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    Clinical Trial Results:
    A Randomized, Double Blind, Double Dummy, Placebo Controlled, Parallel Group, 12 Week Clinical Study to Assess the Efficacy and Safety Of 320 or 640 mcg/Day of Beclomethasone Dipropionate Delivered via Breath Actuated Inhaler (BAI) or Metered Dose Inhaler (MDI) in Adolescent and Adult Patients 12 Years of Age and Older with Persistent Asthma

    Summary
    EudraCT number
    2013-003397-27
    Trial protocol
    HU   PL  
    Global end of trial date
    20 Nov 2014

    Results information
    Results version number
    v3(current)
    This version publication date
    23 Feb 2017
    First version publication date
    06 Aug 2015
    Other versions
    v1 (removed from public view) , v2
    Version creation reason
    • Correction of full data set
    AE timeframe needs to be updated

    Trial information

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    Trial identification
    Sponsor protocol code
    BDB-AS-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02031640
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products R&D, Inc.
    Sponsor organisation address
    41 Moores Road, Frazer, Pennsylvania, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc. , 1 215-591-3000, ustevatrials@tevapharm.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc. , 1 215-591-3000, ustevatrials@tevapharm.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
    21 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of beclomethasone dipropionate (320 or 640 mcg/day) administered via BAI and MDI compared with placebo treatment in patients with persistent asthma as assessed by the standardized baseline-adjusted trough morning forced expiratory volume in 1 second (FEV1) area under the effect curve from time 0 to 12 weeks (AUEC(0-12wk)).
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) GCP Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; European Union (EU) Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). Information regarding any investigational study centers participating in this study that could not comply with these standards was documented. Written and/or oral information about the study was provided to all patients (or legal guardian of patients under the age of 18) in a language understandable by the patients and per applicable local regulations. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study procedures or assessments were done. It was explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in a consent form that was signed by the patient/parent/guardian with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the patients.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Jan 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: 415
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Hungary: 40
    Worldwide total number of subjects
    532
    EEA total number of subjects
    117
    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)
    26
    Adults (18-64 years)
    457
    From 65 to 84 years
    48
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Of the 1113 patients screened, 701 were enrolled. Of the 412 patients who were not enrolled, 342 were excluded on the basis of inclusion/exclusion criteria, 29 patients withdrew consent, 26 patients for other reasons, 14 patients were lost to follow up before the baseline visit, and 1 patient due to an adverse event.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Patients administered 4 inhalations from each of the 2 devices twice daily as per the double dummy study design: 1 treatment device or placebo and 1 placebo device for a total of 8 inhalations each time.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Patients took 4 inhalations of matching placebo breath actuated inhaler (BAI) (twice daily) plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo MDI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study drug was administered twice each day, in the morning and in the evening, after the completion of the asthma symptoms score and the peak expiratory flow (PEF) measurements, in that order. Each administration consisted of four inhalations. Placebo was delivered via the metered-dose inhaler (MDI) in order to maintain the blind.

    Investigational medicinal product name
    Placebo BAI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study drug was administered twice each day, in the morning and in the evening, after the completion of the asthma symptoms score and the peak expiratory flow (PEF) measurements, in that order. Each administration consisted of four inhalations. Placebo was delivered via the breath-actuated inhaler (BAI) in order to maintain the blind.

    Arm title
    BAI 320 mcg/day
    Arm description
    Patients took 4 inhalations of 40 mcg of beclomethasone dipropionate per inhalation delivered via breath actuated inhaler (BAI) (twice daily) totaling 320 mcg/day. Plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    beclomethasone dipropionate BAI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study drug was administered twice each day, in the morning and in the evening, after the completion of the asthma symptoms score and the peak expiratory flow (PEF) measurements, in that order. Each administration consisted of four inhalations of 40 mcg of beclomethasone dipropionate per inhalation delivered via breath actuated inhaler (BAI) (twice daily) totaling 320 mcg/day.

    Investigational medicinal product name
    Placebo MDI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study drug was administered twice each day, in the morning and in the evening, after the completion of the asthma symptoms score and the peak expiratory flow (PEF) measurements, in that order. Each administration consisted of four inhalations. Placebo was delivered via the metered-dose inhaler (MDI) in order to maintain the blind.

