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    Clinical Trial Results:
    A Phase 3, 12-Week, Double-Blind, Randomized, Parallel-Group, Multicenter Study Investigating the Efficacy and Safety of Symbicort pMDI 80/2.25 μg, 2 Actuations Twice Daily, and Symbicort pMDI 80/4.5 μg, 2 Actuations Twice Daily, Compared with Budesonide pMDI 80 μg, 2 Actuations Twice Daily, in Children Ages 6 to <12 Years with Asthma

    Summary
    EudraCT number
    		 2013-005293-22
    Trial protocol
    		 SK  
    Global end of trial date
    14 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Oct 2016
    First version publication date
    27 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D589GC00003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden,
    Public contact
    Global Clinical Lead Göran Eckerwall, AstraZeneca, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead Göran Eckerwall, Astrazeneca Research and Development, 0046 +46 31 7761000, 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate the efficacy of Symbicort pMDI 80/4.5, 2 inhalations bid and Symbicort pMDI 80/2.25, 2 inhalations bid, compared with budesonide pMDI 80 µg, 2 inhalations bid, in children ages 6 to <12 years with asthma.
    Protection of trial subjects
    Before subjects can be enrolled into the study or starting the study procedure, an informed consent and child assent forms following the relevant local regulations of subject protection and data privacy must be signed by the subjects and their legal guardian(s). The study data was stored in a computer database, maintaining confidentiality in accordance with relevant regulations. All data computer-processed by AstraZeneca or representative will be identified by patient enrollment number, randomization number, and study code. The master informed consent and child assent forms will also explain that for data verification purposes, authorized representatives of AstraZeneca, a regulatory authority, an IRB or Independent Ethics Committee (IEC) may require direct access to parts of the hospital or practice records relevant to the study, including the patient’s medical history. The study protocol, Informed Consent/Child Assent Forms and any other written information and/or materials to be provided to the patients were approved by the Institutional Review Board or Ethic committee in accordance with local country regulations. Patient safety was monitored by the CRO, Quintiles safety group throughout the study conduct. Any reportable adverse events were submitted to the relevant regulatory authorities including IRBs/ECs according to local requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Apr 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
    United States: 226
    Country: Number of subjects enrolled
    Panama: 25
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Slovakia: 20
    Worldwide total number of subjects
    279
    EEA total number of subjects
    20
    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)
    279
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 881 patients were screened; 237 patients were screen failures and 644 patients received run in medication. Of the patients who received run-in medication, 365 patients were not randomized and 279 patients were randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Symbicort pMDI 80/4.5 ug
    Arm description
    		 Symbicort pMDI 80/4.5 ug x 2 BID
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide/formoterol pMDI 80/4.5 ug
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    pMDI HFA for oral inhalation with ACM budesonide/formoterol fumarate dihydrate

    Arm title
    		 Symbicort pMDI 80/2.25 ug
    Arm description
    		 Symbicort pMDI 80/2.25 ug x 2 BID
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide/formoterol pMDI 80/2.25 ug
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    pMDI HFA for oral inhalation with ACM budesonide/formoterol fumarate dihydrate 80/2.25 ug

    Arm title
    		 Budesonide pMDI 80 ug
    Arm description
    		 Budesonide pMDI 80 ug x 2 BID
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide pMDI 80 ug
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    pMDI HFA for oral inhalation with ACM Budesonide 80 ug

    Number of subjects in period 1
    		Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Started
    92
    95
    92
    Completed
    85
    84
    84
    Not completed
    7
    11
    8
         Consent withdrawn by subject
    4
    8
    3
         Adverse event, non-fatal
    -
    -
    2
         7 rand in error 1 patient decision
    2
    3
    3
         Lost to follow-up
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Symbicort pMDI 80/4.5 ug
    Reporting group description
    		 Symbicort pMDI 80/4.5 ug x 2 BID

    Reporting group title
    Symbicort pMDI 80/2.25 ug
    Reporting group description
    		 Symbicort pMDI 80/2.25 ug x 2 BID

    Reporting group title
    Budesonide pMDI 80 ug
    Reporting group description
    		 Budesonide pMDI 80 ug x 2 BID

