Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3850
Healthy volunteers: no

Brief summary:
The purpose of this study is to test if Symbicort® (budesonide/formoterol) Turbuhaler® is effective in treating asthma when used 'as needed' in patients with milder asthma. The efficacy of Symbicort® 'as needed' will be compared with: 1) terbutaline Turbuhaler® 'as needed' and with 2) Pulmicort (budesonide) Turbuhaler® twice daily plus terbutaline Turbuhaler® 'as needed'.

Detailed description:
A 52-week, double-blind, randomised, multi-centre, parallel-group, Phase III study in patients 12 years and older with asthma, evaluating the efficacy and safety of Symbicort® (budesonide/formoterol) Turbuhaler® 160/4.5 μg 'as needed' compared with terbutaline Turbuhaler® 0.4 mg 'as needed' and with Pulmicort® (budesonide) Turbuhaler® 200 μg twice daily plus terbutaline Turbuhaler® 0.4 mg 'as needed'

Arms:
arm 1: Symbicort (budesonide/formoterol) Turbuhaler 160/4.5 μg 'as needed' + Placebo Pulmicort Turbuhaler 200 μg bid arm 2: terbutaline Turbuhaler 0.4 mg 'as needed' + placebo Pulmicort 200 μg Turbuhaler bid arm 3: Pulmicort 200 μg Turbuhaler bid + terbutaline 0.4 mg Turbuhaler 'as needed'

Interventions: intervention 1: budesonide/formoterol 'as needed' + budesonide placebo bid intervention 2: terbutaline 'as needed' + placebo budesonide bid intervention 3: budesonide bid + terbutaline 'as needed'
Intervention descriptions: intervention 1: Symbicort (budesonide/ formoterol) 160/4.5 μg powder for inhalation 'as needed' plus Pulmicort placebo 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening), 52-week treatment intervention 2: Terbutaline 0.4 mg powder for inhalation 'as needed' plus placebo Pulmicort (budesonide) 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening), 52-week treatment intervention 3: Pulmicort (budesonide) 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening) plus terbutaline 0.4 mg powder for inhalation 'as needed', 52-week treatment

Protocol document:
Prot_002.pdf: 


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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PROTOCOL SYNOPSIS
A 52-week, double-blind, randomised, multi-centre, parallel-group,
Phase III study in patients 12 years and older with asthma, evaluating the 
efficacy and safety of Symbicort® (budesonide/formoterol) Turbuhaler®
160/4.5 μg ‘as needed’ compared with terbutaline Turbuhaler® 0.4 mg ‘as 
needed’ and with Pulmicort® (budesonide) Turbuhaler® 200 μg twice daily 
plus terbutaline Turbuhaler® 0.4 mg ‘as needed’
International Co-ordinating Investigator
Paul M. O’Byrne MB, FRCPC, FRSC
 Canada
Study site(s) and number of patients planned
This study will recruit patients worldwide at approximately 265 sites.  The target is to 
randomise 3750 male and female patients.
Study period
Phase of development
Estimated date of first patient enrolled
QII 2014
III
Estimated date of last patient completed
QIII 2017
Study design
This is a 52-week, double-blind, randomised, multi-centre, parallel-group, Phase III study in 
patients 12 years and older with asthma, evaluating the efficacy and safety of Symbicort®
(budesonide/formoterol) Turbuhaler® 160/4.5 μg ‘as needed’ compared with terbutaline 
Turbuhaler® 0.4 mg ‘as needed’ and with Pulmicort® (budesonide) Turbuhaler® 200 μg twice 
daily plus terbutaline Turbuhaler® 0.4 mg ‘as needed’.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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Objectives
Primary Objective:
Outcome Measure:
To demonstrate that Symbicort Turbuhaler 
160/4.5 μg ‘as needed’ is superior to 
terbutaline Turbuhaler 0.4 mg ‘as needed’
Evaluation of asthma control as measured by well-
controlled asthma weeks as the primary variable
Secondary Objectives:
Outcome Measure:
To evaluate the relative efficacy of Symbicort 
Turbuhaler 160/4.5 μg ‘as needed’ and 
Pulmicort Turbuhaler 200 μg twice daily plus 
terbutaline Turbuhaler 0.4 mg ‘as needed’
Evaluation of asthma control as measured by well-
controlled asthma weeks as the primary variable
To evaluate the efficacy of Symbicort 
Turbuhaler 160/4.5 μg as compared to both:
terbutaline Turbuhaler 0.4 mg ‘as needed’
And:
Pulmicort Turbuhaler 200 μg twice daily plus 
terbutaline Turbuhaler 0.4 mg ‘as needed’
Secondary variables:
Time to first severe asthma exacerbation
Time to first moderate or severe asthma exacerbation
Average change from baseline in pre-dose Forced 
Expiratory Volume in one second
Average change from baseline in Morning Peak 
Expiratory Flow
Average change from baseline in Evening Peak 
Expiratory Flow
Average change from baseline in number of 
inhalations of ‘as needed’ medication
Average change from baseline in symptom score
Percentage of Nighttime awakenings due to asthma
Percentage of Symptom-free days
Percentage of ‘As needed’ free days
Percentage of Asthma control days
Percentage of controller use days
Time to asthma related discontinuation
Poorly controlled asthma weeks
Time to additional steroids for asthma
Average change from baseline in Asthma Control 
Questionnaire 5-item version
Average change from baseline in Asthma Quality of 
Life Questionnaire standard version 


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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Safety Objective:
Outcome Measure :
To compare the safety of Symbicort 
Turbuhaler 160/4.5 μg ‘as needed’ with that of 
terbutaline Turbuhaler 0.4 mg ‘as needed’, and 
with that of Pulmicort Turbuhaler 200 μg twice 
daily plus terbutaline Turbuhaler 0.4 mg ‘as 
needed’
Adverse events (nature, incidence and severity); 
pulse, blood pressure and physical examination
Target patient population
The target population includes male and female patients who are ≥12 years old and who have 
a documented clinical diagnosis of asthma for at least 6 months prior to Visit 1.  Patients who 
are either uncontrolled on inhaled short acting bronchodilator(s)‘as needed’ (short acting β2 
agonist and/or short acting anticholinergic agent) or who are controlled on mono-maintenance 
therapy with either a low stable dose of an inhaled glucocorticosteroid or a leukotriene 
receptor antagonist in addition to 'as needed' use of inhaled short-acting bronchodilator (short 
acting β2 agonist and/or short acting anticholinergic agent) for the last 30 days before Visit 2 
will be eligible for the study.
The patients should have reversible airway obstruction.  Patients should have used short acting 
β2 agonist on at least 3 separate days during the last week of the run-in period.
Duration of treatment
This study starts with an enrolment visit (Visit 1) where informed consent is obtained and 
inclusion and exclusion criteria are reviewed.  At Visit 2 patients will enter a 2-4 week run-in 
period during which all of them will be treated with a short acting β2 agonist (Bricanyl) ‘as 
needed’ only.  Eligible patients will be randomised at Visit 3 and enter a 52-week double-
blind treatment period.  Two weeks after the completion of study treatment a follow-up 
telephone contact will be performed. The total expected duration of the study for a patient will 
be 56-59 weeks.
Investigational product, dosage and mode of administration
Symbicort Turbuhaler® 160/4.5 μg (budesonide 160 μg and formoterol fumarate dihydrate 4.5 
μg per inhalation, powder for inhalation in a dry powder inhaler) used ‘as needed’ (to relieve 
asthma symptoms) in addition to Placebo for budesonide (powder for inhalation in a dry 
powder inhaler matching the Pulmicort Turbuhaler®) administered two times daily
Comparators, dosage and mode of administration
Terbutaline Turbuhaler® 0.4 mg (terbutaline sulphate 0.4 mg per inhalation, powder for 
inhalation in a dry powder inhaler) used ‘as needed’ (to relieve asthma symptoms) in addition 
to Placebo for budesonide (powder for inhalation in a dry powder inhaler matching the 
Pulmicort Turbuhaler®) administered two times daily


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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Terbutaline Turbuhaler® 0.4 mg (terbutaline sulphate 0.4 mg per inhalation, powder for 
inhalation in a dry powder inhaler) used ‘as needed’ (to relieve asthma symptoms) in addition
to Pulmicort Turbuhaler® 200 μg (budesonide 200 μg per inhalation, powder for inhalation in 
a dry powder inhaler) administered two times daily
Non-investigational medicinal product, dosage and mode of administration
Bricanyl Turbuhaler® 0.5 mg (terbutaline sulphate 0.5 mg per inhalation, powder for 
inhalation in a dry powder inhaler) - used ‘as needed’ during the run-in period and as a 
bronchodilator for the lung function measurements
Statistical methods
Analysis of the primary variable:
The primary variable ‘well-controlled asthma weeks’ (binary) will be analysed by a repeated 
measures logistic regression.  The analysis will be based on the efficacy analysis set which 
includes all randomised patients receiving any investigational product, irrespective of their 
protocol adherence and continued participation in the study.  The planned treatment 
comparisons are:
1.
Symbicort versus terbutaline (superiority, primary objective)
2.
Symbicort versus Pulmicort plus terbutaline (non-inferiority)
Formally, the null and alternative hypothesis for comparison 1 is:
H0: odds-ratio (Symbicort vs terbutaline) = 1
HA: odds-ratio (Symbicort vs terbutaline) ≠ 1
And for comparison 2:
H0: lower 95% confidence limit of odds-ratio (Symbicort vs Pulmicort plus 
terbutaline) < 0.8
HA: lower 95% confidence limit of odds-ratio (Symbicort vs Pulmicort plus 
terbutaline) ≥ 0.8
Analysis of the secondary variables:
For all secondary variables stated below the following treatment comparisons will be made:
1.
Symbicort versus terbutaline
2.
Symbicort versus Pulmicort plus terbutaline
Time to first moderate-to-severe asthma exacerbation, time to first severe asthma 
exacerbation, time to the administration of additional steroids for asthma, and time to study 


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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discontinuation due to asthma related events will be analysed by a Cox proportional hazards 
model.
Forced Expiratory Volume in one second, Asthma Control Questionnaire 5 item version and 
Asthma Quality of Life Questionnaire (Standardised Version) will be analysed by a mixed 
model repeated measures analysis model.
The change from baseline in morning- and evening Peak Expiratory Flow, asthma symptom
score, use of ‘as needed’ medication, awakening(s) due to asthma symptoms, symptom-free
days, asthma-control days, ‘as needed’- free days and the percentage of controller use days 
will be analysed by analysis of covariance.
Poorly controlled asthma weeks will be analysed in the same way as well controlled asthma 
weeks.
The total inhaled steroid load and the number of days with systemic glucocorticoids, 
respectively, will be presented descriptively by treatment.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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TABLE OF CONTENTS
PAGE
PROTOCOL SYNOPSIS.........................................................................................3
TABLE OF CONTENTS.........................................................................................8
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................13
1.
INTRODUCTION .................................................................................................15
1.1
Background and rationale for conducting this study .............................................15
1.2
Rationale for study design, doses and control groups............................................16
1.3
Benefit/risk and ethical assessment........................................................................17
1.4
Study Design..........................................................................................................18
2.
STUDY OBJECTIVES..........................................................................................19
2.1
Primary objective...................................................................................................19
2.2
Secondary objective...............................................................................................19
2.3
Safety objective......................................................................................................20
2.4
Exploratory objectives ...........................................................................................20
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................20
3.1
Inclusion criteria ....................................................................................................21
3.2
Exclusion criteria ...................................................................................................22
3.3
Patient enrolment and randomisation.....................................................................23
3.4
Procedures for handling incorrectly enrolled or randomised patients ...................24
3.5
Methods for assigning treatment groups................................................................24
3.6
Methods for ensuring blinding...............................................................................24
3.7
Methods for unblinding..........................................................................................25
3.8
Restrictions ............................................................................................................25
3.9
Discontinuation of investigational product............................................................25
3.9.1
Procedures for discontinuation of a patient from investigational product.............26
3.9.2
Enrolment failures..................................................................................................26
3.9.3
Withdrawal of the informed consent......................................................................27
3.10
Discontinuation of the study..................................................................................27
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................28


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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4.1
Enrolment and run-in periods ................................................................................31
4.1.1
Enrolment procedures at Visit 1 ............................................................................31
4.1.2
Run-in procedures at Visit 2 ..................................................................................31
4.2
Treatment period....................................................................................................32
4.3
Follow-up period....................................................................................................32
5.
STUDY ASSESSMENTS .....................................................................................32
5.1
Efficacy assessments..............................................................................................33
5.1.1
Asthma exacerbations ............................................................................................33
5.1.2
Lung function measurement by spirometry (FEV1, FVC) at the study site ..........34
5.1.2.1
Pre-bronchodilator and post-bronchodilator FEV1 and FVC including 
reversibility testing and calculation of predicted normal values (PN)...................36
5.1.2.2
Reversibility test ....................................................................................................36
5.1.3
Recorded electronic diary variables.......................................................................37
5.1.4
Triggers of patient alerts in the eDiary ..................................................................38
5.1.5
Asthma Control Questionnaire (5-item Version)...................................................39
5.1.6
Asthma Quality of Life Questionnaire (Standardised Version).............................39
5.1.7
Administration of patient reported outcome questionnaires..................................40
5.1.8
Turbuhaler Usage Monitor (TUM) ........................................................................40
5.2
Safety assessments.................................................................................................40
5.2.1
Physical examination .............................................................................................40
5.2.2
Vital signs ..............................................................................................................41
5.2.2.1
Pulse and blood pressure........................................................................................41
5.3
Other Assessments.................................................................................................41
5.3.1
Qualitative Sub-study.............................................................................................41
5.4
Pharmacokinetics ...................................................................................................41
5.5
Pharmacodynamics ................................................................................................41
5.6
Pharmacogenetics ..................................................................................................41
5.7
Biomarker analysis.................................................................................................41
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................41
6.1
Definition of adverse events ..................................................................................42
6.2
Definitions of serious adverse event......................................................................42
6.3
Recording of adverse events ..................................................................................42
6.3.1
Time period for collection of adverse events.........................................................42
6.3.2
Follow-up of unresolved adverse events................................................................42
6.3.3
Symptoms of the disease under study....................................................................43
6.3.4
Variables ................................................................................................................43
6.3.5
Causality collection................................................................................................44
6.3.6
Adverse events based on signs and symptoms.......................................................45
6.3.7
Adverse events based on examinations..................................................................45


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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6.3.8
Hy’s Law................................................................................................................45
6.4
Reporting of serious adverse events.......................................................................45
6.5
Overdose ................................................................................................................46
6.6
Pregnancy...............................................................................................................47
6.6.1
Maternal exposure..................................................................................................47
6.6.2
Paternal exposure...................................................................................................48
6.7
Management of IP related toxicities ......................................................................48
6.8
Study governance and oversight ............................................................................48
6.8.1
Independent adjudication committee for fatal events ............................................48
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................49
7.1
Identity of investigational product(s).....................................................................49
7.1.1
Non-investigational medicinal product for run-in and for post-
bronchodilator lung function measurements..........................................................49
7.2
Dose and treatment regimens.................................................................................50
7.3
Labelling ................................................................................................................51
7.4
Storage ...................................................................................................................51
7.5
Compliance ............................................................................................................51
7.6
Accountability........................................................................................................51
7.7
Concomitant and other treatments .........................................................................52
7.7.1
Prohibited Medication............................................................................................52
7.7.2
Concomitant asthma treatment ..............................................................................53
7.7.2.1
Prescribed inhaled budesonide 200 μg BID...........................................................54
7.7.3
Other concomitant treatment..................................................................................54
7.8
Post Study Access to Study Treatment ..................................................................54
8.
STATISTICAL ANALYSES BY ASTRAZENECA............................................54
8.1
Statistical considerations........................................................................................54
8.2
Sample size estimate..............................................................................................54
8.3
Definitions of analysis sets ....................................................................................56
8.3.1
Full analysis set......................................................................................................56
8.3.2
All patients analysis set..........................................................................................56
8.3.3
Safety analysis set..................................................................................................56
8.4
Outcome measures for analyses.............................................................................56
8.4.1
Derivation of efficacy variables.............................................................................56
8.4.1.1
Derivation of well-controlled asthma weeks (primary variable) ...........................56
8.4.1.2
Derivation of time to first moderate, severe and moderate-to-severe asthma 
exacerbation ...........................................................................................................57


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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8.4.1.3
Derivation of the number of moderate, severe and moderate-to-severe 
asthma exacerbations .............................................................................................57
8.4.1.4
Derivation of time to administration of additional steroids for asthma.................58
8.4.1.5
Derivation of total inhaled steroid load and number of days with systemic 
GCS treatment........................................................................................................58
8.4.1.6
Derivation of controller use days...........................................................................58
8.4.1.7
Derivation of time to asthma related discontinuation............................................59
8.4.1.8
Derivation of lung function variables ....................................................................59
8.4.1.9
Derivation of electronic diary variables.................................................................59
8.4.2
Derivation of patient reported outcome variables..................................................61
8.4.2.1
Derivation of ACQ-5 .............................................................................................61
8.4.2.2
Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) .........................61
8.4.3
Derivation of safety variables ................................................................................62
8.4.3.1
Vital signs ..............................................................................................................62
8.4.3.2
Other significant adverse events (OAE) ................................................................62
8.5
Methods for statistical analyses .............................................................................62
8.5.1
Analysis of the primary variable............................................................................62
8.5.2
Analysis of the secondary variables.......................................................................63
8.5.3
Subgroup analysis ..................................................................................................65
8.5.4
Sensitivity analysis.................................................................................................65
8.5.5
Analysis methods for safety variables ...................................................................66
8.5.6
Analysis methods for exploratory variables ..........................................................66
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ..........................66
9.1
Training of study site personnel.............................................................................66
9.2
Monitoring of the study .........................................................................................66
9.2.1
Source data.............................................................................................................67
9.2.2
Study agreements...................................................................................................67
9.2.3
Archiving of study documents...............................................................................67
9.3
Study timetable and end of study...........................................................................67
9.4
Data management by Cognizant Data Management Centre..................................67
10.
ETHICAL AND REGULATORY REQUIREMENTS.........................................68
10.1
Ethical conduct of the study...................................................................................68
10.2
Patient data protection............................................................................................68
10.3
Ethics and regulatory review..................................................................................68
10.4
Informed consent ...................................................................................................69
10.5
Changes to the protocol and informed consent form.............................................70
10.6
Audits and inspections ...........................................................................................70
11.
LIST OF REFERENCES.......................................................................................70


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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LIST OF TABLES
Table 1
Study Plan detailing the procedures .........................................................28
Table 2
Medications which may affect the reversibility test at Visit 2 
and/or  at Visit 3 .......................................................................................52
Table 3
Medications Not Allowed from Visit 2 to Visit 8 ....................................53
LIST OF FIGURES
Figure 1
Study Flow Chart......................................................................................18
LIST OF APPENDICES
Appendix A
Signatures
Appendix B
Additional Safety Information
Appendix C
Asthma Control Questionnaire (5-item Version)
Appendix D
Asthma Quality of Life Questionnaire (Standard Version)
Appendix E
Inhaled Glucocorticosteroid Equivalence Table
Appendix F
Sub-study with Qualitative Interviews


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ACQ
Asthma Control Questionnaire (5-item Version)
AE
Adverse Event (See definition in Section 6.1)
‘As needed’
Administered as needed in response to symptoms; similar to reliever or 
rescue medication
AQLQ(S)
Asthma Quality of Life Questionnaire (Standardised Version)
BID
Twice daily
CI
Confidence Interval
CHMP
Committee for Medicinal Products for Human Use (formerly: Committee 
for Proprietary Medicinal Products)
(e)CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
CSR
Clinical Study Report
DAE
Discontinuation of Investigational Product due to Adverse Event
DMC
Data Management Centre
DPI
Dry Powder Inhaler
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
eDiary
Electronic Patient Diary
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCS
Glucocorticosteroid
GINA
Global Initiative for Asthma (GINA). Strategy for Asthma Management 
and Prevention 2012.
GRand
AstraZeneca Global Randomisation System
HRA
Health Research Associates
ICH
International Conference on Harmonisation
ICS
Inhaled corticosteroid


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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Abbreviation or 
special term
Explanation
International 
Co-ordinating 
Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally.
IP
Investigational Product
ISF
Investigator Study File
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
L
Litre
LABA
Long-acting β2 agonist
LTRA
Leukotriene Receptor Antagonist
MID
Minimal Important Difference
MMRM
Mixed Model Repeated Measures
mL
Millilitre
OAE
Other Significant Adverse Event 
PEF
Peak Expiratory Flow
PI
Principal Investigator
PN
Predicted Normal
SABA
Short-acting β2 agonist
SAE
Serious Adverse Event (see definition in Section 6.2)
SAP
Statistical Analysis Plan
TUM
Turbuhaler Usage Monitor
VC
Vital Capacity
vs
Versus
WBDC
Web Based Data Capture
WCAW
Well Controlled Asthma Weeks


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Asthma is a respiratory disease characterized by chronic inflammation and obstruction of the 
airways that vary over time.  The main aim of asthma management is to achieve and maintain 
asthma control.  For this purpose a stepwise treatment approach increasing in intensity, is 
recommended (GINA 2012).  Using a rapid acting β2-agonist, commonly salbutamol or 
terbutaline, on an as-needed basis in response to symptoms is the first treatment step (GINA 
step 1).  If asthma is not controlled on rapid-acting β2-agonists alone, a controller medication 
is added, usually a low dose inhaled corticosteroid (ICS) taken regularly (GINA step 2).  Thus 
adding a controller medication that addresses the underlying inflammation is important to 
improve asthma control and decrease the risk of severe asthma exacerbations in patients with 
mild asthma (Pauwels et al 2003).
Despite the availability of these conventional treatment regimens, many patients with mild 
asthma are still uncontrolled and are at risk of severe exacerbations.  For example, severe 
exacerbations in mild asthma patients represent 30–40% of all asthma exacerbations requiring 
emergency consultation (Dusser et al 2007).  Furthermore, some patients over-rely on their 
rapid-acting β2-agonist for symptomatic improvement (Rabe et al 2004).  Overuse of rapid-
acting β2-agonists often leads to delayed introduction of ICS: even if ICS is prescribed 
adherence to ICS treatment is low (Horne et al 2006).  The purpose of the current study is to 
test the hypothesis that in patients in need of low dose ICS (GINA step 2), asthma control can 
be achieved with "as needed" administration of both the controller and the bronchodilator 
medications in response to symptoms.
Symbicort® is a fixed combination of the ICS budesonide and the rapid- and long-acting β2-
agonist formoterol (LABA).  As formoterol has been shown to be as effective as short-acting 
β2-agonists (SABA) for symptom relief (Chuchalin et al 2005), (Pauwels et al 2003b), 
(Tattersfield et al 2001), Symbicort® can also be used as a reliever medication (Palmqvist et 
al 2001).  Such use of Symbicort® is approved for administration as Symbicort® Maintenance 
and Reliever Therapy (SMART) in moderate-to-severe asthma.  According to the SMART 
concept, Symbicort® is taken as a regular maintenance treatment and ‘as needed’ in response 
to symptoms.  Symbicort® SMART has been shown to reduce exacerbations and improve 
asthma control (O'Byrne et al 2005), (Scicchitano et al 2004), (Rabe et al 2006), (Vogelmeier 
et al 2005), (Atienza et al 2013).
In mild asthma, initial studies where treatment was administered ‘as needed’ in response to 
symptoms, have shown promising results for Symbicort and similar combination products 
(Haahtela et al 2006, Papi et al 2007).  In patients with mild intermittent asthma (i.e., requiring 
GINA step 1 treatment) and having signs of airway inflammation, Symbicort ‘as needed’ was 
more efficacious than Oxis (i.e., formoterol) ‘as needed’ in reducing fractional exhaled nitric 
oxide (FeNO) and improving lung function (Haahtela et al 2006).  Symptom-driven, ‘as 
needed’ use of a combination of a SABA (albuterol) and ICS (beclomethasone) in a single 


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
16(73)
inhaler was equivalent to regular treatment with inhaled ICS (beclomethasone) in controlling 
patients with mild persistent asthma (i.e., requiring GINA step 2 treatment), (Papi et al 2007).
When administered on an as-needed basis without daily maintenance medication, Symbicort®
will provide both an anti-inflammatory and a reliever medication adapted to the patient’s
current asthma symptoms.  Such an approach will address the need for a timely administration 
and adherence to ICS in asthma patients in need of GINA step 2 treatment.  In addition this 
will be a simplified and convenient treatment regimen as the patients will use one inhaler only 
instead of two (1 for controller medication and 1 for ‘as needed’ use).
1.2
Rationale for study design, doses and control groups
The design of the study incorporates features that are consistent with the Committee for 
Medicinal Products for Human Use Asthma guideline (CHMP 2013).  A randomised, double-
blind, parallel-group design is standard in asthma clinical trials.  Patients who are either 
uncontrolled on an inhaled short acting bronchodilator ‘as needed’ (SABA and/or short acting 
anticholinergic agent) or controlled on mono-maintenance therapy with either a low dose ICS 
or a leukotriene receptor antagonist (LTRA) in addition to 'as needed' use of inhaled short-
acting bronchodilator (SABA and/or short acting anticholinergic agent) will be included in the 
study.  The study will begin with a 2 to 4 week-long run in period in order to collect patients’ 
baseline data and to ensure that the recruited patients are in need of GINA step 2 treatment.  A 
12-month treatment period has been chosen as this study investigates a new treatment regimen 
with Symbicort® Turbuhaler® in a new patient population, which will include both adult and 
adolescent patients.
The efficacy and safety of Symbicort ‘as needed’ will be compared with a commonly used 
SABA, terbutaline.  In addition Symbicort ‘as needed’ will also be compared with Pulmicort®
(budesonide) Turbuhaler® 200 μg twice daily plus terbutaline ‘as needed’ which is one of the 
current standard treatments for patients at GINA step 2.  Symbicort (budesonide/formoterol) 
Turbuhaler 160/4.5 μg ‘as needed’ is the strength mostly used on ‘as needed’ basis with the 
Symbicort SMART concept.  It is considered to provide adequate anti-inflammatory effect 
due to the budesonide component, and yet is safe to use as evidenced by Symbicort SMART 
data.  The formoterol component of Symbicort® Turbuhaler® provides rapid and effective 
symptom relief.
During the treatment period of the study terbutaline will be provided in a Turbuhaler (dry 
powder inhaler - DPI) that is identical to the Symbicort® Turbuhaler® for blinding purposes.  
The dose of active substance in the terbutaline Turbuhaler (0.4 mg terbutaline per inhalation) 
is expressed as delivered dose that corresponds to 0.5 mg per inhalation in the commercially 
available product, Bricanyl® Turbuhaler® (expressed as metered dose).  Bricanyl®
Turbuhaler® will be used during the run in period (see Section 7.1 ‘Identity of investigational 
products’).
Evaluating asthma control is important in patients with asthma, especially in patients with 
mild asthma.  Well controlled asthma weeks (WCAW) are a well-known and well-accepted 
composite measure of asthma control (Bateman et al 2004).  Therefore WCAW on the 


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
17(73)
randomised treatment has been chosen as the primary variable in the study.  WCAW consists 
of several parameters including symptoms, nighttime awakenings, lung function and as 
needed use measured on a daily basis.  In addition WCAW on randomised treatment take into 
consideration any additional asthma therapy received by the patients.  Moderate and severe 
asthma exacerbations, another important aspect of asthma control, will be collected as 
secondary end-points.
Patients’ recruitment will be balanced based on their pre-study treatment (i.e., patients who 
are uncontrolled on an inhaled short acting bronchodilator (SABA and/or short acting 
anticholinergic agent) ‘as needed’ or controlled on mono-maintenance therapy with either a 
low dose ICS or a leukotriene receptor antagonist (LTRA) in addition to 'as needed' use of
inhaled short-acting bronchodilator (SABA and/or short acting anticholinergic agent).  
Patients will be randomised to the three treatment arms in 1:1:1 proportion.
1.3
Benefit/risk and ethical assessment
Symbicort, terbutaline Turbuhaler as well as Pulmicort are well known medications with 
efficacy and safety profiles established in numerous clinical studies and vast postmarketing 
experience.
Symbicort is effective as a reliever medication (Palmqvist et al 2001).  In this study patients 
will be instructed to contact the investigator if using more than 12 as needed inhalations with 
Symbicort Turbuhaler per day.  In the Symbicort SMART program the patients have been 
allowed to use up to 12 inhalations per day (10 ‘as needed’ inhalations in addition to their 
maintenance treatment) and the safety profile of Symbicort was no different from that of a 
fixed dose maintenance treatment.  Furthermore a study in which patients took 10 inhalations 
of Symbicort Turbuhaler 160/4.5 μg per inhalation as an addition to a daily Symbicort 
maintenance dose of 640/18 μg revealed no new safety concerns compared to what was 
already known for ICS and LABA (Ankerst et al 2003) demonstrating that occasional high 
doses of Symbicort Turbuhaler are safe and well tolerated.
Terbutaline Turbuhaler is a well-known and frequently used short acting β2 agonists (SABAs).  
It is widely acknowledged that terbutaline has a rapid onset of action within minutes of 
inhalation and a favourable safety profile (Sears and Lötvall 2005).  The maximum dose to be 
allowed in the study is within the approved dose range in most countries.  The patients will be 
instructed to contact the investigator if using more than 12 as needed inhalations with 
terbutaline Turbuhaler per day.
Pulmicort which will be used as a maintenance treatment in the other comparator arm, is 
effective and safe controller medication in asthma (GINA 2012).
All patients will be thoroughly monitored during the course of the study with clinic visits at 4, 
16, 28, 40 and 52 weeks of treatment and daily recording of  Peak Expiratory Flow (PEF), 
asthma symptoms, use of maintenance and ‘as needed’ investigational product (IP) and 
nighttime awakenings.  Furthermore there will be triggers in the electronic diary (eDiary) to 
generate alerts warning the patients for worsening of their asthma.  Upon receiving such an 


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
18(73)
alert the patients will be asked to contact the investigators for a consultation.  In addition the 
patients will be instructed to contact the investigator at any time they feel a need for medical 
assistance even without an alert.  The investigators may prescribe additional 
glucocorticosteroid (GCS) treatment to patients having asthma exacerbations or poor long-
term asthma control.  Strict discontinuation criteria are applied for an individual patient in 
case of severe asthma exacerbations, see Section 3.9.
To conclude, the overall benefit/risk ratio is considered acceptable.
1.4
Study Design 
Figure 1
Study Flow Chart 
Period
Enrolment
Run-in
Visit
Week
FU=Follow-up phone call
               1               2                3               4               5              6               7               8        FU
                          -2 to - 4           0                4              16             28             40             52       54  
Randomisation
Bricanyl 
0.5 mg
 'as 
needed'
 Placebo bid + Symbicort 160/4.5 μg 'as needed'
 Pulmicort 200 μg bid + terbutaline 0.4 mg 'as needed'
 Placebo bid + terbutaline 0.4 mg 'as needed'
Treatment


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
19(73)
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To demonstrate that Symbicort Turbuhaler 
160/4.5 μg ‘as needed’ is superior to 
terbutaline Turbuhaler 0.4 mg ‘as needed’.
Evaluation of asthma control as measured by well-
controlled asthma weeks as the primary variable.
2.2
Secondary objective
Secondary Objectives:
Outcome Measure:
To evaluate the relative efficacy of Symbicort 
Turbuhaler 160/4.5 μg ‘as needed’ and 
Pulmicort Turbuhaler 200 μg twice daily plus 
terbutaline Turbuhaler 0.4 mg ‘as needed’.
Evaluation of asthma control as measured by well-
controlled asthma weeks as the primary variable 
To evaluate the efficacy of Symbicort 
Turbuhaler 160/4.5 μg as compared to both:
terbutaline Turbuhaler 0.4 mg ‘as needed’
And:
Pulmicort Turbuhaler 200 μg twice daily plus 
terbutaline Turbuhaler 0.4 mg ‘as needed’.
Secondary variables:
Time to first severe asthma exacerbation
Time to first moderate or severe asthma exacerbation
Average change from baseline in pre-dose FEV1
Average change from baseline in Morning PEF
Average change from baseline in Evening PEF
Average change from baseline in number of 
inhalations of ‘as needed’ medication
Average change from baseline in symptom score
Percentage of Nighttime awakenings due to asthma
Percentage of Symptom-free days
Percentage of ‘As needed’ free days
Percentage of Asthma control days
Percentage of controller use days
Time to asthma related discontinuation
Poorly controlled asthma weeks
Time to additional steroids for asthma
Average change from baseline in Asthma Control 
Questionnaire  (ACQ-5)
Average change from baseline in Asthma Quality of 
Life Questionnaire; standard version (AQLQ(S))


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
20(73)
2.3
Safety objective
Safety Objective:
Outcome Measure:
To compare the safety of Symbicort 
Turbuhaler 160/4.5 μg ‘as needed’ with that of 
terbutaline Turbuhaler 0.4 mg ‘as needed’, and 
with that of Pulmicort Turbuhaler 200 μg twice 
daily plus terbutaline Turbuhaler 0.4 mg ‘as 
needed’.
Adverse events (nature, incidence and severity); 
pulse, blood pressure and physical examination.
2.4
Exploratory objectives
Exploratory Objective:
Outcome Measure:
To understand patient usage of study inhalers 
during the clinical study (particularly when 
and why study inhalers are used) from a 
qualitative patient-centred perspective.
Coded transcriptions of patient interviews 
(qualitative summary).
To understand:
The patient experience of asthma control 
during the clinical study;
Whether or not patients believe their asthma 
control has changed during their participation 
in the clinical study;
What the term ‘asthma control’ means to the 
patient.
Coded transcriptions of patient interviews 
(qualitative summary).
The exploratory objectives outlined above are part of a qualitative sub-study that will be 
conducted in a sub-set of participating countries and sites.  See Appendix F for an overview of 
the qualitative sub-study.  Countries and sites not participating in the sub-study will not enrol 
any patients in the sub-study.
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
In this study, both patients who are either uncontrolled on an inhaled short acting 
bronchodilator ‘as needed’ (SABA and/or short acting anticholinergic agent) or controlled on 
mono-maintenance therapy with either a low dose ICS or a LTRA in addition to 'as needed' 
use of inhaled short-acting bronchodilator (SABA and/or short acting anticholinergic agent),
are eligible for enrolment and the proportion of these two groups should be approximately 
equal (see Section 3.5).


