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    Clinical Trial Results:
    A comparison of Symbicort® Maintenance and Reliever Therapy (Symbicort Turbuhaler® 160/4.5 μg, one inhalation bid plus as needed) and Symbicort Turbuhaler 160/4.5 μg, one inhalation bid plus terbutaline Turbuhaler 0.4 mg/inhalation as needed, for treatment of asthma – a 12-month, randomized, double-blind, parallel group, active-controlled, multinational phase III study in asthmatic patients aged 16 years and above.

    Summary
    EudraCT number
    2008-006869-86
    Trial protocol
    HU  
    Global end of trial date
    28 May 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Feb 2017
    First version publication date
    02 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D589LC00001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    AstraZeneca R&D, SE-221 87 Lund, Sweden,
    Public contact
    Carin Jorup, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Carin Jorup, AstraZeneca, ClinicalTrialTransparency@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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 May 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 May 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the efficacy of Symbicort® Maintenance and Reliever Therapy (SMART) (Symbicort Turbuhaler® 160/4.5μg, one inhalation bid plus as needed) with Symbicort Turbuhaler 160/4.5μg, one inhalation bid plus terbutaline Turbuhaler 0.4 mg as needed, as asthma therapy by evaluation of time to first asthma exacerbation.
    Protection of trial subjects
    The final study protocol and amendments (Appendix 12.1.1), including the final version of the Informed Consent Form (Appendix 12.1.3), and the Case Report Form (CRF) (Appendix 12.1.2) were approved or given a favourable opinion in writing by an Institutional Review Board (IRB) as appropriate. The principal investigator at each centre ensured that the patient was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study. Patients were also notified that they were free to discontinue from the study at any time. Patients were given the opportunity to ask questions and allowed time to consider the information provided. Parents and the legal representatives (if patient was minor) signed and dated informed consent before conducting any procedure specifically for the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Feb 2009
    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
    Thailand: 61
    Country: Number of subjects enrolled
    Argentina: 266
    Country: Number of subjects enrolled
    Brazil: 95
    Country: Number of subjects enrolled
    China: 189
    Country: Number of subjects enrolled
    Costa Rica: 41
    Country: Number of subjects enrolled
    Hungary: 173
    Country: Number of subjects enrolled
    India: 249
    Country: Number of subjects enrolled
    Japan: 400
    Country: Number of subjects enrolled
    Korea, Republic of: 105
    Country: Number of subjects enrolled
    Malaysia: 100
    Country: Number of subjects enrolled
    Peru: 70
    Country: Number of subjects enrolled
    Philippines: 198
    Country: Number of subjects enrolled
    Russian Federation: 144
    Worldwide total number of subjects
    2091
    EEA total number of subjects
    173
    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)
    21
    Adults (18-64 years)
    1865
    From 65 to 84 years
    204
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 148 centres in Japan and in 12 other countries in Asia, America and Europe between 16 February 2009 and 23 February 2011.

    Pre-assignment
    Screening details
    The study consisted of an enrolment visit, a 2-week run-in (standardization) period at Visit 2, randomization at Visit 3, and 5 further visits (Visits 4-8) at 4, 12, 24, 36 and 52 weeks. Subjects received 1 of 2 double-blinded treatments allocated in a random order.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Symbicort SMART
    Arm description
    Symbicort Turbuhaler® 160/4.5 μg/inhalation
    Arm type
    Experimental

    Investigational medicinal product name
    Symbicort® Turbuhaler® 160/4.5 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    160/4.5 μg

    Arm title
    Symbicort + Terbutaline
    Arm description
    Symbicort Turbuhaler 160/4.5 μg + terbutaline Turbuhaler 0.4 mg/inhalation
    Arm type
    Active comparator

    Investigational medicinal product name
    Symbicort® Turbuhaler® 160/4.5 μg + terbutaline Turbuhaler® 0.4 mg/inhalation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    160/4.5 μg

    Number of subjects in period 1
    Symbicort SMART Symbicort + Terbutaline
    Started
    1049
    1042
    Completed
    956
    932
    Not completed
    93
    110
         Protocol deviation
    6
    13
         Adverse event, non-fatal
    8
    12
         Other reasons
    20
    25
         Consent withdrawn by subject
    28
    34
         Lost to follow-up
    31
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Symbicort SMART
    Reporting group description
    Symbicort Turbuhaler® 160/4.5 μg/inhalation

    Reporting group title
    Symbicort + Terbutaline
    Reporting group description
    Symbicort Turbuhaler 160/4.5 μg + terbutaline Turbuhaler 0.4 mg/inhalation

    Reporting group values
    Symbicort SMART Symbicort + Terbutaline Total
    Number of subjects
    1049 1042 2091
    Age Categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    5 16 21
        Adults (18-64 years)
    938 927 1865
        From 65-84 years
    106 98 204
        85 years and over
    0 1 1
    Age Continuous
    Units: years
        arithmetic mean (full range (min-max))
    45.7 (16 to 84) 45.6 (16 to 85) -
    Gender Categorical
    Units: Subjects
        Female
    722 692 1414
        Male
    327 350 677
    Japanese/Non-Japanese
    Units: Subjects
        Japanese
    201 199 400
        Non-Japanese
    848 843 1691

