Conditions: Asthma
Keywords: Cluster Randomization Peak Expiratory Flow Forced Expiratory Volume Standardized Asthma Quality of Life Questionnaire Asthma Control Test
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 530
Healthy volunteers: no

Brief summary:
This study is aimed to evaluate the effectiveness of Asthma Control Test (ACT) guided treatment compared with usual care in asthma subjects in China. It is designed to assist Chinese subjects and physicians improving adherence to the guidelines through the inclusion of the ACT in the patient's asthma management plan. This is a prospective, multicentre, cluster-randomized, open-label 24-week study. In this cluster-randomization design, each study center, considered as a cluster, will be randomized to either ACT guided treatment group or control group (usual care group). For the subjects who are recruited in the ACT centers, they will be treated based on the ACT score. If ACT score are equal to (=) 25 for more than equal to (\>=) 3 months then the treatment will stepped-down; if ACT score \>=20, less than (\<) 25 or ACT=25 for \<3 months then there will be no change and if ACT score less than (\<=) 19 then the treatment will stepped-up. For subjects who are recruited in the control centers, they will be treated based on doctor's subjective judgment. Assignment to a treatment will not occur, as no treatment intervention is provided for this study. A total of 528 asthma subjects are planned in the study. The randomization will be stratified according to the Tier of the hospitals (Tier 3 verses Tier 2).

Detailed description:

Arms:
arm 1: For the subjects who will be recruited in the ACT centers, they will be treated based on the ACT score. If ACT score are = 25 for \>=3 months then step-down the treatment; if ACT score \>=20, \<25 or ACT=25 for \<3 months then there will be no change and if ACT score less than (\<=) 19 then step-up the treatment. arm 2: For subjects who will be recruited in the control centers, they will be treated based on doctor's subjective judgment.

Interventions: intervention 1: ACT guided Routine Treatment intervention 2: Routine Treatment
Intervention descriptions: intervention 1: The ACT is a validated, short, easy to use, and self-administered instrument used to assess asthma control. Subjects in this group received routine treatment as per ACT score. intervention 2: Subjects in the controlled treatment group will receive usual care of asthma. This treatment was monitored and adjusted as usual by the patient's general practitioner.

Protocol document:
Prot_000.pdf: 
2013N186640_00
CONFIDENTIAL
GlaxoSmithKline group of companies
201097
1
TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
The effectiveness of Asthma Control Test guided treatment 
compared with usual care in China adult asthma patients
Compound Number:
None
Development Phase
IV
Effective Date:
27-JUN-2016
Author(s):
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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
 
5F The 
Headquarters 
Building
No 168, Middle 
Tibet Road
Shanghai, 
China
Secondary 
Medical 
Monitor
 
5F The 
Headquarters 
Building
No 168, Middle 
Tibet Road
Shanghai, 
China
SAE contact  
information 
NA
NA
NA
Building 1, 917 
Halei Road 
Zhangjiang Hi-
tech Park, 
Pudong 
Shanghai 
201203, China
Sponsor Legal Registered Address:
GlaxoSmithKline(China) Investment Co., Ltd. 
9F Tower A, Ocean International Center 
No.56 Mid 4th East Ring Road, Chaoyang District 
Beijing, 100025, China 
Telephone: (
) 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial submission.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201097........................................................7
2.
INTRODUCTION....................................................................................................11
2.1.
Study Rationale ..........................................................................................11
2.2.
Brief Background ........................................................................................11
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................12
4.
STUDY DESIGN ....................................................................................................13
4.1.
Overall Design ............................................................................................13
4.2.
Treatment Arms and Duration.....................................................................14
4.3.
Type and Number of Subjects.....................................................................15
4.4.
Design Justification.....................................................................................15
4.5.
Benefit:Risk Assessment ............................................................................15
4.5.1.
Risk Assessment .........................................................................16
4.5.2.
Benefit Assessment.....................................................................16
4.5.3.
Overall Benefit: Risk Conclusion..................................................16
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............16
5.1.
Inclusion Criteria.........................................................................................16
5.2.
Exclusion Criteria........................................................................................17
5.3.
Withdrawal/Stopping Criteria.......................................................................19
5.4.
Subject and Study Completion....................................................................21
6.
STUDY TREATMENT ............................................................................................21
6.1.
Treatment Assignment................................................................................21
6.2.
Blinding.......................................................................................................21
6.3.
Treatment after the End of the Study ..........................................................21
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................22
7.1.
Time and Events Table...............................................................................22
7.2.
Screening and Critical Baseline Assessments ............................................23
7.3.
Efficacy.......................................................................................................23
7.3.1.
Primary Endpoint (s) ....................................................................23
7.3.2.
Secondary Endpoint (s) ...............................................................24
7.3.3.
Other Endpoint (s) .......................................................................26
7.3.4.
Guidance for Questionnaires Administration................................28
7.4.
Safety .........................................................................................................29
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........29
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................29
7.4.1.2.
Method of Detecting AEs and SAEs ...........................30
7.4.1.3.
Follow-up of AEs and SAEs........................................30
7.4.1.4.
Cardiovascular and Death Events ..............................31
7.4.1.5.
Regulatory Reporting Requirements for SAEs
and ADRs...................................................................31
7.4.2.
Pregnancy ...................................................................................32
7.4.3.
Physical Exams ...........................................................................32
7.4.4.
Vital Signs....................................................................................32


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8.
DATA MANAGEMENT ...........................................................................................32
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................33
9.1.
Hypotheses.................................................................................................33
9.2.
Sample Size Considerations.......................................................................33
9.2.1.
Sample Size Assumptions ...........................................................33
9.2.2.
Sample Size Sensitivity................................................................34
9.2.3.
Sample Size Re-estimation or Adjustment...................................35
9.3.
Data Analysis Considerations .....................................................................35
9.3.1.
Analysis Populations....................................................................35
9.3.2.
Consideration on Missing Data Handling .....................................36
9.3.3.
Interim Analysis ...........................................................................36
9.4.
Key Elements of Analysis Plan ...................................................................36
9.4.1.
Primary Analyses.........................................................................37
9.4.2.
Secondary Analyses ....................................................................37
9.4.3.
Other Analyses ............................................................................37
10. STUDY GOVERNANCE CONSIDERATIONS........................................................38
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............38
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................38
10.3.
Quality Control (Study Monitoring) ..............................................................39
10.4.
Quality Assurance.......................................................................................40
10.5.
Study and Site Closure ...............................................................................40
10.6.
Records Retention......................................................................................41
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................42
11. REFERENCES.......................................................................................................43
12. APPENDICES........................................................................................................44
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................44
12.2.
Appendix 2 : Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ............................46
12.2.1.
Definition of Adverse Events........................................................46
12.2.2.
Definition of Serious Adverse Events...........................................47
12.2.3.
Definition of Cardiovascular Events .............................................48
12.2.4.
Recording of AEs and SAEs ........................................................49
12.2.5.
Evaluating AEs and SAEs............................................................49
12.2.6.
Reporting of SAEs/ADR to GSK ..................................................51
12.3.
Appendix 3 - Country Specific Requirements..............................................52
12.4.
Appendix 4: Asthma Control Test ...............................................................53
12.5.
Appendix 5: Standardised Asthma Quality of Life Questionnaire
(AQLQ(S)) ..................................................................................................54


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1.
PROTOCOL SYNOPSIS FOR STUDY 201097
Rationale
Current levels of asthma control in China fall short of the goals specified in international 
guidelines for asthma management (GINA). A nationwide multi-centre epidemiologic 
survey performed by China Asthma Alliance also showed that only 28.7% of the patients 
with asthma in China achieved complete asthma control. There is a large gap between 
what can be achieved with modern asthma management and what is currently being 
achieved. One of the main reasons for this is a lack of recognition of asthma control and 
the requirement for more effective treatment. Physicians can select appropriate treatment
regimen only after they identify those patients with uncontrolled asthma. Simple methods 
aiming to improve the assessment of asthma control have been developed. The Asthma 
Control Test (ACT) is a validated, short, easy to use, and self-administered instrument 
used to assess asthma control. However, physicians do not use it, even though it was 
designed to assess the level of asthma control in patients and so guide physicians 
treatment decisions. This study is aimed at evaluating the effectiveness of ACT guided 
treatment compared with usual care in asthma patients in China. It is designed to assist
Chinese patients and physicians improving adherence to the guidelines through the 
inclusion of the ACT in the patient’s asthma management plan.


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Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the effectiveness of ACT 
guided treatment versus usual care in 
achieving asthma control

the percentage of subjects who have an 
ACT score ≥20 or an improvement of 
more than 3 points in ACT during the 24-
week treatment period
Secondary

To compare the effectiveness of ACT 
guided treatment versus usual care in 
asthma subjects with respect to the 
following parameters:
•
Symptoms
•
Forced Expiratory Volume in 
one second (FEV1)
•
Peak Expiratory Flow(PEF)
•
The quality of life
•
Time to asthma control

Mean daytime symptom score over the 
24-week treatment period

Mean night-time symptom score over the 
24-week treatment period

Mean change from baseline to the end of 
study in FEV1 

Mean morning(AM) PEF over the 24-
week treatment period

Mean evening(PM) PEF over the 24-
week treatment period

Mean change from baseline to the end of 
study in Standardised Asthma Quality of 
Life Questionnaire (AQLQ[S]) score

Time to first ACT score ≥20 or 
improvement of more than 3 points in 
ACT over the 24-week treatment period
Others

To compare the effectiveness of ACT 
guided treatment versus usual care in 
asthma exacerbation

Rate of moderate/severe asthma 
exacerbation over the 24-week treatment 
period
Overall Design
This is a prospective, multicentre, cluster-randomised, open-label study.
Treatment Arms and Duration
The study is planned to be a 24-week study.
Baseline (week 0, visit 0): ACT, AQLQ(S) and lung function test will be completed as 
the baseline measurement in sequence.
Treatment period (week 0-week 24): a 24 week treatment period. Subsequent scheduled 
visits occur as follows: Week 4 (Visit 1), Week 8 (Visit 2), Week 12 (Visit 3), Week 16 
(Visit 4), Week 20 (Visit 5) and Week 24 (Visit 6).