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
21(73)
3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
Provision of informed consent prior to any study specific procedures.  For patients 
under-age, signed informed consent from both the patient and the patient’s 
parent/legal guardian is required
2.
Outpatients of either gender aged ≥12 years at Visit 1
3.
Diagnosis of asthma according to GINA criteria based on symptoms with a 
documented history of at least 6 months prior to Visit 1.  Lung function and 
reversibility tests performed as part of Visit 2 and 3 can be used as a confirmation 
of asthma diagnosis according to GINA criteria if there is no measure of lung 
function available before Visit 1.
4.
Patients who are in need of GINA (2012) step 2 treatment:
-
uncontrolled on inhaled short-acting bronchodilator(s) ‘as needed’ (SABA 
and/or short acting anticholinergic agent) as judged by the investigator for the 
last 30 days before Visit 2, or
-
controlled on mono-maintenance therapy - with low stable dose ICS (≤ 400 μg 
budesonide per day or corresponding dose of other ICS) (see Appendix E for 
conversion) or LTRA - in addition to 'as needed' use of inhaled short-acting 
bronchodilator(s) (SABA and/or short acting anticholinergic agent), as judged 
by the investigator for the last 30 days prior to Visit 2
5.
Based on lung function tests (see Section 5.1.2) at Visit 2, patients pre-treated with
!
an inhaled short acting bronchodilator only should have pre-bronchodilator 
FEV1 ≥ 60 % of predicted normal (PN) and post-bronchodilator FEV1 ≥ 80 % 
PN according to the European Respiratory Society (ERS) guidelines (Quanjer 
et al 2012)
-
low dose ICS or LTRA medication in addition to inhaled short-acting 
bronchodilator(s) should have pre-bronchodilator FEV1 ≥80 % PN according to 
the ERS guidelines
6.
Reversible airway obstruction according to a reversibility test (see Section 5.1.2.2) 
performed at Visit 2 defined as an increase in FEV1 ≥12% and 200 ml relative to 
baseline, after inhalation of 1 mg Bricanyl Turbuhaler.  The test can be repeated at 
Visit 3 in case the patients fail at Visit 2.  If patients fail at both occasions, they can 
still be included if they have a documented historical reversibility within the last 12 
months prior to Visit 3, with an increase in FEV1 ≥12% and 200 ml relative to 
baseline after administration of a rapid acting β2-agonist


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
22(73)
For randomisation at Visit 3, patients should fulfil the following criteria:
7.
Use of Bricanyl Turbuhaler ‘as needed’ due to asthma symptoms on at least 
3 separate days during the last week of the run-in period
8.
Ability to use Turbuhaler correctly and to complete the eDiary correctly.  Morning 
and evening data must be recorded for at least 8 days (any 8) of the last 10 days of 
the run-in period
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)
2.
Previous randomisation in the present study
3.
Participation in another clinical study with a non-biologic investigational product or 
new formulation of a marketed non-biologic drug during the last 30 days prior to 
Visit 1
4.
Participation in another clinical trial with any marketed or investigational biologic 
drug within 4 months or 5 half-lives whichever is longer, prior to Visit 1
5.
Any asthma worsening requiring change in asthma treatment other than inhaled
short-acting bronchodilator(s) (SABA and/or short acting anticholinergic agent) 
within 30 days prior to Visit 1
6.
Use of oral, rectal or parenteral GCS within 30 days and/or depot parenteral GCS 
within 12 weeks prior to Visit 1
7.
Use of any β-blocking agent including eye-drops
8.
Known or suspected hypersensitivity to study drugs or excipient
9.
Smoker (current or previous) with a smoking history of ≥ 10 pack years 
10.
Medical history of life- threatening asthma including intubation and intensive care 
unit admission
11.
Any significant disease or disorder (e.g., cardiovascular, pulmonary other than 
asthma, gastrointestinal, hepatic, renal, neurological, musculoskeletal, endocrine, 
metabolic, malignant, psychiatric, major physical impairment) which, in the opinion 
of the investigator, may either put the patient at risk because of participation in the 
study, or may influence the results of the study, or the patient’s ability to participate 
in the study


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
23(73)
12.
Any clinically relevant abnormal findings in physical examination and/or vital signs 
at Visit 2, which, in the opinion of the investigator, may put the patient at risk if 
participating in the study
13.
Pregnancy, breast-feeding or planned pregnancy during the study.  Fertile women 
not using acceptable contraceptive measures, as judged by the investigator
14.
Planned hospitalisation during the study
15.
Suspected poor capability, as judged by the investigator, of following instructions 
of the study.
For randomisation at Visit 3, patients should not fulfil any of the following criteria:
16.
Use of ≥ 6 Bricanyl Turbuhaler ‘as needed’ inhalations per day, for a certain 
number of days depending on the actual length of run-in:  for ≥ 2 days out of 14 
days; for ≥3 days out of 15-21 days;  for ≥ 4 days out of 22 or more days of run-in.
17.
Any asthma worsening requiring change in asthma treatment other than inhaled 
short-acting bronchodilator(s) (SABA and/or short acting anticholinergic agent) 
from Visit 1 until Visit 2 and/or requiring any asthma treatment other than run-in 
study medication from Visit 2 until randomisation
See procedures for handling of incorrectly enrolled patients in Section 3.4.
3.3
Patient enrolment and randomisation
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the patient or their guardian/legal
representative before any study specific procedures are performed
2.
Assign potential patient a unique enrolment number, beginning with ‘E#’
3.
Determine patient eligibility.  See Sections 3.1 and 3.2
4.
Re-assess patient eligibility at the start and end of the run-in period
5.
Assign eligible patient unique randomisation code
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.
Randomisation codes will be assigned strictly sequentially as patients become eligible for 
randomisation.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
24(73)
3.4
Procedures for handling incorrectly enrolled or randomised 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Patients who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomised or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the investigator regarding whether to continue or discontinue the patient from 
treatment.  The AstraZeneca Study Physician must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups
An Interactive Voice or Web Response System (IVRS/IWRS) will be utilized to stratify 
patients, to assign enrolment and randomisation codes to the patients and to dispense 
investigational product (IP) at Visit 3 and at subsequent visits.  Detailed instructions regarding 
the use of the IVRS/IWRS will be provided in a manual.
The randomisation codes will be computer generated by AstraZeneca R&D using GRand (AZ 
Global Randomisation system) using balanced blocks.  Country and pre-study treatment 
groups will be used as stratification factors ensuring approximately equal number of patients 
per treatment group within each country and equal number of patients per treatment group for 
each pre-study treatment group, respectively.  The randomisation codes will be loaded into the 
IVRS/IWRS database.  As patients become eligible, they will be assigned to a treatment group 
in balanced blocks supplied to that country in accordance with the randomisation scheme.  
Randomisation codes will be assigned strictly sequentially as patients become eligible for 
randomisation.
The total study population should contain approximately equal number of patients in the two 
subgroups (previously treated with inhaled short-acting bronchodilator(s) (SABA and/or short 
acting anticholinergic agent) only and previously treated with additional low dose ICS/anti-
inflammatory medication). This ratio will be monitored by the IVRS/IWRS and if one 
subgroup has completed the recruitment target it may only be possible to enrol patients 
belonging to the other group.  In addition, the study will aim to achieve approximately 10% 
proportion of adolescents among the randomised patients.
3.6
Methods for ensuring blinding
This study will be double blind.  All packaging and labelling will be done in such a way as to 
ensure blinding.  Symbicort and terbutaline Turbuhalers will be identical, and the Pulmicort 
and placebo Turbuhalers will be identical.
The following personnel will have access to the randomisation list:


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
25(73)
∀
Personnel carrying out the packaging and labelling of investigational product (IP)
∀
Personnel generating the randomisation list.
Personnel other than the above involved in the conduct of the study will not have access to the 
information in the randomisation list.  It will be kept in a secure location until the end of the 
study.
3.7
Methods for unblinding
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the Investigator(s) or pharmacists from the IVRS/IWRS.  Routines 
for this will be described in the IVRS/IWRS user manual that will be provided to each site.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation.  The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for Serious Adverse Events (SAEs) that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities.  Treatment codes will not be 
broken for the planned analyses of data until all decisions on the evaluability of the data from 
each individual patient have been made and documented.
3.8
Restrictions
Patients should avoid strenuous exercise for at least 30 minutes, smoking for at least 1 hour or 
having a large meal for at least 2 hours before the planned visits to the study site.
Patients should avoid intake of ‘as needed’ IP 6 hours prior to a study site visit if possible.
Restrictions regarding concomitant medication are described in Section 7.7
3.9
Discontinuation of investigational product
Patients may be discontinued from IP in the following situations:
∀
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment
∀
Adverse Event
∀
Severe non-compliance with the study protocol
∀
Safety reason as judged by the investigator and/or AstraZeneca


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
26(73)
∀
Pregnancy.  IP should be discontinued immediately if a patient becomes pregnant 
during the course of the study. See section 6.6.1
∀
Development of any of the following study specific discontinuation criteria will 
necessitate discontinuation of IP (for definition of severe asthma exacerbation, see 
Section 5.1.1):
!
A severe asthma exacerbation with duration of more than 3 weeks
!
Two severe asthma exacerbations within a period of 3 months
!
Three severe asthma exacerbations in total during the study.
3.9.1
Procedures for discontinuation of a patient from investigational product
Discontinuation of investigational product means that the patient has to be withdrawn from the 
study.
If possible, the patient will be seen and assessed by an Investigator; Visit 8 should be 
performed (see Table 1).  Adverse events will be followed up (see Section 6).
Discontinuation of the IP should be recorded in IVRS/IWRS.
3.9.2
Enrolment failures
Enrolment failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (i.e., patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for enrolment failures (not 
randomised patients).
The patient can be re-enrolled, due to the following reasons only:
∀
Enrolment failure due to technical reason (e.g., study equipment not working 
properly), if agreed with AstraZeneca Study Physician.
∀
Enrolment failure due to inclusion criterion 5 not met at Visit 2 if according to 
investigator’s clinical judgment patient is likely to demonstrate FEV1 within the 
required ranges at a later occasion.  Re-enrolment due to this reason can only be 
allowed once.
∀
Enrolment failure due to inclusion criterion 6 not met for patients on inhaled short-
acting bronchodilator(s) as needed who were screen-failed prior to approval of CSP 
Amendment 2 and who have documented historical reversibility.  Re-enrolment due to 
this reason can only be allowed once.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
27(73)
Re-enrolled patient should re-sign informed consent, and assent where applicable, at the re-
enrolment Visit 1, and a new E-code will be assigned. All procedures for the enrolment/run-in 
period should be repeated.
Each re-enrolment must be documented in medical records at the study site and in the 
electronic Case Report Form (eCRF).
3.9.3
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up AEs outside of the clinical study. 
The eDiary, Turbuhaler Usage Monitor (TUM) and all study drugs should be returned by the 
patient.
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.  Withdrawn patients will not be replaced.
3.10
Discontinuation of the study
In case early study termination would occur for any unforeseen reason, the following steps 
have to be taken:
Regardless of the reason for early study termination, all data available for the patient at the 
time of discontinuation must be recorded in the CRF.
The Sponsor will ensure that adequate consideration is given to the protection of the patients' 
interests.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
28(73)
4.
STUDY PLAN AND TIMING OF PROCEDURES
Table 1
Study Plan detailing the procedures
Enrol-
ment
Run-in
Rando-
misation
Treatment
Follow-
up
For details 
see Section
VISIT
1
2
3
4
5
6
7
8
TC
Section 
WEEK
- 2 to - 4
0
4
16
28
40
52
54
Visit window (days)
0 – 7 
before 
Visit 2
14 – 28 
before 
Visit 3
±3
±7
±7
±7
±7
±3
Re. Visits 1-
2: 4.1.2
Informed consent
X
3.3
Allocation of enrolment code 
(IVRS/IWRS)
X
4.1.1
Demography 
(date of birth, gender, race)
X
Inclusion/exclusion criteria
X
X
X
0, 3.2
Medical, surgical history
X
Asthma history (including 
history of severe asthma 
exacerbations)
X
Smoking history
X
4.1.2
Patient training in eDiary, 
Turbuhaler (inhalation 
technique), TUM and PEF 
meter use
X
4.1.2
ACQ and AQLQ(S)
at study site 
X
X
only 
ACQ
X
X
X
X
5.1.5
5.1.6
SAEs (from Visit 1) /
AEs (from Visit 2)
X
X
X
X
X
X
X
X
X
6


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
29(73)
Enrol-
ment
Run-in
Rando-
misation
Treatment
Follow-
up
For details 
see Section
VISIT
1
2
3
4
5
6
7
8
TC
Section 
WEEK
- 2 to - 4
0
4
16
28
40
52
54
Visit window (days)
0 – 7 
before 
Visit 2
14 – 28 
before 
Visit 3
±3
±7
±7
±7
±7
±3
Re. Visits 1-
2: 4.1.2
Weight and height
(height only for adolescents at 
Visit 8)
X
X
4.1.2
Physical examination
X
X
5.2.1
Pulse and blood pressure
X
X
5.2.2.1
Pregnancy test
X
4.1.2
Adjustment of current asthma 
medication
X
4.1.2
Randomisation 
X
3.3, 3.5
Bricanyl for run-in 
dispense / return
d
r
4.1.2, 7.2
Lung function (FEV1, FVC 
pre- and post Bricanyl 
administration )
X
X
X
X
X
X
X
5.1.2,
7.2 for 
Bricanyl
Reversibility test (calculated 
at Visit 2 and if needed, 
calculated at Visit 3 as well)
X
X
5.1.2.2
Inclusion 6
Concomitant medication
X
X
X
X
X
X
X
7.7
Investigational product 
(dispense/return/check)
d
d/r/c
d/r/c
d/r/c
d/r/c
r/c
7
Intake of maintenance 
treatment morning dose
X
X
X
X
X
7.2


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
30(73)
Enrol-
ment
Run-in
Rando-
misation
Treatment
Follow-
up
For details 
see Section
VISIT
1
2
3
4
5
6
7
8
TC
Section 
WEEK
- 2 to - 4
0
4
16
28
40
52
54
Visit window (days)
0 – 7 
before 
Visit 2
14 – 28 
before 
Visit 3
±3
±7
±7
±7
±7
±3
Re. Visits 1-
2: 4.1.2
Review of PEF, asthma 
symptoms, nighttime 
awakenings, maintenance and 
‘as needed’ IP intake
and Turbuhaler user technique;
re-training of patient if neededb
Xb
Xb
Xb
Xb
Xb
Xb
5.1.3
For TUM 
see 5.1.8
Review of patient’s 
compliance with eDiary
X
X
X
X
X
X
Hand over the ‘Participant 
Letter’ to patientc
Xc
Xc
Xc
Xc
Informed consent 
(qualitative sub-study)a
Xa
a Obtaining informed consent of patients into the qualitative sub-study is only applicable to the subset of sites selected to participate.  
Informed consent into the sub-study is to be obtained before any interview-related activities. Informed consent can occur at any 
time at Visit 4 (Week 4) or later, however, the qualitative patient interview conducted with the patient should occur between
Week 12 and Week 50 for each patient who has elected to participate.  The exact time point of the interview will be determined by 
Health Research Associates (Contract Research Organization).  Refer to Appendix F.
b Training Turbuhalers can be used only until the expiry date of 31 March 2017
c Participant Letter is to be handed over by site staff to patient at one of the site visits between Visit 4 and Visit 7


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
31(73)
4.1
Enrolment and run-in periods
4.1.1
Enrolment procedures at Visit 1
Procedures will be performed according to the Study Plan, see Table 1.
At enrolment, consenting patients are assessed to ensure that they meet eligibility criteria.  
Patients who do not meet these criteria must not be enrolled in the study.
Patients will sign informed consent for the study at enrolment and will then receive an 
enrolment code, allocated by IVRS/IWRS.  Serious Adverse event recording will start at 
enrolment after signing the informed consent.
Patients will continue taking their prescribed medication until Visit 2 and will be informed by 
the investigator about medication restrictions applicable before Visit 2 (see Section 7.7.1).
4.1.2
Run-in procedures at Visit 2
Visit 2 can be performed within 7 days after Visit 1.
Visit 1 and Visit 2 can be performed on the same day only in cases where the patient has not 
taken any medication which could affect the lung function measurements (see details in
Section 7.7.1, Table 2).
Procedures will be performed according to the Study Plan, see Table 1.
Patients who fulfil the inclusion and none of the exclusion criteria (Visit 2) will enter a 
2-4 week run-in period.
Patients will be asked to stop their prescribed asthma medication (including maintenance 
treatment with ICS or LTRA) used at the time of study entry and during the enrolment period 
in accordance with Section 7.7.  All patients will receive Bricanyl Turbuhaler for ‘as needed’ 
use during the run-in period.
At Visit 2 instructions will be given to the patients on how to use the Turbuhaler (inhalation 
technique), theTUM, the eDiary and the PEF meter.  Before taking the first dose of run-in 
medication the patient will be instructed by the study personnel how to take the medication.  
In order to inhale properly according to instructions the patient will practice inhalation 
technique with a training device, as many times as judged necessary by the supervising study 
personnel.  Patients will complete ACQ and AQLQ questionnaires.  Patients will be asked to 
fill in the eDiary twice daily during the run-in period.  PEF (morning and evening 
measurements), asthma symptoms and nighttime awakenings due to asthma will be recorded.  
To verify eligibility, lung function measurement including reversibility test will be performed 
by spirometry.
Height will be measured in cm (without shoes) and weight in kg (light clothes and without 
shoes).


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
32(73)
Pregnancy test by urine dipstick should be performed for female patients aged ≤60 years.
For the evaluation of smoking history, pack years will be calculated as follows:
10 pack years =
1 cigar = 5 cigarettes
1 pack (20 cigarettes) per day for 10 years
1 cigarillo = 2 cigarettes
or 2 pack (40 cigarettes) per day for 5 years
50 g pipe tobacco = 65 cigarettes
or ½ pack (10 cigarettes) per day for 20 years
Hand rolled cigarettes can be calculated as
cigarettes or pipe tobacco
During the run-in period, the patients and investigators will get an alert if the patients fulfil 
exclusion criterion 16.  The patients will be instructed to contact their investigators.  The 
investigators should discontinue these patients from the study.
4.2
Treatment period
At Visit 3 investigator should check eligibility before randomisation.
Descriptions of the procedures for this period are included in the Study Plan, see Table 1.
For timing of visits appointment for spirometry procedure (± 1 hour related to spirometry 
procedure at Visit 2 ) has to be taken into account (see Section 5.1.2 for details)
Additional treatment for patients experiencing deterioration of asthma or having long-term 
poor asthma control will be allowed.  The conditions and detailed procedures are described in 
Section 5.1.1.
4.3
Follow-up period
A follow-up telephone contact will be performed 2 weeks after the last investigational product 
administration, i.e., 2 weeks after Visit 8 or if the patient is withdrawn from the study, 2 
weeks after the last visit.
At the follow-up telephone call, the investigator will check for adverse events.
5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The investigator will ensure that data are recorded on the electronic Case 
Report Forms (eCRF) as specified in the study protocol and in accordance with the 
instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement.  The 


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
33(73)
investigator will sign the completed electronic Case Report Forms.  A copy of the completed 
electronic Case Report Forms will be archived at the study site.
5.1
Efficacy assessments
5.1.1
Asthma exacerbations
In this study asthma exacerbations are defined as deterioration in asthma that is associated 
with a medical intervention.  Deterioration of asthma defined as worsening of asthma 
symptoms, increased use of ‘as needed’ medication, or deterioration of lung function which 
lasts for two or more days (from diary data) or which happens acutely (≤24 h) (from clinic 
data) will be recorded in the eCRF by the investigator.
A severe exacerbation is defined as
a deterioration of asthma requiring any of the following:
∀
Use of systemic steroids for at least 3 days1
∀
Inpatient hospitalization
∀
Emergency room visit2 due to asthma that required systemic steroids.
1 An injection of depot glucocorticosteroids due to asthma worsening is considered equivalent 
to at least 3 days of systemic glucocorticosteroids 
2 Emergency room visit or other urgent unscheduled health care visit
A moderate exacerbation is defined as:
a deterioration of asthma requiring a change in treatment i.e., initiation of prescribed ICS 
treatment (inhaled budesonide 200 μg twice daily), to avoid progression of the worsening of 
asthma to a severe exacerbation.
The start and end date of each asthma exacerbation will be recorded in the eCRF at the site 
visits.  For severe exacerbations the start date is defined as the first day of hospitalisation/-
emergency room treatment or the first day of systemic (i.e. not inhaled) GCS treatment.  The 
end date is defined as the last day of hospitalisation/emergency room treatment or the last day 
of systemic GCS treatment.  If the same asthma exacerbation includes both 
hospitalisation/emergency room treatment and systemic GCS treatment, the start and end 
dates are the first and last day that either of the criteria was fulfilled.  For moderate 
exacerbations the start date is defined as the first day of additional prescribed ICS treatment 
(inhaled budesonide 200 μg twice daily) and the end date is defined as the last day of this 
treatment.
Additional hospitalisations/emergency room treatments and systemic GCS treatments 
occurring during a severe asthma exacerbation should not be regarded as a new exacerbation.  


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
34(73)
For a severe asthma exacerbation to be counted as a separate event, it must be preceded by at 
least seven days in which no criteria for severe exacerbations are fulfilled.
For a moderate asthma exacerbation to be counted as a separate event, it must be preceded by 
at least seven days in which no criteria for severe or moderate exacerbations are fulfilled.
If a patient has a severe asthma exacerbation with a duration of more than 3 weeks or 2 severe 
asthma exacerbations during 3 months or 3 severe asthma exacerbations during the study, 
he/she should discontinue the study participation and the reason should be recorded as ‘Study 
specific discontinuation criteria met’ on the termination form in the eCRF.
For the purpose of reporting in this study, asthma exacerbations should be distinguished from 
long term poor asthma control. Exacerbations are acute deteriorations of asthma as defined 
above. Chronic loss of asthma control (i.e. without evidence of an acute asthma 
deterioration), which does not meet exacerbation criteria but requires additional ICS treatment 
is to be reported as long term poor asthma control.
Additional treatment with prescribed inhaled budesonide 200 μg twice daily
Based on the investigator’s individual assessment of the patient, additional treatment with 
prescribed inhaled budesonide can be added to the blinded maintenance treatment, see Section 
7.7.2:
∀
During any severe exacerbation for at least 2 weeks
∀
In case of a moderate exacerbation for at least 2 weeks
∀
In case of a long-term poor asthma control for at least 4 weeks, see Section 7.7.2
After 2 and 4 weeks respectively of such an additional treatment, the investigator should 
evaluate the patient and step down to the blinded maintenance treatment if possible.  After two 
occasions of additional budesonide treatment either for a moderate exacerbation or for long-
term poorly controlled asthma, the investigator should consider continuing with the additional 
budesonide for the rest of the study.
5.1.2
Lung function measurement by spirometry (FEV1, FVC) at the study site
Equipment and conditions
Spirometry will be performed by the Investigator or authorized delegate according to 
American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines (Miller et al 
2005). The study site personnel who will be performing the testing should be properly 
certified / trained.
The spirometer must meet ATS/ERS recommendations (Miller et al 2005).  The 
monitor/vendor is responsible for checking that the spirometer in use meets these 
recommendations.  It should be serviced once a year or according to the manufacturer’s 
instruction at an authorised facility.  All service measures and repairs must be documented.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
35(73)
Due to diurnal variation of lung function it is important that all spirometry assessments at 
Visits 3, 4, 5, 6, 7, and 8 are performed ±1 hour in relation to the time of spirometry at Visit 2 
and preferably after 7 am and no later than 11 am.
The spirometry should be conducted with the same spirometer within patients and for all 
patients at each site.  Preferably, the same study personnel should test the patient’s lung 
function throughout the study to reach optimal performance and to enhance reproducibility.  
The patient should rest at least 15 minutes prior to the test.  For repeated measurements e.g., to 
assess best of 3, a short pause (1 min.) between measurements is recommended.
The measurements are to be made with the patient seated in an upright position (preferably), 
or if not comfortable standing position is also acceptable.  The same position should be used 
for all spirometry measure during the entire study.  The head must not be tilted during 
measurements.  During the breathing manoeuvres, the thorax should be able to move freely; 
hence tight clothing should be loosened.
A nose-clip should be used for the manoeuvre.  Mouthpieces of the same dimension and shape 
should be used throughout the study.  Spirometry data should be performed at body 
temperature, barometric pressure and saturated with water vapour (BTPS), using a calibrated 
spirometer.
Calibration should be in accordance with each trademark specification.  If nothing else is 
specified, calibration should be performed every day when a patient visits the study site.  
Instead of using a 3 L syringe, a 1 L can be used 3 times.  The accuracy of the calibration must 
be within ± 3% of the reading or ± 0.05 L, whichever is greater.  All calibration reports should 
be signed, dated and filed in the ISF along with a signed and dated copy (if the calibration 
reports are not on archive-quality paper).  If a calibration report cannot be printed, the results 
should be documented in writing in the Investigator Study File (ISF).
FEV1 and FVC
The forced expiratory manoeuvre should start with a maximal inspiration and then be 
followed by a fast and forceful expiration that should last for at least 6 seconds.  It is 
important to encourage the patient to continue the expiration to be fast and forceful throughout 
the manoeuvre.  Check that none of the following has occurred; coughing during the first 
second, glottis closure, leak or obstruction of mouthpiece (by the tongue).
At least 3 technically satisfactory forced vital capacity (FVC) manoeuvres should be 
performed.  The difference between highest and second highest FVC and FEV1, separately, 
should not be more than 150 mL.  A maximum of 8 manoeuvres should be performed in 
attempting to meet reproducibility criteria.  If the reproducibility criteria cannot be met within 
8 manoeuvres, the highest FEV1 value should be recorded, and a comment should be entered 
on the printout.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
36(73)
FEV1 values will be taken from the FVC curves.  After examining the data from all acceptable 
curves, the highest FEV1 value and the highest FVC value should be recorded, even if the 2 
values do not come from the same curve.
Signed and dated copies of the 3 best manoeuvres printouts must be kept in the ISF for source 
data verification.  The printouts must be marked with study code, enrolment code, date and 
time of measurements, visit number and patient initials.
5.1.2.1
Pre-bronchodilator and post-bronchodilator FEV1 and FVC including 
reversibility testing and calculation of predicted normal values (PN)
Pre-bronchodilator and post-bronchodilator FEV1 and FVC expressed in liters (L) will be 
performed at Visits 2 to 8.
The assessment will be performed as follows:
1.
Pre-bronchodilator FEV1 measurement
2.
Inhalation of Bricanyl Turbuhaler 2 x 0.5 mg
3.
Wait 15 to 30 minutes
4.
Post-bronchodilator FEV1 measurement.
At Visit 2 these measurements are performed for inclusion verification and characterisation of 
the patient population.  Thus at this visit pre-bronchodilator and post-bronchodilator FEV1 PN 
will be calculated.  FEV1 PN value will be based on the reference values from European 
Respiratory Society (ERS) guidelines for adult and adolescent patients (Quanjer et al 2012).
At Visits 3 to 8 the purpose of the assessment is to get pre-bronchodilator and post-
bronchodilator values of FEV1 and FVC as part of the evaluation of lung function.
5.1.2.2
Reversibility test
To fulfil the reversibility inclusion criterion at Visit 2 the increase in FEV1 relative to baseline 
must be ≥12% and 200 ml 15-30 minutes after inhalation of 2 x 0.5 mg Bricanyl Turbuhaler.
The reversibility is calculated as follows:
100
)
(
1
)
(
1
)
(1
X
FEV
FEV
FEV
ity
Reversibil
before
before
after !
#
The investigator should record the pre- and post-bronchodilator FEV1 in the eCRF and the 
calculation will be performed by the eCRF.
If the reversibility inclusion criterion is not met at Visit 2, the reversibility test may be 
repeated at Visit 3.  If patients on low dose ICS or LTRA in addition to inhaled short-acting 
bronchodilator(s)fail at both occasions, they can still be included if they have a documented 


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
37(73)
historical reversibility within the last 12 months prior to Visit 3, see also inclusion criterion 6, 
Section 3.1.
5.1.3
Recorded electronic diary variables
Patients will complete an electronic diary (eDiary) and measure PEF with a handheld PEF 
meter (Vitalograph ASMA-1) twice daily during the run-in and the treatment periods.  At 
Visit 2, all patients will be carefully instructed and trained in how to complete the eDiary and 
how to handle the devices (eDiary, PEF meter and Turbuhaler Usage Monitor (TUM See 
section 5.1.8).  The patients must understand and be willing to complete the eDiary twice 
daily.  Patients will also be instructed how and where to request help if problems should 
occur.
The patients will be informed that the recordings made electronically in the eDiary cannot be 
retrospectively or prospectively entered.  The recordings must be completed within a defined 
time window.
The eDiary will be completed twice each day from the evening of Visit 2 until the morning of 
Visit 8.  The following will be recorded:
∀
Morning and evening PEF (transferred from PEF meter)
∀
Asthma symptoms (entered by patient)
∀
Nights with awakenings due to asthma symptoms (entered by patient)
∀
Use of ‘as needed’ and randomised maintenance treatment (transferred from TUM) 
See section 5.1.8.
PEF measurement
Measurements of morning and evening PEF will be performed during the entire run-in and 
treatment period (Visit 2 to Visit 8).
The patients will be requested to perform 3 manoeuvres twice daily (morning and evening), 
where the highest reading will be recorded.  The measurements should be made while 
standing.  The measurements should be performed before the maintenance IP administration 
upon rising in the morning and at bedtime in the evening.
Asthma symptoms
Asthma symptoms during nighttime and daytime will be recorded by the patient each morning 
and evening in the eDiary, from Visit 2 to Visit 8, according to the following scoring system:
0 = no asthma symptoms
1 = you are aware of your asthma symptoms but you can easily tolerate the symptoms


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
38(73)
2 = your asthma is causing you enough discomfort to cause problems with normal 
activities (or with sleep)
3 = you are unable to do your normal activities (or to sleep) because of your asthma
Daytime is defined as the time period between the morning lung function assessment (upon 
rising in the morning) and the evening lung function assessment.
Nighttime is defined as the time period between the evening lung function assessment (at 
bedtime) and the morning lung function assessment.
Nighttime awakenings due to asthma symptoms
Each morning the patient will record in the eDiary whether he/she woke up during the night 
due to asthma symptoms by a “yes” or “no” response.
Use of ‘as needed’ and randomised maintenance treatment
The use of ‘as needed’ treatment between the morning and evening assessments will be 
regarded as daytime use.  The use of ‘as needed’ treatment between the evening and morning 
assessments will be regarded as nighttime use.
Randomised maintenance treatment is taken regularly twice a day in the morning and in the 
evening.
The number of times the grip of the Turbuhaler is turned back and forth as well as the timing 
will be recorded by the TUM as data about the use of these treatments.
5.1.4
Triggers of patient alerts in the eDiary
Triggers in the eDiary will alert patients to signs of worsening of asthma and prompt them to 
contact the investigator.
The alerts will be triggered if one or both of the following criteria are fulfilled:
1. Decrease in morning PEF >20% on at least two consecutive days, compared with 
baseline (last 10 days of run-in)
2. Increase in total daily asthma symptom score of ≥3 units (the sum of morning and 
evening score) compared with baseline (last 10 days of run-in) on at least two 
consecutive days.
The patient will be instructed to contact the investigator as soon as possible when an alert 
appears in the eDiary.  Investigator’s judgement regarding the need for a patient visit has to be 
documented in the medical records.  If judged necessary, the investigator will arrange for a 
visit as soon as possible (if this coincides with the visit window for a scheduled study visit, the 
scheduled assessments may be performed).  Additional asthma treatment could be prescribed 
by the investigator during such a visit after having the patient’s status assessed (for additional 