    Arm title
    BAI 640 mcg/day
    Arm description
    Patients took 4 inhalations of 80 mcg of beclomethasone dipropionate per inhalation delivered via breath actuated inhaler (BAI) (twice daily) totaling 640 mcg/day. Plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    beclomethasone dipropionate BAI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study drug was administered twice each day, in the morning and in the evening, after the completion of the asthma symptoms score and the peak expiratory flow (PEF) measurements, in that order. Each administration consisted of four inhalations of 80 mcg of beclomethasone dipropionate per inhalation delivered via breath actuated inhaler (BAI) (twice daily) totaling 640 mcg/day.

    Investigational medicinal product name
    Placebo MDI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study drug was administered twice each day, in the morning and in the evening, after the completion of the asthma symptoms score and the peak expiratory flow (PEF) measurements, in that order. Each administration consisted of four inhalations. Placebo was delivered via the metered-dose inhaler (MDI) in order to maintain the blind.

    Arm title
    MDI 320 mcg/day
    Arm description
    Patients took 4 inhalations of 40 mcg of beclomethasone dipropionate per inhalation delivered via metered-dose inhaler (MDI) (twice daily) totaling 320 mcg/day. Plus 4 inhalations of placebo breath-actuated inhaler (BAI) (twice daily) for 12 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    beclomethasone dipropionate MDI
    Investigational medicinal product code
    Other name
    QVAR® Inhalation Aerosol
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study drug was administered twice each day, in the morning and in the evening, after the completion of the asthma symptoms score and the peak expiratory flow (PEF) measurements, in that order. Each administration consisted of four inhalations of 40 mcg of beclomethasone dipropionate per inhalation delivered via metered-dose inhaler (MDI) (twice daily) totaling 320 mcg/day.

    Investigational medicinal product name
    Placebo BAI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study drug was administered twice each day, in the morning and in the evening, after the completion of the asthma symptoms score and the peak expiratory flow (PEF) measurements, in that order. Each administration consisted of four inhalations. Placebo was delivered via the breath-actuated inhaler (BAI) in order to maintain the blind.

    Arm title
    MDI 640 mcg/day
    Arm description
    Patients took 4 inhalations of 80 mcg of beclomethasone dipropionate per inhalation delivered via metered dose inhaler (MDI) (twice daily) totaling 640 mcg/day. Plus 4 inhalations of placebo breath actuated inhaler (BAI) (twice daily) for 12 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    beclomethasone dipropionate MDI
    Investigational medicinal product code
    Other name
    QVAR® Inhalation Aerosol
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study drug was administered twice each day, in the morning and in the evening, after the completion of the asthma symptoms score and the peak expiratory flow (PEF) measurements, in that order. Each administration consisted of four inhalations of 80 mcg of beclomethasone dipropionate per inhalation delivered via metered-dose inhaler (MDI) (twice daily) totaling 640 mcg/day.

    Investigational medicinal product name
    Placebo BAI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Study drug was administered twice each day, in the morning and in the evening, after the completion of the asthma symptoms score and the peak expiratory flow (PEF) measurements, in that order. Each administration consisted of four inhalations. Placebo was delivered via the breath-actuated inhaler (BAI) in order to maintain the blind.

    Number of subjects in period 1
    Placebo BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day
    Started
    106
    106
    106
    107
    107
    Completed
    84
    100
    99
    96
    104
    Not completed
    22
    6
    7
    11
    3
         Protocol deviation
    2
    -
    1
    3
    1
         Non-compliance
    1
    -
    1
    1
    -
         Lack of efficacy
    14
    3
    2
    5
    1
         Adverse event, non-fatal
    -
    -
    2
    -
    -
         Consent withdrawn by subject
    2
    3
    1
    1
    1
         Lost to follow-up
    3
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Patients took 4 inhalations of matching placebo breath actuated inhaler (BAI) (twice daily) plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.

