A Clinical Study Comparing Symbicort 'as Needed' With Pulmicort Twice Daily Plus Terbutaline 'as Needed' in Adult and Adolescent Patients With Asthma
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca



Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
2(70)
PROTOCOL SYNOPSIS
A 52-week, double-blind, randomised, multi-centre, phase III, parallel-
group 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 Pulmicort (budesonide) Turbuhaler  
200 μg twice daily plus terbutaline Turbuhaler  0.4 mg ‘as needed’
International Co-ordinating Investigator
Eric D Bateman Prof, MB ChB, MD, FRCP, DCH
South Africa
Study site(s) and number of patients planned
This study will recruit patients worldwide at approximately 330 sites in about 25 countries.  
The target is to randomise 4114 male and female patients. The sample size will be re-
estimated based on blinded review during the study.  The number of patients might be 
increased up to a maximum of 6171 patients.
Study period
Phase of development
Estimated date of first patient enrolled
QIII 2014
III
Estimated date of last patient completed
QII 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 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 D589SC00003
Edition Number 4
Date 12 October 2016
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Objectives
Primary Objective:
Outcome Measure:
To demonstrate that Symbicort Turbuhaler 
160/4.5 μg ‘as needed’ is non-inferior to 
Pulmicort Turbuhaler 200 μg twice daily plus 
terbutaline Turbuhaler 0.4 mg ‘as needed’. 
Annual severe asthma exacerbation rate
Secondary Objective:
Outcome Measure :
To estimate the difference in efficacy between 
Symbicort Turbuhaler 160/4.5 μg ‘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
•Average change from baseline in pre-dose FEV1
•Time to study specific asthma related 
discontinuation
•Average change from baseline in ‘as needed’ use 
• Change from baseline in percent of ‘as needed’ free 
days
•Percentage of controller use days
•Average change from baseline in Asthma Control 
Questionnaire (5-item version) - ACQ-5 score
•Average change from baseline in Asthma Quality of 
Life Questionnaire Standardised Version - AQLQ(S) 
score
Safety Objective:
Outcome Measure :
To compare the safety of Symbicort 
Turbuhaler 160/4.5 μg ‘as needed’ 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 an 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.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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Patients should have used the 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’.  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 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 annual severe asthma exacerbation rate will be analysed by a negative 
binomial regression model.  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 
comparison will be Symbicort ‘as needed’ versus Pulmicort twice daily + terbutaline ‘as 
needed’ (non-inferiority, primary objective).
Formally, the null and alternative hypothesis is:
H0: rate-ratio (Symbicort vs Pulmicort) ≥1.2
HA: rate-ratio (Symbicort vs Pulmicort) < 1.2

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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If the upper 95% 1-sided confidence limit of the relative risk ratio is < 1.2 then non-inferiority 
can be declared.
If the criteria for the alternative hypothesis is met then superiority of Symbicort vs Pulmicort 
in terms of annual severe asthma exacerbation will be assessed.
Formally, the null and alternative hypothesis for superiority testing is:
H0: rate-ratio (Symbicort vs Pulmicort) = 1
HA: rate-ratio (Symbicort vs Pulmicort) ≠1
Analysis of the secondary variables:
For all secondary variables stated below the treatment difference between Symbicort ‘as 
needed’ and Pulmicort twice daily + terbutaline ‘as needed’ will be estimated.
Time to first severe asthma exacerbation and time to discontinuation of investigational 
product 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 the use of ‘as needed’ medication, and the percentage of ‘as 
needed’-free days will be analysed by analysis of covariance.
The percentage of controller use days will be analysed by analysis of covariance.
The total inhaled steroid load and the number of days with systemic glucocorticosteroids, 
respectively will be presented descriptively by treatment adjusted by the patients follow-up 
time.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
PROTOCOL SYNOPSIS.........................................................................................2
TABLE OF CONTENTS.........................................................................................6
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................11
1.
INTRODUCTION .................................................................................................13
1.1
Background and rationale for conducting this study .............................................13
1.2
Rationale for study design, doses and control groups............................................14
1.3
Benefit/risk and ethical assessment........................................................................15
1.4
Study Design..........................................................................................................16
2.
STUDY OBJECTIVES..........................................................................................16
2.1
Primary objective...................................................................................................16
2.2
Secondary objectives .............................................................................................17
2.3
Safety objectives ....................................................................................................17
2.4
Exploratory objectives ...........................................................................................17
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................17
3.1
Inclusion criteria ....................................................................................................18
3.2
Exclusion criteria ...................................................................................................19
3.3
Patient enrolment and randomisation.....................................................................20
3.4
Procedures for handling incorrectly enrolled or randomised patients ...................21
3.5
Methods for assigning treatment groups................................................................21
3.6
Methods for ensuring blinding...............................................................................21
3.7
Methods for unblinding..........................................................................................22
3.8
Restrictions ............................................................................................................22
3.9
Discontinuation of investigational product............................................................22
3.9.1
Procedures for discontinuation of a patient from investigational product.............23
3.10
Criteria for withdrawal...........................................................................................23
3.10.1
Enrolment failures..................................................................................................23
3.10.2
Withdrawal of the informed consent......................................................................24

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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3.11
Discontinuation of the study..................................................................................24
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................25
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...............................................................................................................33
4.4
Follow-up in case of discontinuation of IP............................................................34
5.
STUDY ASSESSMENTS .....................................................................................34
5.1
Efficacy assessments..............................................................................................34
5.1.1
Severe asthma exacerbation...................................................................................34
5.1.2
Lung function measurement by spirometry (FEV1, FVC) at the study site...........35
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 ....................................................................................................37
5.1.3
Asthma Control Questionnaire (5-item Version)...................................................37
5.1.4
Asthma Quality of Life Questionnaire (Standardised Version).............................38
5.1.5
Administration of patient reported outcome questionnaires..................................38
5.1.6
Turbuhaler Usage Monitor (TUM) ........................................................................38
5.2
Safety assessments.................................................................................................39
5.2.1
Physical examination .............................................................................................39
5.2.2
Vital signs ..............................................................................................................39
5.2.2.1
Pulse and blood pressure........................................................................................39
5.3
Health Economics ..................................................................................................39
5.3.1
Health care resource utilisation..............................................................................40
5.3.1.1
Methods of assessment EQ-5D-5L ........................................................................40
5.3.1.2
Administration of EQ-5D-5L questionnaire ..........................................................40
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 ..................................................................................41
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....................................................................42

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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6.3.4
Variables ................................................................................................................43
6.3.5
Causality collection................................................................................................44
6.3.6
Adverse events based on signs and symptoms.......................................................44
6.3.7
Adverse events based on examinations and tests...................................................45
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 product for run-in and for post-bronchodilator lung 
function measurements ..........................................................................................49
7.2
Dose and treatment regimens.................................................................................49
7.3
Labelling ................................................................................................................51
7.4
Storage ...................................................................................................................51
7.5
Compliance ............................................................................................................51
7.6
Accountability........................................................................................................51
7.7
Concomitant and other treatments .........................................................................51
7.7.1
Prohibited Medications ..........................................................................................51
7.7.2
Concomitant asthma treatment ..............................................................................53
7.7.3
Other concomitant treatment..................................................................................53
7.8
Post Study Access to Study Treatment ..................................................................53
8.
STATISTICAL ANALYSES BY ASTRAZENECA............................................53
8.1
Statistical considerations........................................................................................53
8.2
Sample size estimate..............................................................................................54
8.3
Definitions of analysis sets ....................................................................................55
8.3.1
Full analysis set......................................................................................................55
8.3.2
All patients analysis set..........................................................................................55
8.3.3
Safety analysis set..................................................................................................55
8.4
Outcome measures for analyses.............................................................................56
8.4.1
Derivation of efficacy variables.............................................................................56
8.4.1.1
Derivation of annual severe asthma exacerbation rate (primary variable) ............56

