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    Clinical Trial Results:
    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’

    Summary
    EudraCT number
    		 2013-004473-28
    Trial protocol
    		 SE   DE   HU   CZ   SK   BG   ES   PL  
    Global end of trial date
    16 Aug 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 May 2018
    First version publication date
    28 Feb 2018
    Other versions
    		 v1 (removed from public view)
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    D589SC00003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1157-4476
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Prepparedsleden 1, Molndal, Sweden,
    Public contact
    AstraZeneca, Information Center, information.center@astrazeneca.com
    Scientific contact
    Millie Wang (Senior Medical Lead), AstraZeneca, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    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’
    Protection of trial subjects
    The final protocol, informed consent form (ICF) and other written materials provided to patients were submitted to and approved by an Independent Ethics Committee (IEC). The investigator at each study centre ensured that patients were given full and adequate oral and written information about the nature, purpose, possible risks and benefits of the study. Patients were told they were free to discontinue the study at any time. Each patient was given the chance to ask questions and allowed time to consider the information. The PI ensured that each patient provided a signed ICF before any study procedures and ensured that any incentives or provisions for patients harmed as a result of study participation were described in the ICF. Patients with a history of life-threatening asthma, including intubation and intensive care unit admission, or other significant disease or disorder were ineligible for the study. Patients attended clinic visits at 17, 34 and 52 wks of treatment and phone calls were made by site staff at wks 8, 25 and 42. Study specific treatment discontinuation criteria were applied for patients in case of severe asthma exacerbation with length greater than 3 wks or 3 severe exacerbations within 6 mths. Patients were instructed to contact their investigator for reassessment if they needed to take more than 12 inhalations of as needed study medication and any time they needed medical assistance. An Adjudication Committee (AC) provided an independent, external and unbiased assessment of fatal events reported during the study in order to determine whether any death might be asthma-related. The AC was blinded to patients’ allocation to randomised study treatment. Unblinding of the asthma-related events could be triggered and a data safety monitoring board set up if there was a total of ≥3 deaths adjudicated to be asthma related across the SYGMA 1 and SYGMA 2 trials. The number of deaths adjudicated to be asthma related was not high enough to trigger unblinding.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 378
    Country: Number of subjects enrolled
    Bulgaria: 274
    Country: Number of subjects enrolled
    Hungary: 265
    Country: Number of subjects enrolled
    Germany: 201
    Country: Number of subjects enrolled
    Romania: 174
    Country: Number of subjects enrolled
    Slovakia: 135
    Country: Number of subjects enrolled
    Czech Republic: 88
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Russian Federation: 579
    Country: Number of subjects enrolled
    Ukraine: 370
    Country: Number of subjects enrolled
    South Africa: 160
    Country: Number of subjects enrolled
    New Zealand: 91
    Country: Number of subjects enrolled
    Saudi Arabia: 48
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Vietnam: 288
    Country: Number of subjects enrolled
    Philippines: 172
    Country: Number of subjects enrolled
    Thailand: 139
    Country: Number of subjects enrolled
    Korea, Republic of: 133
    Country: Number of subjects enrolled
    Peru: 213
    Country: Number of subjects enrolled
    Mexico: 187
    Country: Number of subjects enrolled
    Brazil: 107
    Country: Number of subjects enrolled
    Chile: 97
    Country: Number of subjects enrolled
    Colombia: 29
    Worldwide total number of subjects
    4176
    EEA total number of subjects
    1556
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    411
    Adults (18-64 years)
    3396
    From 65 to 84 years
    369
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 6634 patients enrolled; 5740 entered run-in period. Of these, 4215 were randomised,1525 not randomised due to the following reasons: 1407 did not meet inclusion/exclusion criteria, 21 adverse events, 3 severe non-compliance to protocol, 68 subject decision, 14 subject lost to follow-up, 12 other.

    Pre-assignment
    Screening details
    		 Eligibility was assessed at Visits 1, 2 and 3. IC was obtained at V1. At V2, patients stopped pre-study asthma medications and entered a 2 to 4 week run-in period on SABA as needed only (Bricanyl Turbuhaler 0.5 mg). Lung function was assessed by spirometry to confirm eligibility. Eligible patients were randomised at V3.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo bid + Symbicort 'as needed'
    Arm description
    		 Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo for budesonide (Placebo Turbuhaler)+Symbicort Turbuhaler 160/4.5 μg (Budesonide / formoterol fumarate dihydrate 160/4.5 μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo powder for inhalation, 200 doses + Budesonide / formoterol fumarate dehydrate powder for inhalation, 160 μg budesonide and 4.5 μg formoterol per inhalation, 120 doses