    Reporting group title
    BAI 320 mcg/day
    Reporting group description
    Patients took 4 inhalations of 40 mcg of beclomethasone dipropionate per inhalation delivered via breath actuated inhaler (BAI) (twice daily) totaling 320 mcg/day. Plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.

    Reporting group title
    BAI 640 mcg/day
    Reporting group description
    Patients took 4 inhalations of 80 mcg of beclomethasone dipropionate per inhalation delivered via breath actuated inhaler (BAI) (twice daily) totaling 640 mcg/day. Plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.

    Reporting group title
    MDI 320 mcg/day
    Reporting group description
    Patients took 4 inhalations of 40 mcg of beclomethasone dipropionate per inhalation delivered via metered-dose inhaler (MDI) (twice daily) totaling 320 mcg/day. Plus 4 inhalations of placebo breath-actuated inhaler (BAI) (twice daily) for 12 weeks.

    Reporting group title
    MDI 640 mcg/day
    Reporting group description
    Patients took 4 inhalations of 80 mcg of beclomethasone dipropionate per inhalation delivered via metered dose inhaler (MDI) (twice daily) totaling 640 mcg/day. Plus 4 inhalations of placebo breath actuated inhaler (BAI) (twice daily) for 12 weeks.

    Reporting group values
    Placebo BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day Total
    Number of subjects
    106 106 106 107 107 532
    Age categorical
    Units: Subjects
        12-17 years
    4 5 7 4 6 26
        18-64 years
    94 86 92 93 92 457
        >=65 years
    8 15 7 10 9 49
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    43.7 ± 15.41 47.9 ± 15.54 46.2 ± 14.78 46.6 ± 15.41 46.2 ± 15.03 -
    Gender categorical
    Units: Subjects
        Female
    68 69 67 65 66 335
        Male
    38 37 39 42 41 197
    Race
    Units: Subjects
        White
    73 85 87 89 81 415
        Black
    27 18 14 16 24 99
        Other
    6 3 5 2 2 18
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    97 95 100 100 101 493
        Hispanic or Latino
    9 11 6 7 6 39
    Duration of Asthma
    Units: Subjects
        < 3 months
    0 0 0 0 0 0
        3 months to < 6 months
    0 0 0 1 0 1
        6 months to < 1 year
    1 1 0 0 1 3
        1 year to < 5 years
    2 4 10 11 7 34
        5 years to < 10 years
    15 11 19 12 7 64
        10 years to < 15 years
    19 10 22 15 16 82
        >= 15 years
    69 80 55 68 76 348
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    84.54 ± 25.426 86.17 ± 22.399 86.26 ± 21.675 81.6 ± 20.277 85.5 ± 19.504 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    167.59 ± 9.112 169.35 ± 9.435 168.42 ± 9.465 167.23 ± 9.387 169.39 ± 10.858 -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    30.08 ± 8.8862 30.01 ± 7.4355 30.371 ± 7.2111 29.091 ± 6.1292 29.804 ± 6.461 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Patients took 4 inhalations of matching placebo breath actuated inhaler (BAI) (twice daily) plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.

    Reporting group title
    BAI 320 mcg/day
    Reporting group description
    Patients took 4 inhalations of 40 mcg of beclomethasone dipropionate per inhalation delivered via breath actuated inhaler (BAI) (twice daily) totaling 320 mcg/day. Plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.

    Reporting group title
    BAI 640 mcg/day
    Reporting group description
    Patients took 4 inhalations of 80 mcg of beclomethasone dipropionate per inhalation delivered via breath actuated inhaler (BAI) (twice daily) totaling 640 mcg/day. Plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.

    Reporting group title
    MDI 320 mcg/day
    Reporting group description
    Patients took 4 inhalations of 40 mcg of beclomethasone dipropionate per inhalation delivered via metered-dose inhaler (MDI) (twice daily) totaling 320 mcg/day. Plus 4 inhalations of placebo breath-actuated inhaler (BAI) (twice daily) for 12 weeks.

    Reporting group title
    MDI 640 mcg/day
    Reporting group description
    Patients took 4 inhalations of 80 mcg of beclomethasone dipropionate per inhalation delivered via metered dose inhaler (MDI) (twice daily) totaling 640 mcg/day. Plus 4 inhalations of placebo breath actuated inhaler (BAI) (twice daily) for 12 weeks.