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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8.4.1.2
Derivation of time to first severe asthma exacerbation .........................................56
8.4.1.3
Derivation of total inhaled steroid load and number of days with systemic 
GCS treatment........................................................................................................56
8.4.1.4
Derivation of ‘as-needed’ use ................................................................................56
8.4.1.5
Derivation of controller-use days...........................................................................57
8.4.1.6
Derivation of percent ‘as-needed’-free days..........................................................57
8.4.1.7
Derivation of time to asthma related discontinuation............................................58
8.4.1.8
Derivation of lung function variables ....................................................................58
8.4.2
Derivation of patient reported outcome variables..................................................58
8.4.2.1
Derivation of ACQ-5 .............................................................................................58
8.4.2.2
Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) .........................59
8.4.3
Derivation of safety variables ................................................................................59
8.4.3.1
Vital signs ..............................................................................................................59
8.4.3.2
Other significant adverse events (OAE) ................................................................59
8.5
Methods for statistical analyses .............................................................................60
8.5.1
Analysis of the primary variable............................................................................60
8.5.2
Analysis of the secondary and other variables.......................................................60
8.5.3
Subgroup analysis ..................................................................................................62
8.5.4
Blinded sample size re-estimation .........................................................................62
8.5.5
Sensitivity analysis.................................................................................................62
8.5.6
Exploratory analysis...............................................................................................63
8.5.7
Analyses related to exploratory objective..............................................................63
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ..........................63
9.1
Training of study site personnel.............................................................................63
9.2
Monitoring of the study .........................................................................................63
9.2.1
Source data.............................................................................................................64
9.2.2
Study agreements...................................................................................................64
9.2.3
Archiving of study documents...............................................................................64
9.3
Study timetable and end of study...........................................................................64
9.4
Data management by Cognizant Data Management Centre..................................64
10.
ETHICAL AND REGULATORY REQUIREMENTS.........................................65
10.1
Ethical conduct of the study...................................................................................65
10.2
Patient data protection............................................................................................65
10.3
Ethics and regulatory review..................................................................................65
10.4
Informed consent ...................................................................................................66
10.5
Changes to the protocol and informed consent form.............................................67
10.6
Audits and inspections ...........................................................................................67
11.
LIST OF REFERENCES.......................................................................................67

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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LIST OF TABLES
Table 1
Study Plan detailing the procedures .........................................................25
Table 2
Medications which may affect the reversibility test at Visit 2 
and/or at Visit 3 ........................................................................................52
Table 3
Medications Not allowed during the run-in period and while on IP ........52
LIST OF FIGURES
Figure 1
Study flow chart .......................................................................................16
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 with Standardised Activities 
                  (AQLQ(S)) self administered ≥ 12 years of age (Standardised Version)
Appendix E
Inhaled Glucocorticosteroid Equivalence Table
Appendix F
EQ-5D-5L Health Questionnaire

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 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-5
Asthma Control Questionnaire (5-item Version)
AE
Adverse event
‘As-needed’
Administered as needed in response to symptoms; similar to reliever or
rescue medication
AQLQ(S)
Asthma Quality of Life Questionnaire (Standardised Version)
ATS/ERS
American Thoracic Society/European Respiratory Society
BID
Twice daily
(e)CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
CSR
Clinical Study Report
DAE
Discontinuation of Investigational Product due to Adverse Event
DPI
Dry Powder Inhaler
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
EoT
End of Treatment
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
EuroQol Quality of Life Questionnaire
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.
GMP
Good Manufacturing Practice
Grand
AstraZeneca Global Randomisation System
ICH
International Conference on Harmonisation
ICS
Inhaled glucocorticosteroid
ICU
Intensive Care Unit

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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Abbreviation or 
special term
Explanation
International 
Coordinating 
investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the Investigator coordinating 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
mg
Milligramm
MID
Minimal important difference
ML
Millilitre
MMRM
Mixed Model Repeated Measures
OAE
Other Significant Adverse Event
PN
Predicted Normal
μg
Microgramm
SABA
Short-acting β2 agonist
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SMART
Symbicort Maintenance and Reliever Therapy
TUM
Turbuhaler Usage Monitor
ULN
Upper Limit of Normal
Vs
Versus
WBDC
Web Based Data Capture

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 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 largely reversible 
obstruction of the airways which 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 glucocorticosteroid (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 are 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 by ‘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 (LABA) formoterol.  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 in an acute 
asthma setting  (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 2004), (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 and having 
signs of airway inflammation, Symbicort ‘as needed’ was more efficacious than Oxis (ie 
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 inhaler was equivalent to regular 