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
39(73)
treatments due to asthma exacerbations, see Section 5.1.1).  Any action taken during such a 
visit will be recorded in the eCRF.
Even in the absence of eDiary triggers, patients experiencing worsening of asthma during the 
study should always be instructed to contact the investigator who should act according to 
medical judgment.
5.1.5
Asthma Control Questionnaire (5-item Version)
The ACQ was developed by Juniper (Juniper et al 1999).  The ACQ includes 7 items covering 
all the criteria (symptoms, FEV1, and SABA used as rescue medication) deemed necessary by 
international guidelines committees for determining the adequacy of asthma control.  The 
ACQ has undergone rigorous validation and has been shown to have strong evaluative and 
discriminative measurement properties (Juniper et al 1999).  In this study, the FEV1 and 
SABA use questions will be excluded, and patients will be responding to the five symptom 
questions (ACQ-5).  It has been shown that exclusion of the questions for SABA use and/or 
the FEV1 does not alter the validity and the measurement properties of the questionnaire 
(Juniper et al 2001).  Linguistically validated translations of the ACQ-5 into the local 
languages will be used.  The original North American English version is included in 
Appendix C.
The ACQ will be self-administered at clinical visits within the eDiary at the time points 
indicated in Table 1.  The questions take approximately 2 to 3 minutes to complete.
5.1.6
Asthma Quality of Life Questionnaire (Standardised Version)
The AQLQ has been developed by Juniper (Juniper et al 1992) and includes 32 questions in 
4 domains: activity limitation, symptoms, emotional function and exposure to environmental 
stimuli.  A feature of the AQLQ is that patients themselves select 5 of the 11 activity 
questions.  The standardised version of the AQLQ, the AQLQ(S), in which 5 generic activities 
replace the 5 patient-specific activities of the AQLQ (Juniper et al 1999) will be used in this 
study.  The AQLQ(S) is more appropriate than AQLQ for long-term clinical studies, when 
patients’ activities and priorities may change over time.  The AQLQ(S) evaluates the impact 
of asthma on patients every day functioning and wellbeing.  The AQLQ(S) has been validated 
for use from the age of 12 years (Juniper et al 2005).  Linguistically validated translations of 
AQLQ(S) into the local languages will be used.  The North American English version is 
included in Appendix D.
The AQLQ(S) will be self-administered within the eDiary at the time points indicated in Table 
1.  The questionnaire takes approximately 15 minutes to complete.  The patient needs to be 
able to read and to be fluent in the local language to be able to answer the questions.  Patients 
who are not fluent in the local language will not perform the AQLQ(S) assessments, but they 
can still participate in the study.  The assessment of AQLQ(S) will only be performed in 
countries where validated translations are available.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
40(73)
5.1.7
Administration of patient reported outcome questionnaires
The questionnaires (ACQ and AQLQ[S]) should be completed in the eDiary at the scheduled 
visits before any other study-related procedures are performed to avoid biased responses.  At 
Visit 2 only, the questionnaires can be completed following the lung function measurements.  
At Visit 2, all patients will be carefully instructed and trained in how to complete the eDiary.  
Written instructions will be provided to each patient in the local language.
The patient should be informed about the purpose and importance of completing the 
questionnaires and be given adequate time to complete all items.  It is important to administer 
the questionnaires according to the guidelines for standardised administration.  The questions 
should be completed in a quiet place without influence from family, friends, or study 
personnel.  Family, friends, or study personnel should never help the patient to choose an 
answer, interpret, or rephrase the questions for the patient.
5.1.8
Turbuhaler Usage Monitor (TUM)
The Turbuhaler Usage Monitor (TUM, a SmartTurbo™ version manufactured by Nexus6 Ltd, 
New Zealand) is a battery powered electronic data logger designed to be attached to a 
Turbuhaler (DPI).  The TUM contains an internal electronic clock and calendar that logs 
through a microprocessor the date and time when the Turbuhaler base grip is rotated back and 
forth.
The TUM will be applicable for the ‘as needed’ and maintenance study medication 
Turbuhalers, as well as the Bricanyl Turbuhaler used during the run-in phase (see Turbuhalers 
described in Section 7).
The colour of the main body of all the TUMs will be white. The colour of the locking ring of 
the TUM will be:
!
white for the ‘as needed’ study medication and the Bricanyl Turbuhaler
!
brown for the maintenance study medication
Patients will be informed about the TUM at Visit 2 (see Section 4.1.2) and receive written 
user instructions.
5.2
Safety assessments
5.2.1
Physical examination
A physical examination will be performed at Visit 2 and Visit 8 and include an assessment of 
the following: general appearance, respiratory, cardiovascular, abdomen, head and neck 
(including head, ears, eyes, nose and throat).  The examination at Visit 2 is regarded as 
baseline data.  Physical examination will also be performed in case of premature 
discontinuation from the study (see also Section 3.9.1 Procedures for withdrawal).  For 
reporting of AEs based on examinations, see Section 6.3.6.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
41(73)
5.2.2
Vital signs
For reporting of AEs based on vital signs, see Section 6.3.6.
5.2.2.1
Pulse and blood pressure
Blood pressure and pulse rate measurements will be performed at Visit 2 and Visit 8. The 
measurements at Visit 2 are regarded as baseline data.  Blood pressure and pulse rate will also 
be measured in case of withdrawal from study (see also Section 3.9.3 Procedures for 
withdrawal).
Pulse rate (beats/min) will be measured over 30 seconds in a sitting position, after 5 minute 
rest.  Thereafter systolic and diastolic blood pressure (mmHg) will be measured using the 
same cuff size, appropriate for arm circumference, throughout the study.
5.3
Other Assessments
Pharmacokinetic samples will not be taken during the study.
5.3.1
Qualitative Sub-study
A patient interview will be conducted as part of a qualitative sub-study at a subset of sites in 
selected countries.  Patients will be consented separately for the qualitative sub-study and 
once informed consent is obtained each patient will complete an interview over the telephone 
with a trained interviewer.  Refer to Appendix F for additional information on the design and 
conduct of the sub-study.
5.4
Pharmacokinetics
Pharmacokinetic samples will not be taken during the study.
5.5
Pharmacodynamics
Pharmacodynamic samples will not be taken during the study.
5.6
Pharmacogenetics
Pharmacogenetic samples will not be taken during the study.
5.7
Biomarker analysis
Biological samples will not be taken during the study.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
42(73)
6.1
Definition of adverse events
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
∀
Results in death
∀
Is immediately life-threatening
∀
Requires in-patient hospitalisation or prolongation of existing hospitalisation
∀
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions
∀
Is a congenital abnormality or birth defect
∀
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events will be collected from Visit 2 throughout the treatment period and including 
the follow-up period until the last telephone follow-up, or the last contact.
SAEs will be recorded from the time of informed consent.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last AE assessment in the study are 
followed up by the Investigator for as long as medically indicated, but without 
further recording in the eCRF.  AstraZeneca retains the right to request additional 


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
6.3.3
Symptoms of the disease under study
Asthma symptoms or signs, such as wheeze, cough, chest tightness, dyspnoea, breathlessness 
and phlegm, will be recorded as AEs only when:
∀
The sign or symptom is serious according to definitions, see Section 6.2 and/or
∀
The patient discontinues the study due to the sign or symptom and/or
∀
The sign or symptom is new to the patient or not consistent with the patient’s pre-
existing asthma history (defined as within 1 year of Visit 1) as judged by the 
investigator.
If a patient discontinues IP/study due to a study specific discontinuation criterion 
this should always be recorded as ’Development of study specific withdrawal’ on 
the termination form (TERM) in the eCRF.  In addition, the investigator has to 
report asthma deterioration as an AE leading to discontinuation with 
investigational product (DAE)/AE leading to withdrawal from study on the AE 
form.
6.3.4
Variables
The following variables will be collected for each AE:
∀
AE (verbatim)
∀
The date when the AE started and stopped
∀
Maximum intensity
∀
Whether the AE is serious or not
∀
Investigator causality rating against the IP (yes or no)
∀
Action taken with regard to investigational product
∀
AE caused patient’s withdrawal from study (yes or no)
∀
Outcome.
In addition, the following variables will be collected for SAEs:
∀
Date AE met criteria for serious AE
∀
Date Investigator became aware of serious AE


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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∀
AE is serious due to
∀
Date of hospitalisation
∀
Date of discharge
∀
Probable cause of death
∀
Date of death
∀
Autopsy performed
∀
Causality assessment in relation to Study procedure(s)
∀
Causality assessment in relation to Other medication
∀
Description of AE.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
Maximum intensity refers to the complete course of the AE.  The patient (parents/legal 
guardians) will be asked to assess the maximum intensity of the reported AEs according to the 
following scale:
∀
Mild (awareness of sign or symptom, but easily tolerated)
∀
Moderate (discomfort sufficient to cause interference with normal activities)
∀
Severe (incapacitating, with inability to perform normal activities).
6.3.5
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
6.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study personnel: ‘Have you/the child had any health problems since 
the previous visit/you were last asked?’, or revealed by observation will be collected and 
recorded in the eCRF.  The question will be put to each patient (or parent/legal guardian) in 
local language from Visit 2 to the last follow-up telephone contact.  When collecting AEs, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms.  
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately.
6.3.7
Adverse events based on examinations
Vital signs data will be summarised in the clinical study report.  Deterioration as compared to 
baseline in protocol-mandated vital signs should therefore only be reported as AEs if they 
fulfil any of the SAE criteria or are the reason for discontinuation of treatment with the 
investigational product.
If deterioration in a vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an AE and the associated vital sign will be considered as 
additional information.  In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
6.3.8
Hy’s Law
Cases where any labs that are collected from a patient show an AST or ALT ≥3xULN* 
or total bilirubin ≥2xULN may need to be reported as SAEs according to handling of cases 
representing Hy’s Law.  In such case, the investigator should contact the AstraZeneca Study 
Physician.
* AST: Aspartate Aminotransferase, ALT: Alanine Aminotransferase , ULN: Upper Limit of Normal
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the Web Based Data 
Capture (WBDC) system, an automated email alert is sent to the designated AstraZeneca 
representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug and the EU Summary of Product Characteristics for the active comparator product 
(including AstraZeneca comparator).
6.5
Overdose
Background
The risks associated with overdosage of Symbicort are considered to be small, as the safety 
margins for inhaled budesonide and formoterol are substantial.  Administration of a Symbicort 
Turbuhaler dose of 1600/45 μg over one hour on top of maintenance treatment with daily 
doses of 640 μg budesonide and 18 μg formoterol in asthma patients raised no safety 
concerns, nor did a formoterol dose of 90 μg over three hours in adult patients with acute 
bronchoconstriction or a budesonide dose of 7200 μg in healthy volunteers.
In high-dose formoterol studies where terbutaline was given as an active comparator, a 
terbutaline dose up to 10 mg over three hours in adult patients with acute bronchoconstriction 
raised no safety concerns.
Symptoms
Glucocorticosteroids have a low toxicity, and are virtually without harmful effects after a 
single or a few doses, even if the doses are very high.  Thus, acute overdosage with 
budesonide - even in excessive doses - is not a clinical problem.  As with all GCSs, systemic 
glucocorticoid effects may appear if used chronically in excessive doses.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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There is limited clinical experience regarding overdosage with inhaled formoterol.  An 
overdose would likely lead to effects that are typical of β2-agonists such as tremor, headache 
and palpitations.  Symptoms and signs reported with formoterol from isolated cases are 
tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and 
vomiting.
Experience with other β2-agonists has shown that overdoses may also cause restlessness, 
irritability, excitation, somnolence, convulsions and hyper- or hypotension.  Metabolic effects 
may include acidosis and in serious cases, possibly rhabdomyolysis and renal failure.
Treatment suggestions
Normally, an overdose with Symbicort or terbutaline should not require any special treatment.  
However if signs of adrenergic effects occur these should be counteracted by supportive and 
symptomatic treatment, according to local routines.
Procedures for reporting
For the purpose of this study, an accidental or deliberate intake of blinded treatment of more 
than 20 inhalations (> 3200/90 μg Symbicort or 8 mg terbutaline delivered dose) during one 
day is defined as an overdose and must be reported as such as described below:
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module.  An overdose without associated 
symptoms is only reported on the Overdose eCRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
Pregnant women, as well as those who are planning pregnancy or are breast-feeding, are 
excluded from the study.  In addition, fertile women not using acceptable contraceptive 
measures, as judged by the investigator, should not be included in the study.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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Clinical experience with Symbicort in pregnant women is limited and patients that become 
pregnant must be discontinued from the study.  However, reports from clinical studies and 
post-marketing surveillance do not indicate an increased risk when using Symbicort 
Turbuhaler during pregnancy.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT paper 
form is used to report the outcome of the pregnancy.
6.6.2
Paternal exposure
There is no restriction on fathering children or donating sperm during the study.
6.7
Management of IP related toxicities
Treatment related toxicity is not expected from budesonide/formoterol, when used as directed.  
For overdose, see Section 6.5.
6.8
Study governance and oversight
6.8.1
Independent adjudication committee for fatal events
An independent external adjudication committee will be constituted to provide an 
independent, external and unbiased assessment of fatal events reported during the study in 
order to determine whether the death may have been related to asthma.  The committee will 
operate in accordance with an Adjudication Committee Charter, which will also provide detail 
on specific information the committee requires to enable the adjudication.
Following adjudication a notification will be sent to the AstraZeneca senior medical officer in 
order to decide whether a Data Safety Monitoring Board should be appointed for further 
review of safety data in the studies.


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Investigational product
Dosage form and strength
Manufacturer
Symbicort Turbuhaler 160/4.5 μg
(Budesonide / formoterol fumarate 
dihydrate 160/4.5 μg)
Budesonide / formoterol fumarate dehydrate 
powder for inhalation, 160 μg budesonide and 
4.5 μg formoterol per inhalation, 120 doses
AstraZeneca
Terbutaline Turbuhaler 0.4 mg
(terbutaline sulphate 0.4mg)
Terbutaline sulphate powder for inhalation, 
0.4 mg terbutaline per inhalation, 120 doses
AstraZeneca
Pulmicort Turbuhaler 200 μg 
(budesonide 200 μg)
Budesonide powder for inhalation, 200 μg per 
inhalation, 200 doses
AstraZeneca
Placebo for budesonide (Placebo 
Turbuhaler) 
Placebo powder for inhalation, 200 doses
AstraZeneca
Budesonide/formoterol, terbutaline, budesonide and placebo for budesonide will all be 
dispensed as inhalers (Turbuhaler).  Budesonide/formoterol, terbutaline and placebo for 
budesonide inhalers contain lactose as part of the filling material whereas the budesonide 
inhaler and the Bricanyl Turbuhaler do not.
The terbutaline Turbuhaler 0.4 mg corresponds to Bricanyl Turbuhaler 0.5 mg with regards to 
the dose delivered.  The terbutaline Turbuhaler 0.4 mg dose is expressed as delivered dose 
whereas the Bricanyl Turbuhaler 0.5 mg dose is expressed as metered dose.  The terbutaline 
Turbuhaler 0.4 mg product is a clinical trial product that is blinded against the Symbicort 
Turbuhaler.
The budesonide dose in Pulmicort Turbuhaler, 200 μg expressed as metered dose, corresponds 
to the budesonide dose in Symbicort Turbuhaler, 160 μg expressed as delivered dose.
7.1.1
Non-investigational medicinal product for run-in and for post-bronchodilator 
lung function measurements
Additional study drug
Dosage form and strength
Manufacturer
Bricanyl Turbuhaler
0.5 mg 
Terbutaline sulphate powder for inhalation, 
0.5 mg terbutaline per inhalation, 100 doses
AstraZeneca
Bricanyl is a non-investigational medicinal product since it is used only ‘as needed’ during the 
run-in period and as a bronchodilator during the lung function measurements.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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7.2
Dose and treatment regimens
Priming of the Turbuhaler
All Turbuhaler inhalers need to be primed before their initial use.  The priming should only be 
executed once per Turbuhaler (priming should not be repeated even if the inhaler is not used 
regularly).  The Investigator will prime the Bricanyl Turbuhaler at Visit 2 before attaching a 
TUM and giving it to the patient.  At subsequent visits this procedure should be repeated for 
all Turbuhalers.  Instructions on how to use the Turbuhaler will be provided in local language 
to the patients.
The priming procedure:
Remove cover.  Hold the inhaler in an upright position and turn the grip as far as possible in 
both directions.  Perform this step twice.  The first dose can now be loaded.
Run-in period (Visit 2 to Visit 3)
An empty Turbuhaler will be used for training purpose.  The training Turbuhaler should be 
kept at the study site and should not be taken home by the patients.  The training Turbuhaler 
will be labelled with an English label only.
Bricanyl Turbuhaler will be dispensed from Visit 2 and will be used as ‘as needed’ medication 
during the run-in period.  Bricanyl Turbuhaler will have blue grip and blue label.  Patients will 
be instructed to use Bricanyl Turbuhaler whenever needed to relieve asthma symptoms but not 
for prophylactic reasons.  In addition, those patients who are treated with low-dose ICS or 
LTRA at study entry will be asked to stop taking these medications at Visit 2.
The Bricanyl Turbuhaler will also be used for the post-bronchodilator FEV1 and FVC 
measurements at Visits 2-8.
Treatment period (Visits 3 to 8)
At Visit 3 patients will be randomised to one of the 3 treatment groups with IP:
∀
Maintenance Placebo BID (twice daily) + Symbicort 160/4.5 μg ‘as needed’
∀
Maintenance Pulmicort 200 μg BID + terbutaline 0.4 mg ‘as needed’
∀
Maintenance Placebo BID + terbutaline 0.4 mg ‘as needed’.
At Visit 3 all randomised patients will receive maintenance study drug containing either 
Pulmicort or placebo as well as ‘as needed’ study drug, containing either Symbicort or 
terbutaline.
To avoid confusion, the maintenance Turbuhalers and the Turbuhalers for ‘as needed’ 
treatment will have labels with different colours and the Turbuhaler grip will have different 
colours for the two different treatments.  The maintenance Turbuhaler will have brown grip 
and yellow label. During the treatment period the Turbuhaler for ’as needed’ treatment will 


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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have white grip and white label.  The patients will be instructed to take one inhalation from 
the inhaler with the brown grip every morning upon rising and every evening before going to 
bed.  Patients will further be instructed to take one inhalation from the inhaler with the white 
grip whenever needed to relieve asthma symptoms but not for prophylactic use.
The patient should take the first dose of maintenance IP (morning dose) at the study site.
During the treatment period, the patients are allowed to use up to 12 inhalations of the ‘as 
needed’ medication during one single day.  If a patient needs more ‘as needed’ medication in 
one single day, the patient will be instructed to contact the investigator for reassessment of 
condition.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the inhaler specifies the appropriate storage.
7.5
Compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF.
Indication of study drug intake will be captured by TUM (see Section 5.1.8).  The eDiary will 
facilitate patient compliance.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study site personnel will also account for all study drugs dispensed to and returned from 
the patient.
Study site personnel will account for all study drugs received at the site, unused study drugs 
and drugs for appropriate destruction.  Certificates of delivery, destruction and return should 
be signed.
Study Drug is destroyed once there are satisfactory records of product accountability by the 
Monitor and the Study Leader has given authorisation.  The destruction of used and unused 
Study Drugs should preferably be done at the study site.  If destruction at the study site is not 
possible, the study site personnel should work with the Monitor to ensure Study Drugs are 
destroyed at a site approved by the local regulatory authority and in accordance with local 
regulations.  A Certificate of Destruction should be filed.


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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7.7
Concomitant and other treatments 
7.7.1
Prohibited Medication
In order not to affect the reversibility test at Visit 2 and/or at Visit3, patients should not have 
received the medications listed in Table 2 below within the given time limits prior to the visit.  
Asthma medication before study start is defined by inclusion criterion 4 not by Table 2.
Table 2
Medications which may affect the reversibility test at Visit 2 and/or 
at Visit 3
Not allowed before Visit 2
Time limit prior to Visit 2
1.*
Inhaled disodium cromoglycate or inhaled nedocromil sodium
6 hours
2.*
Inhaled short-acting anticholinergics
6 hours
3.
Inhaled SABAs
6 hours
4.*
Inhaled long-acting β2-agonists (LABA)
formoterol
salmeterol
oladaterol
indacaterol
24 hours
24 hours
48 hours
72 hours
5.*
Oral ∃2-agonists as follows:
short-acting
depot
long-acting
6 hours
24 hours
48 hours
6.*
Transdermal ∃2-agonists
24 hours
7.*
Leukotriene receptor antagonist or 5-lipoxygenase inhibitors
48 hours
8.*
Xanthines:
once daily
twice daily
24 hours
12 hours
9.*
Inhaled anticholinergics:
acledinium
tiotropium
glycopyrrolate
24 hours
48 hours
48 hours
10.*
Medications containing ephedrine
24 hours
* Not allowed during run-in


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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Table 3
Medications Not Allowed from Visit 2 to Visit 8
Not allowed from Visit 2 to Visit 8
1.
Oral, parenteral or rectal GCS 
2.
Any ICS other than study medication
3.
Any β2-agonist other than the study medication
4.
Inhaled disodium cromoglycate or inhaled nedocromil sodium
5.
Leukotriene receptor antagonists or 5-lipoxygenase inhibitors 
6.
Xanthines
7.
Inhaled anticholinergics
8.
Phosphodiesterase inhibitors
9.
Omalizumab or any other monoclonal or polyclonal therapy for any reason
10.
Beta-adrenergic blockers including eye-drops
11.
Systemic treatment with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazol and 
ritonavir)
For exceptions see Section 7.7.2 below.
7.7.2
Concomitant asthma treatment
Severe asthma exacerbation treatment: Oral or parenteral GCS are allowed in case of a 
suspected severe asthma exacerbation, see Section 5.1.1.  During a severe asthma 
exacerbation, treatment with the concomitant medications included in Number 2-7 (Table 3) is 
also allowed.
Moderate asthma exacerbation treatment: Addition of prescribed ICS (budesonide 200 μg bid) 
to the blinded maintenance treatment is allowed in case of a moderate asthma exacerbation, 
see Section 5.1.1.
Long-term poor asthma control treatment: Addition of prescribed ICS (budesonide 200 μg 
bid) to the blinded maintenance treatment is allowed in case of long-term poor asthma control, 
see Section 5.1.1.
Other allowed asthma-related medications:
∀
Mucolytics and expectorants not containing bronchodilators
∀
Patients on allergen-specific immunotherapy (desensitization) must have been on a 
maintenance regimen for at least 4 weeks prior to Visit 2 and remain on a 
maintenance regimen during the study.  Patients should not begin allergen-specific 
immunotherapy during the course of the study
∀
Topical, nasal or ocular formulations of GCS, disodium chromoglycate and/or 
nedocromil sodium


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Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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7.7.2.1
Prescribed inhaled budesonide 200 μg BID
Budesonide 200 μg (metered dose) BID as additional ICS treatment in case of exacerbation or 
long term poor asthma control is not regarded as an investigational product.  It shall be 
prescribed by the investigator and reimbursed (to the prescribing investigator, patient, site 
institution or vendor, as appropriate) by AstraZeneca as permitted by local regulations, to 
maintain oversight and access to this concomitant medication.
The administration of prescribed ICS should be recorded in the appropriate section of the 
eCRF.
7.7.3
Other concomitant treatment
Medication other than that described above, which is considered necessary for the patient’s 
safety and well being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF.
7.8
Post Study Access to Study Treatment
After completion of study treatment patients will receive asthma medication prescribed 
according to the investigator's judgment and local medical practice.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violators identified.
Analyses will be performed by AstraZeneca or its representatives.
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first patient 
randomised and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data.
8.2
Sample size estimate
In this section the following brief terms are used to describe the three treatment arms:
Treatment arm
Brief term used
Maintenance Placebo BID (twice daily) + 
Symbicort 160/4.5 μg ‘as needed’
Symbicort
Maintenance Pulmicort 200 μg BID + 
terbutaline 0.4 mg ‘as needed’
Pulmicort plus terbutaline
Maintenance Placebo BID + terbutaline 
0.4 mg ‘as needed’
terbutaline


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
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The study is powered to assess both the primary objective of comparing Symbicort versus (vs) 
terbutaline and the secondary objective to estimate the relative efficacy of Symbicort vs 
Pulmicort plus terbutaline in the overall population and pre-study treatment groups.  The 
estimation of relative efficacy between the 2 treatments will be done as described in the 
“EMA reflection paper on the need for active control in therapeutic areas where the use of 
placebo is deemed ethical.” (EMA 2010).  It is planned to estimate the relative efficacy of 
Symbicort and to conclude that Symbicort is non-inferior to Pulmicort plus terbutaline if the 
lower limit of the 95% confidence interval of the relative efficacy is ≥0.8 (assessed using an 
odds ratio).
This number (≥0.8) is based on the assumption that this study will show similar efficacy 
between Symbicort and Pulmicort plus terbutaline for the primary endpoint, well controlled 
asthma weeks.  Moreover, it has been assumed both treatments will demonstrate superiority to 
terbutaline.  There is limited data regarding the relative efficacy of Symbicort vs Pulmicort
plus terbutaline.  In the assessment of benefit/risk, the potential risk of a lower efficacy will be 
assessed in the context of any benefits on other variables including effects on exacerbations 
and potentially reduced steroid load.
Thus, after demonstration of superiority vs terbutaline, relative efficacy will be evaluated.  
The relative efficacy of Symbicort vs Pulmicort plus terbutaline will be estimated as the odds 
ratio of well-controlled weeks on the Symbicort arm as compared to Pulmicort plus terbutaline 
arm.
The number of patients required for the analyses was estimated to be 3750 overall 
(625/treatment group/pre-study treatment group).  This was based on the following 
assumptions:
∀
The treatment effect of Pulmicort plus terbutaline vs terbutaline is an odds ratio of 
1.39 (based on results from post-hoc analyses of study SD-037-0345, data on file)
∀
Symbicort as has the same level of efficacy as Pulmicort plus terbutaline
∀
Data will follow a similar pattern to that observed in study SD-037-0345, which 
was performed in a similar patient population.
Simulations were performed on the pattern of data observed in the study SD-037-0345. The 
sample size of 3750 patients gives:
∀
Overall, >95% power to detect a difference between Symbicort and terbutaline
∀
Overall 90% power to achieve non-inferiority of Symbicort vs Pulmicort plus 
terbutaline with a pre-defined NI limit of 0.8 - i.e., the lower 95% confidence 
interval of the odds ratio for Symbicort compared to Pulmicort plus terbutaline is
≥0.8.


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Since it is also important to estimate the treatment effects within each of the strata (defined by 
pre-study treatment) the sample size assessments were also done assuming that 1875 were 
recruited in each group and this gives:
∀
80% power to detect a difference between Symbicort and terbutaline
∀
80% power to achieve non-inferiority of Symbicort vs Pulmicort plus terbutaline
with a pre-defined NI limit of 0.78 - i.e., the lower 95% confidence interval of the 
odds ratio for Symbicort compared to Pulmicort plus terbutaline is ≥0.78.
8.3
Definitions of analysis sets
8.3.1
Full analysis set
All patients randomised and receiving any investigational product will be included in the full 
analysis set, irrespective of their protocol adherence and continued participation in the study.  
Patients will be analysed according to their randomised treatment.
The efficacy analysis set will be based on the ‘full analysis set’ in line with the ICH E9 
guideline.
8.3.2
All patients analysis set
This analysis set comprises all patients screened for the study and will be used for reporting of 
disposition and enrolment failures.
8.3.3
Safety analysis set
All patients receiving any investigational product will be included in the safety analysis 
population.  Patients will be classified according to the treatment they actually received.  
Erroneously treated patients (e.g., those randomised to treatment A but actually given 
treatment B) will be accounted for in the actual treatment group.  The classification of patients 
will be finalised prior to database lock and documented in the Statistical Analysis Plan.  All 
safety summaries will be based on this analysis set.
8.4
Outcome measures for analyses
8.4.1
Derivation of efficacy variables
8.4.1.1
Derivation of well-controlled asthma weeks (primary variable)
Well-controlled asthma weeks
A well-controlled asthma week is defined as the fulfilment of both conditions below:
∀
Two or more of the following criteria are fulfilled:
!
No more than 2 days with a daily asthma symptom score >1


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!
No more than 2 days of ‘as needed’ medication use, up to a maximum of 
4 occasions per week (multiple occasions per day should be regarded as 
separate occasions)
!
Morning PEF ≥80% of PN every day
∀
Both of the following criteria are fulfilled:
!
No nighttime awakenings due to asthma
!
No additional inhaled and/or systemic glucocorticosteroid treatment due to 
asthma.
For each patient and study week, the binary variable well-controlled asthma week will be 
derived. In addition, for each week the percent of patients with well-controlled asthma week 
will also be derived.
It is required that the eDiary has to be completed on at least 5 days in a week to be a well-
controlled asthma week.
8.4.1.2
Derivation of time to first moderate, severe and moderate-to-severe asthma 
exacerbation
Time to first moderate, severe and moderate-to-severe asthma exacerbation (see Section 5.1.1) 
will be calculated as the time from randomisation until the start date of the first asthma 
exacerbation (moderate or severe) i.e.:
Start Date of first asthma exacerbation – Date of Randomisation + 1
Patients not having any asthma exacerbation will be considered as censored at the date of their 
last visit or, for patients discontinuing the study, the day when it was decided that the patient 
should discontinue the study.
Maximum follow-up time for a patient is approximately 52 weeks; defined as the time from 
randomisation to the date of Visit 8.  For a patient lost to follow-up, this will be defined as the 
time from randomisation to the time point after which an exacerbation could not be assessed.
8.4.1.3
Derivation of the number of moderate, severe and moderate-to-severe asthma 
exacerbations
The total number of moderate, severe, and moderate-to-severe asthma exacerbations (see 
Section 5.1.1), respectively will be calculated for each patient during the 52-week randomised 
treatment period according to the following principle:


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For the production of summary statistics, the annual exacerbation rate per patient is calculated, 
and standardized using data from the 52-week double-blind treatment period according to the 
formula described below:
Annual Exacerbation Rate = Number of Exacerbations*365.25 / (Follow-up date –
Visit 3 date + 1)
8.4.1.4
Derivation of time to administration of additional steroids for asthma
Time to administration of additional steroids for asthma will be calculated as the time from 
randomisation until the start date of administration of additional steroids for asthma i.e.:
Start Date of administration of additional steroids – Date of Randomisation + 1
Patients not receiving additional steroids will be considered as censored at the date of their last
visit or, for patients discontinuing the study, the day when it was decided that the patient 
should discontinue the study.
Maximum follow-up time for a patient is approximately 52 weeks; defined as the time from 
randomisation to the date of Visit 8.
8.4.1.5
Derivation of total inhaled steroid load and number of days with systemic GCS 
treatment
Total inhaled steroid load during the randomised 52 week treatment period will be calculated 
for each patient as the sum of the cumulative doses of maintenance ICS (budesonide), ‘as 
needed’ ICS as part of Symbicort (budesonide), and prescribed inhaled budesonide.  Data on 
IP will be recorded via the TUM, while prescribed inhaled budesonide will be collected via 
the appropriate CRF module.
The number of days with systemic GCS will be recorded via the appropriate CRF module.
8.4.1.6
Derivation of controller use days
Controller use days during the randomised treatment period will be calculated as the 
cumulative days when any controller medication containing ICS (including Pulmicort, 
Symbicort and any other inhaled corticosteroid) was taken divided by the follow-up time 
(number of days).
Controller use will be defined as the ‘as needed’ use for the Symbicort treatment arm, the 
maintenance use for the Pulmicort treatment arm, and any additional prescribed inhaled 
corticosteroid which is applicable for all treatment arms. Data on IP will be recorded via the 
TUM, while prescribed inhaled corticosteroid will be collected via the appropriate CRF 
module.


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8.4.1.7
Derivation of time to asthma related discontinuation
Study specific asthma related discontinuation criteria are given by:
∀
A severe asthma exacerbation with duration for more than 3 weeks
∀
Two severe asthma exacerbations during 3 months
∀
Three severe asthma exacerbations in total during the study
Time to discontinuation due to any of the specified asthma related events will be calculated as:
Date of study termination due to any asthma related event – Date of Randomisation + 1
Patients not discontinuing the study due to asthma related events will be considered as 
censored at the date of their last visit or, for patients discontinuing the study, the day when it 
was decided that the patient should discontinue the study for whatever reason.
8.4.1.8
Derivation of lung function variables
Change from baseline (Visit 3) to Visits 4, 5, 6, 7 and 8 will be calculated for each patient for 
the following lung function variables:
∀
Pre- and post-bronchodilator FEV1 (L)
∀
Pre- and post-bronchodilator FEV1 % of predicted normal
∀
Pre- and post-bronchodilator FVC (L)
If the baseline measurement is missing, the last non-missing value before Visit 3 will be used 
as baseline instead.
Percent predicted of normal for pre- and post-bronchodilator FEV1 will be calculated 
according to Quanjer et al 2012.
8.4.1.9
Derivation of electronic diary variables
The following variables will be derived for the electronic diary variables:
∀
Morning and evening PEF
∀
‘As needed’ medication (nighttime, daytime and total)
∀
Asthma symptom score (nighttime, daytime and total)
∀
Nights with awakening(s) due to asthma symptoms


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Change from baseline will be calculated for each patient as defined by the change in all post-
randomisation observations to baseline, where baseline is defined as the mean of the 
measurements 10 days prior to randomisation during run-in.
Symptom-free days
A symptom-free day is defined as the fulfilment of both of the following criteria:
∀
A day and night with no asthma symptoms (i.e.: asthma symptom score=0)
∀
A night with no awakenings due to asthma symptoms
‘As needed’-free days
An ‘as needed’-free day is defined as a day and night with no use of ‘as needed’ medication.
Asthma-control days
An asthma control day is defined as the fulfilment of all of the following criteria:
∀
A day and night with no asthma symptoms (i.e., asthma symptom score=0)
∀
A night with no awakenings due to asthma symptoms
∀
A day and night with no use of ‘as needed’ medication
Well-controlled asthma weeks (see definition in Section 8.4.1.1)
Poorly controlled asthma weeks
A poorly controlled asthma week is defined as the fulfilment of one of the following 
conditions:
∀
Two or more consecutive days with awakenings due to asthma on both nights
∀
A recorded use of ‘as needed’ medication for symptom relief of at least 3 occasions 
per day, for at least 2 consecutive days
∀
Additional systemic GCS treatment required for severe exacerbation
Partly controlled asthma weeks
A partly controlled asthma week is defined as, if the patient does not fulfil neither the criteria 
of a well-controlled asthma week nor of a poorly controlled asthma week.