    Primary: Standardized baseline adjusted trough morning forced expiratory volume in 1 second (FEV1) area under the effect curve from time 0 to 12 weeks [FEV1 AUEC(0-12wk)]

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    End point title
    Standardized baseline adjusted trough morning forced expiratory volume in 1 second (FEV1) area under the effect curve from time 0 to 12 weeks [FEV1 AUEC(0-12wk)]
    End point description
    The baseline pulmonary function measurement was defined as the measurement obtained at randomization visit (Day 1). Pulmonary function measurements (including FEV1) were obtained electronically by spirometry. All pulmonary function test data were submitted to a central reading center for evaluation. The highest FEV1 value from 3 acceptable and 2 repeatable maneuvers (maximum of 5 attempts) was used.
    End point type
    Primary
    End point timeframe
    Day 1 (baseline), Weeks 2, 4, 8, 12
    End point values
    Placebo BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day
    Number of subjects analysed
    105 [1]
    104 [2]
    106 [3]
    106 [4]
    107 [5]
    Units: liters
        least squares mean (standard error)
    0.056 ± 0.0219
    0.09 ± 0.0221
    0.101 ± 0.0221
    0.041 ± 0.0217
    0.096 ± 0.0216
    Notes
    [1] - Full analysis set- randomized patients with atleast 1 dose of drug and 1 postbaseline trough am FEV1
    [2] - Full analysis set- randomized patients with atleast 1 dose of drug and 1 postbaseline trough am FEV1
    [3] - Full analysis set- randomized patients with atleast 1 dose of drug and 1 postbaseline trough am FEV1
    [4] - Full analysis set- randomized patients with atleast 1 dose of drug and 1 postbaseline trough am FEV1
    [5] - Full analysis set- randomized patients with atleast 1 dose of drug and 1 postbaseline trough am FEV1
    Statistical analysis title
    Primary Analysis: Placebo to BAI 320 mcg/day
    Statistical analysis description
    The primary variable was analyzed using an ANCOVA model with effects due to baseline trough morning FEV1, sex, age, and treatment.
    Comparison groups
    Placebo v BAI 320 mcg/day
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.272 [7]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.034
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.027
         upper limit
    0.095
    Notes
    [6] - The study was to be considered positive if the result from the comparison of the highest beclomethasone dipropionate dose (640 mcg/day via BAI) with placebo using the ANCOVA was positive, regardless of the results from the comparisons of all the other beclomethasone dipropionate dose-by-device levels with placebo.
    [7] - Statistical significance is <=0.05.
    Statistical analysis title
    Primary Analysis: Placebo to BAI 640 m...
    Statistical analysis description
    The primary variable was analyzed using an ANCOVA model with effects due to baseline trough morning FEV1, sex, age, and treatment.
    Comparison groups
    Placebo v BAI 640 mcg/day
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.1415 [9]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.045
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.015
         upper limit
    0.106
    Notes
    [8] - The study was to be considered positive if the result from the comparison of the highest beclomethasone dipropionate dose (640 mcg/day via BAI) with placebo using the ANCOVA was positive, regardless of the results from the comparisons of all the other beclomethasone dipropionate dose-by-device levels with placebo.
    [9] - Statistical significance is <=0.05.
    Statistical analysis title
    Primary Analysis: Placebo to MDI 320 m...
    Statistical analysis description
    The primary variable was analyzed using an ANCOVA model with effects due to baseline trough morning FEV1, sex, age, and treatment.
    Comparison groups
    Placebo v MDI 320 mcg/day
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.6356 [11]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.075
         upper limit
    0.046
    Notes
    [10] - The study was to be considered positive if the result from the comparison of the highest beclomethasone dipropionate dose (640 mcg/day via BAI) with placebo using the ANCOVA was positive, regardless of the results from the comparisons of all the other beclomethasone dipropionate dose-by-device levels with placebo.
    [11] - Statistical significance is <=0.05.
    Statistical analysis title
    Primary Analysis: Placebo to MDI 640 m...
    Statistical analysis description
    The primary variable was analyzed using an ANCOVA model with effects due to baseline trough morning FEV1, sex, age, and treatment.
    Comparison groups
    Placebo v MDI 640 mcg/day
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    = 0.1932 [13]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    0.1
    Notes
    [12] - The study was to be considered positive if the result from the comparison of the highest beclomethasone dipropionate dose (640 mcg/day via BAI) with placebo using the ANCOVA was positive, regardless of the results from the comparisons of all the other beclomethasone dipropionate dose-by-device levels with placebo.
    [13] - Statistical significance is <=0.05.