    Reporting group values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug Total
    Number of subjects
    		 92 95 92 279
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 92 95 92 279
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 9 ( 1.6 ) 9 ( 1.6 ) 9 ( 1.4 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 42 34 37 113
        Male
    		 50 61 55 166
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 2 3 3 8
        Asian
    		 0 0 2 2
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 1
        Black or African American
    		 24 26 26 76
        White
    		 61 60 53 174
        More than one race
    		 4 4 7 15
        Unknown or Not Reported
    		 0 2 1 3
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 38 36 32 106
        Not Hispanic or Latino
    		 54 59 60 173
        Unknown or Not Reported
    		 0 0 0 0
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    		 38 ( 12.9 ) 38 ( 12.9 ) 40 ( 13.6 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 139 ( 11.1 ) 138 ( 10.9 ) 141 ( 10.5 ) -
    Duration of asthma
    Units: years
        arithmetic mean (standard deviation)
    		 5.8 ( 3 ) 5.9 ( 3.3 ) 6.2 ( 3.1 ) -
    FEV1 at randomisation
    Units: Liters
        arithmetic mean (standard deviation)
    		 1.58 ( 0.42 ) 1.57 ( 0.33 ) 1.62 ( 0.36 ) -

    End points

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    End points reporting groups
    Reporting group title
    Symbicort pMDI 80/4.5 ug
    Reporting group description
    		 Symbicort pMDI 80/4.5 ug x 2 BID

    Reporting group title
    Symbicort pMDI 80/2.25 ug
    Reporting group description
    		 Symbicort pMDI 80/2.25 ug x 2 BID

    Reporting group title
    Budesonide pMDI 80 ug
    Reporting group description
    		 Budesonide pMDI 80 ug x 2 BID

    Primary: Change from baseline to Week 12 in 1h post-dose FEV1

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    End point title
    		 Change from baseline to Week 12 in 1h post-dose FEV1
    End point description
    1h post-dose FEV1 is defined as the 1-hour post-dose measurement taken at Week 12 minus the pre dose measurement taken at randomization for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    89
    93
    90
    Units: Liters
        least squares mean (confidence interval 95%)
    0.28 (0.22 to 0.34)
    0.24 (0.18 to 0.31)
    0.17 (0.1 to 0.23)
    Statistical analysis title
    		 FEV1 1h post-dose Change from baseline to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.2
    Notes
    [1] - 2-sided p-value
    Statistical analysis title
    		 FEV1 1h post-dose Change from baseline to week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.373 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.12
    Notes
    [2] - 2-sided
    Statistical analysis title
    		 FEV1 1h post-dose Change from baseline to week 12
    Comparison groups
    Budesonide pMDI 80 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.063 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.08
         upper limit
    		 0.16
    Notes
    [3] - 2-sided

    Secondary: Change from baseline to Week 12 in 1h post-dose PEF

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    End point title
    		 Change from baseline to Week 12 in 1h post-dose PEF
    End point description
    1h post-dose PEF is defined as the 1-hour post-dose measurement taken at Week 12 minus the pre dose measurement taken at randomization for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    89
    93
    90
    Units: Liters per minute
        least squares mean (confidence interval 95%)
    57.04 (46.12 to 67.97)
    41.14 (30.26 to 52.01)
    31.57 (20.78 to 42.36)
    Statistical analysis title
    		 PEF 1h post dose Change from baseline to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    25.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.94
         upper limit
    		 40
    Notes
    [4] - 2-sided
    Statistical analysis title
    		 PEF 1h post dose Change from baseline to Week 12
    Comparison groups
    Budesonide pMDI 80 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.195 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.92
         upper limit
    		 24.05
    Notes
    [5] - 2-sided
    Statistical analysis title
    		 PEF 1h post dose Change from baseline to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    15.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.34
         upper limit
    		 30.47
    Notes
    [6] - 2-sided

    Secondary: Change from baseline to Week 12 in 1h post-dose FEF25-75

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    End point title
    		 Change from baseline to Week 12 in 1h post-dose FEF25-75
    End point description
    1h post-dose FEF25-75 is defined as the 1-hour post-dose measurement taken at Week 12 minus the pre dose measurement taken at randomization for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    89
    93
    90
    Units: Liters per second
        least squares mean (confidence interval 95%)
    0.55 (0.43 to 0.67)
    0.47 (0.35 to 0.59)
    0.23 (0.11 to 0.35)
    Statistical analysis title
    		 FEF25-75 1h post-dose Change from basel to week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.48
    Notes
    [7] - 2-sided
    Statistical analysis title
    		 FEF25-75 1h post-dose Change from basel to week 12
    Comparison groups
    Budesonide pMDI 80 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.4
    Statistical analysis title
    		 FEF25-75 1h post-dose Change from basel to week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.326 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.25
    Notes
    [8] - 2-sided

