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    Clinical Trial Results:
    A Phase 2, double-blind, randomized, parallel-group, placebo-controlled, multicenter study, comparing budesonide pMDI 160 μg bid with placebo: a 6-week efficacy and safety study in children aged 6 to <12 years with asthma

    Summary
    EudraCT number
    		 2010-018315-15
    Trial protocol
    		 SK   LV   HU   PL   BG  
    Global end of trial date
    23 Sep 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    D589GC00001
    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-431 83 Mölndal, Sweden,
    Public contact
    Göran Eckerwall, MD, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Göran Eckerwall, MD, 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
    23 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the efficacy of budesonide pMDI 160 μg bid (80 μg x 2 inhalations bid) as a single ingredient product over a 6-week period in children aged 6 to <12 years who demonstrated the need for ICS controller therapy.
    Protection of trial subjects
    An Independent Ethics Committee/Institutional Review Board approved the final clinical study protocol, including the final version of the Informed Consent Form and Child Assent Forms and any other written information and/or materials, to be provided to the patients in accordance with national regulations. The investigator ensured the distribution of these documents to the applicable IEC/IRB, and to the study site staff. The principal investigator at each center ensured that both the patient (assent) and the parent or legal guardian (consent) were given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study. Patients were notified that they were free to withdraw from the study at any time. The patient was given the opportunity to ask questions and allowed time to consider the information provided. The patient’s signed and dated informed assent and the parent or legal guardian’s consent were obtained and documented before conducting any study procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Aug 2011
    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
    Bulgaria: 24
    Country: Number of subjects enrolled
    Hungary: 112
    Country: Number of subjects enrolled
    Latvia: 17
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    South Africa: 11
    Country: Number of subjects enrolled
    United States: 110
    Worldwide total number of subjects
    304
    EEA total number of subjects
    183
    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)
    304
    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
    		 This multicenter study was conducted in Bulgaria, Hungary, Latvia, Poland, Slovakia, South Africa, and the United States between 07 August 2011 and 05 April 2013.

    Pre-assignment
    Screening details
    		 The study consisted of a screening visit (Visit 1), an enrollment visit (Visit 2), a 7- to 21-day run-in/qualification period, a randomization visit (Visit 3), and 6 further weekly visits during a treatment period of 6 weeks. A telephone follow-up was conducted approximately 2 weeks after the final study visit.

    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
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo pMDI bid
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo pMDI bid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations bid

    Arm title
    		 Budesonide
    Arm description
    		 Budesonide pMDI 160 mcg bid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide pMDI 160 μg bid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    80 μg x 2 inhalations bid

    Number of subjects in period 1
    		Placebo Budesonide
    Started
    152
    152
    Completed
    92
    121
    Not completed
    60
    31
         Consent withdrawn by subject
    4
    1
         Other reasons
    8
    5
         Study-Specific Withdrawal Criteria
    48
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo pMDI bid

    Reporting group title
    Budesonide
    Reporting group description
    		 Budesonide pMDI 160 mcg bid

    Reporting group values
    		 Placebo Budesonide Total
    Number of subjects
    		 152 152 304
    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)
    		 152 152 304
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 9 ± 1.62 9 ± 1.63 -
    Gender, Male/Female
    Units: participants
        Female
    		 58 54 112
        Male
    		 94 98 192
    Age group (<8, >=8 years)
    Units: Subjects
        <8 years
    		 33 33 66
        >= 8 years
    		 119 119 238

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo pMDI bid

    Reporting group title
    Budesonide
    Reporting group description
    		 Budesonide pMDI 160 mcg bid

    Primary: Change in morning peak expiratory flow (PEF) from baseline to the treatment period average

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    End point title
    		 Change in morning peak expiratory flow (PEF) from baseline to the treatment period average
    End point description
    The peak expiratory flow rate is the maximal rate that a person can exhale during a short maximal expiratory effort after a full inspiration. Baseline was calculated using the mean of the data recorded during the last 7 days of the run-in period, and the treatment period average was calculated as the mean of all available data recorded during the entire treatment period.
    End point type
    Primary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    151
    151
    Units: liters/minute
        least squares mean (standard error)
    4.1 ± 3.19
    17.8 ± 3.24
    Statistical analysis title
    		 Morning PEF
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an analysis of covariance (ANCOVA) model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    13.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.5
         upper limit
    		 19.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.1
    Notes
    [1] - To address multiplicity, a step-down procedure was used. If the treatment difference for the primary variable, morning PEF, was statistically significant (p<0.05), then the key secondary variable, FEV1, was tested at the 0.05 level of significance.