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8.4.2
Derivation of patient reported outcome variables
8.4.2.1
Derivation of ACQ-5
All 5 symptom questions are assessed on a 7-point scale from 0 to 6 where 0 represents good 
control and 6 represents poor control.  The overall score is the mean of the 5 items.  At least 
4 out of the 5 symptom items are needed to provide an ACQ score.
The minimal important difference (MID) has been defined as “the minimal change in score 
which clinicians consider to be clinically important and which would mandate, in the absence 
of troublesome side effects and undue cost, a change in the patient’s management”.  For the 
ACQ, it has been estimated to be a change in score of 0.5 (Juniper et al 2005 /2).
Baseline is defined as the ACQ-5 assessment at Visit 3.  In case of a missing value the Visit 2 
value will be used instead.
Based on MID the following variables will be derived:
∀
Patients improved (end of treatment – baseline) ≤-0.5
∀
Patients unchanged (end of treatment – baseline) within (-0.5; 0.5)
∀
Patients worsened (end of treatment – baseline) ≥0.5.
In addition, an asthma control variable based on ACQ-5 will be derived as:
∀
If the ACQ-5 value at the last visit (or last available value) is less than 0.75 the 
patient would be considered to be ‘in control’.  Otherwise ‘not in control’.
8.4.2.2
Standardised Asthma Quality of Life Questionnaire (AQLQ(S))
AQLQ(S) consists of 32 questions all assessed on a 7-point Likert scale from 1 to 7, with 
higher values indicating better health-related quality of life.  Domain scores as well as the 
overall scores are calculated from the unweighted arithmetic means of the individual question 
scores.  Differences between the follow-up visits and the baseline measure (Visit 3) for each 
of the domains and the overall scores will be calculated.  In addition the difference between 
the patients last measurements and baseline will be calculated.  For overall health-related 
quality of life and for each of the domains, the MID has been determined to be a change in 
score of 0.5 (Juniper et al 1994).
Baseline is defined as the assessment at Visit 3.  In case of a missing value the Visit 2 value 
will be used instead.
Based on MID the following variables will be derived:
∀
Patients improved (end of treatment – baseline) ≥0.5
∀
Patients unchanged (end of treatment – baseline) within (-0.5; 0.5)
∀
Patients worsened (end of treatment – baseline) ≤-0.5.


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8.4.3
Derivation of safety variables
8.4.3.1
Vital signs
Change from baseline (Visit 2) to week 52 (Visit 8) in pulse and blood pressure will be 
calculated for each patient.
8.4.3.2
Other significant adverse events (OAE)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs.  Based on the expert’s judgement, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such in the Clinical 
Study Report.  A similar review of vital signs data will be performed for identification of 
OAEs.
8.5
Methods for statistical analyses
∀
All tests will be 2-sided and at 5% level of significance unless otherwise stated.
∀
For all repeated measures analyses, missing at random (MAR) will be assumed.
∀
In addition the analyses described below, all variables will be summarised 
descriptively, as appropriate.
8.5.1
Analysis of the primary variable
The primary variable well-controlled asthma weeks (binary) will be analysed by a repeated 
measures logistic regression model with treatment, pre-study treatment, region as fixed 
effects, study week as a categorical variable, and patient as a random effect.  
Exchangeable structure of the correlation matrix will be used in the model i.e., correlations 
between all time points assumed equal.  The statistical inference will be based on the 
estimated odds-ratio (treatment A vs treatment B) and corresponding 95% confidence interval 
averaged over the whole randomised treatment period. The planned treatment comparisons 
are:
1.
Symbicort vs terbutaline (superiority, primary objective)
2.
Symbicort vs Pulmicort plus terbutaline (non-inferiority)
Formally, the null and alternative hypothesis for comparison 1 is:
H0: odds-ratio (Symbicort vs terbutaline) = 1
HA: odds-ratio (Symbicort vs terbutaline) ≠ 1
Hence, the odds of a well-controlled asthma week on Symbicort must be greater than the odds 
of a well-controlled asthma week on terbutaline in order to declare superiority.


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And for comparison 2:
H0: lower 95% confidence limit of odds-ratio (Symbicort vs Pulmicort plus 
terbutaline) <0.8
HA: lower 95% confidence limit of odds-ratio (Symbicort vs Pulmicort plus 
terbutaline) ≥0.8
Hence, the odds of a well-controlled asthma week on Symbicort must be ≥ 0.8 of the odds of a 
well-controlled asthma week on Pulmicort plus terbutaline in order to declare non-inferiority.  
The selection of 0.8 of the non-inferiority margin is detailed in section 8.2 of the protocol.
The two hypotheses will be tested sequentially.  If the comparison 1 fails, no formal statistical
inference will be made for comparison 2.
An important consideration when interpreting the results of the comparison of Symbicort to 
Pulmicort plus terbutaline is the extent to which the primary endpoint is driven by ‘as needed’ 
medication use.  A key component of the primary endpoint is the use of ‘as needed 
medication’ which is confounded with the different treatment regimes. In particular the use of 
Pulmicort maintenance treatment may result in a higher proportion of well controlled asthma
weeks, due to less 'as needed' medication use, even if overall asthma control is truly similar to 
Symbicort as needed treatment (as all Symbicort use is counted as ‘as needed medication’). 
Several supportive analyses will be conducted, including analysis of the individual 
components of the primary endpoint, adjusting the as needed threshold in the primary 
endpoint and thoroughly describing the pattern of as needed use. The aim is to look for 
consistency of the treatment effect, across the analyses and secondary endpoints to aid 
interpretation. More details of the analyses will be given in the SAP.
Missing data: If not all elements of the electronic diary are available, then the available data 
will be used to derive the presence or absence of a well controlled asthma week whenever 
possible, if the data are indeterminate then the week will be recorded as missing.  Sensitivity 
analyses to explore the potential impact of any missing data will be defined in the SAP.
8.5.2
Analysis of the secondary variables
For all secondary variables stated below the following treatment comparisons will be made:
1.
Symbicort vs terbutaline
2.
Symbicort vs Pulmicort plus terbutaline
The two hypotheses will be tested sequentially for each secondary endpoint if the primary 
endpoint is significant.  If the comparison 1 fails, no formal statistical inference will be made 
for comparison 2.


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Exacerbations:  The number of moderate-to-severe and severe asthma exacerbations will be 
analysed by a negative binomial regression model.  The response variable in the model will be 
the number of moderate-to-severe and severe asthma exacerbations over the 52-week 
treatment period, respectively.  The model will include covariates of treatment, pre-study 
treatment and region as factors.  The logarithm of the follow-up time will be used as an offset 
variable.  From the negative binomial model the annual moderate-to-severe and severe 
exacerbation rates will be estimated and treatments effects will be expressed as the rate ratio 
along with its corresponding 95% confidence intervals.
Time to first moderate-to-severe and time to first severe asthma exacerbation will be analysed 
by a Cox proportional hazards model with treatment, pre-study treatment and region as 
factors.  The hazard ratio and its corresponding 95% confidence interval will be estimated 
from the model.
Additional steroids for asthma:  Time to the administration of additional steroids for asthma 
will be analysed by a Cox proportional hazards model with treatment, pre-study treatment and 
region as factors.  The hazard ratio and its corresponding 95% confidence interval will be 
estimated from the model.
Steroid load:  The total inhaled steroid load and the number of days with systemic GCS, 
respectively will be presented descriptively by treatment.
Controller use days: The percentage of controller use days will be analysed by analysis of 
covariance (ANCOVA) with treatment, pre-study treatment group and region as factors.  
Least squared means by treatment and differences in least squared means (between 
treatments) along with corresponding 95% confidence intervals will be estimated.
Discontinuation due to asthma related events:  Time to study discontinuation due to asthma 
related events will be analysed by Cox proportional hazards model with treatment, pre-study 
treatment and region as factors.  The hazard ratio and its corresponding 95% confidence 
interval will be estimated from the model.
FEV1:  The treatment effect for change from baseline (Visit 3) in FEV1, will be estimated 
using a mixed model repeated measures (MMRM) analysis.  FEV1 data from visits 4, 5, 6, 7 
and 8 will be included in the model, with terms for treatment, pre-study treatment, region, visit 
and treatment*visit.  Baseline FEV1 (Visit 3) will be included as a covariate.  Visit will be 
fitted as a categorical variable, and the variance-covariance matrix will be assumed to be 
unstructured.  If the procedure does not converge then a compound symmetric variance-
covariance matrix will be used instead.
This model will be used to give an overall assessment of the treatment effect as well as 95% 
confidence intervals.


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Summary statistics will be presented for change from baseline across all the time points in the 
trial for FEV1 (L) by treatment.
PRO variables:  ACQ-5 and AQLQ will be analysed in the same way as FEV1 using MMRM 
analysis.  In addition, change from baseline to the end of treatment will also be analysed from 
the model.
Responder variables based on MID for ACQ-5 and AQLQ(S) will be analysed using a logistic 
regression model with treatment, region and pre-study treatment as factors, and baseline as a 
covariate.  From the logistic regression model treatment effects will be estimated by odds-
ratio and its corresponding 95% confidence interval.
The responder variable ACQ-5 <0.75 at the end of treatment will be analyzed using a logistic 
regression model with treatment, region and pre-study treatment as factors, and baseline as a 
covariate.  From the logistic regression model treatment effects will be estimated by odds-
ratio and its corresponding 95% confidence interval.
Electronic diary variables:  The change in the mean morning PEF during run-in period to the 
mean value of available data during the randomised treatment period will be analysed by 
analysis of covariance (ANCOVA) with treatment, pre-study treatment and region as factors, 
and the mean PEF value during run-in as a continuous covariate.  Least squared means by 
treatment and differences in least squared means (between treatments) along with 
corresponding 95% confidence intervals will be estimated.
The change from baseline in evening PEF, asthma symptom score (day, night and total), use 
of ‘as needed’ medication (day, night and total), awakening(s) due to asthma symptoms, 
symptom-free days, asthma-control days, and ‘as needed’-free days will all be analysed in the 
same way as described for morning PEF above.
Poorly controlled asthma weeks will be analysed in the same way as well-controlled asthma 
weeks (see Section 8.5.1).
Well-controlled asthma weeks, partly controlled asthma weeks and poorly controlled asthma 
weeks will be jointly depicted graphically by week and treatment.
8.5.3
Subgroup analysis
The assessment of treatment effect will also be investigated in the 2 subgroups as defined by 
pre-study treatment to assess the consistency of the treatment effect.  This will be done for 
each of the primary and secondary variables by including a pre-study treatment*treatment 
interaction term in the models.
8.5.4
Sensitivity analysis
Sensitivity analyses of the primary and key secondary variables will be carried out and will be 
specified in the SAP.


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8.5.5
Analysis methods for safety variables
AEs will be summarized by means of count summaries.  AEs will be listed for each patient 
and summarized by System Organ Class and Preferred Term assigned to the event by 
MedDRA.  Other safety variables will be summarized as appropriate.  Further details will be 
provided in the SAP.
8.5.6
Analysis methods for exploratory variables
The exploratory variables will be analysed from qualitative interviews with patients who 
participated in the sub-study.  Due to the qualitative nature of the data and the analysis, the 
results will be presented in a separate report (i.e. not in the clinical study report) and the data 
(i.e. transcriptions) will not be entered into the study database.  Refer to Appendix F.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC, 
IVRS/IWRS and electronic PRO (eDiary) system(s) utilised.
The investigator and study site staff should have prior experience in performing spirometry.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
∀
Provide information and support to the Investigator(s)
∀
Confirm that facilities remain acceptable
∀
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs and that study drug accountability 
checks are being performed
∀
Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients.  This 
will require direct access to all original records for each patient (e.g., clinic charts).


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The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the site needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
9.2.2
Study agreements
The Principal Investigator at each site should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study is expected to start in Quarter II in 2014 and to end by Quarter III in 2017.
The study may be terminated at individual sites if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with budesonide/formoterol.
9.4
Data management by Cognizant Data Management Centre
Data management will be performed by Cognizant Data Management Centre staff, according 
to the Data Management Plan. Adverse events and medical/surgical history will be classified 
according to the terminology of the latest version the Medical Dictionary for Regulatory 
Activities (MedDRA).  Medications will be classified according to the AstraZeneca Drug 
Dictionary.  Classification coding will be performed by the Medical Coding Team at the 
AstraZeneca Data Management Centre.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail.


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The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database.
Management of external data
Data Management determines the format of the data to be received from external vendors and 
coordinates the flow of data to the clinical database.  Data Management will ensure that the 
data collection tool (e.g., eDiary, TUM and IVRS etc) will be tested and validated.  External 
data reconciliation will be done with the clinical database as applicable.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements, applicable regulatory requirements and the AstraZeneca policy on 
Bioethics and Human Biological Samples.
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final study protocol, including the final version of 
the Informed Consent Form and any other written information and/or materials to be provided 
to the patients.  The Investigator will ensure the distribution of these documents to the 
applicable Ethics Committee, and to the study site staff.
The opinion of the Ethics Committee should be given in writing.  The Investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study.
The Ethics Committee should approve all advertising used to recruit patients for the study.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
69(73)
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
In countries where applicable: Each Principal Investigator is responsible for providing the 
Ethics Committees/Institutional Review Boards (IRB) with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the investigational 
product.  AstraZeneca will provide this information to the Principal Investigator so that he/she 
can meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each site will:
∀
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study
∀
Ensure each patient is notified that they are free to discontinue from the study at any 
time
∀
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided
∀
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study
∀
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File
∀
Ensure a copy of the signed Informed Consent Form is given to the patient
∀
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an Ethics Committee.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
70(73)
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s).  For distribution to Ethics Committee see Section 10.3.
If a protocol amendment requires a change to a site’s Informed Consent Form, AstraZeneca 
and the site’s Ethics Committee are to approve the revised Informed Consent Form before the 
revised form is used.
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the site, including source data verification.  The purpose 
of an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analysed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the site.
11.
LIST OF REFERENCES
Ankerst et al 2003
Ankerst J, Persson G, Weibull E. Tolerability of high dose of budesonide/formoterol in a 
single inhaler in patients with asthma. Pulm Pharmacol Ther 2003;13(3):147-51.
Atienza et al 2013
Atienza T, Aquino T, Fernández M, Boonsawat W, Kawai M, Kudo T et al. 
Budesonide/formoterol maintenance and reliever therapy via Turbuhaler versus fixed-dose 
budesonide/formoterol plus terbutaline in patients with asthma: phase III study results. 
Respirology 2013 Feb;18(2):354-63.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
71(73)
Bateman et al 2004
Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels R, et al (2004) Can 
guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL 
(GOAL) Study. Am J Respir Crit Care Med, 170:836-44.
Chuchalin et al 2005
Chuchalin A, Kasl M, Bengtsson T, Nihlen U, Rosenborg J. Formoterol used as needed in 
patients with intermittent or mild persistent asthma. Respir Med 2005;99:461-70.
CHMP 2013
The European Agency for the Evaluation of Medicinal Products. Note for guidance on the 
clinical investigation of medicinal products in the treatment of asthma. CHMP/EWP/2922/01,
Rev.1, June 2013.
Dusser et al 2007
Dusser D, Montani D, Chanez P, de Blic J, Delacourt C, Deschildre A et al. Mild asthma: an 
expert review on epidemiology, clinical characteristics and treatment recommendations. 
Allergy 2007;62:591-604.
EMA 2010
European Medicines Agency. Reflection paper on the need for active control in therapeutic 
areas where use of placebo is deemed ethical and one or more established medicines are 
available. November 2010.
GINA 2012
Global Initiative for Asthma (GINA). Strategy for Asthma Management and Prevention 2012.
Haahtela et al 2006
Haahtela T, Tamminen K, Malmberg LP, Zetterstrom O, Karjalainen J, Yla-Outinen H, et al. 
Formoterol as needed with or without budesonide in patients with intermittent asthma and 
raised NO levels in exhaled air: A SOMA study. Eur Respir J 2006;28(4):748-55.
Horne et al 2006
Horne R. Compliance, adherence and concordance: Implications for asthma treatment. Chest 
2006;130(1 suppl):65-72.
Juniper et al 1992
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;47:76-83. 
Juniper et al 1994
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;47:81-7.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
72(73)
Juniper et al 1999
Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Validation of a standardized version of 
the Asthma Quality of Life Questionnaire. Chest 1999;115:1265-70. 
Juniper et al 2001
Juniper EF, O’Byrne PM, Roberts JN. Measuring asthma control in group studies: do we need 
airway calibre and rescue β2-agonist use? Respir Med 2001;95:319-23. 
Juniper et al 2005
Juniper EF, Svensson K, Mörk AC, Ståhl E. Modification of the asthma quality of life 
questionnaire (standardised) for patients 12 years and older. Health Qual Life Outcomes 
2005;3:58.
Juniper et al 2005 /2
Juniper EF, Svensson K, Mörk A-C, Ståhl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respiratory Medicine 2005; 
99:553-558.
Miller et al 2005
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A et al. Standardisation 
of Spirometry. Eur Respir J 2005;26:319-38.
O'Byrne et al 2005
O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y et al. 
Budesonide/formoterol combination therapy as both maintenance and reliever medication in 
asthma. Am J Respir Crit Care Med. 2005;171:129-36.
Palmqvist et al 2001
Palmqvist M, Arvidsson P, Beckman O, Peterson S, Lötvall J. Onset of bronchodilation of 
budesonide/formoterol vs. salmeterol/fluticasone in single inhalers. Pulm Pharm Ther 
2001;14:29-34.
Papi et al 2007
Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, et al; BEST Study 
Group. Rescue Use of Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma. N 
Engl J Med 2007; 356:2040-2052.
Pauwels et al 2003
Pauwels RA, Pedersen S, Busse WW, Tan WC, ChenYZ, Ohlsson SV et al, on behalf of the 
START Investigators Group. Early intervention with budesonide in mild persistent asthma: a 
randomised, double-blind trial. Lancet 2003;361:1071-6.
Pauwels et al 2003b
Pauwels RA, Sears M, Campell M, Villasante C, Huang S, Lindh A. Formoterol as relief 
medication in asthma: a worldwide safety and effectiveness trial. Eur Resp J 2003;22:787-94.


Revised Clinical Study Protocol
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 4
Date 22 December 2016
73(73)
Quanjer et al 2012
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J 2012;40(6):1324-43.
Rabe et al 2004
Rabe KF, Adachi M, Lai CK, Soriano JB, Vermeire PA, Weiss KB et al. Worldwide severity 
and control of asthma in children and adults: the global asthma insights and reality surveys. 
J Allergy Clin Immunol 2004;114(1):40-7.
Rabe et al 2006
Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in 
combination with formoterol for reliever therapy in asthma exacerbations: a randomised 
controlled, double-blind study. Lancet 2006;368:744-53.
Scicchitano et al 2004
Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centanni S et al. Efficacy and 
safety of budesonide/formoterol single inhaler therapy vs a higher dose of budesonide in 
moderate to severe asthma. Curr Med Res Opin 2004;20:1403-18.
Sears and Lötvall 2005
Sears MR, Lötvall J. Past, present and future - β2 adrenoceptor agonists in asthma 
management. Resp Med 2005;99(2):152-70.
Tattersfield et al 2001
Tattersfield AE, Löfdahl CG, Postma DS, Eivindson A, Schreurs AG, Rasidakis A, et al. 
Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomised 
trial. Lancet 2001;357:257-61.
Vogelmeier et al 2005
Vogelmeier C, D'Urzo A, Pauwels R, Merino JM, Jaspal M, Boutet S et al. 
Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment 
option? Eur Respir J 2005;26:819-28.


 
 
Clinical Study Protocol Appendix B 
 
Drug Substance 
budesonide/formoterol 
 
Study Code 
D589SC00001 
 
Edition Number 
1 
 
Date 
17 January 2014 
 
 
 
 
 
 
 
 
 
 
Appendix B 
Additional Safety Information 
 
 


Clinical Study Protocol Appendix B 
Drug Substance budesonide/formoterol 
Study Code D589SC00001 
Edition Number 1 
Date 17 January 2014 
2(3) 
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE) 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
Examples of such events are: 
x
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
x
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 
x
Intensive treatment in an emergency room or at home for allergic bronchospasm 
x
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation 
x
Development of drug dependency or drug abuse. 
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug. 


Clinical Study Protocol Appendix B 
Drug Substance budesonide/formoterol 
Study Code D589SC00001 
Edition Number 1 
Date 17 January 2014 
3(3) 
x
Time Course. Exposure to suspect drug. Has the subject actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
x
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties? 
x
Dechallenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
x
No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors. 
x
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge. 
x
Laboratory tests. A specific laboratory investigation (if performed) has confirmed 
the relationship? 
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist. 
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE. 
In difficult cases, other factors could be considered such as: 
x
Is this a recognised feature of overdose of the drug? 
x
Is there a known mechanism? 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this. Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility. 


 
 
 
Clinical Study Protocol Appendix C 
 
Drug Substance 
budesonide/formoterol 
 
Study Code 
D589SC00001 
 
Edition Number 
1 
 
Date 
17 January 2014 
 
 
 
 
 
 
 
 
 
 
Appendix C 
Asthma Control Questionnaire (5-item version)  
 


ASTHMA CONTROL 
QUESTIONNAIRE
(SYMPTOMS ONLY) 
© 1997
QOL TECHNOLOGIES Ltd. 
™
For further information: 
Elizabeth Juniper, MCSP, MSc 
Professor
20 Marcuse Fields, 
Bosham,
West Sussex,
PO18 8NA.  UK 
Telephone: + 44 (0) 1243 572124 
Fax: + 44 (0) 1243 573680 
E-mail: juniper@qoltech.co.uk 
Web: www.qoltech.co.uk 
© The Asthma Control Questionnaire is copyrighted. It may not be altered, sold
(paper or electronic), translated or adapted for another medium without the 
permission of Elizabeth Juniper.
December 2002
SYMPTOMS ONLY MODIFIED 30 JAN 04
 NORTH AMERICAN ENGLISH
2


ASTHMA CONTROL QUESTIONNAIRE© 
Page 1 of 1 
Please answer questions 1 - 5 
Circle the number of the response that best describes how you have been during the past week. 
1.
On average, during the past week, 
how often were you woken by your
 
asthma during the night?
0 
Never 
1 
Hardly ever
2
A few times 
3 
Several times
4 
Many times
5
A great many times 
6
Unable to sleep because of asthma 
2.
On average, during the past week, 
 
how bad were your asthma symptoms
when you woke up in the morning? 
0 
No symptoms
1
Very mild symptoms 
2 
Mild symptoms
3 
Moderate symptoms
4
Quite severe symptoms 
5 
Severe symptoms
6
Very severe symptoms 
3.
In general, during the past week, how 
limited were you in your activities
because of your asthma?
0
Not limited at all 
1
Very slightly limited 
2 
Slightly limited
3 
Moderately limited
4 
Very limited
5 
Extremely limited
6 
Totally limited
4.
In general, during the past week, how 
 
much shortness of breath did you 
experience because of your asthma? 
0 
None 
1
A very little 
2 
A little
3
A moderate amount 
4
Quite a lot 
5
A great deal 
6
A very great deal 
5.
In general, during the past week, how 
much of the time did you wheeze?
0
Not at all 
1
Hardly any of the time 
2
A little of the time 
3
A moderate amount of the time 
4
A lot of the time 
5
Most of the time 
6
All the time 
SYMPTOMS ONLY MODIFIED 30 JAN 04
 NORTH AMERICAN ENGLISH
3


Clinical Study Protocol Appendix D
Drug Substance
budesonide/formoterol
Study Code
D589SC00001
Edition Number
2
Date
16 December 2014
Appendix D
Asthma Quality of Life Questionnaire with Standardised Activities 
(AQLQ(S)) self administered ≥ 12 years of age


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6


Clinical Study Protocol Appendix E
Drug Substance
budesonide/formoterol
Study Code
D589SC00001
Edition Number
2
Date
17 August 2015
Appendix E
Inhaled Glucocorticosteroids Equivalence Table


Clinical Study Protocol Appendix E
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 2
Date 17 August 2015
2(2)
Inhaled Glucocorticosteroids Equivalence Table
Asthma Therapy
Total Daily Dose (μg/day)
Inhaled Glucocorticosteroid
Low
Beclomethasone dipropionate (non HFA 
propellant)
200 to 500
Beclomethasone HFA*
100 to 250 
Ciclesonide 
80 to 160
Triamcinolone acetonide 
400 to 1000
Flunisolide 
500 to 1000
Fluticasone propionate 
100 to 250
Budesonide 
200 to 400
Mometasone furoate 
200 
* For some HFA beclomethasone products dose ranges related to non-HFA beclomethasone may 
apply depending on formulation.  Formulations with smaller particles size have greater lung 
disposition.  The manufacturer’s information should be reviewed in order to determine patient’s 
eligibility with regard to ICS daily dose.


Clinical Study Protocol Appendix F
Drug Substance
budesonide/formoterol
Study Code
D589SC00001
Edition Number
1
Date
24 February 2016
Appendix F
Sub-study with Qualitative Interviews


Clinical Study Protocol Appendix F
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 1
Date 24 February 2016
2 (7)
1.
INTRODUCTION
In the primary study for D589SC00001, the efficacy and safety of Symbicort®
(budesonide/formoterol) Turbuhaler® 160/4.5 μg ‘as needed’ compared with terbutaline 
Turbuhaler® 0.4 mg ‘as needed’ and with Pulmicort® (budesonide) Turbuhaler® 200 μg twice 
daily plus terbutaline Turbuhaler® 0.4 mg ‘as needed’ is evaluated. The primary endpoint in 
clinical study D589SC00001 is well controlled asthma weeks (WCAW), a well-recognized 
composite score (Bateman et al 2004) that was based on then-current guideline definitions of 
asthma control.  This composite score included the frequency of use of ‘as needed’ 
medication, and at the time of development of the composite score, this medication was 
usually a short-acting bronchodilator.  Although there have been some changes over time, 
guidelines at the time clinical study D589SC00001 was planned (Reddel et al 2009; GINA 
2012) and current guidelines (GINA 2015) also include use of ‘as needed’ medication in the 
assessment of current asthma control.  Asthma control is now accepted as having two 
domains: current control (also called symptom control) and future risk (e.g. of exacerbations).  
The guidelines’ approach is that higher use of ‘as needed’ medication is a flag that the patient 
needs anti-inflammatory treatment (or needs more treatment), to both reduce the burden of 
symptoms and to reduce their future risk of exacerbations.  This is supported by the 
association between higher ‘as needed’ medication use and higher risk of asthma 
exacerbations, and by the reduction in ‘as-needed’ medication use after patients are 
commenced on regular anti-inflammatory treatment such as inhaled corticosteroids (ICS).
However, guideline developers have not specifically evaluated their criteria for assessment of 
current asthma control when the ‘as needed’ bronchodilator is long-acting (as well as fast-
onset), nor when it also includes ICS.  The latter issue is particularly important for the context 
of an ‘as needed’ budesonide/formoterol regimen, when the patient’s anti-inflammatory 
treatment is delivered as part of their reliever medication rather than as a separate inhaler 
prescribed for regular use.  The inclusion of ‘as needed’ medication use in the assessment of 
asthma control may not be applicable to this regimen in the same way as when the ‘as needed’
medication only contains a bronchodilator.  For example, the level of symptoms that would 
influence a patient to take a dose of an ‘as needed’ medication containing ICS vs one 
containing only a bronchodilator may be different, and the relationship between frequency of 
‘as needed’ medication use and risk of exacerbations may also differ for these two regimens.
Therefore, this qualitative patient interview sub-study with a subset of patients participating in 
the primary study D589SC00001 will aim to provide a deeper understanding of study inhaler 
use and patient perception of asthma control.


Clinical Study Protocol Appendix F
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 1
Date 24 February 2016
3 (7)
2.
SUB-STUDY OBJECTIVES
The objective of this sub-study is to understand patient usage of study inhalers during the 
clinical study (particularly when and why study inhalers are used) from a qualitative patient-
centred perspective.
The additional objectives are to:
-
Understand the patient experience of asthma control during the clinical study
-
Understand whether or not patients believe their asthma control has changed during 
their participation in the clinical study
-
Understand what the term ‘asthma control’ means to the patient
3.
SUB-STUDY PLAN AND PROCEDURES
3.1
Study Design
This is a qualitative patient interview study, where telephone interviews will be conducted by 
trained interviewers in the native language of the country using a semi-structured interview 
guide.  A subset of patients participating in the primary study for D589SC00001 will be 
recruited to participate in the qualitative interviews.  Participation in the qualitative part is 
optional.
In qualitative research, sample size estimation is based on projections of the number of 
patients needed to reach saturation of concept (i.e. the point in the data collection process after 
which no further relevant information is being obtained).  An initial set of 80 patients overall 
is planned to be recruited for a first round of interviews.  After this initial round of interviews, 
an evaluation of saturation will be performed.  If saturation is not achieved then further 
interviews (in rounds of 5 patients) will be conducted on an iterative basis until saturation is 
reached.  It is expected no more than 120 patients will be enrolled.
3.2
Study Sample
Patients from the primary D589SC00001 study will be recruited to participate in this 
qualitative study, and enrolment criteria will be tied to the ongoing clinical study.  The 
primary D589SC00001 study has three blinded arms, and since it cannot be known ahead of 
time, or during the study, what groups these patients will fall into, a sufficient sample size is 
needed to ensure coverage of patients from all three arms.


Clinical Study Protocol Appendix F
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 1
Date 24 February 2016
4 (7)
Recruitment will be monitored across study sites to prevent clustering around key 
demographic variables and to ensure a good distribution of age-groups and gender are 
included.  Therefore, other variables such as type of pre-study treatment status (previously 
treated with inhaled short-acting bronchodilator(s) (SABA and/or short acting anticholinergic 
agent) only and previously treated with additional low dose ICS/LTRA) and amount of time in 
study (e.g. 3-5 months; 6-8 months; 9-11 months) will be asked when the patient is enrolled in 
the interview study in order to ensure there is at least some of each group present in the 
sample.  These latter variables will be described, but will not constitute defined recruitment 
quotas.
3.2.1
Inclusion Criteria
For inclusion in this sub-study, patients must fulfil all of the inclusion criteria described in the 
main body of the Clinical Study Protocol and:
1. Provision of signed and dated written informed consent for the qualitative sub study.  
Informed consent is to be obtained before any interview-related activities.  
Participation in the sub-study is optional (and not required for participation in the 
primary D589SC00001 study).
2. Have been randomised and are currently receiving investigational product, irrespective 
of their protocol adherence.
3.2.2
Exclusion Criteria
Exclusion from this qualitative research may be for any of the exclusion criteria specified in 
the main study or any of the following:
1. Not fluent in native language of the country of enrolment
3.3
Recruitment
Staff at enrolling sites will be asked to work with an interviewer at Health Research 
Associates (known as HRA, a Contract Research Organization) assigned to their site in order 
to identify, recruit, consent patients for interviews and assist with communications and 
scheduling of the patients to be interviewed from their sites.  Staff will be provided with a 
script for describing the topic of the qualitative study to potential interviewees, in order to 
avoid prompting patients about specific issues.  Once the patient agrees to the interview, their 
contact information (name and phone number) will be provided to the HRA interviewer, who 
will contact the patient and schedule a time at the patient’s convenience to complete a 
telephone interview.  Patients enrolled in the sub-study may choose to discontinue 
participation at any point prior to or during the qualitative interview.  Site staff should gauge 
patient interest in participating in the sub-study starting at Visit 4 (Week 4).  Patients may 
consent to participate in the sub-study as early as Visit 4 (Week 4), however the interview 


Clinical Study Protocol Appendix F
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 1
Date 24 February 2016
5 (7)
conducted by HRA with the patient should occur at study Week 12 or later, but not exceeding 
Week 50.  Once a patient has signed the informed consent (or assent, in the case of an 
adolescent patient), then the site staff should contact their assigned HRA interviewer 
(alternatively, HRA will contact site staff regularly to discuss enrolment and potential patients 
for the sub-study).  The HRA interviewer will ensure the patient is still on study treatment at 
the time of the interview.
3.4
Conduct of Interviews
All interviews will be conducted in the native language of the country of enrolment using an 
interview guide and audio recorded, with permission obtained through the informed consent 
process.  Each patient will be interviewed only once and interviews will last approximately 40 
minutes each.  A closing statement at the end of the interview will emphasise that nothing 
which has been discussed is intended to change the patient’s use of their study inhalers.  
English transcript files will be provided to AstraZeneca after final analysis has been 
performed.
3.5
Interviewers
Interviewers are experienced in qualitative research, possessing interviewing skills and will all 
be trained specifically to the needs of this study and monitored by HRA.  All interviewers will 
be bilingual in the native language and English.
3.6
Ethics
Each patient will be given full and adequate oral and written information about the nature, 
purpose, possible risk and benefit of the study.  The patient will be provided with the 
information and consent form and allowed to read it, with opportunity to ask any questions.  
In the case of adolescent patients their guardian/legal representative will sign the consent form 
on their behalf.  The investigator will ensure the original, signed Informed Consent Form(s) 
is/are stored in the Investigator’s Study File.  A copy of the signed Informed Consent Form is 
to be provided to the patient and/or their guardian/legal representative.  The investigator 
should ensure the patient is notified they are free to discontinue from the sub-study at any 
time.
This appendix detailing the sub-study along with the Informed Consent Form and Interview 
Guide should be approved by an Ethics Committee and the national Regulatory Authority, 
including the final version of the separate Informed Consent Form and any other written 
information and/or materials to be provided to the patients.  AstraZeneca should approve any 
modifications to the Informed Consent Form that are needed to meet local requirements.