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In this cluster-randomization design, each study centre, considered as a cluster, will be 
randomized to either ACT guided treatment group or control group (usual care group).
The randomization will be stratified according to the hospital level (Tier 3 vs. Tier 2).
The hospital level is determined in accordance with the uniform requirements of the 
government. A Tier 3 hospital is on a larger scale and provides superior medical care than 
a Tier 2 hospital.
For the subjects who are recruited in the ACT centres, they will be treated based on the 
ACT score. For subjects who are recruited in the control centres, they will be treated 
based on doctor’s subjective judgment.
ACT score
Treatment adjustment
ACT=25, ≥3 months
Step-down treatment
ACT20, <25 or ACT=25, <3 
months
No change
ACT≤19
Step-up treatment
Type and Number of Subjects
A total of 528 subjects are required in a total of 12 centres (6 centres per group) and 
around 44 asthma subjects per centre.
Analysis
The null hypothesis for this study is that there is no difference between ACT guided 
treatment and usual care in the percentage of subjects who have an ACT score ≥20 or an 
improvement of more than 3 points in ACT during the 24-week treatment period for the 
intention-to-treat (ITT) population.
The alternative hypothesis for this study is that there is a difference between ACT guided 
treatment and usual care in the percentage of subjects who have an ACT score ≥20 or an 
improvement of more than 3 points in ACT during the 24-week treatment period for the
ITT population.


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The primary endpoints will be analyzed using logistic regression. The statistical model on 
which the inference will be based will include terms for treatment, centre, type of 
baseline controller (inhaled corticosteroids [ICS] alone vs. ICS/long-acting β2 agonist 
[LABA]), gender and age. Centre, as the unit of randomization, will be treated as a 
random effect. The results of the primary analyses will be presented as point estimates, 
95% confidence intervals and associated p-values for the adjusted mean differences 
between ACT guided treatment and usual care.


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2.
INTRODUCTION
2.1.
Study Rationale
Current levels of asthma control in China fall short of the goals specified in international 
guidelines for asthma management (GINA). A nationwide multi-centre epidemiologic 
survey performed by China Asthma Alliance also showed that only 28.7% of the patients 
with asthma in China achieved complete asthma control [Nan, 2013]. There is a major 
gap between what can be achieved with modern asthma management and what is 
currently being achieved. One of the main reasons for this is a lack of recognition of 
asthma control and the requirement for more effective treatment. Physicians can select 
appropriate treatment regimen only after they identify those patients with uncontrolled 
asthma. Simple methods aiming to improve the assessment of asthma control have been 
developed. The asthma control test (ACT) is a validated, short, easy to use, and self-
administered instrument used to assess asthma control [Nathan, 2004]. However, 
physicians do not use it, even though it was designed to assess the level of asthma control 
in patients and so guide physicians treatment decisions. This study is aimed to evaluate 
the effectiveness of ACT guided treatment compared with usual care in asthma patients 
in China. It is designed to assist Chinese patients and physicians improving adherence to 
the guidelines through the inclusion of the ACT in the patient’s asthma management plan.
2.2.
Brief Background
GINA has adopted a five-step approach to control asthma, where each step represents a 
different treatment option with increasing efficacy [GINA, 2013]. The five-step approach 
provides treatment options to achieve and maintain control, with the least amount of 
medication. Asthma control assessment is very important to assess what is the
appropriate treatment for the patient. In a questionnaire survey in Canada, primary care 
physicians were given questionnaires to guide them through control assessments. They 
were also asked to indicate whether or not they considered the patient’s asthma to be
under control. It was found that physicians significantly overestimated control among 
their patients and were discordant with guideline classification of control as 31% of the 
patients were assessed as uncontrolled patients, 13% were well-controlled and 2% were
totally controlled [Chapman, 2008]. In China, poor physician:patient dialogue has made 
the situation worse. During busy clinical practice, physicians often make management 


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decisions based on their subjective perceived level of asthma control. This potentially 
leads to under-treatment and consequently sub-optimal asthma control.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To compare the effectiveness of ACT 
guided treatment versus usual care in 
achieving asthma control

the percentage of subjects who have an 
ACT score ≥20 or an improvement of 
more than 3 points in ACT during the 24-
week treatment period
Secondary

To compare the effectiveness of ACT 
guided treatment versus usual care in 
asthma subjects with respect to the 
following parameters:
•
Symptoms
•
Forced Expiratory Volume in 
one second (FEV1)
•
Peak Expiratory Flow(PEF)
•
The quality of life
•
Time to asthma control

Mean daytime symptom score over the 
24-week treatment period

Mean night-time symptom score over the 
24-week treatment period

Mean change from baseline to the end of 
study in FEV1 

Mean morning (AM) PEF over the 24-
week treatment period

Mean evening (PM) PEF over the 24-
week treatment period

Mean change from baseline to the end of 
study in Standardised Asthma Quality of 
Life Questionnaire (AQLQ(S)) score

Time to first ACT score ≥20 or 
improvement of more than 3 points in 
ACT over the 24-week treatment period
Others

To compare the effectiveness of ACT 
guided treatment versus usual care in 
asthma exacerbation

Rate of moderate/severe asthma 
exacerbation over the 24-week treatment 
period


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4.
STUDY DESIGN
4.1.
Overall Design
This is a prospective, multicentre, cluster-randomized, open-label study.
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.


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4.2.
Treatment Arms and Duration

The study is planned to be a 24-week study.

Baseline (week 0, visit 0): Subjects eligible for inclusion criteria will sign informed 
consent form at Visit 0. At this visit, investigators should collect baseline data, 
including demographic data (gender, age, height, weight, education level and 
smoking history), history of asthma (disease duration, disease severity and 
exacerbation history), and past and concurrent medical conditions and medication 
(both asthma and non-asthma). ACT, AQLQ(S) and lung function test will be 
completed as the baseline measurement in sequence.

Treatment period (week 0-week 24): a 24 week treatment period. Subsequent 
scheduled visits occur as follows: Week 4 (Visit 1), Week 8 (Visit 2), Week 12 
(Visit 3), Week 16 (Visit 4), Week 20 (Visit 5) and Week 24 (Visit 6).

In this cluster-randomization design, each study centre, considered as a cluster, will 
be randomized to either ACT guided treatment group or control group (usual care 
group). The randomization will be stratified according to the hospital level (Tier 3 vs. 
Tier 2). The hospital level is determined in accordance with the uniform requirements 
of the government. And a Tier 3 hospital is on a larger scale and provides superior 
medical care than a Tier 2 hospital.

For the subjects who are recruited in the ACT centres, they will be treated based on 
the ACT score. For subjects who are recruited in the control centres, they will be 
treated based on doctor’s subjective judgment.
Table 1
ACT-guided treatment
ACT score
Treatment adjustment
ACT=25, ≥3 months
Step-down treatment
ACT20, <25 or ACT=25, <3 
months
No change


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ACT score
Treatment adjustment
ACT≤19
Step-up treatment

During the treatment period, subjects should fill in the paper diary record card (DRC)
every morning and evening, record their morning and evening PEF, symptom and 
medication. At each visit, subjects should complete the ACT at clinic. For the ACT 
guided group, the ACT must be completed prior to any other assessments are 
conducted. For the control group, subjects should complete the ACT after investigator 
making the treatment decision. This will ensure the investigators make treatment 
decision based on his/her clinical judgement, not based on ACT. For the control 
group, all subsequent assessments should be conducted in the same order as the ACT 
guided group. Investigators will be responsible for checking the subjects’ DRC, 
including symptom score and evaluating therapeutic compliance.
4.3.
Type and Number of Subjects
A total of 528 subjects are required including a total of 12 centres (6 centres per group) 
and around 44 asthma subjects per centre.
4.4.
Design Justification

We design our study to address the effectiveness of the intervention if implemented in 
a system without other enhanced healthcare options; we therefore use a usual care 
control group. 

Randomization by individual subjects may result the contamination due to the same 
investigator looking after both intervention and control group. Randomization by
clusters (i.e., study centre) will reduce such bias.
4.5.
Benefit:Risk Assessment
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
Study Procedures
Patients’
inappropriate
understanding 
on 
ACT 
questionnaire
ACT is consisted of five 
questions, which each have a 
five-point rating scale and 
relate to the past month. It is 
not an objective tool.
Once a subject is enrolled 
into 
the 
study, 
the 
investigator is responsible for 
training 
the 
subject 
to 
understand and use the ACT.
4.5.2.
Benefit Assessment
Usage of the ACT is beneficial for patients. The ACT as an easy and patient-friendly tool 
for asthma control assessment has been fully validated and used in interventional studies 
and routine clinical practice in many countries. The ACT empowers patients to take 
charge of their condition and work in partnership with their physicians, which could 
facilitate the achievement of guideline-defined asthma control.
4.5.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with inappropriate understanding on 
ACT questionnaire are justified by the anticipated benefits that may be afforded to 
subjects with asthma.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
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
Inclusion criteria for study centre (clusters):
A study centre (cluster) will be eligible for inclusion in this study only if all of the 
following criteria apply:


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1. General practice;
2. Located in Shanghai;
3. Providing asthma care.
Inclusion criteria for subjects at Visit 0:
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
4. Age:18 to 70 years inclusive;
5. Gender: Male or Female;
6. Documented clinical history of asthma for at least 6 months prior to Visit 0;
7. At Visit 0, a demonstrable reversible increase in FEV1 of at least 12% (and
≥200 mL), 15 minutes after inhaling a short-acting bronchodilator or; at any time in 
the last 2 years documentary evidence of a reversible increase in FEV1 of at least 
12% (and ≥200 mL) 15 mins after inhaling a short-acting bronchodilator; or 
demonstrable reversible increase  in morning PEF of at least 15% (and ≥200 mL) 
either spontaneously or after inhalation of a short-acting bronchodilator;
8. History of using inhaled corticosteroids (ICS) alone or combined with an inhaled 
long-acting β2 agonist (LABA) treatment within 1 year prior to Visit 0;
9. Subjects must have an ACT score <20 at Visit 0;
10. Subject must have been able to read, comprehend, and record information in Chinese;
11. A signed and dated written informed consent must be obtained from the subject prior 
to study participation.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:


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1. History of Life-threatening asthma: Defined for this protocol as an asthma episode
that required intubation and/or was associated with hypercapnea, respiratory arrest or
hypoxic seizures within the last 6 months before Visit 0.
2. Subjects having severe and unstable asthma, with ACT score <12 at Visit 0, history 
of repeated severe exacerbations (3/year) and/or a severe exacerbation in the previous 
6 weeks before Visit 0.
3. A current evidence of clinically significant uncontrolled medical condition or disease
(e.g., psychological disorders, mental deficiency, severe hepatic and renal dysfunction, 
malignancy);
4. Current smoker or ex-smoker with a more than 10 pack-year history of smoking;
5. Current clinically significant respiratory diseases other than asthma, (e.g lung cancer, 
lung fibrosis, sarcoidosis, tuberculosis, chronic obstructive pulmonary disease 
[COPD]);
6. History of alcohol or medication abuse;
7. History of upper or lower respiratory tract infection within 4 weeks prior to Visit 0;
8. Enrolled in an asthma clinic or outpatient service in the past 12 months that provides 
comprehensive asthma management;
9. Subjects with a history of adverse reaction including immediate or delayed
hypersensitivity to any intranasal, inhaled, or systemic corticosteroid and LABA
therapy and to components of the inhalation powder (e.g., lactose) at Visit 0. In 
addition, subjects with a history of severe milk protein allergy that, in the opinion of 
the Investigator, contraindicates the subject’s participation will also be excluded.
10. Females who are currently pregnant and lactating;
11. Subjects who have received any of the following medications in the 6 weeks 
preceding visit 0: oral/parenteral corticosteroids, oral β2-agonists or slow-release 


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bronchodilators, 
sodium 
cromoglycate 
or 
nedocromil 
sodium, 
ketotifen,  
anticholinergics, and anti-IgE treatment;
12. Subjects who comply poorly with asthma treatment in the opinion of the 
investigator/inability or unwillingness to take asthma medication (non-compliance), 
follow directions or unable to complete a written paper daily record card and self-
rating questionnaires;
13. Concurrently participating in another clinical study in which the subject is or will be 
exposed to an investigational or a non-investigational medication or device, or has 
participated in a clinical trial and has received an investigational product within 30 
days, 5 half-lives or twice the duration of the biological effect of the investigational 
product (whichever is longer).
14. Subjects with contraindications to any asthma medications they will be taking during 
the study period, or whom should be excluded on account of the special warnings and 
precautions within the label of the asthma medication they are to be treated with 
during the study period.
15. Affiliation with Investigator Site: Is an investigator, sub-investigator, study
coordinator, employee of a participating investigator or study site, or immediate
family member of the afore mentioned that is involved in this study.
16. Subjects who plan to move away from the geographical area where the study is being 
conducted during the study.
5.3.
Withdrawal/Stopping Criteria
The primary reason for the subject discontinuing from the study will be recorded in the 
Case Record Form. The investigator must determine the primary reason for 
discontinuation. The end of study/early discontinuation procedures must be performed at 
the time of discontinuation from the clinical study.
The subject must be discontinued from the study for any of the following reasons:


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1. A subject is significantly non-compliant with treatment or the requirements of the 
protocol;
2. Lost to follow up;
3. Subject’s decision not to participate any further (withdrawal of consent);
4. In the investigator’s opinion, it is in the subject’s best interest;
5. Subjects experience a protocol-defined asthma exacerbation;
6. The study is terminated by the Sponsor or designee;
7. Pregnancy (Subject should notify investigator immediately on becoming pregnant).
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.
The reason(s) for subjects not completing the study will be recorded in the Case Report 
Form (CRF), and that the investigator must document, if applicable, the reason (if 
specified by the subject) for withdrawal of consent.
The end of study/early 
discontinuation procedures must be performed at the time of discontinuation from the
clinical 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 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 based on previous non-compliance.

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 


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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”. 
5.4.
Subject and Study Completion
A completed subject is one who has completed all visits of the study.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Treatment Assignment
The study is a trial with the study centre as the unit of randomization. Computer
generated randomization schedule for centres will be provided by GlaxoSmithKline 
(GSK) or its designee. Once a randomization number has been assigned, it is not re-
assigned. Each centre will be randomized to either ACT guided treatment group or 
control group (usual care group). The randomization will be stratified according to the 
Tier of the hospitals (Tier 3 vs. Tier 2). Assignment to a treatment will not occur, as no 
treatment intervention is provided for this study. Each centre will be asked to recruit 44 
consecutive patients with asthma attending the practice. For the subjects who are 
recruited in the ACT centres, they will be treated based on the ACT score. For subjects 
who are recruited in the control centres, they will be treated based on doctor’s subjective 
judgment.
The subject number will be documented in the subject’s clinic notes and in the CRF.
6.2.
Blinding
This will be an open-label study.
6.3.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study.


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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.
7.
STUDY ASSESSMENTS AND PROCEDURES
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. 
7.1.
Time and Events Table
ACTIVITY
Visit 
0
Visit 
1
Visit 
2
Visit 3
Visit 4
Visit 5
Visit 6
( or Early 
Withdrawal)
Study Week (Visit Window）
0
4w±1
8w±1
12w±1
16w±1
20w±1
24w±1
Informed consent
x
Randomization/Allocation of clusters
x
Subject Demography
x
Medical history
x
Verification of inclusion/exclusion 
criteria
x
Efficacy Evaluation
Verification of withdrawal criteria
x
x
x
x
x
x
Issue diary record cards
x
x
x
x
x
x
Collect/Review diary record cards
x
x
x
x
x
x
Compliance assessment 
x
x
x
x
x
x
Asthma control Test (ACT) score
x
x
x
x
x
x
x
AQLQ(S)
x
x
Lung function Test
x
x
Safety Evaluation
Adverse event assessment1
x
x
x
x
x
x
x
1.
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.
Screening and Critical Baseline Assessments
Baseline Assessments
Demographic information
Gender
ethnic origin
date of birth, height
weight
education level 
smoking history
History of asthma including duration of asthma
History of asthma exacerbations in the 12 months prior to Visit 0
Concurrent medical conditions and concurrent medication
Medical history
Use of corticosteroids for asthma in the 12 
months prior to Visit 0
duration of inhaled corticosteroid treatment
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication will be assessed as related to the inclusion/exclusion criteria listed in 
Section 5.
7.3.
Efficacy
7.3.1.
Primary Endpoint (s)

The primary endpoint for the study is the percentage of subjects who have an ACT 
score ≥20 or an improvement of more than 3 points in ACT during the 24-week 
treatment period.
Asthma control test (ACT)
ACT is a self-administered questionnaire comprising five questions [Nathan, 2004]. Each 
of the five items in the ACT is assessed on a five point scale and the scores are summed 


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to give a total score ranging from 5 to 25, with a score of ≥20 denoting ‘well-controlled 
asthma’, a score of 16-19 denoting ‘not well-controlled asthma’, and a score of ≤ 15 
denoting ‘very poorly controlled asthma’. The recall period of the questionnaire is four 
weeks. ACT must be completed by the subject at each visit. For the control group, 
subjects should complete the ACT after investigator making the treatment decision.
Differences of 3 points in mean ACT scores between 2 groups or over time in an 
individual patient are clinically significant [Schatz, 2009]. An improvement of more 
than 3 points in ACT from baseline will also serve as primary endpoint.
The questionnaire will be attached separately.
7.3.2.
Secondary Endpoint (s)

Mean daytime symptom score over the 24-week treatment period

Mean night-time symptom score over the 24-week treatment period

Mean change from baseline to the end of study in FEV1 

Mean morning(AM) PEF over the 24-week treatment period

Mean evening(PM) PEF over the 24-week treatment period

Mean change from baseline to the end of study in AQLQ(S) score

Time to first ACT score ≥20 or improvement of more than 3 points in ACT over the 
24-week treatment period
Asthma symptom score
Subjects will be instructed to record daytime and night-time asthma symptom scores prior 
to taking the morning or evening dose of study medication or rescue medication. Any
asthma-related symptoms, such as wheeze, shortness of breath, cough or chest tightness
experienced during the previous 12 hours will be rated as follows. The following will be 
recorded on DRC.
Daytime symptom score
0 = No symptoms during the day


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1 = Symptoms for one short period during the day
2 = Symptoms for two or more short periods during the day
3 = Symptoms for most of the day which did not affect my daily activities
4 = Symptoms for most of the day which did affect my normal daily activities
5 = Symptoms so severe that I could not go to work or perform normal daily activities
Night-time symptom score

0 = No symptoms during the night

1 = Symptoms causing me to wake once or wake early

2 = Symptoms causing me to wake twice or more (including waking early)

3 = Symptoms causing me to be awake for most of the night

4 = Symptoms so severe that I did not sleep at all
FEV1
FEV1 will be measured at visit 0 and 6. Subjects should refrain from using short-acting 
bronchodilators for at least 6 hours prior to performing FEV1 measurements. The highest 
of three technically acceptable measurements of FEV1 will be taken.
Peak Expiratory Flow (PEF)
At Visit 0, the subject will be given a Mini-Wright Peak Flow Meter and taught how to 
measure and record their PEF. At each visit, the subjects’ ability to measure their PEF 
will be checked and, if the investigator has any concerns, the subject will be retrained. 
The instructions for use will be provided with each Peak Flow Meter. PEF should be 
measured while subject is in the sitting position.
Subjects should record on diary card the best of three PEF measurements, using a mini-
Wright peak flow meter in the morning (7:00-10:00 AM) and evening (6:00-9:00 PM) 
before taking any asthma drug. Bronchodilator therapy (e.g. salbutamol) is withheld, 
where possible, for 4 hours before recording PEF. Otherwise, the use of salbutamol will 
be recorded on diary card.
GSK will provide each centre with a supply of standard mini-Wright peak flow meters.