    Secondary: Change in Forced expiratory volume in 1 second (FEV1) from baseline to treatment period average

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    End point title
    		 Change in Forced expiratory volume in 1 second (FEV1) from baseline to treatment period average
    End point description
    FEV1 is the volume exhaled during the first second of a forced expiratory maneuver started from the level of total lung capacity. Baseline was defined as the pre-dose assessment value measured at randomization (Visit 3), and the treatment period average was calculated as the mean of all available data recorded during the entire treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    149
    152
    Units: liters
        least squares mean (standard error)
    0 ± 0.023
    0.06 ± 0.023
    Statistical analysis title
    		 FEV1
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an analysis of covariance (ANCOVA) model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0047 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.022
    Notes
    [2] - To address multiplicity, a step-down procedure was used. If the treatment difference for the primary variable, morning PEF, was statistically significant (p<0.05), then the key secondary variable, FEV1, was tested at the 0.05 level of significance.

    Secondary: Change in evening PEF from baseline to the treatment period average

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    End point title
    		 Change in evening PEF from baseline to the treatment period average
    End point description
    The peak expiratory flow rate is the maximal rate that a person can exhale during a short maximal expiratory effort after a full inspiration. Baseline was calculated using the mean of the data recorded during the last 7 days of the run-in period, and the treatment period average was calculated as the mean of all available data recorded during the entire treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    150
    151
    Units: liters/minute
        least squares mean (standard error)
    4 ± 3.08
    14.7 ± 3.13
    Statistical analysis title
    		 Evening PEF
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    10.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.9
         upper limit
    		 16.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3

    Secondary: Change in forced vital capacity (FVC) from baseline to treatment period average

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    End point title
    		 Change in forced vital capacity (FVC) from baseline to treatment period average
    End point description
    FVC is the total volume of air expired after a full inspiration. Baseline was defined as the pre-dose assessment value measured at randomization (Visit 3), and the treatment period average was calculated as the mean of all available data recorded during the entire treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    149
    152
    Units: liters
        least squares mean (standard error)
    0 ± 0.021
    0.04 ± 0.021
    Statistical analysis title
    		 FVC
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0673
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02

    Secondary: Change in forced mid-expiratory flow between 25% and 75% of the FVC (FEF25-75) from baseline to treatment period average

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    End point title
    		 Change in forced mid-expiratory flow between 25% and 75% of the FVC (FEF25-75) from baseline to treatment period average
    End point description
    FEF25-75 is the average rate of airflow during the midportion of the forced vital capacity. Baseline was defined as the pre-dose assessment value measured at randomization (Visit 3), and the treatment period average was calculated as the mean of all available data recorded during the entire treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    149
    152
    Units: liters/second
        least squares mean (standard error)
    0.01 ± 0.045
    0.11 ± 0.045
    Statistical analysis title
    		 FEF25-75
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0216
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.044

    Secondary: Change in total daily and daytime asthma symptom scores from baseline to treatment period average

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    End point title
    		 Change in total daily and daytime asthma symptom scores from baseline to treatment period average
    End point description
    Patients, with the help of their caregiver, were required to rate and document their asthma symptoms twice daily as an overall symptom score for the time period since their previous recording. The following rating scales were used: 0 = None; no symptoms of asthma; 1 = Mild symptoms; awareness of asthma symptoms and/or signs that are easily tolerated; 2 = Moderate symptoms, asthma symptoms with some discomfort, causing some interference with daily activities or sleep; 3 = Severe symptoms; incapacitating asthma symptoms and/or signs, with inability to perform daily activities or to sleep.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    151
    152
    Units: units on a scale
    least squares mean (standard error)
        Daytime asthma symptom score
    -0.2 ± 0.06
    -0.4 ± 0.06
        Total asthma symptom score
    -0.5 ± 0.11
    -0.8 ± 0.11
    Statistical analysis title
    		 Daytime asthma symptom scores
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 -0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [3] - Analysis for change in daytime asthma symptom score from baseline to treatment period average.
    Statistical analysis title
    		 Total daily asthma symptom scores
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 -0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [4] - Analysis for change in total asthma symptom score from baseline to treatment period average.