    Arm title
    		 Pulmicort bid + terbutaline 'as needed'
    Arm description
    		 Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pulmicort Turbuhaler 200 μg (budesonide 200 μg) + Terbutaline Turbuhaler 0.4 mg/dose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Budesonide powder for inhalation, 200 μg per inhalation, 200 doses + Terbutaline sulphate powder for inhalation, 0.4 mg terbutaline per inhalation, 120 doses

    Number of subjects in period 1
    		Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Started
    2089
    2087
    Completed
    1983
    1979
    Not completed
    106
    108
         Severe non-compliance to protocol
    2
    2
         Adverse event, serious fatal
    1
    1
         Eligibility criteria not fulfilled
    4
    7
         Subject decision
    58
    50
         Adverse event, non-fatal
    1
    3
         Investigator decision
    4
    3
         Subject moved
    -
    1
         Sponsor decision (prematurely closed site)
    7
    6
         Lost to follow-up
    27
    35
         Pregnancy
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo bid + Symbicort 'as needed'
    Reporting group description
    		 Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)

    Reporting group title
    Pulmicort bid + terbutaline 'as needed'
    Reporting group description
    		 Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

    Reporting group values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed' Total
    Number of subjects
    		 2089 2087 4176
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 205 206 411
        Adults (18-64 years)
    		 1705 1691 3396
        From 65-84 years
    		 179 190 369
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.3 ( 16.8 ) 40.7 ( 17.1 ) -
    Sex/Gender, Customized
    Units: Subjects
        Female
    		 1308 1289 2597
        Male
    		 781 798 1579

    End points

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    End points reporting groups
    Reporting group title
    Placebo bid + Symbicort 'as needed'
    Reporting group description
    		 Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)

    Reporting group title
    Pulmicort bid + terbutaline 'as needed'
    Reporting group description
    		 Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'

    Primary: Annual severe asthma exacerbation rate - Non-inferiority analysis

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    End point title
    		 Annual severe asthma exacerbation rate - Non-inferiority analysis [1]
    End point description
    End point type
    Primary
    End point timeframe
    up to 52 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Manuscript in press
    End point values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Number of subjects analysed
    2084
    2083
    Units: Annual rate of exacerbations
        least squares mean (confidence interval 95%)
    0.11 (0.10 to 0.13)
    0.12 (0.10 to 0.14)
    No statistical analyses for this end point

    Primary: Annual severe asthma exacerbation rate - Superiority analysis

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    End point title
    		 Annual severe asthma exacerbation rate - Superiority analysis [2]
    End point description
    End point type
    Primary
    End point timeframe
    up to 52 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Manuscript in press
    End point values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Number of subjects analysed
    2089
    2087
    Units: Annual rate of exacerbations
        least squares mean (confidence interval 95%)
    0.11 (0.10 to 0.13)
    0.12 (0.10 to 0.14)
    No statistical analyses for this end point

    Secondary: Time to first severe asthma exacerbation

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    End point title
    		 Time to first severe asthma exacerbation
    End point description
    End point type
    Secondary
    End point timeframe
    up to 52 weeks
    End point values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Number of subjects analysed
    2089
    2087
    Units: N patients with sev. asthma exacerbation
    177
    184
    No statistical analyses for this end point

    Secondary: Average change from baseline in pre-dose FEV1

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    End point title
    		 Average change from baseline in pre-dose FEV1
    End point description
    End point type
    Secondary
    End point timeframe
    Study weeks 0,17, 34, 52
    End point values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Number of subjects analysed
    1996
    1981
    Units: mL
        least squares mean (confidence interval 95%)
    104.0 (88.5 to 119.6)
    136.6 (121.1 to 152.2)
    No statistical analyses for this end point

    Secondary: Time to study specific asthma related discontinuation

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    End point title
    		 Time to study specific asthma related discontinuation
    End point description
    Study specific discontinuation of IP criteria: - A severe asthma exacerbation with a duration for more than 3 weeks - Three severe asthma exacerbations during 6 months
    End point type
    Secondary
    End point timeframe
    up to 52 weeks
    End point values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Number of subjects analysed
    2089
    2087
    Units: Participants
    0
    4
    No statistical analyses for this end point

    Secondary: Average change from baseline in ‘as needed’ use

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    End point title
    		 Average change from baseline in ‘as needed’ use
    End point description
    End point type
    Secondary
    End point timeframe
    Week 0 up to 52 weeks
    End point values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Number of subjects analysed
    2089
    2084
    Units: Number of inhalations per day
        least squares mean (confidence interval 95%)
    -0.84 (-0.86 to -0.81)
    -0.87 (-0.89 to -0.84)
    No statistical analyses for this end point