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Standardised Asthma Quality of Life Questionnaire (AQLQ(S))
The Asthma Quality of Life Questionnaire (AQLQ) is a self-administered questionnaire 
consisting of 32 questions to measure the functional problem that are most troublesome 
to patients with asthma [Juniper, 1992]. There are 32 questions in 4 domains (symptoms, 
activity limitation, emotional function and environmental stimuli). Patients are asked to 
think about how they have been during the previous two weeks and to respond to each of 
the 32 questions on a 7-point scale (7 = not impaired at all - 1 = severely impaired). A 
change in score of greater than 0.5 can be considered clinically important [Juniper, 1994]. 
In the present study, the AQLQ(S) will be used with 5 standardised activities to replace 
the patient-specific ones in the AQLQ. These five generic activities incorporate the 
activities that were most frequently chosen by patients in studies in which the original 
AQLQ was used; Strenuous activities, Moderate activities, Social activities, Work-related 
activities, and Sleeping [Juniper, 1999]. At visit 0 and 6, the investigator will provide 
each subject with the AQLQ(S).
The questionnaire will be attached separately.
ACT, AQLQ(S) and lung function test should be completed in sequence at Visit 0 and 6.
7.3.3.
Other Endpoint (s)

Rate of moderate/severe asthma exacerbation over the 24-week treatment period
Asthma Exacerbations
Subjects who experience worsening of symptoms should:

increase relief medication usage for relief of symptoms

contact the investigator or primary physician immediately and report to the 
clinic as soon as possible (ideally within 24 hours)

record their symptoms, PEF and relief medication usage in their DRC, as 
previously instructed


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
if intervention therapy is required during a treatment period, subjects may 
receive oral corticosteroids (40-60 mg prednisolone daily, or equivalent, 
for 10 days), over and above their usual asthma medication.
Exacerbations will be assessed by the physician at each scheduled visit by reviewing the
DRC, as well as specific questioning on adverse events (AEs).
Exacerbations will be defined based on one or more of the following characteristics:
Definition of asthma exacerbation(s)
Moderate
A moderate asthma exacerbation is defined as a deterioration in asthma requiring 
treatment with an oral corticosteroid.
Individual courses of oral corticosteroids are classified as separate exacerbations only if 
they are administered >1 week apart. Any course started within one week of finishing the 
previous course is considered part of the previous exacerbation.
Severe 
A severe asthma exacerbation is defined as a deterioration in asthma which requires 
hospital admission.
Time/date of resolution
Time/date at which the exacerbation has resolved, in the opinion of the investigator 
and/or subject.
Details of exacerbations must be collected in the Asthma Exacerbations page of the CRF 
and DRC as follows at the Visit immediately following the exacerbation:
Date of onset and resolution, daily morning PEF during the exacerbation; details of 
management of the exacerbation (e.g. clinic or emergency room visit, self-managed, 
hospital admission etc.); restriction/prevention from continuing usual activities. An 
exacerbation resulting in hospitalization will be recorded as a serious adverse event (SAE) 
in the Serious Adverse Event pages of the CRF. However, it is not only these 
exacerbations resulting in hospitalization which require collection as SAEs, but those that 
meet any of the definitions of Seriousness, listed in Section 7.4.


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7.3.4.
Guidance for Questionnaires Administration
All questionnaires in the study are self-administered. It is recommended that a subject 
completes all questionnaires before the physical examination and lung function. For the 
ACT guided group, the ACT should be completed first followed by the AQLQ (at visits 
during which the AQLQ is measured) and the treatment decision. The remaining 
assessments should be conducted after the AQLQ has been completed. This order should 
be used throughout the study. For the control group, the ACT must be completed after the 
treatment decision has been made, but the remaining assessments should be conducted in 
the same order as for the ACT guided group.
It is important that in the ACT guided group, the patients are blinded to the treatment 
decision to prevent any potential bias when the patients complete the AQLQ.
The following guidance is applicable to all questionnaires for the present study.
Subjects should be requested to perform the questionnaire as completely and accurately 
as possible. Regardless of when the questionnaire is completed, the subject should be 
given adequate time to complete all questions. No stated or implied time limit for 
completing the questionnaires should be given. The subject should be given a quiet area 
in which to complete the questionnaire.
If a subject has difficulty in completing the questionnaire, a third party (an investigator or 
study personnel) can help the subject to understand and answer the questions. If the 
subject should request help or clarification of any question in the questionnaire, the 
investigator or the study personnel is to instruct the subject to reread the instructions and 
to give the best answer possible to each question. The investigator or study personnel will 
not provide the subject with any possible answer to any question.
A subject may use a black or blue pen to complete the questionnaire. If the subject wishes 
to change a response, the original response should be crossed out with a single line, and 
then dated and initiated by the subject, as applicable and the alternative response should 
be marked. Once the subject returns the questionnaire to the investigator or the study 
personnel, no changes will be allowed except for incomplete items.


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After a subject has completed the questionnaire, the investigator may review the 
questionnaire for completeness. If any portion of the questionnaire is not complete, the 
subject should be given the opportunity to complete any missing items prior to the 
physician evaluation. The investigator or the study personnel is under no obligation to 
review or to validate the accuracy of the completed questionnaire.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 2.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.4.1.1.
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. 

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 2.


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
Once the investigator determines that an AE is identified as explicitly attributed to 
any GSK product (including products not covered in the specific study objective),
the adverse drug reactions (ADR) page should be completed and reported to GSK 
China within 5 calendar days. Any follow-up information on a previously reported 
ADR will also be reported to GSK China within 5 calendar days.

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 2.
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.4.1.3.
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 SAE will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost to 
follow-up (as defined in Section 5.3).


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7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 2 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV medical 
dictionary for regulatory activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.5.
Regulatory Reporting Requirements for SAEs and ADRs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
the use of any GSK products (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.


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7.4.2.
Pregnancy

Any pregnancy exposure to GSK products that is notified during study participation 
must be reported using a pregnancy notification form. To ensure subject safety, each 
pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. 
The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child. Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE. Spontaneous 
abortions must be reported as an SAE. 

In addition, the investigator must attempt to collect pregnancy information on any 
female partners of male study subjects who become pregnant while the subject is 
enrolled in the study. Pregnancy information must be reported to GSK as described 
above.
7.4.3.
Physical Exams

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and nose.
7.4.4.
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.
8.
DATA MANAGEMENT

For this study subject data will be collected using GSK defined CRFs and combined 
with data provided from other sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events will be coded using MedDRA and concomitant medications terms 
will be coded using the World Health Organisation (WHO) Drug system.


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
CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The null hypothesis for this study is that there is no difference between ACT guided 
treatment and usual care in the percentage of subjects who have an ACT score ≥20 or an 
improvement of more than 3 points in ACT during the 24-week treatment period for the 
intention-to-treat (ITT) population.
The alternative hypothesis for this study is that there is a difference between ACT guided 
treatment and usual care in the percentage of subjects who have an ACT score ≥20 or an 
improvement of more than 3 points in ACT during the 24-week treatment period for the
ITT population.
The study is designed to show superiority of ACT guided treatment over usual care.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The study will be powered to demonstrate superiority of ACT guided treatment over 
usual care from baseline over Week 24 in the primary endpoints.
We assume an intra-cluster correlation coefficient (ICC) of ρ=0.01, 29% well-control rate 
for usual care group, and 44% for ACT guided treatment group. It is required to have 6 
centres for each treatment group and a minimum of 35 subjects for each centre (a total of 
420 evaluable subjects) to achieve a power of 80% with two-sided α=0.05. We anticipate
a dropout rate of 20% and therefore planned to recruit 44 subjects in each centre (a total 
of 528 randomized subjects). These sample size calculations are produced based on
Donner [Donner, 1981].
An ACT score ≥20 indicates controlled asthma. The assumed rate of subjects with an 
ACT score ≥20 for usual care group is based on a nationwide epidemiologic survey in 


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China [Nan, 2013], which reported a 29% asthma control rate. The rate for ACT guided 
treatment is assumed based on GOAL study [Bateman, 2004], which reported a 80% rate 
for salmeterol/fluticasone group. An additional adjustment has been made to reduce it to 
44% to account for real life practice. A 15% difference between ACT guided treatment 
group and usual care group is considered clinically meaningful.
Study centres will be randomly assigned to the 2 groups using a computer generated 
randomization list. The randomization will be stratified according to the Tier of the 
hospitals (Tier 3 vs. Tier 2).
9.2.2.
Sample Size Sensitivity
The robustness and sensitivity of the sample size calculation has been considered in order 
to assess the impact on the power of the study should the observed well-control rates for
the primary endpoints be higher or lower than expected. Table 2 displays the estimated 
sample size and power for a variety of rates with other assumptions unchanged. 
Table 2
Sample Size and Power Calculation by Efficacy Rates
Well-control rate 
ACT guided 
treatment
Well-control rate 
usual care
Total sample size 
to achieve 80% 
power
Power if 528 
subjects are 
enrolled
40%
27%
680
69%
40%
29%
970
54%
40%
31%
1474
39%
44%
27%
404
89%
44%
29%
528
80%
44%
31%
718
67%
48%
27%
268
98%
48%
29%
332
94%
48%
31%
422
88%


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9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is currently planned for this study.  However, if during the 
course of the study, new information becomes available about clinically meaningful 
differences for the primary endpoints, a sample size re-estimation may be conducted.  
Full details of the procedure used would be specified in the reporting and analysis plan 
(RAP) and any subsequent change to the target sample size would be documented in a 
protocol amendment.
9.3.
Data Analysis Considerations
All statistical analyses will be conducted by GSK or its designee.
In general, descriptive statistics including the number of observations, mean, standard 
deviation (SD), median, minimum and maximum will be provided for continuous data, 
frequency counts and percentages will be used in tabulation for categorical variables. 
Unless specified otherwise, the percentage calculation will not take the missing values 
into account.
If not specified otherwise, all data will be summarized/listed as observed. Missing values 
will not be imputed.
All tests will be two-tailed, the general two-sided significance level will be α= 0.05.
A complete description of data handling rules and planned statistical analyses are
provided in a separate RAP. The RAP will be finalized before the database lock.
9.3.1.
Analysis Populations
Three populations are defined for this study.

Intent-to-Treat (ITT) Population: all subjects who signed informed consent form,
were randomised and who had at least one post-baseline assessment. The 
ITT population will be the primary population of interest.

Per Protocol (PP) Population: all subjects in the ITT population with no major 
protocol deviations and with ≥80% treatment compliance and diary compliance. The 
PP population will not be analyzed if this population comprises more than 95% or 


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less than 50% of the ITT population. Only the primary efficacy variables will be 
analyzed using the PP population.