    Secondary: Change from baseline to Week 12 in 1h post-dose FVC

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    End point title
    		 Change from baseline to Week 12 in 1h post-dose FVC
    End point description
    1h post-dose FVC is defined as the 1-hour post-dose measurement taken at Week 12 minus the pre dose measurement taken at randomization for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    89
    93
    90
    Units: Liters
        least squares mean (confidence interval 95%)
    0.22 (0.15 to 0.3)
    0.16 (0.09 to 0.23)
    0.17 (0.1 to 0.24)
    Statistical analysis title
    		 FVC 1h post dose Change from basel to week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.276 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.15
    Notes
    [9] - 2-sided
    Statistical analysis title
    		 FVC 1h post dose Change from basel to week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.165
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.16
    Statistical analysis title
    		 FVC 1h post dose Change from basel to week 12
    Comparison groups
    Budesonide pMDI 80 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.759 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.08
    Notes
    [10] - 2-sided

    Secondary: Change from baseline to Week 12 in pre-dose FEV1

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    End point title
    		 Change from baseline to Week 12 in pre-dose FEV1
    End point description
    Pre-dose FEV1 is defined as the pre-dose measurement taken at Week 12 minus the pre dose measurement taken at randomization for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    89
    92
    89
    Units: Liters
        least squares mean (confidence interval 95%)
    0.11 (0.04 to 0.17)
    0.1 (0.03 to 0.16)
    0.09 (0.03 to 0.15)
    Statistical analysis title
    		 FEV1 pre-dose Change from basel to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.724 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.1
    Notes
    [11] - 2-sided
    Statistical analysis title
    		 FEV1 pre-dose Change from basel to Week 12
    Comparison groups
    Budesonide pMDI 80 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.909
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.09
    Statistical analysis title
    		 FEV1 pre-dose Change from basel to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.811
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.09

    Secondary: Change from baseline to Week 12 in pre-dose PEF

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    End point title
    		 Change from baseline to Week 12 in pre-dose PEF
    End point description
    Pre-dose PEF is defined as the pre-dose measurement taken at Week 12 minus the pre dose measurement taken at randomization for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    89
    92
    89
    Units: Liters per minute
        least squares mean (confidence interval 95%)
    27.73 (16.37 to 39.08)
    15.86 (4.39 to 27.33)
    16.01 (4.5 to 27.52)
    Statistical analysis title
    		 PEF pre-dose Change from basel to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.134 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.63
         upper limit
    		 27.06
    Notes
    [12] - 2-sided
    Statistical analysis title
    		 PEF pre-dose Change from basel to Week 12
    Comparison groups
    Budesonide pMDI 80 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.985 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.28
         upper limit
    		 15.28
    Notes
    [13] - 2-sided
    Statistical analysis title
    		 FEV1 pre-dose Change from basel to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.128 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.43
         upper limit
    		 27.16
    Notes
    [14] - 2-sided

    Secondary: Change from baseline to Week 12 in pre-dose FEF25-75

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    End point title
    		 Change from baseline to Week 12 in pre-dose FEF25-75
    End point description
    Pre-dose FEF25-75 is defined as the pre-dose measurement taken at Week 12 minus the pre dose measurement taken at randomization for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    89
    92
    89
    Units: Liters per minute
        least squares mean (confidence interval 95%)
    0.12 (0.01 to 0.24)
    0.13 (0.01 to 0.25)
    0.09 (-0.03 to 0.21)
    Statistical analysis title
    		 FEF25-75 pre-dose Change from basel to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.684 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.19
    Notes
    [15] - 2-sided
    Statistical analysis title
    		 FEF25-75 pre-dose Change from basel to Week 12
    Comparison groups
    Budesonide pMDI 80 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.621 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.2
    Notes
    [16] - 2-sided
    Statistical analysis title
    		 FEF25-75 pre-dose Change from basel to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.929 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.15
    Notes
    [17] - 2-sided

    Secondary: Change from baseline to Week 12 in pre-dose FVC

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    End point title
    		 Change from baseline to Week 12 in pre-dose FVC
    End point description
    Pre-dose FVC is defined as the pre-dose measurement taken at Week 12 minus the pre dose measurement taken at randomization for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    89
    92
    89
    Units: Liters
        least squares mean (confidence interval 95%)
    0.11 (0.03 to 0.18)
    0.11 (0.04 to 0.19)
    0.13 (0.05 to 0.2)
    Statistical analysis title
    		 FVC pre-dose Change from basel to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.664 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.08
    Notes
    [18] - 2-sided
    Statistical analysis title
    		 FVC pre-dose Change from basel to Week 12
    Comparison groups
    Budesonide pMDI 80 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.747 [19]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.08
    Notes
    [19] - 2-sided
    Statistical analysis title
    		 FVC pre-dose Change from basel to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.913 [20]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.09
    Notes
    [20] - 2-sided

