg and complete one follow up visit, including scheduled or unscheduled 
visit. Subjects who retrospectively received will also be included in.  
8.6.4.
Key Elements of Analysis Plan
Safety Analysis
Safety data will be summarized and/or listed for the safety population. 
The duration of exposure to Flixotide 50 μg will be summarized and patient medical 
history will be listed.
Concomitant medication will be coded using WHO drug and will be summarized by 
Anatomical Therapeutic Chemical (ATC) classification. 
AEs will be coded using MedDRA, and grouped by body system. AEs occurring during 
administration of Flixotide 50 μg will be summarized. 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. Separate summaries will be provided for all 
AEs, drug related AEs, SAEs, and for AEs leading treatment discontinuation.

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Analysis methods
No formal hypothesis will be tested in this study. AEs will be listed and summarized
descriptively to provide frequency estimate of ADR (=incidence rate of any drug related 
AEs in safety population) and frequency estimates for any other adverse events reported. 
8.7.
Quality control and Quality Assurance
In accordance with applicable regulations, applicable standards for the conduct of 
observational studies, and GSK procedures, monitors will contact the site prior to the 
inclusion of the first subject to review with the site staff the protocol, program 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.
The sites will be monitored to ensure that the:

Subjects included in the program are authentic.

Safety and rights of subjects are being protected.

The program is conducted in accordance with the currently approved protocol and 
any other program agreements, applicable standards for the conduct of 
observational studies, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor access to all relevant documents in accordance with applicable 
standards for the conduct of observational studies.
To ensure compliance with applicable standards for the conduct of observational studies 
and all applicable regulatory requirements, GSK may conduct a quality assurance audit of 
the site records, and the regulatory agencies may conduct a regulatory inspection at any 
time during or after completion of the program.
In the event of an audit or inspection, the investigator (and institution) must agree to grant 
the auditor(s) and inspector(s) direct access to all relevant documents and to allocate their 
time and the time of their staff to discuss any findings/relevant issues.
8.8.
Limitations of the research methods
8.8.1.
Study closure/uninterpretability of results

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.  

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
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK 
will promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action. 

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the Institutional Review Board (IRB)/
Independent Ethics Committee (IEC) promptly and provide the reason for the 
suspension or premature discontinuation.
8.9.
Other aspects
None.
9.
PROTECTION OF HUMAN SUBJECTS
9.1.
Ethical approval and subject consent
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 must be obtained for each subject (from their 
parent/guardian) 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.

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9.2.
Subject confidentiality
Documented evidence that a potential investigator is aware of and agrees to the 
confidential nature of the information related to the study must be obtained by means of a 
confidentiality agreement.
All information provided by GSK and all data and information generated by the site as 
part of the study (other than a subject’s medical records) will be kept confidential by the 
investigator and other site staff. This information and data will not be used by the 
investigator or other site personnel for any purpose other than conducting the study. 
These restrictions do not apply to: (i) information which becomes publicly available 
through no fault of the investigator or site staff; (ii) information which it is necessary to 
disclose in confidence to an IEC or IRB solely for the evaluation of the study; (iii) 
information which it is necessary to disclose in order to provide appropriate medical care 
to a study subject; or (iv) study results which may be published as described in the next 
paragraph. If a written contract for the conduct of the study which includes 
confidentiality provisions inconsistent with this statement is executed, that contract’s 
confidentiality provisions shall apply rather than this statement.
10.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
10.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
Adverse Event (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. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease (new or exacerbated) temporally associated with the use of a medicinal 
product. For marketed medicinal products, this also includes failure to produce expected 
benefits (i.e., lack of efficacy), abuse or misuse.
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose: 

Results in death, 

Is life-threatening,

Requires hospitalization or prolongation of existing hospitalization, 

Results in disability/incapacity,

Is a congenital anomaly/birth defect, 

Other: medical or scientific judgement 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 hospitalisation but 
may jeopardise 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.

possible drug-induced liver injury

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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). 
10.1.1.
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.