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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treatment with inhaled ICS (beclomethasone) in controlling patients with mild persistent 
asthma (Papi et al 2007).
When administered on an ‘as needed’ basis without daily maintenance medication, Symbicort 
will provide both an anti-inflammatory medication and a reliever medication adapted to the 
patient’s current asthma symptoms.  Such an approach will address possible problems with 
timely administration and adherence to ICS in asthma patients in need of low dose ICS 
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(s) ‘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(s) (SABA and/or short acting anticholinergic agent) will be 
included in the study.  The study will begin with a 2 to 4 weeks 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.
Asthma exacerbations are relatively rare events and more so in mild asthma and thus a 12 
month perspective is necessary owing to power considerations, and, secondly, as adherence to 
regular medications is an issue in mild asthma, a longer trial provides a longer period over 
which to observe patient behaviour which better approaches the intended long-term nature of 
the envisaged treatment, not achieved in a shorter controlled trial.
The efficacy and safety of Symbicort (budesonide/formoterol) Turbuhaler 160/4.5 μg ‘as 
needed’ will be compared with Pulmicort (budesonide) Turbuhaler 200 μg twice daily plus 
terbutaline Turbuhaler 0,4 mg ‘as needed’ which is one of the current standard treatments for 
patients at GINA step 2. Symbicort Turbuhaler 160/4.5 μg ‘as needed’ is the strength mostly 
used on an ‘as needed’ basis with the Symbicort SMART concept. This dose is considered 
adequate to provide an anti-inflammatory effect due to the budesonide component, and the 
formoterol component of Symbicort Turbuhaler provides rapid and effective symptom relief.  
Symbicort Turbuhaler is safe to use as evidenced by Symbicort SMART data.
During the study treatment terbutaline will be provided in a Turbuhaler (dry powder inhaler -
DPI) that is identical to the Symbicort Turbuhaler for blinding purposes.  Bricanyl Turbuhaler 
will be used during the run-in period.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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Prevention of asthma exacerbations is a key goal of asthma management. It has been 
recognized that asthma exacerbations constitute the greatest risk to the patients, are a cause of 
anxiety to the patients and their families, and generate great cost for the society (Reddel et al 
2009). Therefore severe asthma exacerbations have been chosen as the primary variable in this 
study.  The study design includes clinic visits and additional phone contacts -or alternative 
method - to ensure that asthma exacerbation events are collected.  A blinded sample size re-
estimation will be done before the randomisation of the targeted 4114 patients.  The pooled 
blinded event rate will be monitored during the trial to allow for the possibility of an increase 
in sample size up to a maximum of 6171 randomised patients.
1.3
Benefit/risk and ethical assessment
Symbicort Turbuhaler, terbutaline Turbuhaler and  Pulmicort Turbuhaler 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 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 agonist (SABA).  
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.  
In this study patients will be instructed to contact the investigator for reassessment if using 
more than 12 inhalations per day with blinded ‘as needed’ investigational product - Symbicort 
Turbuhaler or terbutaline Turbuhaler - during the treatment period. 
Pulmicort which will be used as a maintenance treatment in the comparator arm is an effective 
and safe controller medication in asthma (GINA 2012).
All patients will be monitored during the course of the study with clinic visits at 17, 34 and 52 
weeks of treatment.  In addition patients will be contacted by phone call (or other methods if 
needed) between site visits at weeks 8, 25 and 42, and asked if they have used any additional 
asthma treatment other than the randomised treatment since the last visit.  The use of 
additional asthma treatment would be a trigger for the investigator to call the patient and ask 
for more information about the additional treatment and asthma worsening.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
16(70)
Patients who have discontinued Investigational Product (IP) prematurely will be followed up 
for severe asthma exacerbations and adverse events according to the original visit schedule 
(see Section 4.4).
Furthermore the patients will be instructed to contact the investigator at any time they feel a 
need for medical assistance.  Study specific treatment 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
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To demonstrate that Symbicort Turbuhaler 
160/4.5 μg ‘as needed’ is non-inferior to 
Pulmicort Turbuhaler 200 μg twice daily plus 
terbutaline Turbuhaler 0.4 mg ‘as needed’
Annual severe asthma exacerbation rate

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
17(70)
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :
To estimate the difference in efficacy between 
Symbicort Turbuhaler 160/4.5 μg ‘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
•Average change from baseline in pre-dose FEV1
•Time to study specific asthma related 
discontinuation
•Average change from baseline in ‘as needed’ use 
• Change from baseline in percent of ‘as needed’ free 
days
•Percentage of controller use days
•Average change from baseline in Asthma Control
Questionnaire (5-item version) - ACQ-5 score
•Average change from baseline in Asthma Quality of 
Life Questionnaire Standardised Version - AQLQ(S) 
score
2.3
Safety objectives
Safety Objective:
Outcome Measure:
To compare the safety of Symbicort 
Turbuhaler 160/4.5 μg ‘as needed’ 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 compare health care resource utilization, 
indirect resource use and health related status  
associated with hospital admissions, health 
care visits and days lost from work/ school 
between treatment arms
•
EuroQol five dimensional 5-level 
questionnaire (EQ-5D-5L)
•
Health Economics Questionnaire for resource 
utilisation
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.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
18(70)
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(s) only should have pre-bronchodilator 
FEV1 ≥ 60 % of predicted normal (PN) and post-bronchodilator FEV1 ≥ 80 % 
of 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 test 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 D589SC00003
Edition Number 4
Date 12 October 2016
19(70)
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.
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 or in the study D589SC00001 
(SYGMA 1)
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 D589SC00003
Edition Number 4
Date 12 October 2016
20(70)
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 withdrawal 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 potential 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 Section 3.1 and 3.2
4.
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 D589SC00003
Edition Number 4
Date 12 October 2016
21(70)
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 assign 
enrolment and randomisation codes to the patients and to dispense run-in study drug at Visit 2 
and investigational product (IP) at Visit 3 and subsequent treatment 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 or delegate using 
GRand (AZ Global Randomisation system).  Randomisation will be made on site level.  The 
randomisation codes will be loaded into the IVRS/IWRS database.  As patients become 
eligible, they will be assigned to a treatment group in accordance with the randomisation 
scheme.  Randomisation codes will be assigned strictly sequentially as patients become 
eligible for randomisation.
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:
∀
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.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
22(70)
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 
and having a large meal for at least 2 hours before the planned visits to the study site.
Patients should if possible avoid intake of ‘as needed’ IP 6 hours prior to a study site visit. 
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:
∀
Patients that are incorrectly randomised to the study
∀
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. 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):

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
23(70)
!
A severe asthma exacerbation with a duration of more than 3 weeks
!
Three severe asthma exacerbations within a period of 6 months
3.9.1
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue administration of investigational product or 
withdraw from the study (ie investigational product and assessments, see Section 3.10), 
without prejudice to further treatment.  A patient who decides to discontinue investigational 
product will always be asked about the reason(s) for this decision and the presence of any 
adverse events.
If possible, all patients who discontinue IP will be seen and Visit 6 / End of Treatment (EoT) 
assessments performed as soon as possible (see Table 1).
A follow-up phone contact will be performed 2 weeks +/-3 days after the last investigational 
product intake to follow adverse events.  If the patient discontinues IP more than 2 weeks +/-
3 days before a site visit, the information to be collected in the follow-up phone call can be 
collected at the visit instead (see Section 4.3).
After discontinuation of IP (ie before Visit 6) patients will be followed up for severe asthma
exacerbations, concomitant medications and adverse events according to the original visit 
schedule including site visits and phone contacts. If it is not possible for the patient to visit the 
study site, the visit(s) may be performed via phone (see Section 4.4 for details).
All Turbuhaler Usage Monitor (TUM) devices and all investigational products should be 
returned by the patient.  Discontinuation of the IP should be recorded in IVRS/IWRS.
If a patient discontinues IP due to a study specific discontinuation criteria this should always 
be recorded as ’Development of study specific discontinuation criteria’ on the IP 
discontinuation form in the eCRF and record asthma deterioration as an AE (see Section 
6.3.3).
If a patient is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal 
3.10.1
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’ (ie patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for enrolment failures (not 
randomised patients).

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
24(70)
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
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).
3.10.2
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) for this decision 
and the presence of any adverse events (AE).  The Investigator will follow up AEs outside of 
the clinical study.  All TUMs and all investigational products 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.
3.11
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 termination must be recorded in the eCRF.
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 D589SC00003
Edition Number 4
Date 12 October 2016
25(70)
4.
STUDY PLAN AND TIMING OF PROCEDURES
Table 1
Study Plan detailing the procedures
Enrol
ment
Run-in
Rando
mi-
sation
Treatment
2 wks 
Follow
-up
For details 
see 
Protocol 
Section
Visit
1
2
3
Phone 
call
4
Phone 
call
5
Phone 
call
6/ 
EoTa,b
Phone 
call
Week
-2 to -4
0
8
17
25
34
42
52
54
Visit window 
(days)
0-7 
days 
before 
Visit 2
14-28 
days 
before 
Visit 3
±7
±7
±7
±7
±7
±7
±3
Written Informed 
consent 
X
3.3, 10.4
Allocation of 
enrolment code
X
4.1.1
Demography
X
4.1.1
Inclusion/exclusi
on criteria
X
X
X
3.1, 3.2
Medical/surgical 
history
X
4.1.1