Safety Population: all subjects who are enrolled into the study and who have at least 
one DRC assessment.
9.3.2.
Consideration on Missing Data Handling
Missing values will not be considered when calculating the ACT score for primary 
endpoint, symptom score and/or PEF over 24-week treatment period. If not specified 
otherwise, missing values will not be imputed.
9.3.3.
Interim Analysis
There are no interim analyses planned for this study.
9.4.
Key Elements of Analysis Plan
All hypothesis tests and confidence intervals will be two-sided. Except where otherwise 
stated, the estimation of treatment effect will be adjusted for the effects of centre, type of 
baseline controller (ICS alone vs. ICS/LABA), gender, and age. Centre, as the unit of 
randomization, will be treated as a random effect.
All efficacy measures over the course of the study will be presented and summarised in 
graphs and tables. Continuous data will be summarised by means, standard deviations, 
medians, minimum and maximum; categorical data will be summarised by counts and 
percentages.
All outcomes will be pertained to the individual participant’s level and the analysis model 
will be adjusted for the effect of centre (cluster).


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9.4.1.
Primary Analyses
The primary endpoints will be analyzed using logistic regression. The statistical model on 
which the inference will be based will include terms for treatment, centre, type of 
baseline controller (ICS alone vs. ICS/LABA), gender and age. Centre, as the unit of 
randomization, will be treated as a random effect. The results of the primary analyses will 
be presented as point estimates, 95% confidence intervals and associated p-values for the 
adjusted mean differences between ACT guided treatment and usual care.
Analyses of the primary endpoints will be performed on the ITT population and the PP 
population; the ITT population is considered primary.
9.4.2.
Secondary Analyses
All secondary endpoints will be confined to the ITT population.
Continuous efficacy endpoints will be analyzed using analysis of covariance (ANCOVA) 
and adjusted for centre as a random effect.  For daytime and night-time symptom score, 
the same method (ANCOVA adjusted by centre) will be used if the parametric model 
assumptions hold. The assumptions of normality and homogeneity of variance will be 
assessed by inspection of normal probability plots and residual plots. If these assumptions 
are not met, alternative methods (e.g., nonparametric methods) may be performed in 
order to assess the robustness of the conclusions from the primary analysis.
For time to event endpoint, stratified log-rank test and Cox regression analysis will be 
performed with centre, type of baseline controller (ICS alone vs. ICS/LABA), gender and 
age as the stratification factors. Kaplan-Meier methodology will be used to estimate
median time for each treatment arm. Kaplan-Meier curves will be constructed to provide 
a visual description of the difference between the two treatment arms.
9.4.3.
Other Analyses
Asthma exacerbation rate will be analyzed using logistic regression as described for the 
primary endpoints.
Interactions between treatment and each of the covariates will be investigated in turn, 
with all main effects in the model regardless of their statistical significance.  Any 


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interaction terms found to be statistically significant will be explored and if necessary 
results will be reported for each level of the covariate.  Investigation of interactions will 
be confined to the primary endpoints. The effect of interactions (e.g., treatment by centre) 
will be assessed at the 10% level of significance.
Adverse events
The number (%) of subjects in each treatment group with treatment emergent AEs will be 
produced.  Counts and percentages will also be presented of subjects with serious adverse 
events (SAEs), AEs leading to withdrawal, AEs by severity and AEs by relationship to 
study drug.
Other safety measures  
Reason for withdrawal will be summarised.
Summary statistics for vital signs evaluations at each visit will be presented by treatment 
group.  In addition, summary statistics for change from baseline for vital signs 
evaluations will be presented by treatment group.
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 Council for 
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:


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
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

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.


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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 multicentre 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 


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investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 


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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.
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
Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA, et al. Can 
guideline defined asthma control be achieved? Am J Respir Crit Care Med 2004; 170:836–
844.
Chapman K.R., Boulet L.P., Rea R.M., Franssen E.. Suboptimal asthma control: prevalence,
detection and consequences in general practice. Eur Respir J 2008; 31: 320–325
Donner A, Birkett N, Buck C. Randomization by cluster sample size requirements and 
analysis. Am. J. Epidemiol. 1981; 114 (6): 906-914.
Global Initiative for Asthma. GINA Report: global strategy for asthma management and 
prevention. www.ginasthma.com; 2013.
Juniper EF, Buist S, Cox F, Ferrie PJ, King DR. Validation of a standardized version of the 
Asthma Quality of Life Questionnaire. Chest 1999;115:1265-70.
Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of 
impairment of health related quality of life in asthma: development of a questionnaire for use 
in clinical trials. Thorax 1992;47(2):76-83. 
Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a 
disease-specific Quality of Life Questionnaire. J Clin Epidemiol 1994;47(1):81-7.
Nan Su, Jiangtao Lin, Ping Chen, Jing Li, Changgui Wu, Kaisheng Yin, et al. Evaluation of 
asthma control and patient’s perception of asthma: findings and analysis of a nationwide 
questionnaire-based survey in China. J Asthma, 2013; 50(8): 861–870
Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, et al. Development of the 
asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol 
2004;113(1):59-65.
Schatz M, Kosinski M, Yarlas AS, et al. The minimally important difference of the Asthma 
Control Test. J Allergy Clin Immunol 2009;124(4):719-23.


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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ACT
ADR
AE
ALT
ANCOVA
AQLQ
AQLQ(S) 
COPD
CRF 
CV
DRC 
ECG  
FEV1 
GCP 
GINA
GSK
IB
ICC
ICH
ICS 
IEC
INR
IRB
ITT 
LABA
Mg
mL
PEF 
PP
RAP
SAE 
SD
ULN
WHO
Asthma Control Test
Adverse Drug Reactions
Adverse Event
Alanine Transaminase
Analysis of Covariance
Asthma Quality of Life Questionnaire 
Standardised Asthma Quality of Life Questionnaire 
Chronic Obstructive Pulmonary Disease
Case Report Form
Cardiovascular
Daily Record Card
Electrocardiogram
Forced Expiratory Volume in one second
Good Clinical Practice
International Guidelines for Asthma Management
GlaxoSmithKline
Investigator Brochure
Intra-cluster Correlation Coefficient
International Council for Harmonisation
Inhaled Corticosteroid
Independent Ethics Committee
International Normalized Ratio
Institutional Review Board 
Intention-to-Treat
Long-acting β2 agonist
Milligram/s
Millilitre/s
Peak Expiratory Flow
Per Protocol
Reporting and Analysis Plan
Serious Adverse Event
Standard Deviation
Upper Limit of Normal
World Health Organisation


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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ACT
AQLQ(S)
Mini-Wright


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12.2.
Appendix 2 : Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.2.1.
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., Electrocardiograms (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).

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
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.


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
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.
12.2.2.
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 
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, 


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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:

Alanine Transaminase (ALT) 3x upper limit of normal (ULN) and total bilirubin*
2xULN (>35% direct), or

ALT 3xULN and International normalized ratio (INR)** >1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.2.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack


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
Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.2.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.2.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
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.


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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.
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.


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12.2.6.
Reporting of SAEs/ADR to GSK
SAE/ADR reporting to GSK via paper CRF

Facsimile transmission of the SAE/ADR paper CRF is the preferred method to 
transmit this information to the SAE/ADR coordinator

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE/ADR data collection tool sent by 
overnight mail

Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE/ADR CRF pages within the designated reporting time 
frames.

Contacts for SAE/ADR receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.3.
Appendix 3 - Country Specific Requirements
This requirement applies to China studies only.


CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which 
are protected by third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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12.5.
Appendix 
5: 
Standardised
Asthma 
Quality 
of 
Life
Questionnaire (AQLQ(S))
CCI - This section contained Clinical Outcome Assessment data collection 
questionnaires or indices, which are protected by third party copyright laws and 
therefore have been excluded.


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CCI - This section contained Clinical Outcome Assessment data collection 
questionnaires or indices, which are protected by third party copyright laws and 
therefore have been excluded.


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CCI - This section contained 
Clinical Outcome Assessment 
data collection questionnaires 
or indices, which are protected 
by third party copyright laws 
and therefore have been 
excluded.
CCI - This section contained 
Clinical Outcome Assessment 
data collection questionnaires 
or indices, which are 
protected by third party 
copyright laws and therefore 
have been excluded.
CCI

SAP_001.pdf: 
CONFIDENTIAL
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Reporting and Analysis Plan (RAP)
The effectiveness of Asthma Control Test guided 
treatment compared with usual care in China adult 
asthma patients
Version: 1.0
Date: 11Sep2019
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.


CONFIDENTIAL
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RAP SIGNATURE PAGE
Author
Date
11Sep2019
Research Statistician
MacroStat China
Approver
Date
11Sep2019
Senior Statistician
GSK, R&D, China
PPD
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..................................................................................................3
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................5
2.3.
Study Design ................................................................................................6
2.4.
Statistical Hypotheses / Statistical Analyses .................................................6
3.
PLANNED ANALYSES ............................................................................................7
3.1.
Interim Analyses ...........................................................................................7
3.2.
Final Analyses ..............................................................................................7
4.
ANALYSIS POPULATIONS .....................................................................................7
4.1.
Protocol Deviations.......................................................................................7
4.2.
Diary Compliance .........................................................................................8
4.3.
Treatment Compliance..................................................................................8
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.......................................................................................................8
5.1.
Study Treatment Display Descriptors............................................................8
5.2.
Baseline Definitions ......................................................................................9
5.3.
Multicentre Studies .......................................................................................9
5.4.
Examination of Covariates, Other Strata and Subgroups..............................9
5.5.
Multiple Comparisons and Multiplicity ...........................................................9
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................10
6.
STUDY POPULATION ANALYSES .......................................................................11
6.1.
Overview of Planned Study Population Analyses........................................11
7.
EFFICACY ANALYSES..........................................................................................11
7.1.
Primary Efficacy Analyses ..........................................................................11
7.1.1.
Endpoint / Variables.....................................................................11
7.1.2.
Primary Analysis Methods ...........................................................12
7.1.3.
Sensitivity and Supportive Analysis Methods...............................12
7.2.
Secondary Efficacy Analyses......................................................................15
7.2.1.
Endpoint / Variables.....................................................................15
7.2.2.
Analysis Methods.........................................................................15
7.3.
Exploratory Efficacy Analyses.....................................................................17
8.
SAFETY ANALYSES .............................................................................................19
8.1.
Adverse Events Analyses ...........................................................................19
8.2.
Adverse Events of Special Interest Analyses..............................................19
8.3.
Clinical Laboratory Analyses.......................................................................19
8.4.
Other Safety Analyses ................................................................................19
9.
REFERENCES.......................................................................................................20