    End points

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    End points reporting groups
    Reporting group title
    Symbicort SMART
    Reporting group description
    Symbicort Turbuhaler® 160/4.5 μg/inhalation

    Reporting group title
    Symbicort + Terbutaline
    Reporting group description
    Symbicort Turbuhaler 160/4.5 μg + terbutaline Turbuhaler 0.4 mg/inhalation

    Primary: Total number of asthma exacerbations

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    End point title
    Total number of asthma exacerbations
    End point description
    Asthma exacerbations, defined as a deterioration in asthma leading to oral GCS treatment,hospitalization, or ER treatment, were recorded, with the primary outcome variable of time tofirst asthma exacerbation and a secondary outcome variable of the total number of asthmaexacerbations
    End point type
    Primary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1049
    1042
    Units: exacerbations
    259
    363
    Statistical analysis title
    The time to first asthma exacerbation
    Statistical analysis description
    Cox-proportional hazards model for time to first event
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2091
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.695
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    0.848
    Statistical analysis title
    Total number of asthma exacerbations
    Statistical analysis description
    Analysis of total number of esthma exacerbations reported per subject.
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2091
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Poisson regression
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.696
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.592
         upper limit
    0.818

    Secondary: Use of as-needed medication

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    End point title
    Use of as-needed medication
    End point description
    Total daily no. of inhalations during the treatment period
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1032
    1026
    Units: days
        arithmetic mean (full range (min-max))
    1.21 (0 to 9.3)
    1.46 (0 to 15)
    Statistical analysis title
    Change from baseline in use of as-needed med.
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2058
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.36
         upper limit
    -0.15

    Secondary: Morning PEF (L/min)

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    End point title
    Morning PEF (L/min)
    End point description
    Mean value during the treatment period
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1034
    1026
    Units: (L/min)
        arithmetic mean (full range (min-max))
    331.8 (98 to 752)
    324.7 (87 to 725)
    Statistical analysis title
    Change from baseline in mean morning PEF (L/min)
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2060
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    5.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.1
         upper limit
    9.5

    Secondary: Evening PEF (L/min)

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    End point title
    Evening PEF (L/min)
    End point description
    Mean evening PEF during the treatment period
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1034
    1026
    Units: (L/min)
        arithmetic mean (full range (min-max))
    334.2 (96 to 725)
    327.8 (85 to 723)
    Statistical analysis title
    Change from baseline in mean evening PEF(L/min)
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2060
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    5.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.1
         upper limit
    9.3

    Secondary: Asthma symptom score

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    End point title
    Asthma symptom score
    End point description
    Mean Total score(0-6) during the treatment period
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1034
    1025
    Units: average score
        arithmetic mean (full range (min-max))
    1.12 (0 to 5.9)
    1.22 (0 to 5.5)
    Statistical analysis title
    Mean asthma symptoms (total score)
    Statistical analysis description
    Change from baseline in mean asthma symptoms (total)
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2059
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.025
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.16
         upper limit
    -0.01

    Secondary: Nights with awakenings due to asthma symptoms(%)

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    End point title
    Nights with awakenings due to asthma symptoms(%)
    End point description
    % nights with awakenings during the treatment period
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1024
    1025
    Units: Proportion of nights
        arithmetic mean (full range (min-max))
    15.7 (0 to 100)
    15.5 (0 to 100)
    Statistical analysis title
    % of nights with awakenings due to asthma
    Statistical analysis description
    Change from baseline in % of nights with awakenings due to asthma
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2049
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.06
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.68
         upper limit
    0.07

    Secondary: Symptom free days (%)

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    End point title
    Symptom free days (%)
    End point description
    % of symptom free days during the treatment period
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1034
    1026
    Units: days
        arithmetic mean (full range (min-max))
    45.5 (0 to 100)
    41.6 (0 to 100)
    Statistical analysis title
    Change from baseline in % Symptom free days
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2060
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.016
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    6.5

    Secondary: Percentage of asthma-control days

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    End point title
    Percentage of asthma-control days
    End point description
    % of asthma control days during the treatment period
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1033
    1026
    Units: percentage
        arithmetic mean (full range (min-max))
    41.7 (0 to 100)
    37.9 (0 to 100)
    Statistical analysis title
    Change from baseline in % of asthma-control days
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2059
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    7.1

    Secondary: Mean FEV1 (L)

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    End point title
    Mean FEV1 (L)
    End point description
    Mean FEV1 during the treatment period
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1049
    1042
    Units: Liters
        arithmetic mean (full range (min-max))
    2.258 (0.64 to 5.05)
    2.222 (0.68 to 5.77)
    Statistical analysis title
    change from baseline in mean FEV1 (L)
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2091
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.015
         upper limit
    0.064