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
26(70)
Enrol
ment
Run-in
Rando
mi-
sation
Treatment
2 wks 
Follow
-up
For details 
see 
Protocol 
Section
Visit
1
2
3
Phone 
call
4
Phone 
call
5
Phone 
call
6/ 
EoTa,b
Phone 
call
Week
-2 to -4
0
8
17
25
34
42
52
54
Visit window 
(days)
0-7 
days 
before 
Visit 2
14-28 
days 
before 
Visit 3
±7
±7
±7
±7
±7
±7
±3
Asthma history 
(including history 
of severe asthma 
exacerbations)
X
4.1.1
Smoking history
X
4.1.1
ACQ-5, 
AQLQ(S) 
X
X
X
X
X
5.1.3, 5.1.4, 
5.1.5
Health Care 
resource 
utilisation 
questionnaire, 
EQ-5D-5L
X
X
X
X
5.3.1
SAE/AEsc
Xc
Xc
X
X
X
X
X
6
Weight and 
height
X
Xd
4.1.2

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
27(70)
Enrol
ment
Run-in
Rando
mi-
sation
Treatment
2 wks 
Follow
-up
For details 
see 
Protocol 
Section
Visit
1
2
3
Phone 
call
4
Phone 
call
5
Phone 
call
6/ 
EoTa,b
Phone 
call
Week
-2 to -4
0
8
17
25
34
42
52
54
Visit window 
(days)
0-7 
days 
before 
Visit 2
14-28 
days 
before 
Visit 3
±7
±7
±7
±7
±7
±7
±3
Physical 
examination
X
X
5.2.1
Vital signs (pulse 
and blood 
pressure)
X
X
5.2.2.1
Pregnancy test (if 
applicable)
X
4.1.2
Adjustment of 
current asthma 
medication
X
4.1.2

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
28(70)
Enrol
ment
Run-in
Rando
mi-
sation
Treatment
2 wks 
Follow
-up
For details 
see 
Protocol 
Section
Visit
1
2
3
Phone 
call
4
Phone 
call
5
Phone 
call
6/ 
EoTa,b
Phone 
call
Week
-2 to -4
0
8
17
25
34
42
52
54
Visit window 
(days)
0-7 
days 
before 
Visit 2
14-28 
days 
before 
Visit 3
±7
±7
±7
±7
±7
±7
±3
Patient training in 
how to use 
Turbuhaler 
(inhalation 
technique) and 
TUM; checking 
inhalation 
technique and re-
training if needed
X
X
X
X
4.1.2
Bricanyl for run-
in 
(dispense/return)
d
r
4.1.2, 7.2
Randomisation 
X
3.3, 3.5
Lung function 
(FEV1, FVC pre-
and post-Bricanyl 
administration)
X
X
X
X
X
5.1.2, 7.2
for 
Bricanyl

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
29(70)
Enrol
ment
Run-in
Rando
mi-
sation
Treatment
2 wks 
Follow
-up
For details 
see 
Protocol 
Section
Visit
1
2
3
Phone 
call
4
Phone 
call
5
Phone 
call
6/ 
EoTa,b
Phone 
call
Week
-2 to -4
0
8
17
25
34
42
52
54
Visit window 
(days)
0-7 
days 
before 
Visit 2
14-28 
days 
before 
Visit 3
±7
±7
±7
±7
±7
±7
±3
Reversibility teste
X
Xe
5.1.2.2, 
Inclusion 
criterion 6
Collection of 
severe asthma 
exacerbations
Xf
Xf
Xf
Xf
Xf
Xf
4.2
Concomitant 
medications 
X
X
X
X
X
7.7
Investigational 
product 
(dispense/return/ 
check)
d
d/r/c
d/r/c
r/c
7
a
After discontinuation of IP (ie before visit 6) patients will be followed up according to the original visit schedule including site visits and phone contacts. 
Only Severe asthma exacerbations, AEs and concomitant medications will be collected.  If it is not possible for the patient to visit the study site, the 
visit(s) may be performed via phone. See section 4.4.
b
EoT is end of treatment visit.
c
Serious adverse events will be collected from time of signing Informed consent. Adverse events will be collected from visit 2.
d
Height only for adolescents.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
30(70)
e
Reversibility test will be performed at Visit 2.  The test can be repeated at Visit 3 in case the patients fail to meet inclusion criterion no. 6 at Visit 2.  See 
section 3.1 for inclusion criteria.
f
Severe asthma exacerbations will be collected from visit 3 through the entire study.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
31(70)
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.
Patients will obtain information regarding the study and sign informed consent for the study 
before any study related procedures are initiated.
Consented patients will be assessed to ensure that they meet eligibility criteria.  Patients who 
do not meet these criteria must not be enrolled in the study.
Eligible patients will receive an enrolment code, allocated by IVRS/IWRS.
Demography, medical, surgical and asthma history including previous asthma exacerbations 
and smoking history will be checked.
For the evaluation of smoking history, pack years will be calculated as follows:
10 pack years =
1 pack (20 cigarettes) per day for 10 years
or 2 pack (40 cigarettes) per day for 5 years
or ½ pack (10 cigarettes) per day for 20 years
1 cigar = 5 cigarettes
1 cigarillo = 2 cigarettes
50 g pipe tobacco = 65 cigarettes
Hand rolled cigarettes can be calculated as 
cigarettes or pipe tobacco.
All serious adverse events occurring after signing the informed consent will be reported. 
Patients will continue taking their prescribed medication until Visit 2 and will be informed 
about medication restrictions applicable before Visit 2 by the investigator (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 
weeks run-in period.
From Visit 2 all adverse events will be collected (see Section 6 for details).

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Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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Height will be measured in cm (without shoes) and weight in kg (light clothes and without 
shoes).  Physical examination will be performed and pulse and blood pressure will also be 
measured.
Pregnancy test by urine dipstick should be performed for female patients aged ≤60 years. 
Patients will be asked to stop their prescribed asthma medication (including maintenance 
treatment with ICS and LTRA) used at the time of study entry and during the enrolment 
period in accordance with Section 7.7.
At Visit 2 patients will complete ACQ-5 and AQLQ(S) questionnaires using the electronic 
Patient Reported Outcome (ePRO) device after receiving detailed information.
Instructions will be given to the patients on how to use the Turbuhaler (inhalation technique) 
and the TUM device.  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 patients will practice inhalation technique with a training device, 
as many times as judged necessary by the supervising study personnel.
All patients will receive Bricanyl Turbuhaler for ‘as needed’ use during the run-in period.
Spirometry – including reversibility test – will preferably be performed between 7 am and 11 
am to measure lung function and verify eligibility of the patient (see Section 5.1.2 for details).
Concomitant medications will be checked.
Patients will be instructed to contact their investigator immediately for reassessment if they 
need to take more than 12 inhalations per day from the run-in medication (white label with 
blue bar Turbuhaler).
4.2
Treatment period
At Visit 3 investigator should check eligibility of the patient before randomisation.
Length of run-in period is flexible from 2 to 4 weeks. Assessment of the Bricanyl ‘as needed’ 
use criterion is allowed more than once during run-in. If inclusion criterion 7 is not fulfilled 
after at least 2 weeks of run-in AND patient has not used Bricanyl Turbuhaler above the limits 
described in exclusion criterion 16, investigator can re-schedule Visit 3. Downloading the 
Turbuhaler Usage Monitor (TUM) data to check inclusion criterion 7 and exclusion criterion 
16 should be the first procedure during this visit. Patient can remain in run-in period for 
maximum 4 weeks.  
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).
Treatment visits will take place at 17, 34 and 52 weeks of treatment after randomisation. 