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10. APPENDICES........................................................................................................21
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................21
10.2.
Appendix 2: Schedule of Activities ..............................................................22
10.2.1.
Protocol Defined Schedule of Events...........................................22
10.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................23
10.4.
Appendix 4: Derived and Transformed Data ...............................................24
10.4.1.
General........................................................................................24
10.5.
Appendix 5: Reporting Standards for Missing Data.....................................25
10.5.1.
Premature Withdrawals................................................................25
10.5.2.
Handling of Missing Data.............................................................25
10.5.2.1.
Handling of Missing and Partial Dates ........................25
10.6.
Appendix 6: Values of Potential Clinical Importance ...................................26
10.6.1.
Laboratory Values........................................................................26
10.6.2.
ECG.............................................................................................26
10.6.3.
Vital Signs....................................................................................26
10.7.
Appendix 7: Abbreviations & Trade Marks ..................................................27
10.7.1.
Abbreviations...............................................................................27
10.7.2.
Trademarks .................................................................................28
10.8.
Appendix 8: List of Data Displays ...............................................................29
10.8.1.
Data Display Numbering..............................................................29


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 201097.
Revision Chronology:
201097
27-Jun-2016
Original
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol, dated 27-Jun-2016. Some sensitivity and supportive analyses 
are added in the primary efficacy analysis in this RAP (See details in Section 7.1.3). 
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To compare the effectiveness of ACT 
guided treatment versus usual care in 
achieving asthma control

The percentage of subjects who have an
ACT total score ≥20 or an improvement of
more than 3 points in ACT total score in at least one post-
baseline assessment during the 24-week treatment 
period
Secondary Objectives
Secondary Endpoints

To compare the effectiveness of ACT
guided treatment versus usual care in
asthma subjects with respect to the
following parameters:
• Symptoms
• Forced Expiratory Volume in one   
   second (FEV1)
• Peak Expiratory Flow(PEF)
• The quality of life
• Time to asthma control

Mean daytime symptom score over the 24-week 
treatment period

Mean night-time symptom score over the
24-week treatment period

Mean change from baseline to the end of
study in FEV1

Mean morning(AM) PEF over the 24-
week treatment period

Mean evening(PM) PEF over the 24-
week treatment period

Mean change from baseline to the end of
study in Standardised Asthma Quality of
Life Questionnaire (AQLQ[S]) score

Time to first ACT total score ≥20 or
improvement of more than 3 points in
ACT over the 24-week treatment period

Time to first ACT total score ≥20 and
improvement of more than 3 points in 
ACT total score over the 24-week treatment 
period
Exploratory Objectives
Exploratory Endpoints

To compare the effectiveness of ACT 
guided treatment versus usual care in 
asthma exacerbation

Rate of moderate/severe asthma exacerbation over the 
24-week treatment period


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2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features

This is a prospective, multicentre, cluster-randomized, open-label study.
Dosing

Not Applicable
Time & 
Events

[Refer to Appendix 2: Schedule of Activities]
Treatment 
Assignment

In this cluster-randomization design, each study centre, considered as a cluster, will 
be randomized to either ACT guided treatment group or control group (usual care 
group).
Interim 
Analysis

No interim analysis is planned.
2.4.
Statistical Hypotheses / Statistical Analyses
The null hypothesis for this study is that there is no difference between ACT guided 
treatment and usual care in the percentage of subjects who have an ACT total score ≥20 
or an improvement of more than 3 points in ACT total score in at least one post-baseline 
assessment during the 24-week treatment period for the intention-to-treat (ITT) 
population. 
The alternative hypothesis for this study is that there is a difference between ACT guided 
treatment and usual care in the percentage of subjects who have an ACT total score ≥20
or an improvement of more than 3 points in ACT total score in at least one post-baseline 
assessment during the 24-week treatment period for the ITT population.
The study is designed to show superiority of ACT guided treatment over usual care.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
There are no interim analyses planned for this study.
3.2.
Final Analyses
The final planned analyses will be performed after all required database cleaning 
activities have been completed and final database release (DBR) and database freeze
(DBF) has been declared by Data Management.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Intent-To-Treat
(ITT)

All subjects who signed informed consent form, were 
randomised and who had at least one post-baseline 
assessment on primary endpoints, second endpoints, 
and/or exploratory endpoints. The ITT population will be 
the primary population of interest. 
Study Population 
Efficacy
Per-Protocol
(PP)

All subjects in the ITT population with no major protocol 
deviations and with ≥80% treatment compliance and 
diary compliance. The PP population will not be 
analyzed if this population comprises more than 95% or 
less than 50% of the ITT population. Only the primary 
efficacy variables will be analyzed using the PP 
population.
Efficacy
Safety

All subjects who are enrolled into the study and who 
have at least one DRC assessment.
Safety 
Refer to Appendix 8: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Important deviations, which result in exclusion from the analysis population, will also be 
summarised and listed. Protocol deviations will be tracked by the study team throughout 
the conduct of the study in accordance with the Protocol Deviation Management Plan
(refer to Appendix 1).
o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.


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A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
4.2.
Diary Compliance
Subjects’ diary compliance will be assessed by the records of diary cards. For the 
subjects to be included in the PP population, there should be at least ≥80% expected 
diary counts in the diary cards according to the visits they have completed.
4.3.
Treatment Compliance
Subjects’ treatment compliance will be calculated as follow:
Treatment 
compliance=
The number of days that the subjects take asthma drugs following the doctor’s advice will 
be captured in the diary cards. For the subjects to be included in the PP population, the 
treatment compliance should ≥80%.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
Continuous data will be summarized by treatment using descriptive statistics: number of 
subjects/observations (n), arithmetic mean values (Mean), median value (Median), 
standard deviation (SD), minimum value (Min), and maximum value (Max). Min and 
Max will be presented with the same number of decimal places as the raw data recorded 
in the database. Mean and Median will be presented using one more additional decimal 
place. SD will be presented with two more decimal places than the raw data recorded in 
the database. 
Categorical data will be summarized by treatment using frequencies and percentages. 
Counts and percentages will be presented for each category. Percentages will be 
presented to one decimal place. 
Statistical tests of treatment effects will be performed at a 2-sided significance level of 
0.05, unless otherwise stated. And all p-values will be rounded up to 3 decimal places.
5.1.
Study Treatment Display Descriptors
Code
Description
Order in TLF 
ACT
Asthma Control Test
1
UC
Usual Care
2


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Treatment comparisons will be displayed as follows using the descriptors as specified:
ACT vs UC.
5.2.
Baseline Definitions
For primary endpoint, baseline will be the measurements taken at visit 0. For secondary 
endpoints, baselines of FEV1 and AQLQ(S) will be the measurements taken at visit 0; for 
symptom score and PEF, baselines are unavailable since the data will be collected daily 
using diary cards from the first day of asthma treatment and baseline assessments before 
treatment will not be conducted.
Unless otherwise stated, if baseline data is missing, no derivation will be performed and 
baseline will be set to missing.
5.3.
Multicentre Studies
In this cluster-randomization design, each study centre, considered as a cluster, will be 
randomized to either ACT guided treatment group or control group (usual care group). 
The randomization will be stratified according to the hospital level (Tier 3 vs. Tier 2). 
The hospital level is determined in accordance with the uniform requirements of the 
government. A Tier 3 hospital is on a larger scale and provides superior medical care than 
a Tier 2 hospital. Centre, as the unit of randomization, will be treated as a random effect 
in generalized linear mixed model (GLMM) used to analyse primary endpoints.
5.4.
Examination of Covariates, Other Strata and Subgroups
The primary endpoints will be analysed using mixed effect logistic regression. In this 
study, generalized linear mixed model (GLMM) will be used to control for centre as a 
random effect since each centre is considered as a cluster in this cluster-randomization 
study. The statistical model on which the inference will be based will include terms for 
treatment, baseline ACT total score, baseline ACT total score squared, centre, type of 
baseline controller (inhaled corticosteroids [ICS] alone vs. ICS/long-acting β2 agonist 
[LABA]), gender and age. The primary endpoints will also be presented in the following 
subgroups: type of baseline controller (inhaled corticosteroids [ICS] alone vs. ICS/long-
acting β2 agonist [LABA]), gender and age (<50 years old vs. >=50 years old).
5.5.
Multiple Comparisons and Multiplicity
The primary comparison of interest is the comparison between ACT and usual care for 
the primary endpoint in the ITT population. Analyses of efficacy endpoints will not be 
subject to any multiplicity adjustment.


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5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
10.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
10.4
Appendix 4: Derived and Transformed Data
10.5
Appendix 5: Reporting Standards for Missing Data
10.6
Appendix 6: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the ITT population, unless otherwise 
specified.
Study population analyses including analyses of subject’s disposition, population, 
protocol deviations, demographic and baseline characteristics, subject’s smoking history, 
alcoholism history, drug abuse history, asthma history, asthma exacerbation history, 
medical history (coded by MedDRA version 21.0 or above), asthma medications, and 
concomitant medications (coded by WHODrug version Global Mar 2018 or above), will 
be summarized and listed. Details of the planned displays are presented in Appendix 8: 
List of Data Displays.
7.
EFFICACY ANALYSES
All hypothesis tests and confidence intervals will be two-sided. All efficacy measures 
over the course of the study will be presented and summarised. Continuous data will be 
summarised by means, standard deviations (SD), medians, minimum and maximum; 
categorical data will be summarised by counts and percentages. 
All outcomes will be pertained to the individual participant’s level and the analysis model 
will be adjusted for the effect of centre (cluster).
Unless otherwise specified, endpoints / variables defined in Section 7.1 and Section 7.2
will be summarised using descriptive statistics, graphically presented (where appropriate) 
and listed.
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The ACT is a validated self-administered questionnaire utilising 5 questions to assess 
asthma control during the past 4 weeks on a 5-point categorical scale (1 to 5).
The total score is calculated as the sum of the scores from all 5 questions, provided all 
scores are non-missing; if any individual scores are missing then the overall score will be 
set to missing.
The primary endpoint for the study is the percentage of subjects who have an ACT total 
score ≥20 or an improvement of more than 3 points in ACT total score in at least one 
post-baseline assessment during the 24-week treatment period.
The calculation of percentage will base on the subjects with at least one post-baseline 
ACT assessment.