Clinical Study Protocol Appendix F
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 1
Date 24 February 2016
6 (7)
3.7
Adverse Event Reporting
The patient’s participation in the sub-study will occur within his/her participation in the main 
protocol, therefore, the Principal Investigator remains responsible for ensuring that all staff 
involved in the study is familiar with the content of section 6 of the protocol on Safety 
Reporting and Medical Management.  If during an interview the patient reports an adverse 
event, serious adverse event, overdose, or pregnancy, then the interviewer will collect the 
relevant information after the end of the qualitative interview and report it to the investigator 
and site staff.  In the case of a serious adverse event, overdose, or pregnancy it must be 
reported within 24 hours for follow-up.  The site investigator and site staff will be responsible 
for checking to see if this AE has already been reported yet or not, and for official reporting in 
the same manner as for the primary D589SC00001 study.  HRA will ensure all interviewers 
are adequately trained to complete the appropriate form and submit it to the site.
4.
ANALYSIS AND REPORTING
4.1
Analysis of Interviews
All data will be confidential and the patient identifiers used will conform to applicable 
regulations, so as to preserve patient confidentiality (e.g., to ensure matching between the 
audio recording and the subsequent transcript).  Data from the audio recordings of the 
interviews will be transcribed to paper and used for exploratory descriptive analysis using a 
number of qualitative techniques particular to this methodology (Ericsson 1980; Campanelli 
1991).
The primary means of analysis will aim at identifying relevant concepts and themes that will 
provide an understanding of the patient’s use of study inhalers, reasons for the patterns of their 
usage behaviours, their perception of asthma control, their experience of asthma control 
during the study, and whether they believe their asthma control has changed.  To accomplish 
this, a coding framework will be developed and expanded during the coding process.  An 
experienced coding team will be trained to the coding framework for this project, and English 
versions of all transcripts will be coded. Coded concepts will be grouped by similar content 
and organized against specific themes and study questions.  Primary analysis of the qualitative 
data from the interviews will be by randomisation group.
4.2
Reporting
Due to the qualitative nature of the data and the analysis, the results will be presented in a 
separate report (i.e., not in the clinical study report) and the data (i.e., transcriptions) will not 
be entered into the study database.  The de-identified English transcripts will be sent to 
AstraZeneca at the conclusion of the primary study for D589SC00001 (after database lock).  
The recorded voice files will remain at HRA in a secure database.


Clinical Study Protocol Appendix F
Drug Substance budesonide/formoterol
Study Code D589SC00001
Edition Number 1
Date 24 February 2016
7 (7)
Copies of the interview transcripts will be stored at HRA in locked files until they are 
packaged for storage in an off-site archive facility, where they will remain for a period of 15 
years and then be destroyed.  Electronic files are all stored on password protected computers 
with routine back up onto a secure, firewalled server system.  Individual files are password 
protected when shipped outside the secured server system.  The voice files from the audio 
recordings are placed on a secure file transfer protocol server where they can be accessed by 
password by the transcription vendor.
5.
LIST OF REFERENCES
Bateman et al 2004
Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels R, et al (2004) Can 
guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL 
(GOAL) Study. Am J Respir Crit Care Med, 170:836-44.
Campanelli 1991
Campanelli PC, Martin EA, Rothgeb JM. The use of respondent and interviewer debriefing 
studies as a way to study response error in survey data. The Statistician. 1991;40:253-264.
Ericsson 1980
Ericsson KA, Simon HA. Verbal reports as data. Psychological Review. 1980; 87: 215-250.
GINA 2012
Global Initiative for Asthma (GINA). Strategy for Asthma Management and Prevention 2012.
GINA 2015
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention, Updated 2015.
Reddel et al 2009
Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al (2009) An 
Official American Thoracic Society/European Respiratory Society Statement: Asthma Control 
and Exacerbations, Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice. 
Am J Respir Crit Care Med, 180:59-99.

SAP_000.pdf: 
Statistical Analysis Plan
Study Code
D589SC00001
Edition Number
4
Date
29 September 2017
A 52-week, double-blind, randomised, multi-centre, parallel-group, Phase 
III study in patients 12 years and older with asthma, evaluating the efficacy 
and safety of Symbicort® (budesonide/formoterol) Turbuhaler® 160/4.5 μg 
‘as needed’ compared with terbutaline Turbuhaler® 0.4 mg ‘as needed’ 
and with Pulmicort® (budesonide) Turbuhaler® 200 μg twice daily plus 
terbutaline Turbuhaler® 0.4 mg ‘as needed’






Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
4
TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................1
SIGNATURE OF STUDY STATISTICIAN.............................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .......................3
TABLE OF CONTENTS..........................................................................4
LIST OF ABBREVIATIONS ...................................................................8
AMENDMENT HISTORY.....................................................................10
1.
STUDY DETAILS..................................................................................11
1.1
Study objectives......................................................................................11
1.1.1
Primary objective....................................................................................11
1.1.2
Secondary objectives...............................................................................11
1.1.3
Safety objective.......................................................................................12
1.1.4
Exploratory objectives ............................................................................12
1.1.5
China submission....................................................................................12
1.2
Study design ...........................................................................................13
1.3
Number of patients..................................................................................17
2.
ANALYSIS SETS ..................................................................................18
2.1
Definition of analysis sets .......................................................................18
2.1.1
All patients analysis set...........................................................................18
2.1.2
Full analysis set.......................................................................................18
2.1.3
Safety analysis set...................................................................................18
2.2
Violations and deviations ........................................................................19
3.
PRIMARY AND SECONDARY VARIABLES......................................20
3.1
General considerations for outcome variables..........................................20
3.1.1
Definition of baseline..............................................................................20
3.1.2
Definition of end of treatment .................................................................22
3.1.3
Timing of weeks for the purpose of assessing weekly asthma control 
status.......................................................................................................22
3.1.3.1
Allocation of study days to weeks ...........................................................22
3.1.3.2
Weeks that are cut short ..........................................................................23
3.1.3.3
Consecutive days spanning multiple weeks .............................................23
3.1.4
Valid maintenance and ‘as-needed’ medication turns ..............................23
3.1.5
Timing of maintenance and ‘as needed’ medication and allocation to 
day/night period......................................................................................23


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
5
3.1.6
Visit windowing......................................................................................25
3.1.7
Definition of completing treatment and completing study........................25
3.2
Primary variable......................................................................................25
3.3
Demography and patient characteristics ..................................................25
3.3.1
Demography, weight, height and lung function .......................................25
3.3.2
Medical, asthma and smoking history......................................................26
3.4
Efficacy variables....................................................................................26
3.4.1
Diary-based outcomes.............................................................................26
3.4.1.1
Daily variables: PEF, asthma symptoms, nighttime awakenings and 
‘as needed’ medication use......................................................................26
3.4.1.2
Daily composite end-points.....................................................................27
3.4.1.3
Weekly composite end-points .................................................................28
3.4.1.4
eDiary compliance ..................................................................................30
3.4.2
Asthma exacerbations .............................................................................30
3.4.2.1
Definitions of exacerbations....................................................................30
3.4.2.2
Time-to-event variables for exacerbations...............................................31
3.4.2.3
Time-to-censoring for exacerbations .......................................................32
3.4.2.4
Number of severe and moderate or severe asthma exacerbations, and 
annual exacerbation rate..........................................................................32
3.4.3
Administration of additional steroids for asthma and long-term poor 
asthma control.........................................................................................32
3.4.4
Total inhaled steroid load........................................................................33
3.4.5
Number of days with systemic GCS treatment due to asthma ..................34
3.4.6
Time to study-specific asthma-related discontinuation.............................34
3.4.7
Lung function variables...........................................................................34
3.4.8
Patient reported outcomes .......................................................................35
3.4.8.1
Asthma Control Questionnaire – 5-item Version (ACQ-5) ......................35
3.4.8.2
Asthma Quality of Life Questionnaire – Standardised Version 
(AQLQ(S)) .............................................................................................36
3.5
Safety variables.......................................................................................37
3.5.1
Vital signs...............................................................................................37
3.5.2
Physical examination ..............................................................................37
3.5.3
Pregnancy ...............................................................................................37
3.5.4
Adverse events (including Serious Adverse Events)................................38
3.5.4.1
Collection of AEs and SAEs ...................................................................38
3.5.4.2
Definition of adverse event leading to discontinuation of investigational 
product (DAE) ........................................................................................39
3.5.4.3
AEs representing potential β2 agonist effects and AEs representing 
potential ICS effects................................................................................39
3.5.4.4
Other significant adverse events (OAEs).................................................39
3.5.4.5
Adverse events data handling..................................................................39
3.6
Other variables........................................................................................40


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
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3.6.1
Concomitant medications........................................................................40
3.6.2
Discontinuation/withdrawal from the study.............................................40
3.6.3
Compliance of study maintenance medication.........................................41
4.
ANALYSIS METHODS.........................................................................41
4.1
General principles...................................................................................41
4.2
Analysis methods....................................................................................43
4.2.1
Patient disposition...................................................................................43
4.2.2
Demography data and patient characteristics ...........................................43
4.2.3
Treatment exposure.................................................................................44
4.2.4
Concomitant medications........................................................................44
4.2.5
Primary analysis: well-controlled asthma weeks......................................44
4.2.6
Secondary efficacy analyses....................................................................46
4.2.6.1
Asthma exacerbations .............................................................................46
4.2.6.2
Additional steroids for asthma.................................................................47
4.2.6.3
Steroid load.............................................................................................48
4.2.6.4
Discontinuation due to study specific asthma related events....................48
4.2.6.5
Lung function measurements...................................................................49
4.2.6.6
Patient reported outcomes .......................................................................49
4.2.6.7
Electronic diary variables........................................................................50
4.2.6.8
Maintenance medication compliance and ‘as needed’ medication use......51
4.2.7
Safety analysis ........................................................................................52
4.2.8
Subgroup, supportive and sensitivity analyses.........................................52
4.2.8.1
Subgroup analysis...................................................................................52
4.2.8.2
Supportive analysis: individual components of well-controlled asthma 
weeks......................................................................................................55
4.2.8.3
Supportive analysis: removing individual components of well-controlled 
asthma weeks..........................................................................................55
4.2.8.4
Sensitivity analysis: the ‘as needed’ component of well-controlled asthma 
weeks......................................................................................................55
4.2.8.5
Sensitivity analysis: effect of missing diary observations on well-
controlled asthma weeks .........................................................................56
5.
INTERIM ANALYSES ..........................................................................57
6.
CHANGES OF ANALYSIS FROM PROTOCOL ..................................58
6.1
Morning PEF on Day 1 occurs before randomisation...............................58
6.2
Baseline measurement for ACQ/AQLQ/FEV1/FVC on visit 3 only ........58
6.3
Exclusion of analysis on partly-controlled weeks ....................................58
6.4
Amendment to daytime/nighttime periods for ‘as needed’ medication.....58
7.
REFERENCES .......................................................................................59
8.
APPENDIX 1: METHOD FOR CALCULATING PREDICTED 
NORMAL FEV1 .....................................................................................60


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
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8.1
Equation for calculating predicted multi-ethnic predicted normal FEV1...60
8.2
Lookup table for final term......................................................................61
9.
APPENDIX 2: IDENTIFICATION OF ADDITIONAL STEROID 
MEDICATIONS FOR ANALYSES .......................................................65
10.
APPENDIX 3: POTENTIAL CLASS EFFECTS Β2-AGONISTS AND 
POTENTIAL ICS EFFECTS ..................................................................67
LIST OF TABLES
Table 1
Study Plan detailing the procedures............................................15
Table 2
Subgroups..................................................................................54
LIST OF FIGURES
Figure 1
Study Flow Chart .......................................................................14


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
8
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ACQ-5
Asthma Control Questionnaire 5-item version
AE
Adverse event
ANCOVA
Analysis of covariance
AQLQ(S)
Asthma Quality of Life Questionnaire (Standardised version)
BID
Twice daily
CSR 
Clinical study report
DAE
Adverse event leading to discontinuation
(e)CRF
(Electronic) Case report form
EU
European Union
FAS
Full analysis set
FCS
Fully conditional specification
FDA
(United States) Food and Drug Administration
FEV1
Forced expiratory volume in one second
FVC
Forced vital capacity
GCS
Glucocorticosteroid
GEE
Generalised estimating equation
GINA
Global Initiative for Asthma
GLI
Global Lung Function Initiative
ICH 
International Conference on Harmonisation (of Technical Requirements for 
Registration of Pharmaceuticals for Human Use)
ICS
Inhaled (gluco)corticosteroid
IP
Investigational product
IVRS/IWRS
Interactive voice/web response system
LTRA
Leukotriene antagonist
MAR 
Missing at random
MID
Minimal important difference
MMRM
Mixed model repeated measures
MNAR
Missing not at random
NI
Non-inferiority
OAE
Other significant adverse event


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
9
Abbreviation or 
special term
Explanation
PEF
Peak expiratory flow
PN
Predicted normal
SABA
Short-acting β-agonist
SAE
Serious adverse event
SAP 
Statistical analysis plan
TUM
Turbuhaler usage monitor
vs
versus


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
10
AMENDMENT HISTORY
Date
Brief description of change
05 June 2014
N/A (Version 1.0)
17 November 2016
Version 1.1
AstraZeneca comments incorporated. 5 out of 7 days of eDiary completion 
were required to be eligible for a well-controlled asthma week (this condition 
is not needed for the evaluation of a not well-controlled asthma week). 
Morning PEF on the day of randomisation excluded from baseline PEF 
calculation. Baseline measurements for FEV1, FVC, ACQ-5 and AQLQ(S) to 
only use measurements at visit 3. Exclusion of analysis of partly-controlled 
asthma weeks. The daytime and nighttime periods for ‘as needed’ medication
was amended. 
11 December 2016
Version 1.11
AstraZeneca updates prior to release to Phastar
09 February 2017
Version 1.12
Updated by Phastar pre-BDR1
18 April 2017
Version 1.2
Updated by Phastar following BDR1 comments review meeting
17 May 2017
Version 1.3
Updated by Phastar following AstraZeneca review and SYGMA 2 BDR1
05 July 2017
Version 1.4
Updated by Phastar following BDR2 comments review meeting
22 August 2017
Version 1.5
Updated by Phastar following AstraZeneca review and SYGMA 2 BDR2 
comments review meeting. Sensitivity analysis for handling the missing data 
in well-controlled asthma weeks was added. 
12 September 2017
Version 1.6
Updated by AstraZeneca to review updates.
18 September 2017
Version 2
Updated by AstraZeneca to review updates.
21 September 2017
Version 3
Updated by AstraZeneca to incorporate history of severe exacerbations as a 
covariate in exacerbation models. 
29 September 2017
Version 4
Updated by AstraZeneca to correct the categorisation of the subgroup average 
use of SABA per day during run-in period.


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
11
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
Primary Objective:
Outcome Measure:
To demonstrate that Symbicort Turbuhaler 
160/4.5 μg ‘as needed’ is superior to 
terbutaline Turbuhaler 0.4 mg ‘as needed’.
Evaluation of asthma control as measured by 
well-controlled asthma weeks as the primary 
variable.
1.1.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To evaluate the relative efficacy of Symbicort 
Turbuhaler 160/4.5 μg ‘as needed’ and 
Pulmicort Turbuhaler 200 μg twice daily plus 
terbutaline Turbuhaler 0.4 mg ‘as needed’.
Evaluation of asthma control as measured by 
well-controlled asthma weeks as the primary 
variable.
To evaluate the efficacy of Symbicort 
Turbuhaler 160/4.5 μg as compared to both:
terbutaline Turbuhaler 0.4 mg ‘as needed’, and
Pulmicort Turbuhaler 200 μg twice daily plus 
terbutaline Turbuhaler 0.4 mg ‘as needed’.
Secondary variables:
Annual severe asthma exacerbation rate
Annual moderate or severe asthma exacerbation
rate  
Time to first severe asthma exacerbation
Time to first moderate or severe asthma 
exacerbation
Time to additional steroids for asthma
Time to asthma related discontinuation
Average change from baseline in pre-dose FEV1
Average change from baseline in post-doseFEV1
Average change from baseline in Asthma 
Control Questionnaire (ACQ-5)
Average change from baseline in Asthma 
Quality of Life Questionnaire; standard version 
(AQLQ(S))
Average change from baseline in Morning PEF
Average change from baseline in Evening PEF
Average change from baseline in symptom score
Average change from baseline in number of
inhalations of ‘as needed’ medication
Percentage of controller use days


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
12
Percentage of Nighttime awakenings due to 
asthma
Percentage of Symptom-free days
Percentage of ‘As needed’ free days
Percentage of Asthma control days
Poorly controlled asthma weeks
1.1.3
Safety objective
Safety Objective:
Outcome Measure
To compare the safety of Symbicort Turbuhaler 
160/4.5 μg ‘as needed’ with that of terbutaline 
Turbuhaler 0.4 mg ‘as needed’, and with that of 
Pulmicort Turbuhaler 200 μg twice daily plus 
terbutaline Turbuhaler 0.4 mg ‘as needed’.
Adverse events (nature, incidence and severity); 
pulse, blood pressure and physical examination.
1.1.4
Exploratory objectives
The exploratory objectives are part of a qualitative sub-study that will be conducted in a sub-
set of participating countries and sites.  See CSP for an overview of the qualitative sub-study.  
Note that the analysis approach is not in scope for this statistical analysis plan (SAP).  
Exploratory Objective:
Outcome Measure
To understand patient usage of study inhalers
during the clinical study (particularly when and 
why study inhalers are used) from a qualitative 
patient-centred perspective.
Coded transcriptions of patient interviews
(qualitative summary).
To understand:
The patient experience of asthma control during 
the clinical study; Whether or not patients 
believe their asthma control has changed during 
their participation in the clinical study;What the 
term ‘asthma control’ means to the patient.
Coded transcriptions of patient interviews
(qualitative summary).
1.1.5
China submission
For filing purposes in China, an independent SAP will be generated to cover specific regional 
needs mainly analysis on Chinese and Asiatic subpopulations.


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
13
1.2
Study design
This is a 52-week, double-blind, randomised, multi-centre, three-way parallel group, Phase III 
study in patients 12 years and older with asthma.  
This study will evaluate the efficacy and safety of Symbicort® (budesonide/formoterol) 
Turbuhaler® 160/4.5 μg ‘as needed’ in comparison with terbutaline Turbuhaler® 0.4 mg 
‘as needed’ and with Pulmicort® (budesonide) Turbuhaler® 200 μg twice daily plus terbutaline 
Turbuhaler® 0.4 mg ‘as needed’.
Patients who have provided informed consent prior to any study specific procedures, and are 
either uncontrolled on an inhaled short acting bronchodilator ‘as needed’ (short acting β2
agonist (SABA) and/or short acting anticholinergic agent) or controlled on mono-maintenance 
therapy with either a low dose inhaled (gluco) corticosteroid (ICS) or a leukotriene receptor 
antagonist (LTRA) in addition to 'as needed' use of inhaled short-acting bronchodilator 
(SABA and/or short acting anticholinergic agent) for the last 30 days before Visit 2 will be 
included in the study.  The patients should have reversible airway obstruction.  Patients should 
have used SABA on at least 3 separate days during the last week of the run-in period.
Patients will be randomised to the three treatment arms in 1:1:1 ratio.  Patients’ recruitment 
will be balanced based on their pre-study treatment (i.e., patients who are uncontrolled on an 
inhaled short acting bronchodilator (SABA and/or short acting anticholinergic agent)
‘as needed’ or controlled on mono-maintenance therapy with either a low dose ICS or a LTRA 
in addition to 'as needed' use of inhaled short-acting bronchodilator (SABA and/or short acting 
anticholinergic agent).  
Figure 1 illustrates the flow of patients through the study from enrolment to study end.  
Patients will begin with a 2-to-4-week run-in period to collect baseline data and to ensure that 
they are in need of Global Initiative for Asthma (GINA) step 2 treatment.  Patients will then 
be randomised to one of the three treatment groups described above and continue on the study 
for 52 weeks.  Patients will receive a final follow-up telephone call to check for adverse 
events.
Table 1 describes the assessments to be performed at each of the scheduled study visits.


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
14
Figure 1
Study Flow Chart 
Period
Enrolment
Run-in
Visit
Week
FU=Follow-up phone call
               1               2                3               4               5              6               7               8        FU
                          -2 to - 4           0                4              16             28             40             52       54  
Randomisation
Bricanyl 
0.5 mg
 'as 
needed'
 Placebo bid + Symbicort 160/4.5 μg 'as needed'
 Pulmicort 200 μg bid + terbutaline 0.4 mg 'as needed'
 Placebo bid + terbutaline 0.4 mg 'as needed'
Treatment


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
15
Table 1
Study Plan detailing the procedures
Enrol-
ment
Run-in
Rando-
misatio
n
Treatment
Follow
-up
VISIT
1
2
3
4
5
6
7
8
TC
WEEK
- 2 to - 4
0
4
16
28
40
52
54
Visit window (days)
0–7 
before 
Visit 
2
14–28 
before 
Visit 3
±3
±7
±7
±7
±7
±3
Informed consent
X
Allocation of 
enrolment code 
(IVRS/IWRS)
X
Demography 
(date of birth, gender, 
race)
X
Inclusion/exclusion 
criteria
X
X
X
Medical, surgical 
history
X
Asthma history 
(including history of 
severe exacerbation)
X
Smoking history
X
Patient training in 
eDiary, Turbuhaler 
(inhalation technique), 
TUM and PEF meter 
use
X
ACQ and AQLQ(S)
at study site 
X
X
only 
ACQ
X
X
X
X
SAEs (from Visit 1) /
AEs (from Visit 2)
X
X
X
X
X
X
X
X
X
Weight and height
(height only for 
adolescents at Visit 8)
X
X
Physical examination
X
X
Pulse and blood 
pressure
X
X
Pregnancy test
X
Adjustment of current 
asthma medication
X
Randomisation 
X
Bricanyl for run-in 
dispense / return
d
r


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
16
Enrol-
ment
Run-in
Rando-
misatio
n
Treatment
Follow
-up
VISIT
1
2
3
4
5
6
7
8
TC
WEEK
- 2 to - 4
0
4
16
28
40
52
54
Visit window (days)
0–7 
before 
Visit 
2
14–28 
before 
Visit 3
±3
±7
±7
±7
±7
±3
Lung function (FEV1, 
FVC pre- and post 
Bricanyl 
administration)
X
X
X
X
X
X
X
Reversibility test 
X
X
Concomitant 
medication
X
X
X
X
X
X
X
Investigational 
product 
(dispense/return/check
)
d
d/r/c
d/r/c
d/r/c
d/r/c
r/c
Intake of maintenance 
treatment morning 
dose
X
X
X
X
X
Review of PEF, 
asthma symptoms, 
nighttime awakenings, 
maintenance and ‘as 
needed’ IP intake and 
Turbuhaler user 
technique;  
re-training of patient 
if needed
X
X
X
X
X
X
Review of patient’s 
compliance with 
eDiary
X
X
X
X
X
X


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
17
1.3
Number of patients
In this section the following brief terms are used to describe the three treatment arms:
Treatment arm
Brief term used in CSP
Brief term used in SAP
Maintenance Placebo BID (twice daily) 
+ Symbicort 160/4.5 μg ‘as needed’
Symbicort
Symbicort ‘as needed’
Maintenance Pulmicort 200 μg BID + 
terbutaline 0.4 mg ‘as needed’
Pulmicort plus 
terbutaline
Pulmicort bid
Maintenance Placebo BID + terbutaline 
0.4 mg ‘as needed’
terbutaline
SABA ‘as needed’
The number of patients required for the analyses was estimated to be 3750 overall 
(625/treatment group/pre-study treatment group), as described in Section 8.2 of the clinical 
study protocol.
The study is powered to assess both the primary objective of comparing Symbicort ‘as 
needed’ vs SABA ‘as needed’ and the secondary objective to estimate the relative efficacy of 
Symbicort ‘as needed’ vs Pulmicort bid in the overall population and pre-study treatment 
groups.
Calculations for estimating sample size were based on the following assumptions:
!
The treatment effect of Pulmicort bid vs SABA ‘as needed’ is an odds ratio of 1.39 
(based on results from post-hoc analyses of study SD-037-0345, data on file)
!
Symbicort ‘as needed’ has the same level of efficacy as Pulmicort bid.
!
Data will follow a similar pattern to that observed in study SD-037-0345, which 
was performed in a similar patient population.
!
Symbicort ‘as needed’ vs SABA ‘as needed’ will be compared using a two-sided 
hypothesis test at the 5% significance level
!
Symbicort ‘as needed’ vs Pulmicort bid will be compared using a one-sided 
hypothesis test at the 2.5% significance level
Simulations were performed on the pattern of data observed in the study SD-037-0345.  The 
sample size of 3750 patients gives:
!
Overall, >95% power to detect a difference between Symbicort ‘as needed’ and 
SABA ‘as needed’


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
18
!
Overall 90% power to achieve non-inferiority (NI) of Symbicort ‘as needed’ vs 
Pulmicort bid with a pre-defined non-inferiority limit of 0.8 - i.e., the lower 95% 
confidence interval of the odds ratio for Symbicort ‘as needed’ compared to 
Pulmicort bid is ≥0.8.
Since it is also important to estimate the treatment effects within each of the pre-study 
treatments (see Section 4.1 for description) the sample size assessments were also done 
assuming that 1875 were recruited in each group and this gives:
!
80% power to detect a difference between Symbicort ‘as needed’ and SABA
‘as needed’
!
80% power to achieve non-inferiority of Symbicort ‘as needed’ vs Pulmicort bid
with a pre-defined NI limit of 0.78 - i.e., the lower 95% confidence interval of the 
odds ratio for Symbicort compared to Pulmicort bid is ≥0.78.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
All patients analysis set
This analysis set comprises all patients screened for the study and will be used for reporting of 
patient disposition and enrolment failures.
2.1.2
Full analysis set
All patients randomised and receiving any investigational product will be included in the full 
analysis set, irrespective of their protocol adherence and continued participation in the study.  
Patients will be analysed according to their randomised treatment.
The efficacy analysis set will be based on the ‘full analysis set’ in line with the ICH E9 
guideline.
For any patient randomised more than once into the study, only data relating to the initial 
randomised period will be included in the full analysis set for summary tables.  Data relating 
to subsequent randomised periods will be described in the clinical study report (CSR).  
2.1.3
Safety analysis set
All patients receiving any investigational product will be included in the safety analysis 
population.  Patients will be classified according to the treatment they actually received.  If a 
patient has a wrong kit id, then the treatment they actually received will be determined based 
on which treatment was used the most.


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
19
All patients should be allocated to the safety analysis set prior to DBL, however the 
classification of treatment received, will not be determined until after unblinding, and will be 
documented.  All safety summaries will be based on this analysis set.
For any patient randomised more than once into the study, only data relating to the initial 
randomised period will be included in the safety analysis set for summary tables.  Data 
relating to subsequent randomised periods will be described in the CSR.
2.2
Violations and deviations
Important protocol deviations will be listed and summarised by randomised treatment group
and discussed in the CSR.  None of the deviations will lead to any patients being excluded 
from any of the analysis sets described in Section 2.1.  A per-protocol analysis excluding 
patients with significant protocol deviation is not planned.  
The following violations of inclusion criteria will be considered important protocol deviations 
when the study physician or principal investigator make a decision to discontinue the patient 
from the study due to one or more of these criteria.  They will be identified using the CRIT 
and TERM case report form (CRF) modules.  
!
Diagnosis of asthma according to GINA criteria based on symptoms with a
documented history of at least 6 months prior to Visit 1.
!
Patients who are in need of GINA (2012) step 2 treatment:
∀
uncontrolled on inhaled short-acting bronchodilator(s) ‘as needed’ (SABA 
and/or short acting anticholinergic agent) as judged by the investigator for the 
last 30 days before Visit 2, or
∀
controlled on mono-maintenance therapy - with low stable dose ICS (≤400 μg 
budesonide per day or corresponding dose of other ICS) (see Appendix E for 
conversion) or LTRA - in addition to 'as needed' use of inhaled short-acting 
bronchodilator(s) (SABA and/or short acting anticholinergic agent), as judged 
by the investigator for the last 30 days prior to Visit 2
!
Based on lung function tests at Visit 2, patients pre-treated with
∀
an inhaled short acting bronchodilator only should have pre-bronchodilator
FEV1 ≥60 % of predicted normal (PN) and post-bronchodilator FEV1 ≥80 %
PN according to the European Respiratory Society (ERS) guidelines (Quanjer
et al 2012)
∀
low dose ICS or LTRA medication in addition to inhaled short-acting
bronchodilator(s) should have pre-bronchodilator FEV1 ≥80 % PN according 
to the ERS guidelines


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
20
!
Reversible airway obstruction according to a reversibility test performed at Visit 2 
defined as an increase in FEV1 ≥12% and ≥200 ml relative to baseline, after 
inhalation of 1 mg Bricanyl Turbuhaler.  
The following violations of exclusion criteria will be considered important protocol 
deviations.  They will be identified using the CRIT eCRF module only.
!
Medical history of life- threatening asthma including intubation and intensive care 
unit admission
!
Any significant disease or disorder which, in the opinion of the investigator, may 
either put the patient at risk because of participation in the study, or may influence 
the results of the study, or the patient’s ability to participate in the study
See the CSP Sections 3.1 and 3.2 for full definitions of the inclusion and exclusion criteria.
In addition to the programmatic determination of the deviations above, monitoring notes or 
summaries will be reviewed to determine any important post entry protocol deviations that are 
not identifiable via programming, and to check that those identified via programming are 
correctly classified.  The final classification will be made prior to database lock.  There are 
two types of non-programmable important protocol deviation:
!
Cases with severe noncompliance with study protocol potentially affecting primary 
endpoint as identified by study team physician during medical monitoring.  Any 
case of a patient randomised twice in error will be considered as severe non-
compliance.
!
Wrong allocation of Kit I.D – Patient received investigational product (IP) from 
different treatment arm than assigned via interactive voice response system (IVRS)
Due to treatment blinding, it will not be possible to identify if the wrong kit is different from 
the randomised treatment until after DBL.  
All randomised patients who failed any inclusion/exclusion criteria will be listed along with 
details of the failed criteria.  This information will also be summarised in terms of the number 
(%) of patient failing any of the inclusion/exclusion criteria and will be based on the FAS.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
General considerations for outcome variables
3.1.1
Definition of baseline
Unless otherwise specified, the following general principles apply for determining the 
baseline for daily diary variables and for variables collected during scheduled visits.


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
21
Daily diary variables
The baseline value for morning PEF, evening PEF, asthma symptom score (day, night and 
total), % nighttime awakenings and % asthma control days, will be defined as the mean (or 
percentage) of the non-missing measurements taken during the last 10 days of the run-in 
period.  Only evaluable days (defined as those with diary data recorded) will contribute to the 
denominator for baseline.  The defined period for these parameters will not include any eDiary 
data collected on the morning of Day 1.
% Symptom free days
The % of symptom free days will be calculated over the 10 days prior to randomisation.  Days 
where eDiary are completed only in the morning or evening and there are no symptoms in the 
available period, or days in this period with no data recorded will not be included in the 
denominator.
‘As needed’medication
‘As needed’ medication at baseline is Bricanyl Turbuhaler 0.5 mg.  Its baseline value is
defined as average number of uses per day in the 10 days prior to randomisation during the
run-in period.  Each day for baseline will begin at 07:00 and end at 06:59:59 on the following 
day.  It includes the last measurement taken on the morning of randomisation (prior to the first 
dose of maintenance medication, or 06:59:59, whichever is earlier).
% ‘As needed’-free days
‘As needed’-free days at baseline is defined as number of days with no ‘as needed’ medication 
use (a day and a night) in the 10 days prior to randomisation during the run-in period.  Percent 
‘as needed’-free days at baseline will then be calculated as the number of ‘as- needed’-free
days at baseline divided by 10 multiplied by 100.  Each day is calculated in the same way as 
the day calculation for ‘as needed’ medication in the previous section.
Other efficacy data collected at scheduled visits
The baseline value for variables collected during scheduled visits will be defined as the last 
measured value prior to first dose of IP on Visit 3 only.  I.e., no data from earlier visits will be 
used if Visit 3 data are missing.
Baseline will be calculated using this method for the following variables:
!
lung function variables:


Statistical Analysis Plan 
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∀
FEV1 (L), pre- and post-bronchodilator   
∀
FEV1 % of predicted normal, pre- and post-bronchodilator
∀
FVC (L), pre- and post-bronchodilator
Note: baseline post-bronchodilator values are calculated post-bricanyl, but before first dose of 
randomised treatment.
Efficacy data with no visit information
Baseline for variables that did not include visit information will be defined as the last 
measured value prior to first dose of IP. Baseline will be calculated using this method for the 
following variables:
!
Patient-reported outcomes:
∀
ACQ-5 score
∀
AQLQ(S) score
Safety data (vital signs and physical examination) and height
The baseline for vital signs (pulse rate and blood pressure), physical examination 
measurements and height is defined as the value recorded at Visit 2.  If the Visit 2 record is 
missing, then baseline will be left as missing.  
3.1.2
Definition of end of treatment
The end of treatment assessment is defined as the last available non-missing assessment, 
defined as Visit 4, 5, 6, 7 or 8, regardless of time on study.  
3.1.3
Timing of weeks for the purpose of assessing weekly asthma control status
3.1.3.1
Allocation of study days to weeks
The timing of the starts and ends of weeks will be based on the first day that the 
investigational product (IP) was taken by the patient.  The first day of ‘Week 1’ will be the 
first day the patient has taken IP.  For the purpose of this SAP, this day shall be referred to as 
‘Day 1’ and denote the start of ‘Week 11’.
                                               
1 This represents a minor difference from the study protocol, where the start of the randomised treatment period 
is referred to as ‘Week 0’.