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Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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Description of the procedures for this period is included in the Study Plan, see Table 1. 
The patient should take the first dose of maintenance IP at the study site.
Patients should bring the study medication to site and take the morning dose of maintenance 
IP at the study site after study procedures are completed. Patient’s inhalation technique will be 
checked by the study personnel at each visit. Patient will be re-trained on how to use the 
Turbuhaler and TUM if needed.
Patients will be instructed to contact their investigator immediately for reassessment if they 
need to take more than 12 inhalations per day with blinded ‘as needed’ investigational product 
- Symbicort Turbuhaler or terbutaline Turbuhaler - during the treatment period.
At randomisation and each treatment visit, the patients will complete ACQ-5, AQLQ(S) and 
EQ-5D-5L questionnaires as the first activity.  Information on health care resource utilization 
will be collected.
Thereafter, spirometry will be performed within the requested time window (see Section 
5.1.2).
In addition patients will be contacted by phone call (or other methods if needed) preferably by 
the study nurse between site visits at weeks 8, 25 and 42 (Figure 1), and be asked if he/she 
since the last study visit
∀
has taken any additional asthma treatment other than the study medication and
∀
has had any asthma worsening that led to hospitalisation or emergency room visit or 
to a doctor’s consultation.
If the answer is “yes” the investigator will call the patient and ask for more detailed 
information in order to collect and document any additional asthma medication and/or severe 
asthma exacerbation events.
Investigators should make all efforts to collect severe asthma exacerbation data and verify the 
information given by the patient to the greatest possible extent using medical records and 
other source data.
4.3
Follow-up 
A follow-up telephone contact will be performed 2 weeks +/- 3 days after the last 
investigational product intake.  At the follow-up telephone call, the investigator will check for 
adverse events ongoing at the end of study treatment or occurred after last treatment visit.
In the event of discontinuation of IP, the procedure described in Section 3.9.1 will be 
followed.  Patients will be treated according to local medical practice.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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4.4
Follow-up in case of discontinuation of IP
After discontinuation of IP (ie before Visit 6) patients will be followed up for severe asthma 
exacerbations, concomitant medications and adverse events according to the original visit 
schedule including site visits and phone contacts.  Patients will be treated according to local 
medical practice. Only Severe asthma exacerbations, AEs and concomitant medications will 
be documented and entered into the eCRF. No more study specific procedures will be required 
for the purpose of this study.
If it is not possible for the patient to visit the study site, the visit(s) may be performed via 
phone.
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 Form (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 
investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be archived 
at the study site.
5.1
Efficacy assessments
5.1.1
Severe asthma exacerbation
In this study severe asthma exacerbation is defined as deterioration of asthma that is 
associated with a medical intervention as described below.  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 or which happens acutely (≤24 h) 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 glucocorticosteroids for at least 3 days1
∀
Inpatient hospitalization
∀
Emergency room visit2 due to asthma that required systemic glucocorticosteroids.
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

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Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
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The start and end date of each severe asthma exacerbation will be recorded in the eCRF.  For 
severe exacerbations the start date is defined as the first day of hospitalisation / emergency 
room treatment or the first day of systemic (ie 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.
Additional hospitalisations/emergency room treatments and systemic GCS treatments 
occurring during a severe asthma exacerbation should not be regarded as a new exacerbation.  
For 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.
If a patient has a severe asthma exacerbation with a duration of more than 3 weeks or 3 severe 
asthma exacerbations during 6 months, patient should discontinue IP and the reason should be 
recorded as ‘Development of study specific discontinuation criteria’ on the IP discontinuation 
form.
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.
Due to diurnal variation of lung function it is important that all spirometry assessments at 
Visits 3, 4, 5 and 6 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 minute) 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 measures 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.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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A nose-clip should be used for the manoeuvre.  Mouthpieces of the same dimension and shape 
should be used throughout the study.  Spirometry should be performed using a calibrated 
spirometer and values are expressed at Body Temperature and ambient Pressure Saturated 
with water vapour.
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, respectively, 
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.
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 6.
The assessment will be performed as follows:
∀
Pre-bronchodilator FEV1 measurement
∀
Inhalation of Bricanyl Turbuhaler 2 x 0.5 mg

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Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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∀
Wait 15 to 30 minutes
∀
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 6 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:
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 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, see also inclusion criterion 6, Section 3.1.
5.1.3
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-5 will be self-administered using ePRO device during site visits as indicated in 
Table 1.  The questions take approximately 2 to 3 minutes to complete.
100
)
(
1
)
(
1
)
(1
X
FEV
FEV
FEV
ity
Reversibil
before
before
after !
#

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Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
38(70)
Patients who are not fluent in the local language will not perform the ACQ-5 assessments, but 
they can still participate in the study.  The assessment of ACQ-5 will only be performed in 
countries where validated translations are available.
5.1.4
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 using ePRO device during site visits as 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.
5.1.5
Administration of patient reported outcome questionnaires
The questionnaires (ACQ-5 and AQLQ[S]) should be completed using ePRO device 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 instructions will be provided to each patient in the local language, 
how to complete the questionnaires.
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.
5.1.6
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 