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7.1.2.
Primary Analysis Methods
The primary endpoints will be analysed using mixed effect logistic regression. In this 
study, generalized linear mixed model (GLMM) will be used to control for centre as a 
random effect since each centre is considered as a cluster in this cluster-randomization 
study. The statistical model on which the inference will be based will include terms for 
treatment, baseline ACT total score, baseline ACT total score squared, centre, type of
baseline controller (ICS alone vs. ICS/LABA), gender and age. Centre, as the unit of
randomization, will be treated as a random effect. Type of baseline controller (ICS alone 
vs. ICS/LABA) derives from the current asthma medication record in visit 0. The results 
of the primary analyses will be presented as adjusted odds ratios, 2-sided 95% confidence 
intervals, and associated p-values comparing ACT guided treatment with usual care. The 
adjusted odds ratios and 95% confidence intervals will be presented by a forest plot.
The example SAS codes are as below:
proc glimmix data=input_data method=quad; 
class invsite rndgrp blcontrol gender; 
model response= rndgrp actbl actblsq blcontrol gender age /s 
dist=binomial oddsratio cl link=logit; 
random intercept/subject= invsite; 
lsmeans rndgrp /diff cl;
run;
where input_data is the name of the input dataset and response is the response variable. In 
terms of the covariates rndgrp, actbl, actblsq, blcontrol, gender and age are variables for 
randomised treatment code, baseline ACT total score, baseline ACT total score squared, 
type of baseline controller, gender and age respectively. For random effect, invsite is 
variable for centre.
Interactions between treatment and each of the covariates will be investigated in turn, 
with all main effects in the model regardless of their statistical significance. Any 
interaction terms found to be statistically significant will be explored and if necessary 
results will be reported for each level of the covariate. Investigation of interactions will 
be confined to the primary endpoints. The effect of interactions (e.g., treatment by centre) 
will be assessed at the 10% level of significance.
Analyses of the primary endpoints will be performed on the ITT population and the PP
population; the ITT population is considered primary. The PP population will not be 
analysed if this population comprises more than 95% or less than 50% of the ITT 
population. Only the primary efficacy variables will be analysed using the PP population.
7.1.3.
Sensitivity and Supportive Analysis Methods

The primary endpoint will be repeatedly analysed in the following subgroups, using 
the same method used in primary analysis method: 
Type of baseline controller (inhaled corticosteroids [ICS] alone vs. ICS/long-
acting β2 agonist [LABA])
Gender (male vs. female)
Age (<50 years old vs. >=50 years old)


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For subgroup analyses, the model will include all the covariates used in the primary 
analysis model except for the subgroup variable itself. Adjusted odds ratios and their 95% 
confidence intervals will be presented by a forest plot. These analyses will be performed 
for the ITT and PP populations.

A supportive analysis of the primary endpoint will be performed using Generalised 
Estimating Equations (GEEs) if the model can converge. 
All non-missing data from visits with scheduled ACT assessments (Weeks 4, 8, 12, 16, 
20 and 24) will be included and an unstructured working correlation matrix will be 
implemented. The model will include terms for treatment, baseline ACT total score, 
baseline ACT total score squared, age, gender, visit and treatment-by-visit interaction. 
The number and percentage of subjects with a response within each treatment group will 
be presented by visit, together with the adjusted odds ratios, 2-sided 95% confidence 
intervals, and associated p-values between ACT guided treatment and usual care. The
adjusted odds ratios and 95% confidence intervals will be presented by a forest plot.
The example SAS codes are as below:
proc genmod data= input_data descending;
class rndgrp gender visit subjid/ ref=first param=ref;
model response=rndgrp actbl actblsq blcontrol age gender visit 
rndgrp*visit/dist=bin;
repeated subject=subjid /within=visit type=un corrw;
estimate "Treatment effect at Visit 1" rndgrp 1 visit 0 0 0 0 0  
rndgrp*visit 0 0 0 0 0/exp;
estimate "Treatment effect at Visit 2" rndgrp 1 visit 0 0 0 0 0  
rndgrp*visit 1 0 0 0 0/exp;
estimate "Treatment effect at Visit 3" rndgrp 1 visit 0 0 0 0 0  
rndgrp*visit 0 1 0 0 0/exp;
estimate "Treatment effect at Visit 4" rndgrp 1 visit 0 0 0 0 0  
rndgrp*visit 0 0 1 0 0/exp;
estimate "Treatment effect at Visit 5" rndgrp 1 visit 0 0 0 0 0  
rndgrp*visit 0 0 0 1 0/exp;
estimate "Treatment effect at Visit 6" rndgrp 1 visit 0 0 0 0 0  
rndgrp*visit 0 0 0 0 1/exp;
run;
where input_data is the name of the input dataset and response is the response variable. In 
terms of the covariates rndgrp, actbl, actblsq, blcontrol, gender, age and visit are variables 
for randomised treatment code, baseline ACT total score, baseline ACT total score 
squared, type of baseline controller, gender, age and visit number, respectively. For 
repeated measures, visit is variable for visit number and subjid is variable for subject’s ID.
This analysis will be performed for the ITT and PP populations.

Percentage of subjects who have an ACT total score ≥20 and an improvement of 
more than 3 points in ACT total score.
The following endpoints will be analysed as sensitivity analyses.


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Percentage of subjects who have an ACT total score ≥20 and an improvement of 
more than 3 points in ACT total score at Week 12. Subjects with missing data at 
Week 12 will be set as non-responders.
Percentage of subjects who have an ACT total score ≥20 and an improvement of 
more than 3 points in ACT total score at Week 24. Subjects with missing data at 
Week 24 will be set as non-responders.
Percentage of subjects who have an ACT total score ≥20 and an improvement of 
more than 3 points in ACT total score at Weeks 16 and 20 and 24. Subjects with 
missing data at Weeks 16, 20 or 24 will be set as non-responders.
These endpoints will be analysed using the same model as defined for primary endpoint 
(GLMM). A supportive analysis will be conducted to analysis the percentage of subjects 
who have an ACT total score≥20 and an improvement of more than 3 points in ACT 
total score, using the same GEEs method as mentioned above. All non-missing data from 
visits with scheduled ACT assessments (Weeks 4, 8, 12, 16, 20 and 24) will be used.
These analyses will be performed for the ITT and PP populations.

Change from baseline in ACT total score in post-baseline visits.
A Mixed Model Repeated Measures (MMRM) will be used with covariates of treatment, 
baseline ACT total score, centre, type of baseline controller (ICS alone vs. ICS/LABA), 
gender, age, visit, treatment-by-visit interaction and treatment-by-baseline ACT total 
score, with centre as a random effect. The least squares (LS) mean and LS mean change 
from baseline for each treatment and the estimated LS mean change from baseline 
treatment difference will be presented at each visit together with the 95% confidence 
interval for the mean difference and P-value.
The example SAS codes are as below:
proc mixed data=input_data;
class invsite rndgrp visit subjid blcontrol gender;
model actchbl=rndgrp actbl blcontrol gender age visit rndgrp*visit 
rndgrp*actbl/ ddfm =kr;
random intercept/subject= invsite;
repeated visit / subject=subjid type=un;
lsmeans rndgrp*visit / cl diff e;
ods output lsmeans=lsmeans;
ods output diffs=diffs; 
run;
quit;
where input_data is the name of the input dataset and actchbl is change from baseline in 
ACT score. In terms of the covariates rndgrp, actbl, blcontrol, gender, age and visit are 
variables for randomised treatment code, baseline ACT total score, type of baseline 
controller, gender, age and visit number, respectively. For random effect, invsite is 
variable for centre. For repeated measures, visit is variable for visit number and subjid is 
variable for subject’s ID.


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This analysis will be performed for the ITT and PP populations.
7.2.
Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables

Mean daytime symptom score over the 24-week treatment period

Mean night-time symptom score over the 24-week treatment period

Mean change from baseline to the end of study in FEV1

Mean morning (AM) PEF over the 24-week treatment period

Mean evening (PM) PEF over the 24-week treatment period

Mean change from baseline to the end of study in AQLQ(S) score

Time to first ACT total score ≥20 or improvement of more than 3 points in ACT 
total score over the 24-week treatment period

Time to first ACT total score ≥20 and improvement of more than 3 points in 
ACT total score over the 24-week treatment period
7.2.2.
Analysis Methods
All secondary endpoints will be confined to the ITT population. The continuous efficacy 
endpoints will be summarized by mean, standard deviation (SD), median, minimum and 
maximum according to scheduled visits. Time to event endpoint will be summarized by 
median time, 95% confidence interval of median time, lower and upper quantiles and 
range.
Continuous efficacy endpoints will be analysed using analysis of covariance (ANCOVA) 
and adjusted for centre as a random effect. 
For mean daytime and night-time symptom score and mean morning and evening PEF,
the mean values will be based on the available data on the diary card over each visit 
assessment period. No imputations will be performed on missing data. The mean values 
will be considered missing if less than 14 days are recorded in each visit assessment 
period. A Mixed Model Repeated Measures (MMRM) will be used with covariates of 
treatment, centre, type of baseline controller (ICS vs. ICS/LABA), gender and age, with 
the centre as a random factor. The results will be presented as LS mean (SE), 95% 
confidence interval for LS mean, treatment difference, 95% confidence interval for 
treatment difference and P-value by visit.
The example SAS codes are as below:
proc mixed data=input_data;
class invsite rndgrp visit subjid blcontrol gender;
model endpoint=rndgrp actbl blcontrol gender age/ ddfm =kr;
random intercept/subject= invsite;
repeated visit / subject=subjid type=un;
lsmeans rndgrp*visit / cl diff e;
ods output lsmeans=lsmeans;
ods output diffs=diffs; 
run;
quit;