    Secondary: Change from baseline to Week 12 in 15 min post-dose FEV1

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    End point title
    		 Change from baseline to Week 12 in 15 min post-dose FEV1
    End point description
    15 min Post-dose FEV1 is defined as the 15 min post-dose measurement taken at Week 12 minus the pre dose measurement taken at randomization for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    79
    78
    80
    Units: Liters
        least squares mean (confidence interval 95%)
    0.25 (0.18 to 0.31)
    0.19 (0.12 to 0.25)
    0.15 (0.08 to 0.21)
    Statistical analysis title
    		 FEV1 15m post-dose Change from basel to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015 [21]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.18
    Notes
    [21] - 2-sided
    Statistical analysis title
    		 FEV1 15m post-dose Change from basel to Week 12
    Comparison groups
    Budesonide pMDI 80 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.342 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.12
    Notes
    [22] - 2-sided
    Statistical analysis title
    		 FEV1 15m post-dose Change from basel to Week 12
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.138 [23]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.15
    Notes
    [23] - 2-sided

    Secondary: Change from baseline to End of Study Average in Total Asthma Symptoms

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    End point title
    		 Change from baseline to End of Study Average in Total Asthma Symptoms
    End point description
    End of study average is defined as the average of available records from 7 days before up to and including the day prior to withdrawal from study or Week 12, minus the baseline measurement at randomization, for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    70
    72
    73
    Units: Asthma symptom scores
        arithmetic mean (standard deviation)
    -0.5 ( 0.73 )
    -0.6 ( 0.73 )
    -0.4 ( 0.55 )
    No statistical analyses for this end point

    Secondary: Change from baseline to End of Study Average in % of night time awakenings due to asthma symptoms

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    End point title
    		 Change from baseline to End of Study Average in % of night time awakenings due to asthma symptoms
    End point description
    End of study average is defined as the percentage of nighttime awakenings due to asthma symptoms from 6 days before up to and additionally including the morning of withdrawal from study or Week 12, minus the baseline measurement at randomization, for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    79
    85
    82
    Units: Percent
        arithmetic mean (standard deviation)
    -14 ( 29.15 )
    -17.3 ( 33.16 )
    -13 ( 21.87 )
    No statistical analyses for this end point

    Secondary: Change from baseline to End of Study Average in Total daily reliever medication

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    End point title
    		 Change from baseline to End of Study Average in Total daily reliever medication
    End point description
    End of study average is defined as the average of available records from 7 days before up to and including the day prior to withdrawal from study or Week 12, minus the baseline measurement at randomization, for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    70
    72
    73
    Units: Number of reliever medication use
        arithmetic mean (standard deviation)
    -0.7 ( 1.75 )
    -1.1 ( 2.37 )
    -0.7 ( 1.37 )
    No statistical analyses for this end point

    Secondary: Change from baseline to Study Period Average in Overall PAQLQ Score

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    End point title
    		 Change from baseline to Study Period Average in Overall PAQLQ Score
    End point description
    Study period average is defined as the average of the post-baseline values during the study taken after first dose of investigational product up to and including withdrawal from study or Week 12, minus the baseline assessment at randomization, for patients who remain in the study (irrespective of whether IP has been discontinued).
    End point type
    Secondary
    End point timeframe
    Randomisation up to week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    79
    80
    82
    Units: PAQLQ Scores
        least squares mean (confidence interval 95%)
    0.46 (0.3 to 0.62)
    0.53 (0.38 to 0.69)
    0.62 (0.47 to 0.78)
    Statistical analysis title
    		 Overall PAQLQ score, study period average
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Budesonide pMDI 80 ug
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.098 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0.03
    Notes
    [24] - 2-sided
    Statistical analysis title
    		 Overall PAQLQ score, study period average
    Comparison groups
    Budesonide pMDI 80 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.367 [25]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.11
    Notes
    [25] - 2-sided
    Statistical analysis title
    		 Overall PAQLQ score, study period average
    Comparison groups
    Symbicort pMDI 80/4.5 ug v Symbicort pMDI 80/2.25 ug
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.449 [26]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.12
    Notes
    [26] - 2-sided