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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through a microprocessor the date and time when the Turbuhaler base grip is rotated back and 
forth.
TUM devices will be used for the Turbuhalers containing ‘as needed’ and maintenance 
investigational product, and for Bricanyl Turbuhaler used during the run-in period as well (see 
also Section 7 for details).
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 and will receive written user instructions 
(see Section 4.1.2).
5.2
Safety assessments 
5.2.1
Physical examination
A physical examination will be performed at Visit 2 and Visit 6 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 discontinuation of IP 
(see Section 3.9.1).  For reporting of AEs based on examinations, see Section 6.3.6.
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 6.  The 
measurements at Visit 2 are regarded as baseline data.  Blood pressure and pulse rate will also 
be measured in case of discontinuation of IP (see also Section 3.9.1).
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
Health Economics
Information on health care resource utilization as well as health related quality of life (EQ-5D-
5L) will be collected at randomisation and at each treatment visits to enable health technology 
assessment, health economic analysis and health economic modelling.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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5.3.1
Health care resource utilisation
At baseline (Visit 3, Randomisation) and at subsequent treatment visits until Visit 6 / EoT the 
patient will be asked questions about asthma-related health care resource use events since last 
visit as well as asthma-related sickness absence, time-off work or education.
The patient will be asked about health care resource use in terms of use of ambulance 
services; emergency room visits; hospital admissions to general or intensive care; ambulatory-
setting or home consultations with specialists, primary care physicians or other healthcare 
professionals; and telephone consultations with physicians or nurse.
For patients in paid employment, they will also be asked how much time they have taken as 
sickness absence due to their asthma.
For patients in education, they will also be asked how much time they have taken as sickness 
absence due to their asthma.
5.3.1.1
Methods of assessment EQ-5D-5L
The EQ-5D is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal (The 
EuroQol Group 1990).
The EQ-5D is applicable to a wide range of health conditions and treatment. It provides a 
simple descriptive profile and a single index value for health status that can be used in 
economic evaluation of health care.  There are two versions of EQ-5D – a three level version 
(EQ-5D-3L) and a five level version (EQ-5D-5L). The EQ-5D-5L will be used in this trial, see 
Appendix F.  The EQ-5D-5L consists of 2 pages - the EQ-5D descriptive system and the EQ 
Visual Analogue Scale (VAS). The descriptive system comprises five dimensions, mobility, 
self-care, usual activity, pain/discomfort and anxiety/depression.  Each dimension has five 
levels (response options): no problems, slight problems, moderate problems, severe problems 
and extreme problems. The EQ VAS records the respondent´s self-rated health on a 20 cm 
vertical visual analogue scale with endpoints labelled “the best health you can imagine” and 
“the worst health you can imagine”
This instrument is extensively validated and is available in several languages that facilitate its 
use in multinational studies.  The translations into local languages have been performed 
according to a linguistic validation process.
The EQ-5D-5L will be self-administered using the paper version.  The questions will be 
assessed at baseline (Randomisation Visit 3) and at subsequent treatment visits until Visit 6 / 
EoT.  The 5 questions will take approximately 5 minutes to answer.  The patients need to be 
able to read and to be fluent in the local language to be able to answer the questions.
5.3.1.2
Administration of EQ-5D-5L questionnaire
The EQ-5D-5L should be given to patients as detailed in the Study Plan (see Table 1), before 
assessments, prior to administration of study drug, and before imparting any news about the 

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Edition Number 4
Date 12 October 2016
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status of their disease.  Patients should be allowed to complete the paper questionnaire in their 
own time, and without any help from relatives or clinic staff.  The patient can receive help 
from a study nurse in reading the instructions and questions. However, under no 
circumstances should help in interpreting the questions or in selecting responses be provided.
The appropriate module of eCRF will be completed by the clinic staff to detail if a 
questionnaire has been completed at each EQ-5D-5L visit, and if not, the reason will be 
recorded.  Each centre must allocate responsibility for the EQ-5D-5L questionnaire to a 
specific individual (ie a Research Nurse).  The AstraZeneca Study Team will provide training 
for relevant personnel in the administration of the EQ-5D-5L questionnaire.  Investigator or 
delegate will transfer the patient´s data from the paper copy to the eCRF.  It is also important 
that the significance and relevance of the data are explained carefully to participating patients 
so that they are motivated to comply with data collection (The EuroQol Group 1990).
Patients who are not fluent in the local language will not perform the EQ-5D-5L assessments, 
but they can still participate in the study.  The assessment of EQ-5D-5L will only be 
performed in countries where validated translations are available.
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 are 
familiar with the content of this section.
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 

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
42(70)
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 (ie run-in, treatment, wash 
out, 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 entire treatment period and 
during 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 
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:

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Drug Substance Budesonide/formoterol  
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Edition Number 4
Date 12 October 2016
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∀
The sign or symptom meets Serious Adverse Event criteria, see Section 6.2 for 
definition
∀
The patient discontinues IP 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 due to a study specific discontinuation criterion this should always 
be recorded as ’Development of study specific discontinuation criteria’ on the IP 
discontinuation form in the eCRF.  In addition, the investigator has to report asthma 
deterioration as an AE leading to discontinuation with investigational product (DAE)/AE 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
∀
AE is serious due to
∀
Date of hospitalisation
∀
Date of discharge

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∀
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’.
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 / your child had any health problems 
since the previous visit/you were last asked?’, or revealed by observation will be collected and 

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Edition Number 4
Date 12 October 2016
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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 and tests
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 lab samples that are collected from a patient show an Aspartate 
Aminotransferase or Alanine Aminotransferase ≥3xUpper Limit of Normal (ULN) 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.
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 ie 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 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 ie immediately but no later than 24 hours of when he or she 
becomes aware of it.

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Edition Number 4
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Once the Investigators or other site personnel indicate an AE is serious in the 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 Investigator’s 
Brochure 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
Inhaled 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 
glucocorticosteroid effects may appear if used chronically in excessive doses.
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.

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Edition Number 4
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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 
methods, as judged by the investigator, should not be included in the study.
Clinical experience with Symbicort in pregnant women is limited and patients that become 
pregnant must be discontinued from the investigational product.  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 

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Edition Number 4
Date 12 October 2016
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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 ie 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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Study Code D589SC00003
Edition Number 4
Date 12 October 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 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.
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 

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Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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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)
At Visit 2 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 at Visit 2 and will be used as ‘as needed’ medication 
during the run-in period.  Bricanyl Turbuhaler will have blue grip and a white label with a 
blue bar.  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.
Bricanyl Turbuhaler will also be used for the post-bronchodilator FEV1 and FVC 
measurements at Visits 2 to 6.
Treatment period (Visits 3 to 6)
At Visit 3 patients will be randomised to one of the 2 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’
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 a white label with a yellow bar. During the treatment period the Turbuhaler for ’as 
needed’ treatment will have white grip and white label with a grey bar.  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.

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Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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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 than 12 inhalations of the 
‘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 Turbuhaler 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 5.1.6).
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 account for all study drugs dispensed to and returned from the 
patient.
Study site personnel will also account for all study drugs received at the site, unused study 
drugs and 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.
7.7
Concomitant and other treatments
7.7.1
Prohibited Medications
In order not to affect the reversibility test at Visit 2 and / or at Visit 3, patients should not have 
received the medications listed in Table 2 within the given time limits prior to the visit.
Asthma medication before study start is defined by inclusion criterion 4 not by Table 2.

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Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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Table 2
Medications which may affect the reversibility test at Visit 2 and/or at 
Visit 3
Not allowed before Visit 
Time limit prior to Visit
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 β2-agonists as follows:
short-acting
depot
long-acting
6 hours
24 hours
48 hours
6.*
Transdermal β2-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
Table 3
Medications Not allowed during the run-in period and while on IP
Not allowed during the run-in period and while on IP - For exceptions see section 7.7.2
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

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Edition Number 4
Date 12 October 2016
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Not allowed during the run-in period and while on IP - For exceptions see section 7.7.2
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)
7.7.2
Concomitant asthma treatment
Severe asthma exacerbation treatment: oral or parenteral GCS are allowed in case of a 
suspected severe asthma exacerbation. During a severe asthma exacerbation, treatment with 
the concomitant medications included in Number 2-7 (Table 3) is also allowed.
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.
7.7.3
Other concomitant treatment
Medications other than that described above, which are 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 discontinuation of IP 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.
Analyses will be performed by AstraZeneca or its representatives.