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where input_data is the name of the input dataset and endpoint is the endpoint variable. In 
terms of the covariates rndgrp, actbl, blcontrol, gender and age are variables for 
randomised treatment code, baseline ACT total score, type of baseline controller, gender 
and age respectively. For random effect, invsite is variable for centre. For repeated 
measures, visit is variable for visit number and subjid is variable for subject’s ID.
The AQLQ(S) contains 32 items in four domains: activity limitation (11 items), 
symptoms (12 items), emotional function (5 items) and environmental stimuli (4 items). 
The following items are included in each of the 4 domains:
•
Symptoms: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30
•
Activity Limitation: 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32
•
Emotional Function: 7, 13, 15, 21, 27
•
Environmental Stimuli: 9, 17, 23, 26
The response format consists of a seven-point scale where a value of 1 indicates “total 
impairment” and a value of 7 indicates “no impairment”. The total AQLQ(S) score is the 
mean of all 32 items in the questionnaire and each individual domain score is calculated
as the mean of the items within that domain. Hence, the total and domain scores are also 
each defined on a range from 1 to 7 with higher scores indicating a higher quality of life. 
For the total AQLQ(S) score, the score for a subject at any time point will only be 
calculated if at least 90% of the questions were answered (calculated as the mean of those 
non-missing questions). If fewer than 90% of the questions were answered then the mean 
score for that subject at that time point will be considered missing.
For each individual domain of the AQLQ(S) score, the score for a subject at any time 
point will only be calculated if at least 90% of the questions for that domain were 
answered (calculated as the mean of those non-missing questions). If fewer than 90% of 
the questions were answered for that domain then the mean score for that subject and 
domain at that time point will be considered missing.
The analysis of changing from baseline to the end of study in FEV1 and AQLQ(S) score 
will only include those who complete the study and change from baseline will be 
calculated as the difference between baseline visit and Visit 6.
For FEV1 and AQLQ(S) changing from baseline, a mixed model will be used with 
covariates of treatment, centre, type of baseline controller (ICS vs. ICS/LABA), gender 
and age, with the centre as a random factor. The results will be presented as LS mean 
(SE), 95% confidence interval for LS mean, treatment difference, 95% confidence 
interval for treatment difference
The example SAS codes are as below:
proc mixed data=input_data;
class invsite rndgrp blcontrol gender;


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model epchbl=rndgrp actbl blcontrol gender age/ ddfm =kr;
random intercept/subject= invsite;
lsmeans rndgrp/ cl diff e;
ods output lsmeans=lsmeans;
ods output diffs=diffs; 
run;
quit;
where input_data is the name of the input dataset and epchbl is the endpoint variable
changing from baseline. In terms of the covariates rndgrp, actbl, blcontrol, gender and 
age are variables for randomised treatment code, baseline ACT total score, type of
baseline controller, gender and age respectively. For random effect, invsite is variable for 
centre.
For time to event endpoint, Cox regression analysis will be performed with treatment, 
baseline ACT total score, centre, type of baseline controller (ICS alone vs. ICS/LABA), 
gender and age as the adjusted factors. The results will be presented as hazard ratio (SE), 
95% confidence interval and P-value. Log-rank test and Kaplan-Meier methodology will 
be used to estimate median time for each treatment arm. Kaplan-Meier curves will be 
constructed to provide a visual description of the difference between the two treatment 
arms.
The example SAS codes are as below:
proc phreg data=input_data;
class rndgrp actbl invsite blcontrol gender;
model timeto1*eventflag(0)= rndgrp actbl invsite blcontrol gender age / 
risklimits ties=exact;
hazardratio rndgrp/ diff=all;
run;
proc lifetest data=input_data outsurv=survest;
time timeto1*eventflag(0);
strata rndgrp;
run;
where input_data is the name of the input dataset, timeto1 is the variable for time to 
response and eventflag is the variable for sensor. In terms of the covariates rndgrp, actbl, 
invsite, blcontrol, gender and age are variables for randomised treatment code, baseline 
ACT total score, centre, type of baseline controller, gender and age respectively.
7.3.
Exploratory Efficacy Analyses
Moderate/severe asthma exacerbations will be summarized, including number of subjects 
with moderate/severe exacerbations, number of moderate/severe exacerbations and 
characteristics of moderate/severe exacerbations. Exacerbations separated by less than 7 
days will be treated as a continuation of the same exacerbation
The moderate/severe exacerbation rate will be analyzed using a generalized linear model, 
assuming the number of exacerbations has a negative binomial probability distribution 
and that its mean is related to covariate factors with a ‘log link’ function. The logarithm 
of time (year) on study will be used as an offset variable. All moderate/severe


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exacerbations observed during the study, with the onset date of event from date of
baseline visit to the end of study visit date or early withdrawal (from study) visit date, 
will be included in the analysis. Missing data due to early withdrawal from the study will 
not be imputed. The model will include covariates for treatment, baseline ACT total 
score, type of baseline controller (ICS alone vs. ICS/LABA), gender and age. The annual 
moderate/severe exacerbation rates and 95% confidence interval for each treatment will be 
presented. The rate ratio and 95% confidence interval, percent reduction in rate and 95% 
confidence interval and P value will also be presented.
The example SAS codes are as below:
proc genmod data= input_data;
    class rndgrp blcontrol gender;
    model no_exac = rndgrp actbl blcontrol gender age / dist=negbin   
link=log offset=logtime wald type3;
    lsmeans rndgrp / cl diff OM exp;
run;
where input_data is the name of the input dataset and no_exac is the number of 
moderate/severe asthma exacerbations per subject during the study. In terms of the 
covariates rndgrp, actbl, blcontrol, gender and age are variables for randomised treatment 
code, baseline ACT total score, type of baseline controller, gender and age respectively. 
For offset, logtime is logarithm of time (year) on study.


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8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
8.1.
Adverse Events Analyses
The number (%) of subjects in each treatment group with treatment emergent AEs will be 
produced. Counts and percentages will also be presented of subjects with serious adverse 
events (SAEs), AEs leading to withdrawal, AEs by severity, AEs by relationship to study 
procedure/study drug, asthma exacerbation and death.
Adverse events will be coded by MedDRA version 21.0 or above. Adverse events will be 
summarized and presented by system organ class (SOC) and preferred term (PT) by 
treatment group. Adverse events analyses including the analysis of AEs, SAEs, non-
serious AE and other significant AEs will be summarized. All AEs and SAEs will be 
listed. The details of the planned displays are provided in Appendix 8: List of Data 
Displays.
8.2.
Adverse Events of Special Interest Analyses
Except for study indication Asthma, there is no other adverse event of special interest.
8.3.
Clinical Laboratory Analyses
Clinical laboratory data is not collected and analysed in this study.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including vital signs and physical 
examination will be summarized and listed by descriptive statistics. The details of the 
planned displays are presented in Appendix 8 List of Data Displays.


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9.
REFERENCES
Zhu, Sammy; Liu, Lian. 3.1 Clinical Study Protocol_201097_20160627_ EN,2016
Zhu, Sammy; Liu, Lian. 3.2 Clinical Study Protocol _201097_20160627_CN,2016


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10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Refer document “PDMP201097  final.docx”


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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
ACTIVITY 
Visit 
Visit 
Visit 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
0 
1 
2 
( or Early 
Withdrawal) 
Study Week (Visit Window）
0 
4w± 
1 
8w± 
1 
12w± 
1 
16w± 
1 
20w± 
1 
24w± 1 
Informed consent 
x 
Randomization/Allocation of 
clusters 
x 
Subject Demography 
x 
Medical history 
x 
Verification of 
inclusion/exclusion 
x 
criteria 
Efficacy Evaluation 
Verification of withdrawal 
criteria 
x 
x 
x 
x 
x 
x
Issue diary record cards 
x 
x 
x 
x 
x 
x 
Collect/Review diary record 
cards 
x 
x 
x 
x 
x 
x 
Compliance assessment 
x 
x 
x 
x 
x 
x 
Asthma control Test (ACT) 
score 
x 
x 
x 
x 
x 
x 
x 
AQLQ(S) 
x 
x 
Lung function Test 
x 
x 
Safety Evaluation 
Adverse event assessment1
x 
x 
x 
x 
x 
x 
x
1. 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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10.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
Assessments and events will not be classified by study phase. All the adverse events and 
concomitant medications are collected during the study as treatment emergent adverse 
events.


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10.4.
Appendix 4: Derived and Transformed Data
10.4.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Not Applicable.


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10.5.
Appendix 5: Reporting Standards for Missing Data
10.5.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as who has 
completed all visits of the study.

Withdrawn subjects were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be slotted as per Appendix 2: Schedule of Activities or will be 
summarised as withdrawal visits.
10.5.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:

These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 

Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.5.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

Completely missing start or end dates will remain missing, with no imputation applied. 

Also no imputation applied for Partial dates.

The recorded partial date will be displayed in listings.
Concomitant 
Medications/
Medical 
History

Completely missing start or end dates will remain missing, with no imputation applied. 

Also no imputation applied for Partial dates.

The recorded partial date will be displayed in listings.


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10.6.
Appendix 6: Values of Potential Clinical Importance
10.6.1.
Laboratory Values
Laboratory values are not collected in this study.
10.6.2.
ECG
ECG values are not collected in this study.
10.6.3.
Vital Signs
Vital Signs Values are only collected at Visit 0 as baseline characteristics, will be listed 
and summarized by descriptive statistics, normal range and clinical concern range will 
not be collected and summarized.


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10.7.
Appendix 7: Abbreviations & Trade Marks
10.7.1.
Abbreviations
Abbreviation
Description
ACT
Asthma Control Test
AE
Adverse Event
ANCOVA
Analysis of Covariance
AQLQ
Asthma Quality of Life Questionnaire
AQLQ(S)
Standardised Asthma Quality of Life Questionnaire
CRF
Case Report Form
DRC
Daily Record Card
ECG
Electrocardiogram
FEV1
Forced Expiratory Volume in one second
GINA
International Guidelines for Asthma Management
GSK
GlaxoSmithKline
ITT
Intention-to-Treat
LABA
Long-acting β2 agonist
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram/s
mL
Millilitre/s
PEF
Peak Expiratory Flow
PP
Per Protocol
PT
Preferred Term
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SOC
System Organ Class
SD
Standard Deviation


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Abbreviation
Description
WHO
World Health Organisation
10.7.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ACT
AQLQ(S)
MedDRA
SAS
WHODrug


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10.8.
Appendix 8: List of Data Displays
10.8.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Listings
Study Population
1.01 to 1.09
1.01 to 1.10
Efficacy
2.01 to 2.28
16
2.01 to 2.04
Safety
3.01 to 3.11
3.01 to 3.03
For Details of Mock Shells for Data Displays, please refer document 
“C_012_RESP_201097_TFL Template_Mock-ups.doc”.