    Secondary: Number of patients with an asthma exacerbation during study

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    End point title
    		 Number of patients with an asthma exacerbation during study
    End point description
    Number of patients that experienced an asthma exacerbation that required either emergency room treatment, hospitalization, systemic steroids, or an increase in, or additional asthma maintenance medication, during the study.
    End point type
    Secondary
    End point timeframe
    Randomisation up to Week 12
    End point values
    		 Symbicort pMDI 80/4.5 ug Symbicort pMDI 80/2.25 ug Budesonide pMDI 80 ug
    Number of subjects analysed
    90
    93
    90
    Units: Partcicipants
    9
    12
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Symbicort pMDI 80/4.5 ug
    Reporting group description
    		 Symbicort pMDI 80/4.5 ug x 2 BID

    Reporting group title
    Budesonide pMDI 80 ug
    Reporting group description
    		 Budesonide pMDI 80 ug x 2 BID

    Reporting group title
    Symbicort pMDI 80/2.25 ug
    Reporting group description
    		 Symbicort pMDI 80/2.25 ug x 2 BID

    Serious adverse events
    		 Symbicort pMDI 80/4.5 ug Budesonide pMDI 80 ug Symbicort pMDI 80/2.25 ug
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 90 (2.22%)
    0 / 93 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Symbicort pMDI 80/4.5 ug Budesonide pMDI 80 ug Symbicort pMDI 80/2.25 ug
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 90 (46.67%)
    40 / 90 (44.44%)
    41 / 93 (44.09%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 90 (4.44%)
    0 / 90 (0.00%)
    4 / 93 (4.30%)
         occurrences all number
    4
    0
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 90 (4.44%)
    4 / 90 (4.44%)
    4 / 93 (4.30%)
         occurrences all number
    4
    4
    4
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 90 (0.00%)
    0 / 93 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 90 (0.00%)
    3 / 93 (3.23%)
         occurrences all number
    2
    0
    3
    Nausea
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 90 (2.22%)
    0 / 93 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    7 / 90 (7.78%)
    10 / 90 (11.11%)
    11 / 93 (11.83%)
         occurrences all number
    7
    10
    11
    Rhinitis allergic
         subjects affected / exposed
    3 / 90 (3.33%)
    4 / 90 (4.44%)
    3 / 93 (3.23%)
         occurrences all number
    3
    5
    3
    Cough
         subjects affected / exposed
    1 / 90 (1.11%)
    4 / 90 (4.44%)
    4 / 93 (4.30%)
         occurrences all number
    1
    5
    4
    Epistaxis
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 90 (1.11%)
    2 / 93 (2.15%)
         occurrences all number
    1
    1
    2
    Nasal congestion
         subjects affected / exposed
    2 / 90 (2.22%)
    2 / 90 (2.22%)
    0 / 93 (0.00%)
         occurrences all number
    2
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 90 (1.11%)
    0 / 93 (0.00%)
         occurrences all number
    2
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 90 (2.22%)
    0 / 93 (0.00%)
         occurrences all number
    1
    2
    0
    Sinus congestion
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 90 (0.00%)
    2 / 93 (2.15%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 90 (10.00%)
    4 / 90 (4.44%)
    12 / 93 (12.90%)
         occurrences all number
    9
    4
    14
    Nasopharyngitis
         subjects affected / exposed
    4 / 90 (4.44%)
    5 / 90 (5.56%)
    2 / 93 (2.15%)
         occurrences all number
    4
    6
    2
    Pharyngitis
         subjects affected / exposed
    5 / 90 (5.56%)
    1 / 90 (1.11%)
    3 / 93 (3.23%)
         occurrences all number
    5
    1
    4
    Sinusitis
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 90 (1.11%)
    1 / 93 (1.08%)
         occurrences all number
    2
    1
    1
    Influenza
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
    2 / 93 (2.15%)
         occurrences all number
    1
    0
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
    2 / 93 (2.15%)
         occurrences all number
    0
    1
    2
    Conjunctivitis
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 90 (2.22%)
    0 / 93 (0.00%)
         occurrences all number
    1
    2
    0
    Rhinitis
         subjects affected / exposed
    3 / 90 (3.33%)
    2 / 90 (2.22%)
    2 / 93 (2.15%)
         occurrences all number
    3
    2
    2
    Viral upper respiratory tract
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 90 (2.22%)
    1 / 93 (1.08%)
         occurrences all number
    0
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2014
    The primary analysis was revised to include all clinic FEV1 data from all patients, regardless of discontinuation of IP. Text was added to clarify a negative urine pregnancy test result should be obtained (where appropriate) prior to certain procedures at Visit 2 and prior to administration of IP at all other visits. For patients who meet pre-defined asthma worsening criteria, contact by the site within 24 to 48 hours was made mandatory, but the necessity of a clinic visit was changed to be at the discretion of the investigator.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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