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3.1.3.2
Weeks that are cut short 
If a week is cut short by early termination (e.g.  by withdrawal of patient consent) or by Visit 
8 taking place earlier than the start of Week 52, and there are fewer than 5 evaluable days in 
the week then the week will be regarded as missing for the purposes of the analysis of weekly 
asthma control.  This rule applies unless asthma control status can be unequivocally 
determined for the whole week using only the data from the days up till the date at which the 
patient ceased to be in the study (for example, if the patient has already had a nighttime
awakening earlier in the week due to asthma, that week will be regarded as not well-
controlled).  Please see Section 3.2 for the definition of a well-controlled asthma week.  
3.1.3.3
Consecutive days spanning multiple weeks
The protocol describes several criteria for evaluating composite endpoints including a 
condition being met for two consecutive days in the week.  Only days within the week in 
question will be considered for this condition.  In circumstances where the condition occurs 
for two consecutive days, but these days fall in different weeks, the condition will not be 
considered to have been met in either week.
3.1.4
Valid maintenance and ‘as-needed’ medication turns 
The use of maintenance and ‘as needed’ medication will be captured via the Turbuhaler Usage 
Monitor (TUM).  This device is fitted to the Turbuhaler and records the timing of each turn of 
the inhaler.
A two-stage approach will be applied to exclude turns from the TUM which are considered 
impossible.  
(i)
Turns taking place within ≤1 second of the previous turn 
(ii)
The number of turns per day per inhaler will be limited to the number of available 
doses in each inhaler (120 ‘as-needed’, 200 maintenance).
Additional sensitivity analysis may be presented if appropriate, such as using a capping rule of 
12 and 30 doses/day to maintenance and as needed medication, respectively.
3.1.5
Timing of maintenance and ‘as needed’ medication and allocation to day/night 
period
The timing of medication for the purposes of defining a well-controlled asthma week is 
described in Section 3.4.1.3.  This section refers to the timing of medication for the purposes 
of evaluating exposure, compliance and secondary efficacy variables.


Statistical Analysis Plan 
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‘As needed’ use (as recorded by the TUM) will be allocated to daytime and nighttime periods 
in the following way:
!
Start of the daytime period is defined as the time when the patient takes their 
morning maintenance dose (between 04:00:00-11:59:59).  If the patient takes their 
morning maintenance dose before or after this time interval, or if there is no 
recorded morning maintenance dose the start of the daytime period will be set to the 
average of the recorded morning maintenance doses (between 04:00:00-11:59:59) 
across the trial for that patient.  The end of the daytime period will be set one 
second prior to the start of the nighttime period.
!
Start of the nighttime period is defined as the time when the patient takes their 
evening maintenance dose (between 18:00:00-23:59:59).  If the patient takes their 
evening maintenance dose before or after this time interval, or if there is no 
recorded evening maintenance dose the start of the nighttime period will be set to 
the average of the recorded evening maintenance doses (between 18:00:00 -
23:59:59) across the trial for that patient.  The end of the nighttime period will be 
set one second prior to the start of the daytime period.
For analyses where full days are assessed they are defined as a day followed by a night, with 
the start of each day defined by the start of the daytime period described above.
On the treatment start day, only those ‘as needed’ medications taken after the first 
maintenance medication (any time after 00:00:00) will be considered to be in the randomised 
treatment period.  Any ‘as needed’ medication taken prior to the first maintenance will be 
considered ‘run-in’ medication.  If there is no maintenance medication on the treatment start 
day, then 12pm will be considered the end of run-in and start of the randomised treatment 
period.  However, only those run-in ‘as needed’ medications recorded up to 06:59:59 will be 
included in baseline calculations.
On the treatment end day, only medications up to 18:59:59 will be included in the randomised 
treatment period 
For the purpose of calculating steroid load, maintenance medication will be assigned to each 
study day using the same windows as defined for the ‘as needed’ medication above.  
For the purpose of study treatment compliance, and exposure, maintenance medication will be 
assigned to each study day if it occurs anytime from 4am on that study day until 3:59:59am on 
the following day (or 18:59:59 for the treatment end day).  On treatment start day the start of 
the window will 00:00:00 instead of 04:00:00.
A low proportion of data collected via the TUM were found to have a timestamp outside of 
the run-in period or the randomised treatment period.  These records are excluded from all 
analysis.


Statistical Analysis Plan 
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3.1.6
Visit windowing 
Details of the method for programming visit windowing is shown in Error! Reference source 
not found..
3.1.7
Definition of completing treatment and completing study.  
A patient will be considered as completing treatment and completing the study if they have 
not discontinued the study prematurely according to the TERM (Termination) module.
3.2
Primary variable
The primary efficacy variable for this analysis will be well-controlled asthma weeks, a 
composite end-point derived from daily patient eDiary data, the asthma exacerbation
(EXACASI) and medication (MED) modules on the CRF, and data from the TUM.
The definition and method for deriving the primary variable is given in Section 3.4.1.3 below.  
3.3
Demography and patient characteristics
3.3.1
Demography, weight, height and lung function
The following demographic data will be collected at enrolment (Visit 1):
!
Date of birth
!
Gender
!
Race/ethnicity/ethnic population 
Race and ethnicity information will be collected as per AstraZeneca standards using the 
standard race and ethnicity categories stipulated in FDA guidance.  However, for the purposes 
of calculating multi-ethnic predicted normal values of FEV1 (Quanjer et al 2012), a different 
categorisation of ethnicity is required.  This variable is collected as “ethnic population” in the 
SC (subject characteristics) module of the eCRF.  See Section 3.4.7 for further details on the 
calculation of predicted normal FEV1.
Weight in kilogram and height in cm will be measured at Visit 2.  For adolescents (i.e.,
patients aged less than 18 years at the date of informed consent), height will additionally be 
measured at Visit 8.  Body mass index [weight in kg / (height in m2)] will be categorised as 
(<25, ≥25 and <30 and ≥ 30).
Age at date of informed consent (in terms of whole years lived) will be derived using date of 
birth and date of consent.  It will be categorised (≥12 and <18, ≥18 and <50, ≥50 and <65, ≥65 
and <85 and ≥ 85 years of age).
Region will be defined as follows:


Statistical Analysis Plan 
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Edition Number 4
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!
Latin America: Argentina, Brazil, Chile, Mexico, Peru
!
EU: Bulgaria, Hungary, Poland, Romania, United Kingdom
!
East Asia: China, Philippines, South Korea, Vietnam
!
Rest of World: Australia, Canada, Russia, South Africa, Ukraine
For the purpose of calculating predicted normal lung function variables (FEV1 and FVC), age 
at the day the test is conducted will be calculated to the nearest 0.01 years.  Height for adults 
will be assumed to be constant throughout the course of the study.  Further details on the use 
of demographic variables for calculating predicted normal is given in the following sections:
For calculating predicted normal FEV1, see Section 3.4.7.
3.3.2
Medical, asthma and smoking history
Medical (incl. surgical), asthma (incl. exacerbations) and smoking history will be recorded 
during the enrolment visit (Visit 1).
3.4
Efficacy variables
3.4.1
Diary-based outcomes
3.4.1.1
Daily variables: PEF, asthma symptoms, nighttime awakenings and 
‘as needed’ medication use
The eDiary will be completed twice each day from the evening of Visit 2 until the morning of 
Visit 8.  The following measurements will be recorded for each day:
!
Morning and evening PEF (transferred from PEF meter)
!
Morning and evening asthma symptoms (entered by patient)
!
Nighttime awakenings due to asthma symptoms (entered by patient morning 
afterwards)
In addition, use of ‘as needed’ and randomised maintenance treatment will be transferred daily 
from the TUM.  
The following variables will be derived from the above measurements and demographic 
variables:
!
PEF Predicted normal (PN), based on the patient’s gender, age (as at the day of the 
test, to the nearest 0.1 of a year) and height (for adults, measured at screening; for 
adolescents, interpolated between measurements taken at Visits 2 and 8).  PN PEF 
is calculated using the formulas in Quanjer (Quanjer et al 2012).  


Statistical Analysis Plan 
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Edition Number 4
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!
Total asthma symptom score (sum of daytime and nighttime scores)
!
Percentage of nighttime awakenings (over the whole randomised treatment period, 
excluding any days with no morning eDiary recorded).
The following change-from-baseline variables will be calculated:
!
Mean change from baseline over the whole treatment randomised period in morning 
and evening PEF, morning, night and total daily asthma symptom score and number 
of ‘as needed’ medication uses per day (morning, night and total means over whole 
randomised treatment period)
If multiple eDiary records occur within 1 morning or evening (PEF/asthma 
symptoms/nighttime awakenings only), only the recording with the earliest completion time
should be used in analysis.  If no time is available and multiple eDiary records share the same 
date for a particular patient, then the diary record with the worst total score will be used.
For the derivation of total daily asthma symptom score, if either day or night are missing, then 
the daily symptom score is set to missing.
For total and night mean number of ‘as needed’ medication uses, the final day of treatment 
will not be included as part of the randomised treatment period.  This is due to the patients 
returning their TUM prior to the final evening.  Similarly, PEF and symptom data collected 
via the diary on the morning of Day 1 and the evening of the final day of treatment will not be 
included as part of the randomised treatment period.  The total asthma symptom score will 
therefore not be calculated for either of these study days.
3.4.1.2
Daily composite end-points
NB: When a definition refers to “a day and night”, this should be taken to mean a night and 
the subsequent day, i.e., the period from one evening maintenance treatment to the evening 
maintenance treatment on the next day.
Where a value for an individual criterion is missing, the composite end-point is defined as 
missing, unless it can be unequivocally determined as non-missing through the other, 
non-missing criteria.
Symptom-free days
A symptom-free day is defined as the fulfilment of both of the following criteria:
!
A day and night with no asthma symptoms (i.e.: asthma symptom score=0)
!
A night with no awakenings due to asthma symptoms


Statistical Analysis Plan 
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Asthma-control days
An asthma control day is defined as the fulfilment of all of the following criteria:
!
A day and night with no asthma symptoms (i.e., asthma symptom score=0)
!
A night with no awakenings due to asthma symptoms
!
A day and night with no use of ‘as needed’ medication
Percentage of symptom-free days and asthma-control days will be calculated over the whole
randomised treatment period (excluding any days without any eDiary data recorded).
Percentage of ‘As needed’-free days
An ‘as needed’-free day is defined as a day and night with no use of ‘as needed’ medication.
Percentage of ICS controller use days
An ICS controller use day is defined as a study day (day or night) with use of a controller 
medication containing ICS (including Pulmicort, Symbicort and any other additional 
prescribed inhaled corticosteroid).  Controller use will be defined as the ‘as needed’ use for 
the Symbicort treatment arm, the maintenance use for the Pulmicort plus terbutaline treatment 
arm, and any additional prescribed inhaled corticosteroid which is applicable for all treatment 
arms.
3.4.1.3
Weekly composite end-points
Well-controlled asthma week (primary outcome variable)
The well-controlled asthma week variable has three possible values: well-controlled, 
not well-controlled and missing.  
A week will be considered as a well-controlled asthma week if both conditions below are 
fulfilled:
!
A) Two or more of the following criteria are fulfilled:
∀
No more than 2 days with a daily asthma symptom score >1
∀
No more than 2 days of ‘as needed’ medication use, up to a maximum of 
4 occasions per week (multiple occasions per day should be regarded as 
separate occasions)
∀
Morning PEF ≥80% of PN every day  
!
B) Both of the following criteria are fulfilled:


Statistical Analysis Plan 
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∀
No nighttime awakenings due to asthma 
∀
No additional inhaled and/or systemic glucocorticosteroid (GCS) treatment due 
to asthma2.
It is required that the eDiary has to be completed on at least 5 days in a week to be evaluable
for a well-controlled asthma week, while this condition is not needed for the evaluation of a
not well-controlled asthma week.  
A not well-controlled asthma week is defined as a week where either condition A or condition 
B is not met.  
A missing asthma control week is defined when it cannot be unequivocally determined 
whether the week is well-controlled or not well-controlled.
For instance, if morning diaries are completed for ≤4 days a well-controlled asthma week 
cannot be observed.  For example, if a nighttime awakening is observed or additional inhaled 
and/or systemic glucocorticosteroid (GCS) treatment is prescribed then this is a not well-
controlled week.  Also, if observed data indicate the 2 out of 3 criteria (PEF, ‘as needed’ use 
and total daily asthma symptom score) is not met it is then known this is a not well-controlled
week.  If no nighttime awakenings and no additional inhaled and/or systemic GCS treatment 
and we cannot unequivocally tell if the 2 out of 3 criteria have been met then the week should 
be regarded as missing.
Poorly-controlled asthma week (secondary outcome variable)
A poorly-controlled asthma week is defined in the protocol as a week meeting any one of the 
following conditions:
!
Two or more consecutive days with awakenings due to asthma on both nights
!
A recorded use of ‘as needed’ medication for symptom relief of at least 3 occasions 
per day, for at least 2 consecutive days
!
Additional systemic GCS treatment required for severe exacerbation
If there are sufficient data within a week available to confirm the week was not 
poorly-controlled, the week will be labelled as does not meet criteria for poorly-controlled.
                                               
2 Note: unlike the other criteria, this criterion will be based on the 24 hour period from midnight to midnight as 
only the dates and not the times of additional GCS treatment will be collected.  See Appendix 2 for definition of 
GCS ‘due to asthma’.


Statistical Analysis Plan 
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A missing asthma week (in terms of PCAW) is defined when it cannot be unequivocally 
determined whether the week is poorly-controlled or does not meet criteria for 
poorly-controlled.  
3.4.1.4
eDiary compliance
eDiary use compliance (%) will be calculated using the ratio of actual number of diary entries 
to expected number of diary entries, during the randomised treatment period.  Morning and 
evening entries are counted as two separate entries and can only be counted once in the 
morning and once in the evening.  Data recorded on the morning of Day 1 and on the evening 
of the last day of treatment are not included in these calculations.  The expected compliance is 
2 times (day of last dose of IP – day of first dose of IP).
eDiary use compliance(%) = 100 x (number of morning diary entries + number of evening 
diary entries during the randomised treatment period) /[ (day of last dose of IP – day of first 
dose of IP)*2]
3.4.2
Asthma exacerbations
3.4.2.1
Definitions of exacerbations
A severe exacerbation is defined as a deterioration of asthma requiring any of the following:
!
use of systemic steroids for at least 3 days1,
!
inpatient hospitalization, or
!
emergency room visit2 due to asthma that required systemic steroids3.
1 An injection of depot glucocorticosteroids due to asthma worsening is considered 
equivalent to at least 3 days of systemic glucocorticosteroids 
2 Emergency room visit or other urgent unscheduled health care visit
3 Systemic steroids used for any length of time.  
For severe exacerbations, the start date is defined as the first day of hospitalisation/emergency 
room treatment or the first day of systemic (i.e., not inhaled) GCS treatment.  The end date is 
defined as the last day of hospitalisation/emergency room treatment or the last day of systemic 
GCS treatment (according to prescription).  If the same asthma exacerbation includes both 
hospitalisation/emergency room treatment and systemic GCS treatment, the start and end 
dates are the first and last day that either of the criteria was fulfilled. No date imputation is 
done for severe exacerbations with missing end dates.  


Statistical Analysis Plan 
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Additional hospitalisations/emergency room treatments and systemic GCS treatments 
occurring during a severe asthma exacerbation should not be regarded as a new exacerbation.  
For a severe asthma exacerbation to be counted as a separate event, it must be preceded by at 
least seven days in which no criteria for severe exacerbations are fulfilled.
A moderate exacerbation is defined as a deterioration of asthma requiring a change in 
treatment, i.e., initiation of prescribed additional ICS treatment to avoid progression of the 
worsening of asthma to a severe exacerbation.
For moderate exacerbations, the start date is defined as the first day of additional prescribed 
ICS treatment.  The end date is defined as the last day of this treatment.
For a moderate asthma exacerbation to be counted as a separate event, it must not be followed 
by criteria for a severe exacerbation within 7 days, and it must be preceded by at least seven 
days in which no criteria for severe or moderate exacerbations are fulfilled.  
A moderate or severe exacerbation is defined as any individual moderate exacerbation or 
severe exacerbation from the above definitions i.e., number of moderate or severe 
exacerbations = number of moderate exacerbations + number of severe exacerbations.
3.4.2.2
Time-to-event variables for exacerbations
The start and end dates of each moderate and severe exacerbation will be recorded in the 
eCRF at the site visits.  From these start dates (and the date of first dose of IP), two
time-to-event variables will be calculated:
!
Time to first severe exacerbation (i.e., disregarding any moderate exacerbations that 
may have occurred first)
!
Time to first moderate or severe exacerbation (i.e., any exacerbation)*
*Note that the earliest severe exacerbation or moderate exacerbation criteria will be used.  
Therefore, if severe exacerbation criteria occur within 7 days of a moderate exacerbation, the 
time of the moderate exacerbation criteria will be used.  
!
Both of the above variables will be derived based on the day of first dose of IP 
using the following formula:
Time to exacerbation event = Start date of exacerbation – Date of first dose of IP + 1


Statistical Analysis Plan 
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3.4.2.3
Time-to-censoring for exacerbations
Patients not having any asthma exacerbation will be considered as censored at their latest 
follow up date.  Latest follow-up date is defined as the end date of dosing if available, 
otherwise date of termination if available, otherwise last visit date.  
Maximum follow-up time for a patient is approximately 52 weeks, defined as the time from 
first dose of IP to the date of Visit 8.  
Time to censoring is then calculated as follows:
Time to censoring = Date of latest follow-up date– Date of first dose if IP + 1
This derivation will be applied independently to both the analyses of time to first severe 
exacerbation and for time to first moderate or severe exacerbation.  
3.4.2.4
Number of severe and moderate or severe asthma exacerbations, and annual 
exacerbation rate
The total number of severe, and moderate or severe asthma exacerbations during the 
randomised treatment period will be calculated for each patient.  
In order to account for varying lengths of follow-up (due to discontinuation, loss to follow-up, 
or minor differences in the timing of Visit 8), the annual exacerbation rate will be presented 
for the purposes of summary statistics.  This will be calculated as follows:
Study level: annual exacerbation rate = Σ Number of exacerbations*365.25 / Σ (Latest follow-
up date – Date of first dose of IP+ 1)
3.4.3
Administration of additional steroids for asthma and long-term poor asthma 
control.
Data on additional inhaled and systemic steroids prescribed for exacerbations will be collected 
via the EXACASI eCRF module.  Data on additional inhaled corticosteroids prescribed for 
poor asthma control will be collected via the MED module as per the table in Appendix 2.  
Data on additional steroid use are used in part to evaluate the weekly composite endpoints (see 
Section 3.4.1.3)
Additional ICS and systemic GCS prescribed on the day of IP discontinuation for an asthma 
exacerbation will be considered as during the randomised treatment period.  If prescribed for 
any other reason, they will be considered as during the follow-up period (See Appendix 2).
Time to administration of additional steroids for asthma will be calculated as the time from 
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Statistical Analysis Plan 
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Edition Number 4
Date 29 September 2017
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Time to first additional steroid administration = Start Date of administration of additional 
steroids – Date of first dose of IP+ 1
Time to censoring will be defined as for censoring for asthma exacerbations (see Section 
3.4.2.3).
The administration of additional steroids for long-term poor asthma control will be calculated, 
and is a subset of the additional steroids for asthma.  Additional steroids for long-term poor
asthma control can be identified from the EXACASI and MED CRF modules as per the table 
in Appendix 2.  
3.4.4
Total inhaled steroid load
Total inhaled steroid load (total ICS dose) during the randomised treatment period will be 
calculated for each patient as the sum of the cumulative doses of maintenance ICS 
(budesonide), ‘as needed’ ICS as part of Symbicort (budesonide), and additional prescribed 
inhaled corticosteroids of any type.
For calculation purposes, the dose for ‘as needed’ ICS part of the Symbicort arm will be the 
delivered dose, 160μg.  The maintenance ICS part of the Pulmicort arm will be converted 
from the metered dose, 200μg, to 160μg, the delivered dose.  For additional ICS, the dose, as 
recorded by the investigators in the eCRF will be used.  
Any dose that was recorded during the randomised treatment period will be included in 
summaries of overall steroid load.  Doses which are not in μg should be converted to μg
before being summed.  For additional prescribed inhaled corticosteroids, 100% compliance 
will be assumed.  
Data on IP usage will be recorded via the TUM, while additional prescribed inhaled 
corticosteroids will be collected via the appropriate CRF module, and can be identified as per 
the table in Appendix 2.  
To account for differences in the length of follow-up, a time-standardised variable, mean daily 
ICS dose, will be estimated.
Total ICS: Mean daily ICS dose = Total ICS dose / (Date of last dose of IP – Date of first 
dose of IP + 1)
The mean daily ICS dose will also be calculated separately for IP [maintenance ICS 
(budesonide), ‘as needed’ ICS as part of Symbicort (budesonide)] and additionally prescribed 
ICS.  Also, additionally prescribed ICS will be separated by individual ICS medications.  
IP: Mean daily ICS dose = Total ICS dose (IP only) / (Date of last dose of IP – Date of first 
dose of IP + 1)


Statistical Analysis Plan 
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Additional ICS: Mean daily ICS dose = Total ICS dose (Additional only) / (Date of last dose 
of IP – Date of first dose of IP + 1)
In addition, the proportion of days prescribed additional ICS will be calculated as:
Proportion of days prescribed additional ICS = Number of days for which additional ICS 
were prescribed/ (Date of last dose of randomised study drug – Date of first dose of IP + 1)
If there is no available end date for additional ICS, then it will be assumed that it continues 
until IP discontinuation.
3.4.5
Number of days with systemic GCS treatment due to asthma
The number of days with systemic GCS due to asthma will be recorded via the eCRF MED 
module (identified as per the table in Appendix 2) at each visit.  The total number of days 
recorded during randomised treatment will then be calculated for each patient.
3.4.6
Time to study-specific asthma-related discontinuation
The following criteria will lead to discontinuation from the study due to asthma related events:
!
A severe asthma exacerbation with duration for more than 3 weeks
!
Two severe asthma exacerbations during 3 months
!
Three severe asthma exacerbations in total during the study
For patients who experience one of these events (and thus are discontinued from the study), 
time to discontinuation due to any of the specified asthma related events will be calculated as:
Time to study-specific asthma-related discontinuation = Date of study termination due to any 
asthma-related event – Date of first dose of IP+ 1
Time to censoring will be defined as for censoring for asthma exacerbations (see Section 
3.4.2.3), with the exception that only patients who discontinued the study for any reason other 
than one of the pre-defined asthma-related events will be censored as of their discontinuation 
date.
3.4.7
Lung function variables
The following lung function measurements will be calculated at Visits 2, 3 (baseline), 4, 5, 6, 
7 and 8, at two time-points per visit (pre- and post-bronchodilator):
!
FEV1 (L)
!
FEV1 % of predicted normal


Statistical Analysis Plan 
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!
FVC (L)
In addition, a treatment average will be calculated within subject as the average of Visits 4 to 
8 (one value per visit, further described in Appendix 4: Visit Windowing).  Change from
baseline for each of these three variables, for both time-points will also be calculated for 
Visits 4, 5, 6, 7, 8 and the treatment average.  Please refer to Section 3.1.1 for the baseline
definition.  
FEV1 predicted normal will be derived using the patient’s age (to the nearest 0.01 years, at the 
time of the visit), height (for adults, measured at screening; for adolescents, interpolated 
between measurements taken at Visits 2 and 8) and ethnic population, following the Global 
Lung Initiative (GLI) 2012 lung function regression equations (Quanjer et al 2012).  Full 
details of how this method is applied can be found in Appendix 1 on page 60.
Percentage of predicted normal FEV1 is then calculated as follows:
FEV1 (% of PN) = 100 × (FEV1 (actual) / FEV1 (predicted))
3.4.8
Patient reported outcomes
3.4.8.1
Asthma Control Questionnaire – 5-item Version (ACQ-5)
The 5-item version of the ACQ questionnaire contains five questions on patients’ symptoms, 
which are assessed on a 7-point scale from 0 (representing good control) to 6 (representing 
poor control).  The ACQ-5 score is the mean score of all questions for which responses are 
provided.  A minimum of 4 out of 5 questions must be answered for a valid ACQ-5 score.
The ACQ-5 is conducted at Visits 2, 3, 4, 5, 6, 7 and 8, with score evaluated at each visit.  
Change from baseline for Visits 4, 5, 6, 7 and 8 (individual visits, treatment average across 
Visits 4 to 8, and end of treatment) will also be calculated (baseline calculated as described in 
Section 3.1.1).
The following categorical outcome variables will be calculated based on ACQ-5 score at the 
end of treatment (as defined in Section 3.1.2):
!
Asthma control at end of study: ACQ-5 score at end of treatment < 0.75, ≥ 0.75
!
Patient improved: ΔBL(ACQ-5 score) at end of treatment ≤ –0.5
!
Patient unchanged: ΔBL(ACQ-5 score) at end of treatment ϵ (–0.5, 0.5)
!
Patient worsened: ΔBL(ACQ-5 score) at end of treatment ≥ 0.5
where ΔBL(x) means “Change from baseline in x”.
Note: Patient improved/unchanged/worsened responses are based on a minimal important 
difference (MID) of 0.5.


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If more than one ACQ-5 is completed on any day, the questionnaire with the worst score 
(highest mean value) will be used in the analysis.  This applies to both baseline and 
post-baseline assessments.
3.4.8.2
Asthma Quality of Life Questionnaire – Standardised Version (AQLQ(S))
The AQLQ(S) includes 32 questions relating to 4 distinct domains:
!
activity limitation (11 questions; minimum 7 questions required for a valid score)
!
symptoms (12 questions; minimum 8)
!
emotional function (5 questions; minimum 3)
!
exposure to environmental stimuli (4 questions; minimum 3)
Each question is answered on a 7-point scale ranging from 1 to 7 with lower values 
representing more severe impairment.
For each of the four domains, a domain score is calculated as the mean score of all its 
constituent items.  An overall score across the whole questionnaire is calculated as the mean 
score of all 32 items.  In case of any missing answers, the overall score is calculated as a 
weighted mean of the domain scores, with the nominal fraction of items in each domain as 
weights.  If one or more domains are missing, the overall score is also missing.  (Note: when 
there are no missing answers, this method is equivalent to the average response of all 32 
questions taken individually).
The four domain scores and an overall score will be calculated for Visits 2, 3, 5, 6, 7 and 8
(individual visits, and treatment average across Visits 5 to 8).  Change from baseline for all 
four domain scores and the overall score will be calculated for Visits 5, 6, 7 and 8, treatment 
average and end of treatment (baseline calculated as described in Section 3.1.1).
The following categorical outcome variables will be calculated based on overall AQLQ(S) 
score at the end of treatment (as defined in Section 3.1.2):
!
Patient improved: ΔBL(AQLQ(S) score) at end of treatment ≥ 0.5
!
Patient unchanged: ΔBL(AQLQ(S) score) at end of treatment ∈(–0.5, 0.5)
!
Patient worsened: ΔBL(AQLQ(S) score) at end of treatment ≤ –0.5
where ΔBL(x) means “Change from baseline in x”.  
Note: Patient improved/unchanged/worsened responses are based on a minimal important 
difference (MID) of 0.5.


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If more than one AQLQ(S) is completed on any day, the questionnaire with the worst overall 
score (lowest mean value) will be used for the analysis.  This applies to both baseline and 
post-baseline assessments.
3.5
Safety variables
3.5.1
Vital signs
The following vital signs measurements will be conducted at Visits 2 and 8 (or when the
patient withdraws from the study):
!
Pulse rate
!
Systolic blood pressure
!
Diastolic blood pressure
Vital signs measurements will also be conducted in the event of an early withdrawal from the 
study.  Change from baseline for all three parameters will be defined as the difference 
between measurements at End of treatment (as per Section 3.1.2) and Visit 2 (as per Section 
3.1.1 above).
3.5.2
Physical examination
The following physical examination assessments will be made at Visits 2 and 8 (or when the 
patient withdraws from study):
!
General appearance
!
Respiratory
!
Cardiovascular
!
Abdomen
!
Head and neck (including head, ears, eyes, nose and throat)
3.5.3
Pregnancy
Results of the dipstick pregnancy test for female patients aged ≤60 years at Visit 2 will be 
recorded.
Pregnancies that occur during the remainder of the study will lead to the patient being 
withdrawn from the study (see Section 3.6.2).


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3.5.4
Adverse events (including Serious Adverse Events)
3.5.4.1
Collection of AEs and SAEs
Adverse Events (AEs) will be collected from Visit 2 throughout the randomised treatment 
period and including the follow-up period until the last telephone follow-up, or the last 
contact.
Serious Adverse Events (SAEs) will be recorded from the time of informed consent (Visit 1).
The following assessments will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity (mild/moderate/severe)
!
Whether the AE is serious or not
!
Investigator causality rating against the IP (yes or no)
!
Action taken with regard to investigational product
!
AE caused patient’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
Reason that AE became serious
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)


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!
Causality assessment in relation to Other medication
!
Description of AE
3.5.4.2
Definition of adverse event leading to discontinuation of investigational 
product (DAE)
Adverse events where “Action taken with regard to investigational product” is answered 
“discontinued” will be defined as DAEs and reported separately (in addition to being reported 
as general AEs).
3.5.4.3
AEs representing potential β2 agonist effects and AEs representing potential 
ICS effects
Summary tables of AEs representing potential β2 agonist effects and AEs representing 
potential ICS effects will be produced.  These AEs are defined in Appendix 3.  
3.5.4.4
Other significant adverse events (OAEs)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs.  Based on the expert’s judgement, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such in the Clinical 
Study Report.  A similar review of vital signs data will be performed for identification of 
OAEs.
OAEs will be reported in a separate table (in addition to being reported as general AEs).
3.5.4.5
Adverse events data handling
Adverse events will be reported as occurring during the run-in period if the start date is on or 
after the first date of run-in medication, and prior to the first dose of randomised medication.
Adverse events will be considered as occurring during the randomised treatment period if the 
onset date is on or after the date of first dose of randomised study medication and onset is not 
later than one day after the last day of randomised treatment.  
Adverse events that start during the run-in period but continue and become serious adverse 
events during the randomised treatment period will be reported in both run-in and also in the 
randomised treatment period.
Adverse events will be considered as occurring during the follow-up period if the onset date is 
later than one day after the last day of randomised treatment.
If an AE has a missing onset date, then, unless the stop date of the AE indicates otherwise, this 
will be considered as occurring during the randomised treatment period.  Similarly, if an AE 
has a partial onset date, then unless the partial onset date or the stop date indicates otherwise, 
this will be considered as occurring during the randomised treatment period.


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3.6
Other variables
3.6.1
Concomitant medications
Concomitant inhaled and systemic asthma treatment as prescribed in response to moderate or 
severe exacerbations or long-term poor asthma control treatment will be recorded in the 
EXACASI and MED modules as per Section 3.4.3 above.
Other concomitant, which is considered necessary for the patient’s safety and wellbeing, may 
be given at the discretion of the Investigator and recorded in the appropriate sections of the 
eCRF.
Additional ICS and systemic GCS prescribed on the day of IP discontinuation for an asthma 
exacerbation will be considered as during the randomised treatment period, otherwise they 
will be considered as during the follow-up period (See Appendix 2).  All other concomitant 
medication prescribed on the day of IP discontinuation will be counted as during the 
randomised treatment period unless the reason is ‘disease under study’ where it will be 
considered as follow-up.
3.6.2
Discontinuation/withdrawal from the study
On leaving the study, either at the scheduled end of treatment and subsequent follow-up, or 
following early withdrawal from the study, or at such time when the patient is considered to 
be lost to follow-up, the date and reason for leaving the study will be recorded.
Patients may be discontinued from IP in the following situations:
!
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment
!
Adverse Event
!
Severe non-compliance with the study protocol
!
Safety reason as judged by the investigator and/or AstraZeneca
!
Pregnancy
!
Development of any of the following study specific criteria for discontinuation:
∀
A severe asthma exacerbation with duration of more than 3 weeks
∀
Two severe asthma exacerbations within a period of 3 months
∀
Three severe asthma exacerbations in total during the study.