    Secondary: Mild asthma exacerbations

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    End point title
    Mild asthma exacerbations
    End point description
    Patients with at least one mild exacerbation
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1049
    1042
    Units: number of exacerbations
    739
    825
    Statistical analysis title
    Time to first mild exacerbation
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2091
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.811
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.734
         upper limit
    0.896
    Statistical analysis title
    Number of mild asthma excerbations (days)
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2091
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0276
    Method
    Poisson regression
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.889
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    0.987

    Secondary: ACQ score

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    End point title
    ACQ score
    End point description
    Mean overall ACQ score during the treatment period
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Symbicort SMART Symbicort + Terbutaline
    Number of subjects analysed
    1040
    1038
    Units: average score
        arithmetic mean (full range (min-max))
    1.162 (0 to 5.88)
    1.289 (0 to 4.68)
    Statistical analysis title
    Change from baseline in mean ACQ score
    Comparison groups
    Symbicort SMART v Symbicort + Terbutaline
    Number of subjects included in analysis
    2078
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.124
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.179
         upper limit
    -0.069

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the run-in visit (visit 2) until visit 8 (52 weeks after randomisation). AEs observed after intake of the investigational product are presented in the summaries below.
    Adverse event reporting additional description
    A total of 1201 patients reported non-serious adverse events; 602 on Symbicort SMART, 599 on Symbicort + Terbutaline. Numbers for non-serious AEs in the reporting group table are based on the 5% threshold frequency.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Symbicort + Terbutaline
    Reporting group description
    Symbicort Turbuhaler 160/4.5 μg + terbutaline Turbuhaler 0.4 mg/inhalation

    Reporting group title
    Symbicort SMART
    Reporting group description
    Symbicort Turbuhaler® 160/4.5 μg/inhalation

    Serious adverse events
    Symbicort + Terbutaline Symbicort SMART
    Total subjects affected by serious adverse events
         subjects affected / exposed
    75 / 1042 (7.20%)
    43 / 1049 (4.10%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Vascular disorders
    hypertension
         subjects affected / exposed
    1 / 1042 (0.10%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer in situ
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal adenocarcinoma
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    metastatic neoplasm
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 1042 (0.00%)
    2 / 1049 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    drug hypersensitivity
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    abortion spontaneous
         subjects affected / exposed
    1 / 1042 (0.10%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abortion threatened
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    premature baby
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    hernia obstructive
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malaise
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    major depression
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    breast calcifications
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysfunctional uterine bleeding
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (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
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infertility male
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         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
    foot fracture
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    joint injury
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lower limb fracture
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    muscle strain
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    patella fracture
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sternal fracture
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    traumatic brain injury
         subjects affected / exposed
    2 / 1042 (0.19%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    acute myocardial infarction
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    angina pectoris
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (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 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    coronary artery disease
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    cleft lip
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    31 / 1042 (2.98%)
    5 / 1049 (0.48%)
         occurrences causally related to treatment / all
    0 / 38
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 1042 (0.19%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal septum deviation
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    convulsion
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dizziness
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (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 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    syncope
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (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
    1 / 1042 (0.10%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    retinal detachment
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    menieres disease
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 1042 (0.00%)
    3 / 1049 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute abdomen
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colonic polyp
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastric polyps
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    haematuria
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholelithiasis
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatotoxicity
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (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
    rash
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         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
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intervertebral disc protrusion
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rheumatoid arthritis
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    basedows disease
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Metabolism and nutrition disorders
    diabetes mellitus
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    type 2 diabetes mellitus
         subjects affected / exposed
    2 / 1042 (0.19%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    3 / 1042 (0.29%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 1042 (0.19%)
    4 / 1049 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    h1n1 influenza
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 1042 (0.00%)
    2 / 1049 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 1042 (0.00%)
    2 / 1049 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 1042 (0.10%)
    0 / 1049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 1042 (0.00%)
    1 / 1049 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Symbicort + Terbutaline Symbicort SMART
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    350 / 1042 (33.59%)
    314 / 1049 (29.93%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    75 / 1042 (7.20%)
    49 / 1049 (4.67%)
         occurrences all number
    102
    60
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    133 / 1042 (12.76%)
    137 / 1049 (13.06%)
         occurrences all number
    2116
    230
    Bronchitis
         subjects affected / exposed
    78 / 1042 (7.49%)
    69 / 1049 (6.58%)
         occurrences all number
    96
    87
    Viral upper respiratory tract infection
         subjects affected / exposed
    72 / 1042 (6.91%)
    60 / 1049 (5.72%)
         occurrences all number
    87
    71
    Pharyngitis
         subjects affected / exposed
    58 / 1042 (5.57%)
    49 / 1049 (4.67%)
         occurrences all number
    69
    65

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2009
    Add the explanation that FEV1 predicted normal values for adolescents (age 16 and 17 years) was calculated according to Polgar and reference.
    14 Jul 2009
    Add humanised monoclonal antibody to IgE. Change the post- bronchodilatory FEV1 to the pre-bronchodilatory FEV1

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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