    Secondary: Change from baseline in percent of ‘as needed’ free days

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    End point title
    		 Change from baseline in percent of ‘as needed’ free days
    End point description
    End point type
    Secondary
    End point timeframe
    Week 0 up to 52 weeks
    End point values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Number of subjects analysed
    2089
    2084
    Units: Percentage of 'as needed' free days
        arithmetic mean (standard deviation)
    41.4 ( 29.6 )
    48.3 ( 29.5 )
    No statistical analyses for this end point

    Secondary: Percentage of controller use days

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    End point title
    		 Percentage of controller use days
    End point description
    End point type
    Secondary
    End point timeframe
    Week 0 up to 52 weeks
    End point values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Number of subjects analysed
    2089
    2084
    Units: Percentage of controller use days
        arithmetic mean (standard deviation)
    30.8 ( 28.2 )
    68.3 ( 28.5 )
    No statistical analyses for this end point

    Secondary: Average change from baseline in Asthma Control Questionnaire (5-item version) - ACQ-5 score

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    End point title
    		 Average change from baseline in Asthma Control Questionnaire (5-item version) - ACQ-5 score
    End point description
    ACQ questionnaire contains five questions on patients' symptoms, which are assessed on a 7-point scale from 0 (representing good control) to 6 (representing poor control). The score is the mean score of all questions for which responses are provided.
    End point type
    Secondary
    End point timeframe
    Study weeks 0, 17, 34, 52
    End point values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Number of subjects analysed
    1963
    1947
    Units: ACQ-5 Score
        least squares mean (confidence interval 95%)
    -0.35 (-0.38 to -0.32)
    -0.46 (-0.49 to -0.43)
    No statistical analyses for this end point

    Secondary: Average change from baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) score

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    End point title
    		 Average change from baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) score
    End point description
    AQLQ(S) consists of 32 questions in 4 domains. Each question is assessed on a 7-point scale from 1 to 7, with higher values indicating better health-related quality of life. The overall score is calculated as the mean score of all 32 items.
    End point type
    Secondary
    End point timeframe
    Study weeks 0,17, 34, 52
    End point values
    		 Placebo bid + Symbicort 'as needed' Pulmicort bid + terbutaline 'as needed'
    Number of subjects analysed
    1907
    1897
    Units: AQLQ(S) overall score
        least squares mean (confidence interval 95%)
    0.335 (0.305 to 0.366)
    0.431 (0.400 to 0.461)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were 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 were recorded from the time of informed consent.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Pulmicort bid + terbutaline ‘as needed’
    Reporting group description
    		 Pulmicort Turbuhaler (budesonide 200ug) + Terbutaline Turbuhaler 0.4 mg ‘as needed’

    Reporting group title
    Placebo bid + Symbicort 'as needed'
    Reporting group description
    		 Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 ug)

    Serious adverse events
    		 Pulmicort bid + terbutaline ‘as needed’ Placebo bid + Symbicort 'as needed'
    Total subjects affected by serious adverse events
         subjects affected / exposed
    73 / 2087 (3.50%)
    66 / 2089 (3.16%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of skin
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer female
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sebaceous adenoma
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    2 / 2087 (0.10%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 2087 (0.00%)
    2 / 2089 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 2087 (0.05%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast mass
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    17 / 2087 (0.81%)
    17 / 2089 (0.81%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 20
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 2087 (0.05%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 2087 (0.05%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod bite
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    2 / 2087 (0.10%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 2087 (0.05%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbosacral plexus injury
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural swelling
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 2087 (0.05%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 2087 (0.05%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Adams-Stokes syndrome
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 2087 (0.05%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrilation
         subjects affected / exposed
    2 / 2087 (0.10%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Degenerative aortic valve disease
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 2087 (0.05%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 2087 (0.00%)
    2 / 2089 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 2087 (0.05%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocholecystitis
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sphincter of Oddi dysfunction
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hirsutism
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystistis interstitial
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protusion
         subjects affected / exposed
    2 / 2087 (0.10%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 2087 (0.10%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 2087 (0.05%)
    2 / 2089 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 2087 (0.00%)
    2 / 2089 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 2087 (0.05%)
    2 / 2089 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 2087 (0.10%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 2087 (0.00%)
    1 / 2089 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 2087 (0.05%)
    0 / 2089 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Pulmicort bid + terbutaline ‘as needed’ Placebo bid + Symbicort 'as needed'
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    883 / 2087 (42.31%)
    863 / 2089 (41.31%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    50 / 2087 (2.40%)
    51 / 2089 (2.44%)
         occurrences all number
    68
    69
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    84 / 2087 (4.02%)
    81 / 2089 (3.88%)
         occurrences all number
    96
    95
    Rhinitis allergic
         subjects affected / exposed
    44 / 2087 (2.11%)
    51 / 2089 (2.44%)
         occurrences all number
    46
    56
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    168 / 2087 (8.05%)
    155 / 2089 (7.42%)
         occurrences all number
    206
    188
    Bronchitis
         subjects affected / exposed
    78 / 2087 (3.74%)
    64 / 2089 (3.06%)
         occurrences all number
    83
    70
    Upper respiratory tract infection
         subjects affected / exposed
    89 / 2087 (4.26%)
    81 / 2089 (3.88%)
         occurrences all number
    112
    90
    Pharyngitis
         subjects affected / exposed
    62 / 2087 (2.97%)
    51 / 2089 (2.44%)
         occurrences all number
    74
    55
    Influenza
         subjects affected / exposed
    42 / 2087 (2.01%)
    33 / 2089 (1.58%)
         occurrences all number
    46
    34