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3.6.3
Compliance of study maintenance medication 
Summary statistics about maintenance medication compliance will be produced.  The 
expected number of maintenance medications is two per day for each day of the randomised 
treatment period, other than the final day, when only one maintenance medication is expected 
to be taken.
Compliance for maintenance medication (%) will be calculated for each patient as: 
(Total actual maintenance inhalations/Total expected maintenance inhalations)*100.
Total expected maintenance inhalations = number of days in the randomised treatment 
period*2 – 1.  
Other compliance metrics includes the proportion of study days where each patient used no 
doses, 1-2 doses only, 2 doses only, and more than 2 doses.  
For the purpose of graphical representation, the proportion of study days where patients used 
≥1 inhalation will also be calculated per week as follows:
!
Derive the percentage per day as number of patients who took at least 1 inhalation 
divided by the number of patients still in the randomised treatment period on the 
respective study day.  
!
For each week take a mean of the percentages for the 7 days of the week.  
4.
ANALYSIS METHODS
4.1
General principles
All tests will be 2-sided and at 5% level of significance unless otherwise stated.  The primary 
efficacy variable will be controlled for multiplicity, whereas no adjustments will be made for 
multiplicity for secondary efficacy variables.
Unless otherwise specified, for all statistical analyses, missing at random (MAR) will be 
assumed.
In addition, the analyses described below, all variables will be summarised descriptively, as 
appropriate.
For efficacy analysis, the following general principles guide the statistical hypotheses to be 
tested:
!
The three treatment groups in the study (with short names defined for clarity) are as 
follows:


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∀
Symbicort Turbuhaler 160/4.5μg ‘as needed’ with no maintenance treatment 
(Symbicort ‘as needed’)
∀
Pulmicort Turbuhaler 200μg twice daily ‘maintenance’ plus terbutaline 
Turbuhaler 0.4mg ‘as needed’ (Pulmicort bid)
∀
terbutaline Turbuhaler 0.4mg ‘as needed’ with no maintenance treatment 
(SABA ‘as needed’)
!
Patients will be stratified at recruitment on the basis of their prescribed treatment 
prior to the study.  For analysis purposes, pre-treatment is derived from the 
MEDENT (Asthma medication at entry) module.  The two stratification groups are 
as follows:
∀
Uncontrolled on BD 
∀
Controlled on ICS or LTRA 
!
For the purpose of this SAP, the treatment that a patient has been randomised to for 
the duration of the study will be referred to simply as ‘randomised treatment’; 
treatment prescribed to a patient prior to the study will be referred to as ‘pre-study 
treatment’.
!
The purpose of the trial is to compare the Symbicort ‘as needed’ group with the 
other two treatment groups, which should both be considered ‘control’ groups for 
two different purposes as described below.
∀
The purpose of comparing Symbicort ‘as needed’ with SABA ‘as needed’ is to 
determine the superiority of the former over the latter.
∀
Conversely, the purpose of comparing Symbicort ‘as needed’ with Pulmicort
plus terbutaline is to determine the non-inferiority of the former as compared to 
the latter.
For non-inferiority analyses, the non-inferiority limit for the lower bound of the two-sided 
95% confidence interval will be 80% (i.e., non-inferiority will be concluded if the lower two-
sided 95% confidence interval of the odds ratio for Symbicort ‘as needed’ compared to
Pulmicort bid plus terbutaline is ≥80%).  
These two hypotheses will be tested sequentially for the primary endpoint: if superiority is not 
concluded for the first comparison, then no formal statistical inference will be made from the 
non-inferiority comparison, but p-values will still be presented.


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If superiority of Symbicort ‘as needed’ compared with SABA ‘as needed’ is not concluded for 
the primary endpoint, then no further formal statistical inference will be made for any of the 
secondary endpoints, but p-values will still be presented.
Unless otherwise stated all efficacy and safety analyses will be conducted using the 
“randomised treatment period” which begins at date of first dose of investigational product 
(maintenance or ‘as needed’ study medication).  It ends at the end date of dosing if available, 
otherwise date of termination if available, otherwise last visit date.
Selected analyses on the well-controlled asthma weeks endpoint use the “52 week study 
period” which begins at date of first dose and ends at 52 weeks.  All full weeks post IP 
discontinuation up to and including 52 weeks will have a missing value for the well-controlled 
asthma weeks endpoint.
The number of patient years each patient contributes will be calculated as 
Number of patient treatment years = (End of randomised treatment period – Start of 
randomised treatment period + 1)/ 365.25
For all efficacy analysis with visit as a covariate, end of treatment should be excluded from 
the analysis unless otherwise stated.  The scheduled 52 week visit (defined by windowing as 
Visit 8) should be included.  
4.2
Analysis methods
4.2.1
Patient disposition
Patient disposition will be summarised using the All Patients analysis set.  The number of 
patients who were enrolled, run-in and not run-in will be summarised.  The number and 
percentage of patients within each treatment group will be presented by the following 
categories; randomised, not randomised (and reasons), randomised who received study 
treatment, randomised who did not receive study treatment (and reasons), completed.
A separate table will present the number and percentage of patients randomised to each 
treatment group, by country.  This table will be based on the Full analysis set.  
A Kaplan-Meier graph will be generated to show the time to IP discontinuation by randomised 
treatment group using the Full analysis set.  This will be the time from first dose of IP to time 
of IP discontinuation or completion (whatever occurs first).  
4.2.2
Demography data and patient characteristics 
Age, gender, race, ethnic group and region will be summarised by treatment group and by 
treatment and pre-treatment group for the full analysis set.  Baseline characteristics will be 
summarised by treatment for the full analysis set.  These include previous disease-related 
treatments, medical and surgical histories, and the eDiary variables.  eDiary variables include 
morning and evening PEF, total asthma symptom score.  ‘as needed’ inhalations, nighttime 


Statistical Analysis Plan 
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awakenings due to asthma (%), symptom-free days (%), ‘as needed’ free days (%) and asthma 
control days (%).  Weight, height, BMI, smoking status, and ACQ-5 and AQLQ(S)
questionnaires will be summarised by treatment, and by treatment and pre-study treatment 
group.  FEV1 (pre- and post-bronchodilator) and reversibility (ml and %) will be summarised 
at screening and baseline by treatment, and by treatment and pre-study treatment.  Asthma 
duration (defined by Time in years since asthma diagnosis, and Time in years since asthma 
symptoms started), a binary variable capturing if the most recent severe exacerbation was in 
last 12 months (Yes/No), and the number of severe exacerbations in the previous 12 months 
will be summarised by randomised treatment group, for all patients and by pre-study treatment
subgroup at the enrolment visit.  
FEV1 % predicted normal (pre-bronchodilator and post-bronchodilator) as assessed at Study 
entry will also be categorized into the following four categories for pre-bronchodilator 
measurements: < 60%, ≥60% to < 80%, ≥80% to <100%, ≥100%., and for post-bronchodilator 
measurements the categories are: <80%, ≥80% to <100%, ≥100%.  The number of patients 
and percentage of patients falling into each of these categories and randomised treatment 
group will be presented both in total, and by each pre-treatment subgroup.  The same table 
will be repeated for FEV1 % predicted normal (pre-bronchodilator and post-bronchodilator) as 
assessed at baseline.  
Medical and surgical histories will be summarised by MedDRA preferred term within 
MedDRA system organ class.  
4.2.3
Treatment exposure
Exposure to the study medication and number and percentage of patients exposed during the 
randomised treatment period (≥ 1 day, >4, >8, >16, >24, >32, >40, >48, and > 52 weeks) will 
be summarised by treatment group, and by pre-study treatment group and treatment group.  
Treatment exposure is defined as the number of days between the date of last dose of the study
medication taken and the date first dose of the study medication taken plus one.  
4.2.4
Concomitant medications
The number and percentage of patients who take allowed concomitant medications, and those 
who take disallowed concomitant medications during the study, will be presented by treatment 
group.  Concomitant medications will be classified according to the AstraZeneca Drug 
Dictionary (AZDD)).  The summary tables will present data by generic term within ATC 
code.
4.2.5
Primary analysis: well-controlled asthma weeks
The primary variable, well-controlled asthma weeks (binary) over the 52-week study period, 
will be analysed by a repeated measures logistic regression model with randomised treatment, 
pre-study treatment, region and study week as fixed effects, with study week included as a 
categorical variable.  If problems with model convergence arise, the model will be rerun with 
study week as a continuous time variable, and this will be documented.  The structure of the 


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correlation matrix to be used in the model will be exchangeable, i.e., correlations between all 
timepoints assumed equal.  The statistical inference will be based on the estimated odds-ratio 
(Symbicort ‘as needed’ vs SABA ‘as needed’ and Symbicort ‘as needed’ vs Pulmicort bid) 
and corresponding 95% confidence interval averaged over the whole 52-week period.
The planned treatment comparisons are:
1.
Symbicort ‘as needed’ vs SABA ‘as needed’ (superiority, primary objective)
2.
Symbicort ‘as needed’ vs Pulmicort bid (non-inferiority)
Formally, the null and alternative hypotheses for comparison 1 are:
H0: odds-ratio (Symbicort ‘as needed’ vs SABA ‘as needed’) = 1
HA: odds-ratio (Symbicort ‘as needed’ vs SABA ‘as needed’) ≠ 1
Hence, the lower confidence level of the odds ratio (Symbicort ‘as needed’ vs SABA 
‘as needed’) must be greater than 1 in order to declare superiority.
And for comparison 2:
H0: lower 95% confidence limit of odds-ratio (Symbicort ‘as needed’ vs Pulmicort
bid) < 0.8
HA: lower 95% confidence limit of odds-ratio (Symbicort ‘as needed’ vs Pulmicort
bid) ≥ 0.8
Hence, the lower confidence level of the odds ratio (Symbicort ‘as needed’ vs Pulmicort bid) 
must be greater than or equal to 0.8 in order to declare non-inferioirity.
The two hypotheses will be tested sequentially.  If comparison 1 does not support the 
hypothesis that Symbicort ‘as needed’ is superior to SABA ‘as needed’, then no formal 
statistical inference will be made for comparison 2, and Symbicort ‘as needed’ compared with 
Pulmicort bid will be considered exploratory.  
The model will be coded using the PROC GENMOD procedure in SAS®, using the following 
code as a guide:
The comparison 1 and 2 hypothesis test result will be displayed using a two-sided 95% 
confidence interval.  


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proc genmod data=indata;
  class trtcd pst region usubjid week;
  model resp = trtcd pst region week / dist=bin ;
  repeated subject=usubjid(trtcd) / type=exch withinsubject=week;
run;
Summary statistics about well-controlled asthma weeks will also be presented, by treatment.  
The percentage of well-controlled asthma weeks will also be examined over the randomised 
treatment period, by treatment.  The number of well-controlled asthma weeks will also be 
categorised into the following four categories: 0-13 weeks, 14-26 weeks, 27-39 weeks, 40-52 
weeks, and for the percentage of well-controlled asthma weeks, the following categories will 
be defined 0% to < 20%, 20% to < 40%, 40% to <60%, 60% to < 80%, 80% to 100%.  For 
both of these categorical variables, the number of patients and the percentage of patients 
falling into each of these categories will be presented, by randomised treatment group, using 
the Full analysis data set.  Additional summaries will show the overall percentage of 
well-controlled, not well controlled and missing (whether due to study discontinuation, or 
not), and summary statistics about the proportion of missing weeks each patient has for the 
52-week study period.  
A box and whisker plot for the mean percentage of well-controlled asthma weeks during the 
randomised treatment period will be presented.  
Percentage of well-controlled asthma weeks (non-modelled data) will be depicted graphically 
by week and treatment.
Supportive analyses to the primary analysis are presented in Section 4.2.8.
4.2.6
Secondary efficacy analyses
4.2.6.1
Asthma exacerbations
The number of severe and moderate or severe asthma exacerbations will be analysed using 
negative binomial regression models.  The response variable in either model will be the 
number of asthma exacerbations (either severe, or moderate or severe) over the randomised 
treatment period.  For both outcome variables, the same modelling method will be used.
The model will include covariates of randomised treatment, pre-study treatment, region and 
number of severe exacerbations 12 months prior to screening (0 or ≥1) as factors.  The 
logarithm of the follow-up time will be used as an offset variable.  From the negative binomial 
model, the annual exacerbation rates will be estimated using least squares means and 
treatments effects will be expressed as the rate ratio along with its corresponding 95% 
confidence intervals.
The model will be coded using the PROC GENMOD procedure in SAS®, using the following 
code as a guide:


Statistical Analysis Plan 
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proc genmod data=indata;
  class trtcd pst region;
  model nexac = trtcd pst region / dist=negbin offset=logfup;
run;
The rate ratio estimates together with the corresponding two-sided 95% confidence interval 
will be shown in a Forest plot.  
Time to first severe and time to first moderate or severe asthma exacerbation will be analysed 
by Cox proportional hazards models.  For both outcome variables, randomised treatment, 
pre-study treatment, region and number of severe exacerbations 12 months prior to screening
(0, or ≥1) will be included as factors.  The hazard ratio and its corresponding 95% confidence 
interval will be estimated from the model.  Reverse Kaplan-Meier plots for time to first severe 
exacerbation and time to first severe or moderate exacerbation will be included.  For patients 
without any exacerbations, the censoring time will be the time to discontinuation/completion.
The Cox proportional hazards model will be coded using PROC PHREG in SAS®, using the 
following code as a guide:                                                                                                                                      
proc phreg data=indata;
class trtcd pst region;
model texac*censor(0) = trtcd pst region;
run;
Summary statistics will be calculated about severe exacerbations and moderate or severe 
exacerbations in terms of exacerbation frequencies and rate, the number of days with an 
exacerbation.  Summary statistics will also be calculated for severe exacerbation types:
exacerbation requiring hospitalisation, exacerbation requiring GCS treatment for at least 
3 days, and exacerbation requiring both emergency room visit and systemic steroids.  
A table presenting the total number of moderate or severe exacerbations, and the total number 
and percentage whether these events were preceded by a worsening of asthma symptoms 
(including type of symptom) will be presented by each randomised treatment group.  The 
same table will also include number of patients and percentage where a worsening in eDiary 
deterioration of symptoms for at least 2 days was observed.  
The two weeks before and after the start of a severe exacerbation and moderate or severe 
exacerbation will be examined further by calculating mean PEF, and mean ‘as needed’ inhaler 
use every day in this period and plotting the treatment means over the 4 week period.
4.2.6.2
Additional steroids for asthma
Time to the administration of additional steroids for asthma will be analysed by a Cox 
proportional hazards model with randomised treatment, pre-study treatment and region as 
factors.  The hazard ratio and its corresponding 95% confidence interval will be estimated 
from the model (as with time to first asthma exacerbations in Section 4.2.6.1).  


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A Kaplan-Meier plot for time to first additional steroids for asthma will be displayed by 
treatment.
An additional table presenting “Additional steroids for asthma and for long-term poor asthma 
control” will also be produced and this table will summarise the following variables: at least 
one administration of additional steroids (binary variable), Total number of days of additional 
steroids for patients who had been prescribed additional steroids for at least one day , at least 
one administration of additional ICS (binary variable), and Total number of days of additional 
ICS, by each randomised treatment group for patients who had been prescribed additional ICS 
for at least one day.  For the binary variables, number of patients and percentage will be 
presented and for the two other variables, descriptive summary statistics will be produced.
4.2.6.3
Steroid load
The mean daily ICS (IP only, additional ICS and total, in μg) and the number of days with 
systemic GCS due to asthma will be presented descriptively by randomised treatment.  A line 
graph will examine the change in mean daily inhaled steroid load over the randomised 
treatment period, by study week.  In addition, a box and whisker plot presenting the mean 
daily ICS dose during the randomised treatment period, by each randomised treatment group 
will be produced.  Within each treatment group there will be three different boxes presented: 
the first box representing the total ICS, the second box presenting the IP only ICS, and the 
third box presenting additional ICS use.  
4.2.6.4
Discontinuation due to study specific asthma related events
Time to study discontinuation due to study specific asthma related events will be analysed by 
Cox proportional hazards model with randomised treatment, pre-study treatment and region as 
factors.  The hazard ratio and its corresponding 95% confidence interval will be estimated 
from the model (as with time to first asthma exacerbations in Section 4.2.6.1).  
Summary statistics alone will be presented if the number of study-specific asthma related 
discontinuations is considered to be too small to enable a meaningful statistical analysis.
In addition, the number of patients and the percentage of patients meeting a study specific 
asthma related discontinuation criterion, will be presented by randomised treatment group for 
the full analysis set (FAS).  The table will include both the total and also each of the three 
discontinuation criteria: Severe asthma exacerbation with duration for more than 3 weeks, 
Two severe asthma exacerbations during 3 months, and Three severe asthma exacerbations 
during the study.  
Forest plots will be produced based on the hazard ratios for the following secondary 
endpoints: Time to first severe asthma exacerbation, time to first moderate or severe asthma 
exacerbation, time to additional steroids for asthma, and time to asthma related 
discontinuation. 


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4.2.6.5
Lung function measurements
The treatment effect for change from baseline in FEV1 (measured in litres) will be estimated 
using a mixed model repeated measures (MMRM) analysis.  Pre- and post-bronchodilator 
FEV1 will be analysed in separate models, using the same modelling method.
For each model (pre- and post-bronchodilator) measurements of the outcome variable will be 
taken at Visits 4, 5, 6, 7 and 8.  Terms for randomised treatment, pre-study treatment, region, 
visit and (randomised treatment*visit) will be included as fixed effects.  Patient will be 
included as a random effect.  Baseline FEV1 will be included as a continuous covariate.  Visit 
will be fitted as an unordered categorical variable, and the variance-covariance matrix will be 
assumed to be unstructured.  The model will be coded using the PROC MIXED procedure in 
SAS® using the following code as a guide:
proc mixed data=indata;
class trtcd pst region visit;
model chg = trtcd pst region visit trtcd*visit base /ddfm=KR;
repeated visit / subject=usubjid type=un;
run;
If the procedure does not converge then a compound symmetric variance-covariance matrix 
will be used instead (replacing type=un with type=cs in the above code).
Kenward-Roger denominator degrees of freedom will be used (Kenward and Roger 1997).
This model will be used to give an overall assessment of the treatment effect as well as 95% 
confidence intervals.  Separate treatment effects per visit will be presented.
Summary statistics will be presented by treatment for pre- and post-bronchodilator FEV1 (L), 
FEV1 (% of predicted normal) and FVC (L) (including change from baseline in those 
variables) by visit and across all the visits in the trial.  Graphical plots of the FEV1 above 
variables over time will also be presented using model estimates.
4.2.6.6
Patient reported outcomes
ACQ-5 and AQLQ(S) will be analysed in the same way as FEV1 using MMRM analysis.  
Responder variables based on a clinical improvement in ACQ-5 and AQLQ(S) of MID at end 
of treatment compared to baseline and the responder variable ACQ-5 < 0.75 at end of 
treatment will be analysed using logistic regression models.  For each outcome variable, the 
model will include randomised treatment, pre-study treatment and region as factors, and 
baseline ACQ-5 or AQLQ(S) score (whichever matches the outcome variable in question) as a 
continuous covariate.  From the logistic regression model, treatment effects will be estimated 
by odds-ratio and its corresponding 95% confidence interval.  The model will be coded using 
the PROC LOGISTIC procedure in SAS® using the following code as a guide:


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proc logistic data=indata;
  class trtcd pst region;
  model resp = trtcd pst region base;
run;
In addition, the proportion of patients who had a clinical worsening or no clinically 
meaningful difference in ACQ-5 and AQLQ(S) based on MID at end of treatment compared 
to baseline will be reported.  
Translation issues were identified in some versions of the ACQ-5/AQLQ(S) questionnaires in 
some countries.  Any patient who completed an ACQ-5 questionnaire with a translation issue 
will be excluded from all ACQ-5 analysis.  Any patient who completed an AQLQ(S)
questionnaire with a translation issue will be excluded from all AQLQ(S) analyses.  A 
document listing all ACQ-5/AQLQ(S) versions with translation issues will be provided.  
The number and percentage of patients complying with ACQ-5 and AQLQ(S) questionnaires 
will be presented by randomised treatment group, both overall and by each study visit 
on-treatment.  
Graphical plots of change from baseline ACQ-5 and AQLQ(S) over time will also be 
presented using model estimates.
4.2.6.7
Electronic diary variables
Change from baseline in PEF averaged over the randomised treatment period will be analysed 
using analysis of covariance (ANCOVA) models.  Morning and evening PEF will be analysed 
using separate models, following the same modelling method.  Change from baseline will be 
calculated as the difference between the mean of all non-missing measurements during the 
randomised treatment period and baseline.  
The ANCOVA models will include randomised treatment, pre-study treatment and region as 
categorical factors, and the mean PEF value during run-in as a continuous covariate.  Least 
squared means by randomised treatment group and differences in least squared means 
(between randomised treatment groups) along with corresponding 95% confidence intervals 
will be estimated.  The model will be coded using the PROC GLM procedure in SAS® using 
the following code as a guide:
proc glm data=indata;
  class trtcd pst region;
  model chg = trtcd pst region base;
run;
The change from baseline in asthma symptom score (day, night, total) and number of 
‘as needed’ medication occasions (day, night, total), percentage of nighttime awakening(s) 
due to asthma symptoms, percentage of symptom-free days, percentage of asthma-control 


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days, percentage of ‘as needed’-free days, and percentage of controller use days will be 
analysed using ANCOVA models following the same method3.
Poorly controlled asthma weeks will be analysed using summary statistics by randomised 
treatment group.  The proportion of poorly-controlled asthma weeks will also be examined 
over the randomised treatment period, by treatment.  The number of poorly-controlled asthma 
weeks will also be categorised into the following four categories: 0-13 weeks, 14-26 weeks, 
27-39 weeks, 40-52 weeks, and for the percentage of well-controlled asthma weeks, the 
following categories will be defined 0% to < 20%, 20% to < 40%, 40% to <60%, 60% to 
< 80%, 80% to 100%.  For both of these categorical variables the number of patients and the 
percentage of patients falling into each of these categories will be presented, by randomised 
treatment group, using the Full analysis data set.  
Summary statistics about the compliance of the eDiary will be collected by time of day 
(morning/evening).  Descriptive statistics for eDiary compliance will be presented by each 
randomised treatment group, in total and also by morning compliance and evening compliance 
presented separately.  The percentage of patients having a compliance ≥80% will also be 
presented by each randomised treatment group, in total and also by morning compliance and 
evening compliance presented separately.  
Descriptive summary statistics for the eDiary variables will also be presented by randomised 
treatment group for baseline period and randomised treatment period, respectively.  
4.2.6.8
Maintenance medication compliance and ‘as needed’ medication use 
Summary statistics about maintenance medication compliance will be produced.  See Section
3.6.3 for metrics.  To examine changes in compliance over time, the proportion of days where 
patients used ≥1 inhalation will be plotted over the randomised treatment period by week.  
Mean maintenance medication use per day will be depicted graphically by week and 
treatment.
Summary statistics about high use of ‘as needed’ medication (>8 and >12 inhalations on one 
day) will be produced.
Summary statistics about ‘as needed’ medication use and change from baseline in ‘as needed’ 
medication use will be produced.  Change from baseline in ‘as needed’ medication use will be 
analysed using ANCOVA models.  Day, night and total ‘as needed’ use will be analysed using 
separate models, following the same modelling method.  Change from baseline will be 
calculated as the difference between the mean of all days during the randomised treatment 
period and the mean of all days during the last 10 days of the run-in period.
The ANCOVA models will include randomised treatment, pre-study treatment and region as 
categorical factors and baseline as needed medication use.as a continuous covariate.  Baseline 
as needed medication use definition is specified in Section 3.1.  Least squared means by 
                                               


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randomised treatment group and differences in least squared means (between randomised 
treatment groups) along with corresponding 95% confidence intervals will be estimated.
4.2.7
Safety analysis
Safety variables will be presented descriptively by actual given treatment and pre-study 
treatment; no formal statistical hypothesis testing will be conducted.
The following safety variables will be summarised:
!
Vital signs (pulse rate, systolic blood pressure, diastolic blood pressure)
∀
Raw measurements (Visits 2, 8 and end of treatment)
∀
Change from baseline (Visit 2 to end of treatment)
!
Physical examination (general appearance, respiratory, cardiovascular, abdomen, 
head/neck)
∀
Baseline vs last scheduled observation on treatment (shift table)
Summary tables of adverse events, SAEs, DAEs and OAEs during the randomised treatment 
period and adverse events during run-in and follow-up will be produced.  The summary 
outputs on AE categories and AE/SAE/DAE frequencies and incidence rate will also be 
presented by pre-study treatment category.  The incidence rate is defined as the number of 
patients who have experienced the event per 100 patient treatment years.  Number of events 
and event rates for AEs and SAEs will also be presented.  Event rates are defined as the total 
number of events across all patients in the treatment group per 100 patient treatment years.  
Additionally, common AEs defined as those with a frequency >= 2% in any treatment group 
will be tabulated.  Common SAEs and AEs leading to discontinuation defined as those with a 
frequency >= 0.2% in any treatment group will also be tabulated.  Summary tables of AEs 
representing potential β2 agonist effects and AEs representing potential ICS effects will be 
produced.  A listing for deaths, SAEs and DAEs will be generated.  
For the subgroup of adolescent patients (≥ 12 and < 18 years of age at enrolment), absolute 
values and change from baseline in height will be summarised descriptively by treatment 
group.  
4.2.8
Subgroup, supportive and sensitivity analyses
For all supportive analyses, if the model does not converge, then just summary statistics will 
be presented.  
4.2.8.1
Subgroup analysis


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Pre-study treatment:
The treatment effect will be investigated in the 2 subgroups as defined by pre-study treatment 
to assess the consistency of the treatment effect across subgroups. An interaction effect will be 
evaluated for the following efficacy variables: well-controlled asthma weeks, severe 
exacerbations rate, time-to severe exacerbation, moderate or severe exacerbations rate, time-to 
moderate or severe exacerbation, time-to additional steroids, PEF, asthma symptom score, 
nighttime awakening, ACQ-5 and FEV1 pre- bronchodilator. For total inhaled steroid load, 
and time to asthma related discontinuation, descriptive statistics by treatment group will be 
presented by pre-study treatment category.
The treatment-by-pre-study treatment interaction term will be used to explore the consistency 
of the treatment effect across pre-study treatment subgroup categories in the below models. 
The interaction p-value from the Type III sums of squares test will be presented. Forest plots 
presenting the overall and pre-study treatment subgroup categories treatment effects and their 
associated 95% CI will be generated.
For well-controlled asthma weeks, severe exacerbation rate, time-to first severe exacerbation, 
moderate or severe exacerbations rate, time-to moderate or severe exacerbation, time-to 
additional steroids, PEF, asthma symptom score and nighttime awakening, similar models to 
the overall population will be carried out but adding treatment-by-pre-study treatment 
interaction as factor into the model. 
For ACQ and FEV1 pre- bronchodilator, similar models to the overall population will be 
carried out but adding treatment-by-pre-study treatment, pre-study treatment-by-visit, and 
treatment-by-visit-by- pre-study treatment. The 3-way interaction will be used to estimate the 
least squares mean of the treatment effect and its corresponding 95% CI by visit. 
Well-controlled asthma weeks and severe asthma exacerbations: 
For well-controlled asthma weeks and severe exacerbations, the consistency of treatment 
effect will also be examined with regards to sex, age, severe exacerbations 12 months prior to 
enrolment, baseline ACQ-5, asthma onset, smoking, region, baseline post-bronchodilator 
FEV1 PN and average use of SABA per day during run-in period.  This will be done by 
including a (subgroup*randomised treatment) interaction term in the models.
Forest plots presenting the rate ratios estimates and their associated 95% CI by subgroup: 
pre-study treatment category will be provided.
Subgroup analysis on exacerbations will not be conducted on an individual subgroup if less 
than 20 exacerbations were experienced in the respective subgroup.  
Subgroups are described in Table 2.


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Table 2
Subgroups
Group
Subgroup
Pre-study treatmenta
Uncontrolled on BD
Controlled on ICS or LTRA
Sex
Male
Female
Age 
Adolescents: ≥12-<18 years
Adults: ≥18 - <65 years
Elderly: ≥65 years
Severe exacerbations 12 months prior to 
screeningb
0
≥1
Baseline ACQ-5
≤0.75
>0.75 - ≤1.5
>1.5
Asthma onset 
New diagnosis: Asthma diagnosed in the last 2 
years.
Not new diagnosis: Asthma diagnosed over 2 years 
ago.
Smoking
Never
Current/Former
Regionc
Latin America
EU
East Asia
Rest of World
FEV1%PN.  Prebronchodilator (baseline)
<80
≥80 to <100
≥ 100
Average use of SABA per day during run-in 
period (inhalations)d
≥0 to <1
1 to 2
>2
a Uncontrolled on BD: Uncontrolled on an inhaled short-acting BD ‘as needed’ (SABA and/or short-acting 
anticholinergic agent); Controlled on ICS or LTRA: Controlled on mono-maintenance therapy with either a 
low dose ICS or a LTRA in addition to 'as needed' use of inhaled short-acting BD (SABA and/or short-


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acting anticholinergic agent).  This will be defined according to the data recorded in the Asthma 
medication, at entry form (MEDENT).
b Severe exacerbation definition at baseline is different to the study definition.
c See Section 3.1 for a list of countries in each region.  
dThe day of randomisation is not included in this calculation
4.2.8.2
Supportive analysis: individual components of well-controlled asthma weeks
The analysis described in Section 4.2.5 will be repeated for each component of the definition 
of well-controlled asthma weeks separately, namely:
!
No more than 2 days with a daily asthma symptom score >1
!
No more than 2 days of ‘as needed’ medication use, up to a maximum of 
4 occasions per week (multiple occasions per day should be regarded as separate 
occasions)
!
Morning PEF≥80% of PN every day
!
No nighttime awakenings due to asthma
!
No additional inhaled and/or systemic GCS treatment due to asthma
These analyses will be accompanied by summary tables of the outcomes across all weeks as 
well as graphs for each component separately week-by-week.
4.2.8.3
Supportive analysis: removing individual components of well-controlled 
asthma weeks 
The analysis described in Section 4.2.5 will be repeated with each component separately 
removed from the definition of well-controlled asthma weeks i.e., we will assume the 
removed criteria has been fulfilled.  Therefore, when one of the first three components are 
removed, the algorithm text for well-controlled asthma weeks in Section 3.4.1.3 “Two or more 
of the following criteria are fulfilled” will be replaced by “One or more of the following 
criteria are fulfilled”.  
These analyses will be displayed as a graph showing response rates for each component 
separately week-by-week.  
4.2.8.4
Sensitivity analysis: the ‘as needed’ component of well-controlled asthma 
weeks
An important consideration when interpreting the results of the comparison of Symbicort 
‘as needed’ to Pulmicort bid is the extent to which the primary endpoint is driven by 
‘as needed’ medication use.  A key component of the primary endpoint is the use of 
‘as needed’ medication which is confounded with the different treatment regimes.  In 
particular, the use of Pulmicort maintenance treatment may result in a higher proportion of 


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well-controlled weeks, due to less ‘as needed’ medication use, even if overall asthma control 
is truly similar to Symbicort as needed treatment (as all Symbicort use is counted as 
‘as needed’ medication).
The following sensitivity analysis is planned:
Effect of changing the threshold for the ‘as needed’ component to less stringent criteria.  
The analysis described in Section 4.2.5 will be repeated with the ‘as needed’ component 
changed to incorporate less stringent criteria of the number of days and number of inhalation 
occasions.  
Less stringent criteria: No more than 5 days of ‘as needed’ medication use, up to a maximum 
of 14 occasions per week (multiple occasions per day should be regarded as separate 
occasions).
4.2.8.5
Sensitivity analysis: effect of missing diary observations on well-controlled 
asthma weeks
A histogram will be produced to show the proportion of patients that had an evaluable week 
(i.e., not missing) from weeks 1 to 52 using the 52-week study period. 
An important practical concern in a study where the primary analysis relies on patient diary 
data is the potential for elements of the diary to be unavailable.  
The following 4 sensitivity analyses will be performed to assess the robustness to variations of 
the missing data assumptions on the primary efficacy variable:
(a)
The primary (protocol specified) analysis will be repeated but with additional 
covariates included in the model (baseline ACQ-5, baseline FEV1, sex, and age).  
This model will be fit using an autoregressive correlation matrix.  Prior to this 
analysis, missing covariate values will be imputed by single imputation using the 
fully conditional specification (FCS) approach (White, Royston and Wood 2011), 
using the information from other covariate values and the first 2 weeks of well-
controlled asthma weeks values.  Each treatment group will have its missing data 
imputed separately.  
(b)
Multiple imputation analysis will be employed to impute the missing data, this 
assumes that the data are MAR.  Each treatment group will have its missing data 
imputed separately.  The imputation will be performed using the FCS approach, 100 
times, and a seed of 24127 will be used.  Logistic regression models will be used to 
impute each missing week, using the information of the 2 preceding and 2 
subsequent weeks and the additional covariates (pre-study treatment, region, 
baseline FEV1, baseline ACQ-5, sex and age factors).  Each imputed dataset will be 
analysed as per the primary analysis as specified in Section 4.2.5.  The final 
inferences will be derived by averaging point estimates and combining within- and 


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between-imputation variability using Rubin’s rules (Rubin, 1987). Note that within 
each iteration, missing covariate values for baseline FEV1 and baseline ACQ-5 will 
be imputed using the FCS approach, using the information from other covariate 
values and values from the first 2 weeks of well-controlled asthma weeks.
(c)
Multiple imputation tipping point analysis under the missing not at random 
(MNAR) assumption will be conducted.  For patients in the Symbicort ‘as needed’ 
group, this method will impute missing values post study discontinuation assuming 
they were less likely to be well-controlled than as implied under the MAR
assumption.  The imputed datasets from (b) will be used, after setting the monotone 
imputations of the Symbicort ‘as needed’ group back to missing.  These missing 
values will then be re-imputed using sequential logistic regression with the previous 
two weeks and the baseline covariates pre-study treatment, region, baseline FEV1, 
baseline ACQ-5, sex and age).  An adjustment will be made to the log-odds of the 
WCAW to the Symbicort ‘as needed’ group using the MNAR option in SAS.  A 
seed of 24127 will be used.  
The adjustment will be included by adding a shift parameter (delta) in the constant 
of the linear predictor function to penalize the probability of being WCAW for the 
Symbicort ‘as needed’ treatment arm.  No MNAR adjustment will be made in the 
SABA ‘as needed’or Pulmicort (bid) arms.  The adjustment will be made at every 
week post study discontinuation.  The procedure will be repeated by decreasing the 
delta in steps of -0.05 until the tipping point are found or an adjustment of -3 is 
reached.  The tipping point is the smallest delta at which the Symbicort ‘as needed’ 
vs SABA ‘as needed’ comparison is not statistically significant.  The Symbicort ‘as 
needed’ vs Pulmicort bid comparison will be calculated using the delta from the 
tipping point of the Symbicort ‘as needed’ vs SABA ‘as needed’ comparison.  
(d)
The analysis described in Section 4.2.5 will be repeated, but the algorithm will be 
modified so that the eDiary has to be completed for all 7 days in a week to 
evaluable for a well-controlled asthma week.
5.
INTERIM ANALYSES
No interim analysis is planned.