    Secondary: Change in nighttime asthma symptom score from baseline to treatment period average

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    End point title
    		 Change in nighttime asthma symptom score from baseline to treatment period average
    End point description
    Patients, with the help of their caregiver, were required to rate and document their asthma symptoms twice daily as an overall symptom score for the time period since their previous recording. The following rating scales were used: 0 = None; no symptoms of asthma; 1 = Mild symptoms; awareness of asthma symptoms and/or signs that are easily tolerated; 2 = Moderate symptoms, asthma symptoms with some discomfort, causing some interference with daily activities or sleep; 3 = Severe symptoms; incapacitating asthma symptoms and/or signs, with inability to perform daily activities or to sleep.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    152
    152
    Units: units on a scale
        least squares mean (standard error)
    -0.3 ± 0.06
    -0.4 ± 0.06
    Statistical analysis title
    		 Nighttime asthma symptom scores
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0079
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 -0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06

    Secondary: Change in nighttime awakenings and nighttime awakenings with reliever medication use from baseline to treatment period average

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    End point title
    		 Change in nighttime awakenings and nighttime awakenings with reliever medication use from baseline to treatment period average
    End point description
    Patients, with the help of their caregiver, were asked to respond to a standard question each morning as they completed their eDiary. The question to be answered was, “Did your asthma cause you to wake-up last night?” If yes, patients were asked, “Did you need to use your reliever medication (albuterol/salbutamol inhaler) before you went back to sleep?” Baseline is defined as the percentage of days where patient experienced nighttime awakenings out of all available days where data was collected during the last 7 days of the run-in period.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    152
    152
    Units: percentage of days with awakenings
    least squares mean (standard error)
        Nighttime awakenings
    -9.8 ± 1.81
    -14.5 ± 1.84
        Nighttime awakenings with reliever use
    -6.1 ± 1.17
    -10 ± 1.18
    Statistical analysis title
    		 Awakenings (%)
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0095 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 -1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.78
    Notes
    [5] - Analysis for change in nighttime awakenings from baseline to treatment period average.
    Statistical analysis title
    		 Awakenings with reliever use (%)
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 -1.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.15
    Notes
    [6] - Analysis for change in nighttime awakenings with reliever medication use from baseline to treatment period average.

    Secondary: Change in total daily and daytime reliever medication use from baseline to treatment period average

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    End point title
    		 Change in total daily and daytime reliever medication use from baseline to treatment period average
    End point description
    The patient, with the help of their caregiver, recorded the number of inhalations of reliever medication used, for relief of asthma symptoms, twice daily in the eDiary. Patients were asked to respond to a standard question twice daily (morning and evening). The question to be answered was, “How many albuterol/salbutamol inhalations since last diary entry?”
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    151
    152
    Units: inhalations per day
    least squares mean (standard error)
        Daytime reliever medication use
    -0.1 ± 0.07
    -0.4 ± 0.07
        Total reliever medication use
    -0.3 ± 0.11
    -0.7 ± 0.11
    Statistical analysis title
    		 Daytime reliever use (inh/day)
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Notes
    [7] - Analysis for change in daytime reliever medication use from baseline to treatment period average.
    Statistical analysis title
    		 Total reliever use (inh/day)
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [8] - Analysis for change in total reliever medication use from baseline to treatment period average.

    Secondary: Change in nighttime reliever medication use from baseline to treatment period average

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    End point title
    		 Change in nighttime reliever medication use from baseline to treatment period average
    End point description
    The patient, with the help of their caregiver, recorded the number of inhalations of reliever medication used, for relief of asthma symptoms, twice daily in the eDiary. Patients were asked to respond to a standard question twice daily (morning and evening). The question to be answered was, “How many albuterol/salbutamol inhalations since last diary entry?”
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    152
    152
    Units: inhalations per day
        least squares mean (standard error)
    -0.1 ± 0.06
    -0.4 ± 0.06
    Statistical analysis title
    		 Nightime reliever use (inh/day)
    Statistical analysis description
    Change from baseline to treatment period average was analyzed using an ANCOVA model with terms for treatment, age group (<8 years and ≥8 years of age) and country with baseline as a covariate.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06