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Oct 2014
    Rationale for study design, doses and control groups amended:To clarify pre-study treatment according to GINA step 2 (GINA 2012). Inclusion criterion 4, 5 and Exclusion criterion 5 and 17 amended:To clarify pre-study treatment according to GINA step 2 (GINA 2012). Discontinuation of IP amended:To clarify that asthma deterioration event fulfilling study specific discontinuation criteria will meet AE criteria in all cases. Details related to enrolment failures amended:Wording added to clarify that re-enrolment of patients who were reported as enrolment failures due to technical reasons is allowed. Run-in procedures at Visit 2 amended: 1) To clarify the importance that concomitant medication may have effect on lung function measurements. 2) To clarify that all asthma-related treatments (including maintenance treatment with ICS or LTRA) will be stopped at Visit 2 Definition of severe asthma exacerbations amended: To provide clarification on depot steroid injection use, emergency room visit and steroid use end date. Details related to maternal exposure amended:To clarify that if a patient becomes pregnant during the course of the study IP should be discontinued immediately, but the patient will remain in the study and will be followed up for severe asthma exacerbation, AEs and concomitant medications.
    17 Aug 2015
    Study period amended: Date of last visit was postponed. Inclusion Criterion 6 amended: Allowing use of documented historical reversibility within 12 months for all patients who failed reversibility test at Visit 2 and Visit 3. Discontinuation of IP amended: To clarify that discontinuation of IP is obligatory in cases of pregnancy or study specific discontinuation criteria met. Details related to enrolment failures amended: Allowing 2 opportunities for patients to demonstrate a pre- and post-bronchodilator morning clinic FEV1 within the specified range as well as allowing re-enrolment of patients on short-acting bronchodilators as-needed who have been screen-failed prior to the current amendment but who have documented historical reversibility. Recording of asthma history amended: To clarify that only severe asthma exacerbations (and not mild/moderate asthma exacerbations) have to be reported as part of asthma history in the medical records and the eCRF. Timing of visits in relation to Patient training in how to use Turbuhaler and TUM amended and checking inhalation technique and re-training if needed added: Run-in procedures at Visit 2 amended: To give flexibility around timing of visit and spirometry at Visit 2. Treatment period amended: To clarify that assessment of inclusion criterion 7 (Bricanyl as-needed use) can be done more than once during the run-in period within the allowed visit windows. Timing of visits in relation to spirometry assessments amended: To clarify that requirement of performing spirometry ±1 hour in relation to the time of spirometry at Visit 2 should be taken into account for timing of visits. Administration of patient reported outcome questionnaires amended: To clarify that at Visit 2 patient can complete questionnaires after it has been verified that patient is eligible to enter run-in period based on lung function criterion (inclusion criterion number 5).
    15 Feb 2016
    Exclusion Criterion 2 amended To exclude patients previously randomised in another study of the same clinical program.
    12 Oct 2016
    • Hypothesis testing for primary objective changed from a superiority to a non-inferiority hypothesis, while keeping the superiority as a secondary comparison. • Implementation of external, independent evaluation of all deaths. The Steering Committee recommended that independent review and adjudication of fatal events be introduced following the first death (triggered by asthma exacerbation), which occurred on 19 July 2016. The rationale for this decision is that asthma related deaths are rare events and a group of specialists acting independently of all individuals associated with the conduct of the study can facilitate the collection of appropriate data and perform unbiased evaluation of each case.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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