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Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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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
The study is powered to assess the primary objective of comparing Symbicort Turbuhaler ‘as-
needed’ versus Pulmicort Turbuhaler bid plus terbutaline Turbuhaler assuming that Symbicort 
Turbuhaler will be superior to Pulmicort Turbuhaler with regard to the annual severe asthma 
exacerbation rate.
Based on a subset of patients from the START study a retrospective estimation of severe 
exacerbation rate was 0.12 events per patient-year in the Pulmicort group (based on Poisson 
regression).  There was no sign of over-dispersion, hence the shape parameter is assumed to 
be 0.  The GOAL study (Bateman et al 2004) indicated a similar exacerbation rate in the 
steroid naïve sub-population 0.12 for patients treated with Fluticasone while for patients pre-
study treated with low-dose steroid the exacerbation rate was 0.17 for patients treated with 
Fluticasone.
The number of patients required for the analyses is estimated to be 4114 overall 
(2057/treatment group).  This was based on the following assumptions using a negative
binomial model (Keene ON et al 2007):
∀
alpha 5%
∀
power 90%
∀
exacerbation rate of 0.16 in the Pulmicort treatment group
∀
25% risk reduction in Symbicort vs Pulmicort
∀
no over-dispersion (shape parameter=0)
Based on these assumptions 3704 patients (1852 per arm) would be required.  Accounting for 
a 10% drop-out give a total sample size of 4114 patients (2057 per arm).
Sample size re-estimation:
Because of lacking phase II data on Symbicort ‘as-needed’ use in the target population there 
are uncertainties about the assumed exacerbation rates as well as the dispersion parameter.  To 
account for that uncertainty the overall exacerbation rate will be monitored during study in a 
blinded fashion and allow for an increase of the sample size by a maximum of 50% ie up to a 
total of 6171 patients.
The exacerbation rate and shape parameter will be estimated using the maximum likelihood 
approach as proposed by (Friede and Schmidli, 2010).  If results of the blinded reviews 
indicate that the projected power falls to below 85%, the sample size may be increased.  Since 

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Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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this monitoring of the exacerbation rate will be performed in a blinded fashion, no adjustment 
for the type I error is needed.  The reviews will be based on pooled, blinded data and will not 
use any treatment information.  The blinding will be strictly maintained and not be affected by 
the reviews in any way.
Decision to change the primary objective from a superiority to non-inferiority hypothesis
In September 2016, the decision was made to change the primary objective to assess whether 
Symbicort Turbuhaler will be non-inferior to Pulmicort Turbuhaler with regard to the annual 
severe asthma exacerbation rate.  Assuming a 25% exacerbation risk reduction in Symbicort 
vs Pulmicort, 0.14 exacerbation rate and no overdispersion, a total sample size of 4114 will 
produce over 90% power to determine if Symbicort Turbuhaler is non-inferior to Pulmicort 
Turbuhaler with regard to the annual severe asthma exacerbation rate when the non-inferiority 
limit is set to 120% at the 5% (one-sided) significance level.
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.
Analysis of primary and secondary variables will be based on data recorded up to the 
discontinuation of IP.  Sensitivity analyses will be provided including the data post 
discontinuation of IP.  Data for subjects who withdraw consent to participate in the study will 
be included up to the date of their study completion.
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.

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Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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8.4
Outcome measures for analyses
8.4.1
Derivation of efficacy variables
The primary analysis will include data from the randomisation visit until the subject 
terminates the use of IP.  Sensitivity analysis will include all data regardless of whether or not 
the subject terminated the use of IP.
8.4.1.1
Derivation of annual severe asthma exacerbation rate (primary variable)
The total number of severe asthma exacerbations will be calculated for each patient during the 
randomised treatment period according to the following principle:
For the production of summary statistics, the annual exacerbation rate per patient is calculated, 
and standardized using data from the double-blind treatment period according to the formula 
described below:
Annual Exacerbation Rate = Number of Exacerbations*365.25 / (Date of Visit6/EoT – Date of 
Randomisation (Visit 3) + 1)
8.4.1.2
Derivation of time to first severe asthma exacerbation
Time to first severe asthma exacerbation (see Section 8.5.2) will be calculated as the time 
from randomisation until the start date of the first severe asthma exacerbation ie:
Start Date of first severe asthma exacerbation – Date of Randomisation (Visit 3) +1
Patients not having any severe asthma exacerbation will be considered as censored at the date 
of their last visit or, for patients discontinuing IP, the day when it was decided that the patient 
should discontinue the IP.
Maximum follow-up time for a patient is approximately 52 weeks; defined as the time from 
randomisation to the date of Visit 6/EoT.  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 total inhaled steroid load and number of days with systemic GCS 
treatment
Total inhaled steroid load 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).  Data on IP will be recorded via the TUM.
The number of days with systemic GCS will be recorded via the appropriate CRF module.
8.4.1.4
Derivation of ‘as-needed’ use
‘As-needed’-use during the randomised treatment period will be calculated as the cumulative 
doses of ‘as-needed’ medication divided by the follow-up time (number of days).

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For Symbicort treatment arm ‘as needed’ will be Symbicort, while for the Pulmicort treatment 
arm ‘as needed’ will be terbutaline.
Change from baseline will be calculated for each patient, where baseline is defined as the ‘as-
needed’ use 10 days prior to randomisation during run-in.
‘As-needed’ use will be captured via the TUM device and measures the number of turns of the 
inhaler.
‘As-needed’ use (as recorded by the TUM) for the day- and night time period will be derived 
in the following way:
∀
Start of the daytime period is defined as the time when the patient takes their 
morning maintenance dose (between 04:00-11:59:59).  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 04:00-11:59:59) 
across the trial for that patient.  The end of the daytime period will be set to the 
second prior to the start of the night-time period.
∀
Start of the night-time period is defined as the time when the patient takes their 
evening maintenance dose (between 18:00-23:59:59).  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 night-time period will be set to 
the average of the recorded evening maintenance doses (between 18:00-23:59:59) 
across the trial for that patient.  The end of the night-time period will be set to the 
second prior to the start of the daytime period.
For analysis where full days are assessed they are a day followed by a night.
8.4.1.5
Derivation of controller-use days
‘Controller’-use during the randomised treatment period will be calculated as the cumulative 
days when any controller medication (containing ICS) was taken divided by the follow-up 
time (number of days).
For Symbicort treatment arm controller will be the ‘as needed’ use, while for the Pulmicort 
treatment arm this will be the maintenance use.  This will be derived from the TUM.
8.4.1.6
Derivation of percent ‘as-needed’-free days
An ‘as needed’-free day is defined as a day and night with no use of ‘as needed’ medication.  
Percent ‘as-needed’ free days will then be calculated as the number of days during the 
randomised treatment period with no record in the TUM device of ‘as-needed’ medication 
divided by the follow-up time (days).  Change from baseline will then be calculated for each 
patient, where baseline is defined as the ‘as-needed’ free days 10 days prior to randomisation 
during run-in.

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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 a duration for more than 3 weeks
∀
Three severe asthma exacerbations during 6 months
Time to discontinuation due to any of the specified asthma related events will be calculated as:
Date of discontinuation due to any of the specified asthma related events – Date of 
Randomisation (Visit 3) + 1
Patients not discontinuing the IP due to asthma related events will be considered as censored 
at the date of their last visit or, for patients discontinuing the IP, the day when it was decided 
that the patient should discontinue IP for whatever reason.
8.4.1.8
Derivation of lung function variables
Change from baseline (Visit 3) to Visits 4, 5 and 6 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.
8.4.2
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.