    Secondary: Number of withdrawals due to pre-defined asthma events

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    End point title
    		 Number of withdrawals due to pre-defined asthma events
    End point description
    Patients were considered to have experienced a “pre-defined asthma event” if any of the following conditions were met during the study: 1. At each visit or follow-up visit, a decrease in morning pre-dose FEV1 >=20% from the Visit 3 (randomization visit) morning pre-dose FEV1 or a decrease to <65% of predicted normal value; 2. The use of >=8 actuations of albuterol/salbutamol per day on 3 or more days within any period of 7 consecutive days following randomization; 3. A decrease in morning PEF >=20% from baseline on 3 or more days within any period of 7 consecutive days after randomization; 4. Two or more nights with an awakening due to asthma, which required the use of reliever medication within any period of 7 consecutive days after randomization; 5. A clinical exacerbation requiring emergency treatment, hospitalization, or use of an asthma medication not allowed by the study protocol.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Placebo Budesonide
    Number of subjects analysed
    152
    152
    Units: participants
    50
    25
    Statistical analysis title
    		 Time to withdrawal due to asthma event
    Statistical analysis description
    Log rank test for time to withdrawal due to predefined asthma event.
    Comparison groups
    Placebo v Budesonide
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from enrollment (Visit 2) throughout the treatment period and included the 2-week follow-up period (last contact by telephone).
    Adverse event reporting additional description
    Only AEs starting on or after the first dose and <=1 day after last dose are included in the summaries below. A total of 153 patients reported non-serious adverse events; 64 on Budesonide pMDI 160mcg b.i.d, 89 on Placebo pMDI b.i.d. Numbers for non-serious AEs in the reporting group table are based on the 2.5% threshold frequency.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo pMDI b.i.d.
    Reporting group description
    		 -

    Reporting group title
    Budesonide pMDI 160mcg b.i.d.
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo pMDI b.i.d. Budesonide pMDI 160mcg b.i.d.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 152 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo pMDI b.i.d. Budesonide pMDI 160mcg b.i.d.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 152 (30.26%)
    29 / 152 (19.08%)
    Respiratory, thoracic and mediastinal disorders
    ASTHMA
         subjects affected / exposed
    11 / 152 (7.24%)
    1 / 152 (0.66%)
         occurrences all number
    11
    1
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    4 / 152 (2.63%)
    3 / 152 (1.97%)
         occurrences all number
    4
    3
    Epistaxis
         subjects affected / exposed
    3 / 152 (1.97%)
    1 / 152 (0.66%)
         occurrences all number
    3
    1
    Cough
         subjects affected / exposed
    3 / 152 (1.97%)
    0 / 152 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    INFLUENZA
         subjects affected / exposed
    4 / 152 (2.63%)
    4 / 152 (2.63%)
         occurrences all number
    5
    5
    NASOPHARYNGITIS
         subjects affected / exposed
    9 / 152 (5.92%)
    12 / 152 (7.89%)
         occurrences all number
    11
    12
    PHARYNGITIS
         subjects affected / exposed
    8 / 152 (5.26%)
    5 / 152 (3.29%)
         occurrences all number
    8
    5
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    8 / 152 (5.26%)
    3 / 152 (1.97%)
         occurrences all number
    9
    3
    Sinusitis
         subjects affected / exposed
    3 / 152 (1.97%)
    1 / 152 (0.66%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 May 2010
    The entry criteria stating that reversibility of FEV1 of ≥15% from prealbuterol/salbutamol level within 15 to 30 minutes after administration of a standard dose of albuterol/salbutamol was updated to ≥12%. It was also stated that only 1 attempt at reversibility would be allowed. The instruction that prophylactic or regularly scheduled use of study reliever medications was not allowed in this study was updated to state that prophylactic or regularly scheduled use of these medications should be avoided.
    27 Sep 2010
    The use of nasal steroids was further restricted to prohibit initiation of nasal steroid treatment, titration of dose, and change of dosing frequency during the study.
    22 Jun 2011
    Within the patient population targeted for recruitment, FEV1 and/or FEV1 reversibility vary over time. Allowing 2 opportunities for patients to demonstrate a pre-bronchodilator morning clinic FEV1 within the specified range and to demonstrate reversibility of FEV1 of ≥12% was expected to enhance recruitment without changing the characterization of the study patient population or jeopardizing patient safety.
    30 Nov 2011
    The purpose of the amendment was to increase the probability of successful patient screening and randomization into the study and to increase the probability of patients who were randomized to complete the treatment period without impacting the characterization of the patient population being studied.

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

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