SAEs will be recorded from the time the consent form is signed through Visit 3; AEs 
will be recorded from the start of Flixotide 50 μg treatment through Visit 3.

Investigators will assess causality within 24 hours. Once the investigator determines 
that an AE/SAE is identified as explicitly attributed to any GSK product (including 
products not covered in the specific study objective), the investigator must report the
ADR to Vendor and GSK China within 5 calendar days upon awareness. All SAEs 
will be recorded and reported to GSK within 24 hours of awareness. GSK standard 
AE and SAE Collection Forms (Appendix 1, Appendix 2) will be used to collect 
safety information. GSK China will forward the information to GCSP following 
internal process.

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.
10.1.1.1.
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?”
10.1.1.2.
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 ADRs and SAEs will be followed until 
resolution, until the condition stabilizes, until the event is otherwise explained, or until 
the subject is lost to follow-up. Any follow-up information on a previously reported ADR 
and SAE must also be reported to vendor and GSK China within the same timeline as 
initial reports.

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11.
REFERENCES
GlaxoSmithKline Document Number RM2004/0187/00. Study ID FAS30030. A 
Randomized (2:1), Stratified, Double-Blind, Parallel-Group, Placebo-Controlled, 12-
week, Multi-Center Trial of Fluticasone Propionate HFA Inhalation Aerosol 88mcg BID 
versus Placebo HFA Delivered via an MDI and a Valved Holding Chamber with 
Facemask in Pediatric Subjects 1 to <4 Years of Age with Asthma (2004).
GlaxoSmithKline Document Number YM2002/00005/00. Expert Report on The Clinical 
Documentation of Inhaled Fluticasone Propionate 100μg Twice Daily in Children Aged 
1-4 Years with Asthma. 2002.
GlaxoSmithKline Report Number GM1996/00033/00. Study ID FLTB3017. A multi-
centre, randomised, double-blind, placebo-controlled parallel group study to determine 
the efficacy and safety of inhaled fluticasone proprionate 100mcg bd and 250mcg bd 
delivered via the Babyhaler and spacer device in the mangement of asthma symptoms in 
children aged 12 47 months inclusive. 1997.
GlaxoSmithKline Report Number GM1996/00034/00. Study ID FLTB3016.  A multi-
centre, randomised, double-blind, placebo-controlled parallel group study to determine 
the efficacy and safety of inhaled fluticasone proprionate 50mcg bd and 100mcg bd 
delivered via the Babyhaler and spacer device in the mangement of asthma symptoms in 
children aged 12 47 months inclusive. 1997.
GlaxoSmithKline Report Number GM2001/00103/00. Study ID FAS30009.  A 
Multicentre, Randomised, Parallel Group, Open Label Study to Assess the Long Term 
Safety (Including Growth) of Fluticasone Propionate 100mcg bd via the Metered Dose 
Inhaler and Babyhaler Spacer Device Compared with Sodium Cromoglycate 5mg qds 
delivered via Metered Dose Inhaler and Nebuhaler Spacer Device in Children aged 12 47 
Months With Documented Evidence of Recurrent/Persistent Asthma like Symptoms over 
a 52 Week Treatment Period. 2001.
GlaxoSmithKline Report Number GM2001/00151/00. Study ID FAS30007.  A 
multicentre, randomised, double-blind, parallel group, placebo-controlled study to 
determine the efficacy and safety of fluticasone propionate 200 mcg/day delivered for 12 
weeks via the Babyhaler in paediatric subjects aged 12 to 47 months with 
recurrent/persistent asthma like symptoms. 2002.
Module 2.5 Clinical Overview for Fluticasone propionate. 2013.
Periodic Benefit Risk Evaluation Report(PBRER). 01Mar2015-29Feb2016.

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12.
APPENDICES
12.1.
Appendix 1 Non-Serious Adverse Events/Adverse Drug Reaction (AE/ADR) Pages

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PPD

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12.2.
Appendix 2 Serious Adverse Events Pages

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PPD

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