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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.
8.4.3
Derivation of safety variables
8.4.3.1
Vital signs
Change from baseline (Visit 2) to week 52 (Visit 6 / EoT) 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 

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Edition Number 4
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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. No 
adjustment will be made for multiplicity.
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 annual severe asthma exacerbation rate will be analysed by a negative 
binomial regression model.  The response variable in the model will be the number of severe 
asthma exacerbations over the treatment period.  The model will include treatment, pre-study 
treatment group 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 severe asthma exacerbation 
rates will be estimated and treatments effects will be expressed as the rate ratio along with its 
corresponding one-sided 95% non-inferiority interval (interval from point estimate to UCL) 
and two-sided 95% confidence interval.  The planned treatment comparison will be:
!
Symbicort vs Pulmicort (non-inferiority, primary objective)
Formally, the null and alternative hypothesis is:
H0: rate-ratio (Symbicort vs Pulmicort) ≥1.2
HA: rate-ratio (Symbicort vs Pulmicort) < 1.2
If the upper 95% 1-sided confidence limit of the relative risk ratio is < 1.2 then non-inferiority 
can be declared.
If the criteria for the alternative hypothesis is met then superiority of Symbicort vs Pulmicort 
in terms of annual severe asthma exacerbation will be assessed.
Formally, the null and alternative hypothesis for superiority testing is:
H0: rate-ratio (Symbicort vs Pulmicort) = 1
HA: rate-ratio (Symbicort vs Pulmicort) ≠1
8.5.2
Analysis of the secondary and other variables
For all secondary variables stated below Symbicort vs Pulmicort will be compared.  

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Exacerbations:  Time to first severe asthma exacerbation will be analysed by a Cox 
proportional hazards model with treatment, pre-study treatment group and region as factors.  
The hazard ratio and its corresponding 95% confidence interval will be estimated from the 
model.
Pre-dose FEV1:  The treatment effect for change from baseline (Visit 3) in pre-dose FEV1, 
will be estimated using a mixed model repeated measures (MMRM) analysis.  FEV1 data from 
visits 4, 5 and 6 will be included in the model, with terms for treatment, pre-study treatment 
group, 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.
Summary statistics will be presented for change from baseline across all the time points in the 
trial for pre- and post-dose FEV1 (L) and FVC, respectively by treatment.
Steroid load:  The total inhaled steroid load and the number of days with systemic GCS, 
respectively will be presented descriptively by treatment adjusted by the patients follow-up 
time.
‘As-needed’ use:  The change from baseline in ‘as-needed’ use will be analysed by analysis 
of covariance (ANCOVA) with treatment, pre-study treatment group and region as factors, 
and the ‘as-needed’ use 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.
More details of eg graphical presentations of pattern of use will be provided in the SAP.  It 
will include summaries of day time and night time use.
Percent ‘as needed’-free days:  The change from baseline in percent ‘as needed’-free days 
will all be analysed in the same way as ‘as-needed’ use described above.
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 discontinuation due to asthma 
related events will be analysed by Cox proportional hazards model with treatment, pre-study 
treatment group and region as factors.  The hazard ratio and its corresponding 95% confidence 
interval will be estimated from the model.

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PRO variables:  ACQ-5 and AQLQ(S) will be analysed in the same way as FEV1 using 
MMRM analysis.  In addition, change from baseline to the end of treatment will be analysed 
using analysis of covariance with treatment, pre-study treatment group and region as factors 
and baseline as a continuous variable.
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 group 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.
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.
8.5.3
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
Blinded sample size re-estimation
As described in Section 8.2, there will be a blinded analysis for the purpose of checking 
assumptions used in the estimation of sample size.  As such, no adjustment for Type I error is 
required.
8.5.5
Sensitivity analysis
Sensitivity analyses of the primary and key secondary variables will be carried out and will be 
specified in the SAP.
For the primary variable a sensitivity analysis will be performed including all data for patients 
who discontinue IP but remain in the study.
The primary analysis assumes that data are missing at random.  Different missing data 
assumptions will be explored if possible.

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Edition Number 4
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8.5.6
Exploratory analysis
8.5.7
Analyses related to exploratory objective
Descriptive reporting of the resource utilization data and health related quality of life data 
based on the EQ-5D-5L will be carried out in the CSR.  The data will be combined with 
economic data collected independently of the study to construct comparative health economic 
analyses between treatment groups.  The economic analyses and cost-effectiveness analyses 
that include data external to the study will be reported in a separate health economic report 
and will not be included in the CSR.
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 ePRO system(s) utilised.
The investigator and study site staff should preferably 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 (eg 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 3 in 2014 and to end by Quarter 2 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/terbutaline.
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 of 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., ePRO, 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 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.

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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/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.

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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
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Ankerst J, Persson G, Weibull E. Tolerability of high dose of budesonide/formoterol in a 
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Atienza T, Aquino T, Fernández M, Boonsawat W, Kawai M, Kudo T et al. 
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Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels R, et al (2004) Can 
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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
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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. 
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Friede and Schmidli, 2010
Friede T and Schmidli H. Blinded sample size reestimation with negative binomial counts in 
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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 
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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 
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Juniper et al 1994
Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a 
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Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
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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.
Keene ON et al 2007
Keene ON, Jones MRK, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and 
chronic obstructive pulmonary disease: example from the TRISTAN study. Pharmaceutical 
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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.

Revised Clinical Study Protocol
Drug Substance Budesonide/formoterol  
Study Code D589SC00003
Edition Number 4
Date 12 October 2016
70(70)
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.
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.
Reddel et al 2009
Reddel HK, Taylor DR, Bateman ED et al. An Official American Thoracic Society/European 
Respiratory Society Statement: Asthma Control and Exacerbations. Am J Respir Crit Care 
2009; 180: 59–99.
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.
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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 
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The EuroQol Group 1990
EuroQol Group. EuroQol – a new facility for the measurement of health related quality of life.  
Health Policy 1990;16:199-208
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
D589SC00003
Edition Number
1
Date
17 June 2014
Appendix B
Additional Safety Information

Clinical Study Protocol Appendix B
Drug Substance budesonide/formoterol
Study Code D589SC00003
Edition Number 1
Date 17 June 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:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse.

Clinical Study Protocol Appendix B
Drug Substance budesonide/formoterol
Study Code D589SC00003
Edition Number 1
Date 17 June 2014
3(3)
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.
!
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?
!
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?
!
Dechallenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
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.
!
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:
!
Is this a recognised feature of overdose of the drug?
!
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
D589SC00003
Edition Number
1
Date
17 June 2014
Appendix C
Asthma Control Questionnaire (5-item version)

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Clinical Study Protocol Appendix D
Drug Substance
budesonide/formoterol
Study Code
D589SC00003
Edition Number
1
Date
17 June 2014
Appendix D
Asthma Quality of Life Questionnaire with Standardised Activities 
(AQLQ(S)) self administered ≥ 12 years of age

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Clinical Study Protocol Appendix E
Drug Substance
Budesonide/formoterol
Study Code
D589SC00003
Edition Number
2
Date
17 August 2015
Appendix E
Inhaled Glucocorticosteroids Equivalence Table

Clinical Study Protocol Appendix E
Drug Substance Budesonide/formoterol
Study Code D589SC00003
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
D589SC00003
Edition Number
1
Date
17 June 2014
Appendix F
EQ-5D-5L Health Questionnaire

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