Statistical Analysis Plan 
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6.
CHANGES OF ANALYSIS FROM PROTOCOL
6.1
Morning PEF on Day 1 occurs before randomisation
During the review process of this SAP, it was noted that the morning PEF assessment is 
scheduled to take place before randomisation, therefore should not contribute to any outcome 
measurements during the randomised treatment period.  In light of this, the following 
adjustments have been made:
!
Morning PEF on Day 1 will not be included in the last of the 10 days’ worth of run-
in results for the purpose of calculating baseline (see Section 3.1.1)
!
For the purpose of evaluating well-controlled asthma weeks for Week 1, the
criterion based on morning PEF will only take six days’ worth of measurements 
into account (i.e., Days 2-7).  The full seven days’ worth of measurements will be 
used from Week 2 onwards (see Section 3.4.1.3)
6.2
Baseline measurement for ACQ/AQLQ/FEV1/FVC on visit 3 only 
Baseline value for ACQ-5, AQLQ(S), FEV1 and FVC were defined as the last measured value 
prior to randomisation (usually Visit 3, but may occasionally be Visit 2 or an unscheduled 
visit).  However, for patients entering the study as controlled on ICS or LTRA, measurements 
of these variables taken at Visit 2 are expected to be considerably different to the values 
measured at Visit 3, therefore screening values for these variables were not to be used.  In 
light of this, the following adjustments have been made:
!
The baseline value for ACQ-5, AQLQ(S), FEV1 and FVC will be defined as the last 
measured value prior to randomisation on Visit 3 only.  For ACQ-5 and AQLQ(S), 
unscheduled assessments up to 2 days prior to Visit 3 are also acceptable for 
baseline.
6.3
Exclusion of analysis on partly-controlled weeks 
No analysis will be conducted on the partly-controlled asthma weeks endpoint as it is not 
considered clinically meaningful.  
6.4
Amendment to daytime/nighttime periods for ‘as needed’ 
medication
For both the baseline period and the randomised treatment period, the algorithm described in 
Section 3.1.4, which was not described in detail in the CSP, will be used.
6.5
Amendment to incorporate severe exacerbations 12 months prior to 
screening in exacerbation models


Statistical Analysis Plan 
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The number of severe exacerbations 12 months prior to screening (0 or ≥1) was added as a 
categorical covariate to the exacerbation statistical models; annual severe exacerbation rate, 
annual moderate or severe exacerbation rate, time to severe exacerbation rate, and time to 
moderate or severe exacerbation rate.   
7.
REFERENCES
Quanjer et al 2012
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al.  Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.  Eur 
Respir J 2012;40(6):1324-43.
Kenward and Roger 1997
Kenward MG and Roger JH.  Small sample inference for fixed effects from restricted 
maximum likelihood.  Biometrics 1997; 53: 983–997
White, Royston and Wood 2011
White IR, Royston P, Wood AM.  Multiple imputation using chained equations: Issues and 
guidance for practice.  Statistics in Medicine 2011; 30(4):377-99
Rubin, 1987
Rubin DB.  Multiple Imputation for Nonresponse in Surveys.  Wiley: New York, 1987


Statistical Analysis Plan 
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8.
APPENDIX 1: METHOD FOR CALCULATING PREDICTED 
NORMAL FEV1
8.1
Equation for calculating predicted multi-ethnic predicted normal 
FEV1
The equation for calculating predicted normal FEV1 is of the form:
PN FEV1 = exp(a0 + a1·ln(Height) + a2·ln(Age) + a3·AfrAm + a4·NEAsia + a5·SEAsia + 
a6·Other + Mspline)
The following input variables are used in the predicted normal FEV1 equation:
!
Height is the patient’s height in cm (to the nearest 0.1 cm)
!
Age is the patient’s age in years (to the nearest 0.1 years) – this should be 
recalculated based on the visit date and patient’s date of birth
!
AfrAm is equal to 1 if the patient’s ethnic population is African American, 0 
otherwise
!
NEAsia is equal to 1 if the patient’s ethnic population is North East Asian, 0 
otherwise
!
SEAsia is equal to 1 if the patient’s ethnic population is South East Asian, 0 
otherwise
!
Other is equal to 1 if the patient’s ethnic population is Other/Mixed, 0 otherwise
The constants a0, a1, a2, a3, a4 and a5 depend on the patient’s sex, as outlined in the table 
below:
Constant
Males
Females
a0
-10.3420
-9.6987
a1
2.2196
2.1211
a2
0.0574
-0.0270
a3
-0.1589
-0.1484
a4
-0.0351
-0.0149
a5
-0.0881
-0.1208
a6
-0.0708
-0.0708
The final term in the predicted normal FEV1 equation, Mspline, is obtained a lookup table (see 
Section 8.2), based on the patient’s age and sex.


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For patients aged 25 or over, the following equation may be used to approximate Mspline in 
place of the lookup tables:
Mspline = b0 + b1·(Age/100) + b2·(Age/100)2 + b3·(Age/100)3 + b4·(Age/100)4 + b5·(Age/100)5
where b0, b1, b2, b3, b4 and b5 are constants that depend on the patient’s sex, as outlined in the 
table below:
Constant
Males
Females
b0
0.3901
0.0552
b1
-1.0579
1.6029
b2
1.4743
-6.4845
b3
-2.1077
10.2723
b4
-0.1215
-9.8630
b5
0.8873
3.8802
8.2
Lookup table for final term
The following lookup table is used for determining the value of Mspline in the equation for 
calculating predicted normal FEV1 (see Section 3.4.7).  For ages other than those listed here, 
the value is derived using linear interpolation of the two nearest ages (i.e., those ages either 
side of the patient’s actual age).
The lookup table is available from the Global Lung Function Initiative website (URL at the 
time of writing: http://www.ers-education.org/guidelines/global-lung-function-
initiative/tools/quanjer-gli-2012-regression-equations-and-lookup-tables.aspx ).
Age
Male
Female
12
-0.0176
0.0274
12.25
-0.0101
0.0386
12.5
-0.0019
0.0496
12.75
0.0071
0.0604
13
0.0169
0.0709
13.25
0.0274
0.0810
13.5
0.0384
0.0907
13.75
0.0497
0.0999
14
0.0612
0.1086
14.25
0.0728
0.1168
14.5
0.0844
0.1244
Age
Male
Female
14.75
0.0958
0.1315
15
0.1068
0.1379
15.25
0.1175
0.1438
15.5
0.1276
0.1492
15.75
0.1371
0.1540
16
0.1460
0.1583
16.25
0.1542
0.1621
16.5
0.1616
0.1655
16.75
0.1684
0.1684
17
0.1744
0.1711
17.25
0.1798
0.1733
Age
Male
Female
17.5
0.1845
0.1753
17.75
0.1887
0.1770
18
0.1924
0.1785
18.25
0.1956
0.1797
18.5
0.1984
0.1808
18.75
0.2008
0.1816
19
0.2029
0.1823
19.25
0.2046
0.1829
19.5
0.2060
0.1833
19.75
0.2072
0.1837
20
0.2081
0.1839


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Age
Male
Female
20.25
0.2087
0.1841
20.5
0.2090
0.1842
20.75
0.2092
0.1842
21
0.2091
0.1841
21.25
0.2089
0.1840
21.5
0.2084
0.1838
21.75
0.2079
0.1835
22
0.2071
0.1832
22.25
0.2063
0.1828
22.5
0.2053
0.1823
22.75
0.2042
0.1818
23
0.2030
0.1812
23.25
0.2016
0.1806
23.5
0.2002
0.1799
23.75
0.1987
0.1792
24
0.1970
0.1785
24.25
0.1954
0.1777
24.5
0.1936
0.1769
24.75
0.1918
0.1761
25
0.1899
0.1753
25.25
0.1880
0.1745
25.5
0.1861
0.1737
25.75
0.1841
0.1729
26
0.1821
0.1721
26.25
0.1801
0.1713
26.5
0.1781
0.1705
26.75
0.1760
0.1697
27
0.1739
0.1690
27.25
0.1718
0.1682
27.5
0.1697
0.1674
27.75
0.1677
0.1666
28
0.1656
0.1658
28.25
0.1635
0.1650
28.5
0.1615
0.1642
28.75
0.1594
0.1634
29
0.1574
0.1625
29.25
0.1554
0.1617
Age
Male
Female
29.5
0.1534
0.1608
29.75
0.1514
0.1599
30
0.1495
0.1590
30.25
0.1475
0.1581
30.5
0.1455
0.1572
30.75
0.1436
0.1562
31
0.1417
0.1553
31.25
0.1397
0.1543
31.5
0.1378
0.1533
31.75
0.1359
0.1523
32
0.1340
0.1512
32.25
0.1321
0.1501
32.5
0.1302
0.1490
32.75
0.1283
0.1479
33
0.1265
0.1467
33.25
0.1246
0.1456
33.5
0.1227
0.1444
33.75
0.1209
0.1431
34
0.1190
0.1418
34.25
0.1172
0.1406
34.5
0.1153
0.1392
34.75
0.1135
0.1379
35
0.1116
0.1365
35.25
0.1097
0.1351
35.5
0.1078
0.1337
35.75
0.1059
0.1322
36
0.1040
0.1308
36.25
0.1021
0.1292
36.5
0.1001
0.1277
36.75
0.0982
0.1262
37
0.0962
0.1246
37.25
0.0943
0.1230
37.5
0.0923
0.1214
37.75
0.0903
0.1197
38
0.0883
0.1180
38.25
0.0863
0.1164
38.5
0.0843
0.1147
Age
Male
Female
38.75
0.0823
0.1129
39
0.0803
0.1112
39.25
0.0782
0.1094
39.5
0.0762
0.1076
39.75
0.0742
0.1058
40
0.0721
0.1040
40.25
0.0700
0.1022
40.5
0.0680
0.1003
40.75
0.0659
0.0985
41
0.0638
0.0966
41.25
0.0617
0.0947
41.5
0.0596
0.0928
41.75
0.0575
0.0909
42
0.0554
0.0889
42.25
0.0533
0.0870
42.5
0.0511
0.0850
42.75
0.0490
0.0830
43
0.0469
0.0811
43.25
0.0448
0.0791
43.5
0.0427
0.0771
43.75
0.0406
0.0751
44
0.0386
0.0731
44.25
0.0365
0.0710
44.5
0.0344
0.0690
44.75
0.0323
0.0670
45
0.0302
0.0650
45.25
0.0281
0.0630
45.5
0.0261
0.0609
45.75
0.0240
0.0589
46
0.0219
0.0568
46.25
0.0198
0.0548
46.5
0.0177
0.0527
46.75
0.0156
0.0507
47
0.0135
0.0486
47.25
0.0114
0.0465
47.5
0.0093
0.0445
47.75
0.0072
0.0424


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
63
Age
Male
Female
48
0.0050
0.0403
48.25
0.0029
0.0382
48.5
0.0007
0.0361
48.75
-0.0015
0.0339
49
-0.0036
0.0318
49.25
-0.0058
0.0297
49.5
-0.0080
0.0275
49.75
-0.0103
0.0254
50
-0.0125
0.0232
50.25
-0.0147
0.0210
50.5
-0.0170
0.0188
50.75
-0.0193
0.0166
51
-0.0216
0.0144
51.25
-0.0239
0.0122
51.5
-0.0262
0.0099
51.75
-0.0285
0.0077
52
-0.0309
0.0054
52.25
-0.0332
0.0032
52.5
-0.0356
0.0009
52.75
-0.0380
-0.0014
53
-0.0404
-0.0037
53.25
-0.0428
-0.0061
53.5
-0.0453
-0.0084
53.75
-0.0478
-0.0108
54
-0.0502
-0.0131
54.25
-0.0527
-0.0155
54.5
-0.0552
-0.0179
54.75
-0.0578
-0.0203
55
-0.0603
-0.0227
55.25
-0.0629
-0.0252
55.5
-0.0654
-0.0276
55.75
-0.0680
-0.0301
56
-0.0706
-0.0326
56.25
-0.0732
-0.0350
56.5
-0.0759
-0.0375
56.75
-0.0785
-0.0401
57
-0.0812
-0.0426
Age
Male
Female
57.25
-0.0839
-0.0451
57.5
-0.0866
-0.0477
57.75
-0.0893
-0.0503
58
-0.0920
-0.0529
58.25
-0.0947
-0.0555
58.5
-0.0975
-0.0581
58.75
-0.1002
-0.0607
59
-0.1030
-0.0634
59.25
-0.1058
-0.0660
59.5
-0.1086
-0.0687
59.75
-0.1114
-0.0714
60
-0.1143
-0.0741
60.25
-0.1171
-0.0768
60.5
-0.1199
-0.0795
60.75
-0.1228
-0.0822
61
-0.1257
-0.0850
61.25
-0.1286
-0.0878
61.5
-0.1315
-0.0905
61.75
-0.1344
-0.0933
62
-0.1373
-0.0961
62.25
-0.1402
-0.0989
62.5
-0.1431
-0.1018
62.75
-0.1461
-0.1046
63
-0.1490
-0.1075
63.25
-0.1519
-0.1103
63.5
-0.1549
-0.1132
63.75
-0.1578
-0.1161
64
-0.1608
-0.1190
64.25
-0.1638
-0.1219
64.5
-0.1667
-0.1249
64.75
-0.1697
-0.1278
65
-0.1727
-0.1308
65.25
-0.1757
-0.1338
65.5
-0.1786
-0.1368
65.75
-0.1816
-0.1398
66
-0.1846
-0.1428
66.25
-0.1876
-0.1458
Age
Male
Female
66.5
-0.1906
-0.1488
66.75
-0.1936
-0.1519
67
-0.1966
-0.1550
67.25
-0.1996
-0.1580
67.5
-0.2026
-0.1611
67.75
-0.2056
-0.1642
68
-0.2086
-0.1674
68.25
-0.2116
-0.1705
68.5
-0.2147
-0.1736
68.75
-0.2177
-0.1768
69
-0.2207
-0.1799
69.25
-0.2237
-0.1831
69.5
-0.2267
-0.1863
69.75
-0.2298
-0.1895
70
-0.2328
-0.1926
70.25
-0.2358
-0.1958
70.5
-0.2388
-0.1991
70.75
-0.2418
-0.2023
71
-0.2449
-0.2055
71.25
-0.2479
-0.2087
71.5
-0.2509
-0.2120
71.75
-0.2539
-0.2152
72
-0.2569
-0.2184
72.25
-0.2599
-0.2217
72.5
-0.2630
-0.2249
72.75
-0.2660
-0.2282
73
-0.2690
-0.2315
73.25
-0.2720
-0.2347
73.5
-0.2750
-0.2380
73.75
-0.2780
-0.2413
74
-0.2810
-0.2445
74.25
-0.2840
-0.2478
74.5
-0.2869
-0.2511
74.75
-0.2899
-0.2543
75
-0.2929
-0.2576
75.25
-0.2959
-0.2609
75.5
-0.2989
-0.2642


Statistical Analysis Plan 
Study Code D589SC00001
Edition Number 4
Date 29 September 2017
64
Age
Male
Female
75.75
-0.3018
-0.2674
76
-0.3048
-0.2707
76.25
-0.3077
-0.2740
76.5
-0.3107
-0.2773
76.75
-0.3136
-0.2805
77
-0.3166
-0.2838
77.25
-0.3195
-0.2871
77.5
-0.3224
-0.2903
77.75
-0.3253
-0.2936
78
-0.3282
-0.2968
78.25
-0.3311
-0.3001
78.5
-0.3340
-0.3033
78.75
-0.3369
-0.3065
79
-0.3398
-0.3098
79.25
-0.3427
-0.3130
79.5
-0.3455
-0.3162
79.75
-0.3484
-0.3194
80
-0.3512
-0.3226
80.25
-0.3541
-0.3258
80.5
-0.3569
-0.3290
80.75
-0.3597
-0.3322
81
-0.3625
-0.3354
81.25
-0.3654
-0.3386
81.5
-0.3682
-0.3417
81.75
-0.3709
-0.3449
82
-0.3737
-0.3480
82.25
-0.3765
-0.3512
Age
Male
Female
82.5
-0.3793
-0.3543
82.75
-0.3820
-0.3574
83
-0.3848
-0.3606
83.25
-0.3875
-0.3637
83.5
-0.3903
-0.3668
83.75
-0.3930
-0.3699
84
-0.3957
-0.3730
84.25
-0.3984
-0.3760
84.5
-0.4011
-0.3791
84.75
-0.4038
-0.3822
85
-0.4065
-0.3852
85.25
-0.4092
-0.3883
85.5
-0.4119
-0.3913
85.75
-0.4145
-0.3944
86
-0.4172
-0.3974
86.25
-0.4198
-0.4004
86.5
-0.4225
-0.4034
86.75
-0.4251
-0.4064
87
-0.4277
-0.4094
87.25
-0.4303
-0.4124
87.5
-0.4329
-0.4153
87.75
-0.4355
-0.4183
88
-0.4381
-0.4213
88.25
-0.4407
-0.4242
88.5
-0.4433
-0.4272
88.75
-0.4459
-0.4301
89
-0.4484
-0.4330
Age
Male
Female
89.25
-0.4510
-0.4359
89.5
-0.4536
-0.4389
89.75
-0.4561
-0.4418
90
-0.4586
-0.4446
90.25
-0.4612
-0.4475
90.5
-0.4637
-0.4504
90.75
-0.4662
-0.4533
91
-0.4687
-0.4561
91.25
-0.4712
-0.4590
91.5
-0.4737
-0.4618
91.75
-0.4762
-0.4647
92
-0.4787
-0.4675
92.25
-0.4811
-0.4703
92.5
-0.4836
-0.4732
92.75
-0.4861
-0.4760
93
-0.4885
-0.4788
93.25
-0.4910
-0.4816
93.5
-0.4934
-0.4844
93.75
-0.4959
-0.4871
94
-0.4983
-0.4899
94.25
-0.5007
-0.4927
94.5
-0.5031
-0.4954
94.75
-0.5055
-0.4982
95
-0.5079
-0.5009


9.
APPENDIX 2: IDENTIFICATION OF ADDITIONAL STEROID 
MEDICATIONS FOR ANALYSES
Relevant SAP 
section
Parameter
Source of data
3.4.3
Additional steroids for 
asthma*
1a.  Inhaled corticosteroids as recorded on the EXACASI 
module
1b.  MED module with ATC codes R03BA or R03AK and 
reason is either ‘Disease under study’ or ‘Protocol defined 
exacerbation of disease under study’.
1c.  MED module with ATC codes R03BA or R03AK and 
Therapy reason is ’Adverse event’ and Reason for therapy 
text in the MED module contains the word ’asthma’ or 
’astma’.  (Note each letter in asthma/astma should be allowed 
to be in upper/lower case)
1d.  MED module with ATC codes R03BA or R03AK and 
Therapy reason is ’Other’ and ”Reason for therapy  contains 
the word ’asthma’ or ’astma’ (Note each letter in 
asthma/astma should be allowed to be in upper/lower case)
2a.  Long term poor asthma control as recorded on the 
EXACASI module
2b.  MED module where ATC code is either R03BA or 
R03AK and reason is ‘Additional inhaled Budesonide for 
long term poor asthma control.’
3.  Systemic corticosteroids given for an exacerbation as per 
the EXACASI module
4a.  Systemic corticosteroids recorded on the MED module 
where ATC code is H02AB and Therapy reason is ‘Disease 
under study’ or ‘Protocol defined exacerbation of disease 
under study’
4b . Systemic corticosteroids recorded on the MED module 
where ATC code is H02AB and Therapy reason is ’Adverse 
event’ and Reason for therapy text in the MED module 
contains the word ’asthma’ or ’astma'.  (Note each letter in 
asthma/astma should be allowed to be in upper/lower case)
4c .Systemic corticosteroids recorded on the MED module 
where ATC code is H02AB and Therapy reason is ’Other’ 
and  Reason for therapy text  contains the word ’asthma’ 
(Note each letter in asthma/astma should be allowed to be in 
upper/lower case)
3.4.3
Additional inhaled 
steroids for long term 
asthma control
2a or 2b as above
65


3.4.3
Time to first additional 
steroid administration*
The first instance of 1a, 1b, 1c, 1d, 2a, 2b, 3 or 4a, 4b, 4c
above
3.4.4
Total inhaled steroid 
load**
1a, 2a, and any medication in the MED module with ATC 
code either R03BA or R03AK (all reasons) plus 
investigational product.  The exception is on the treatment 
end date, when only those steroid prescribed for asthma (1a 
above) are used.
3.4.5
Number of days of 
systemic GCS use due 
to asthma***
3 and 4a, 4b, or 4c above 
3.4.1.3
Criteria: No additional 
inhaled and/or 
systemic GCS 
treatment due to 
asthma*
1a, 1b, 1c, 1d, 2a, 2b, 3 and 4a, 4b, 4c above
* For medications starting on the day of IP discontinuation, the only sources of data are 1a, 3 and 4a
** For medications starting on the day of IP discontinuation, the only source of data is 1a
*** For medications starting on the day of IP discontinuation, the only sources of data are 3 and 4a.  
66


10.
APPENDIX 3: POTENTIAL CLASS EFFECTS Β2-AGONISTS 
AND POTENTIAL ICS EFFECTS
The following is a list of preferred terms, in MedDRA version 20.0, representing potential β2-
agonist effects, presented by medical concept (group of terms describing the same medical 
phenomenon).  The preferred terms and the medical concepts have been defined by 
AstraZeneca and is applicable for the Symbicort development program as needed.  
Potential class effects β2- agonists
Medical concept
MedDRA (version 20.0) Preferred Term
Agitation
Agitation
Aggression
Anxiety
Anxiety
Feeling jittery
Nervousness
Restlessness
Tension
Hyperglycaemia  
Blood glucose increased
Hyperglycaemia
Headache
Headache
Muscle cramp
Muscle spasms
Hypokalaemia
Blood Potassium decreased
Hypokalaemia
Sleep effects
Initial insomnia
Insomnia
Sleep disorder
Tremor
Tremor
Cardiac events
Acute myocardial infarction
Adams-Stokes syndrome
Angina pectoris
Angina unstable
Arrhythmia
Arrhythmia supraventricular
Atrial fibrillation
Atrial flutter
Atrial tachycardia
Blood pressure ambulatory increased
Blood pressure increased
67


Blood pressure systolic increased
Extrasystoles
Heart rate increased
Hypertension
Palpitations
Sinus tachycardia
Supraventricular extrasystoles
Supraventricular tachyarrhythmia
Supraventricular tachycardia
Tachyarrhythmia
Tachycardia
Ventricular extrasystoles
The following list is of preferred terms, in MedDRA version 20.0, representing potential ICS
effects, presented by location and medical concept (group of terms describing the same 
medical phenomenon).  The preferred terms and the medical concepts have been defined by 
AstraZeneca and is applicable for the Symbicort development program as needed.  
Potential Class effects
Inhaled corticosteroids
Location
Medical concept
MedDRA (version 20.0) Preferred 
Term
Local steroid effects
Candidiasis
Candida infection
Oral candidiasis
Oropharyngeal candidiasis
Voice effects
Aphonia
Dysphonia
Systemic steroid effects
Adrenal suppression
Addison´s disease
Adrenal insufficiency
Adrenal suppression
Adrenocortical insufficiency acute
Blood cortisol decreased
Cortisol free urine decreased
Secondary adrenocortical 
insufficiency
Urine cortisol/creatinine ratio 
decreased
Diabetes control
Diabetes mellitus
Diabetes mellitus inadequate control
68


Metabolic bone 
effects and fractures
All Pts in MedDRA Standardised 
MedDRA query (SMQ): 
Osteoporosis/osteopenia, version 
20.0 broad*
Growth retardation
Growth retardation
Body height below normal
Body height decreased
Ocular effects
Cataract
Cataract cortical
Cataract diabetic
Cataract nuclear
Cataract subcapsular
Glaucoma
Angle closure glaucoma
Open angle glaucoma
Intraocular pressure increased
Lenticular opacities
Ocular hypertension
Glaucomatous optic disc atrophy
Intraocular pressure test abnormal
Psychiatric effects
Depressed mood
Depressive symptom
Dysphoria
Euphoric mood
Insomnia
Psychotic disorder
Restlessness
Skin effects
Contusion
Ecchymosis
Increased tendency to bruise
Petechiae
Purpura
Skin atrophy
Taste effects
Dysgeusia
69


11. APPENDIX 4: VISIT 
Visit windowing for run-in, on-treatment and end of treatment measurements will be 
conducted for FEV1, FVC, ACQ, AQLQ, vital signs, height, weight and physical examination. 
For each measurement, the available data will be used to determine which analysis visit 
number the measurement belongs to. Raw visit numbers will not be used in analysis. For each 
analysis visit the acceptable timing range describes the earliest and latest date a measurement 
can occur to be considered as the value for that analysis visit. For instance, the acceptable 
timing range for analysis visit 4 is 2-8 weeks, so measurements occurring before 2 weeks and 
after 8 weeks cannot be considered as an analysis visit 4 measurement. 
Table 1
Acceptable timing range for each visit
Stage
Analysis 
Visit 
number
Timepoint
Endpoints 
collected
Acceptable time range  in 
relation to first dose of IP
Run-in
Visit 2
-
All
FEV1, FVC, ACQ, AQLQ: Visit 
2 measurement from date of visit 
2 until the first run-in medication. 
Vital signs, height weight and 
physical examination: Visit 2
Baseline (for 
variables where 
visit 3 is used as 
baseline)
Visit 3
0 weeks
FEV1, FVC, 
ACQ, AQLQ
Visit 3 measurement up to 2 days 
before actual visit 3 date but no 
later than date of first dose of IP.
On treatment*
Visit 4
4 weeks
FEV1, FVC, 
ACQ, 
2 - 8 weeks
On treatment*
Visit 5
16 weeks
FEV1, FVC, 
ACQ, AQLQ
>12 to 20 weeks
70


On treatment*
Visit 6
28 weeks
FEV1, FVC, 
ACQ, AQLQ
>24 to 32 weeks
On treatment*
Visit 7
40 weeks
FEV1, FVC, 
ACQ, AQLQ
>36 to 44 weeks
On treatment
Visit 8
52 weeks
All, apart from 
height which is 
collected for 
adolescents only. 
≥48 weeks
Acceptable upper range for 
measurements:
FEV1, FVC: date of analysis visit 
8 and no later than the day after IP 
discontinuation.
ACQ, AQLQ, vital signs, height 
(adolescents only), weight and 
physical examination: no later 
than 7 days after IP 
discontinuation.
End of treatment
Visit 9
-
All, apart from 
height which is 
collected for 
adolescents only.
End of treatment can occur 
anytime between Visit 3 and one 
day after IP discontinuation for all 
patients who took at least one 
dose of IP. 
Acceptable upper range for 
measurements:
FEV1, FVC: date of analysis visit 
8 and no later than the day after IP 
discontinuation.
ACQ, AQLQ, vital signs, height 
(adolescents only), weight and 
physical examination: no later 
than 7 days after IP 
discontinuation.
*If a patient discontinues IP early, all measurements up to and including the day after IP 
discontinuation can be considered for on-treatment values. 
Rules for FEV1, FVC, vital signs, height, weight and physical examination:
71


1. Measurements from unscheduled visits (visit number with decimals of format X.0X or 
with a module occurrence number>1000) will not be used in the analysis. The rational 
for this is that normally an unscheduled visit is made in connection to an asthma 
exacerbation or AE, and assessments at such visits will not be representative of 
scheduled visits. There are cases when a measurement cannot be completed at the 
scheduled visits. In these cases the patient returns on another timepoint to complete 
the assessment. In these cases the scheduled visit number is used in combination 
with a recording of the actual assessment date. Such an assessment will not be 
considered unscheduled and can be included in the analysis. 
2. The order of selecting measurements for each visit is specified below. Visit timepoint 
is the CSP specified timepoint, as in CSP Table 1, i.e. visit 4 timepoint is 4 weeks.
Note that a scheduled visit inside another scheduled visits timing window will be
considered for analysis, e.g. a visit 4 occurring in visit 5 window (10-22 weeks). Also 
note that if there is more than one non-missing observation at same date, the one with 
the lowest module occurrence number should be used as that should be the original 
measurement. Refer to Table 1 for acceptable timing range.  
Rules for ACQ and AQLQ:
1. Unlike the other parameters, ACQ and AQLQ should not be measured on 
unscheduled visits in connection to for example and AE or exacerbation. It has been 
decided not to consider the visit numbers for analysis of ACQ and AQLQ, but to only 
look at the assessment date in relation to the date of first dose of IP, according to the 
the acceptable timing range in Table 1.
2. AQLQ(S) should not be assessed on visits 4, and hence no assessment should be 
selected for analysis visit 4.
3. If there is more than one non-missing observation of ACQ and AQLQ at the same 
date the worse assessment should be used. Which assessment is worse is based on 
the total score. For ACQ a higher total score is worse, and for AQLQ a lower total 
score is worse.
Run-in analysis visit:
1. Use scheduled visit 2 if available and within acceptable visit 2 timing range. Include 
assessments recorded as visit 2 even if before visit 2 date and or after until day of run-
in medication
2. If more than one scheduled visit 2 in acceptable visit 2 timing range use earliest 
scheduled visit.  
Baseline visit (for variables where baseline is based on visit 3)
If more than one scheduled visit 3 in acceptable visit 3 timing range use earliest scheduled 
visit.  
On-treatment analysis visits 4 to 7 
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1. Use closest scheduled visit to visit timepoint if within visit acceptable timing range 
and at most one day after IP discontinuation if patient is a non-completer. If 2 or more 
scheduled visits from visit timepoint are equidistant (and not more than 1 day after IP 
discontinuation if patient is a non-completer) use earlier visit.
2. Use closest other scheduled visit if within visit acceptable range and at most one day 
after IP discontinuation if patient is a non-completer. If 2 or more scheduled visits 
from visit timepoint are equidistant (and not more than 1 day after IP discontinuation if 
patient is a non-completer) use earlier visit.
End of treatment analysis visit for FEV1 and FVC 
If a visit 8 measurement according to visit windows is missing, use last available non-missing 
measurement made at a scheduled visit but no later than one day after IP discontinuation.
End of treatment analysis visit for other variables 
Other variables include ACQ, AQLQ, vital signs, height (adolescents only), weight and 
physical examination.
If a visit 8 measurement according to visit windows is missing, use last available non-missing 
measurement made at a scheduled visit but no later than 7 days after IP discontinuation. For 
ACQ and AQLQ, the assessment does not have to be scheduled, since it was decided not to 
consider the visit numbers for analysis of ACQ and AQLQ. 
On-treatment analysis visit 8 
Patients must have completed at least 48 weeks on IP to have a visit 8 measurement. For these 
patients their visit 8 measurements will be the same as their end of treatment measurements.
Treatment average
Treatment average is derived as an average within subject from the values derived according 
to the rules above for each analysis visit. For assessments that are not to be made on each 
visit, only planned visits will be included. Hence, for example, AQLQ(S) should not be 
assessed on visits 4, and hence the treatment average will be derived from the results for 
analysis visits 5-8.
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