    Secondary: Change from Baseline in Weekly Average of Daily Trough Morning Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period

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    End point title
    Change from Baseline in Weekly Average of Daily Trough Morning Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period
    End point description
    A hand-held peak flow meter was provided to patients at the screening visit and used to determine the morning and evening PEF throughout the course of the study.Daily trough morning PEF assessments were taken pre-dose and pre-rescue bronchodilator over the 12-week treatment period. The patient recorded the highest value of 3 measurements obtained in the morning and evening in the patient diary. Baseline in trough morning PEF is defined as the average of recorded trough morning PEF assessments over the 7-day window before randomization, including the morning assessment on Day 1 before randomization.
    End point type
    Secondary
    End point timeframe
    Days -6 to Day 1 (baseline), Day 2 to Week 12
    End point values
    Placebo BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day
    Number of subjects analysed
    106 [14]
    104 [15]
    106 [16]
    106 [17]
    107 [18]
    Units: L/min
        least squares mean (standard error)
    -5.524 ± 2.5944
    5.092 ± 2.5625
    2.895 ± 2.559
    0.48 ± 2.558
    6.988 ± 2.5298
    Notes
    [14] - Full analysis set
    [15] - Full analysis set
    [16] - Full analysis set
    [17] - Full analysis set
    [18] - Full analysis set
    Statistical analysis title
    Change in AM PEF: Placebo to BAI 320 mcg/day
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily trough morning (pre-dose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using a repeated measures mixed model with effects due to baseline weekly average of daily trough morning PEF, sex, age, treatment, time, and time-by-treatment interaction.
    Comparison groups
    Placebo v BAI 320 mcg/day
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0036 [19]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    10.616
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.489
         upper limit
    17.744
    Notes
    [19] - Statistical significance is <=0.05.
    Statistical analysis title
    Change in AM PEF: Placebo to BAI 640 m...
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily trough morning (pre-dose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using a repeated measures mixed model with effects due to baseline weekly average of daily trough morning PEF, sex, age, treatment, time, and time-by-treatment interaction.
    Comparison groups
    Placebo v BAI 640 mcg/day
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0204 [20]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    8.419
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.309
         upper limit
    15.53
    Notes
    [20] - Statistical significance is <=0.05.
    Statistical analysis title
    Change in AM PEF: Placebo to MDI 320 m...
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily trough morning (pre-dose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using a repeated measures mixed model with effects due to baseline weekly average of daily trough morning PEF, sex, age, treatment, time, and time-by-treatment interaction.
    Comparison groups
    Placebo v MDI 320 mcg/day
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0984 [21]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    6.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.121
         upper limit
    13.129
    Notes
    [21] - Statistical significance is <=0.05.
    Statistical analysis title
    Change in AM PEF: Placebo to MDI 640 m...
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily trough morning (pre-dose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using a repeated measures mixed model with effects due to baseline weekly average of daily trough morning PEF, sex, age, treatment, time, and time-by-treatment interaction.
    Comparison groups
    Placebo v MDI 640 mcg/day
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006 [22]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    12.512
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.435
         upper limit
    19.589
    Notes
    [22] - Statistical significance is <=0.05.

    Secondary: Change from Baseline in Weekly Average of Daily Evening Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period

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    End point title
    Change from Baseline in Weekly Average of Daily Evening Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period
    End point description
    A hand-held peak flow meter was provided to patients at the screening visit and used to determine the morning and evening PEF throughout the course of the study. The patient recorded the highest value of 3 measurements obtained in the morning and evening in the patient diary. Baseline in evening PEF is defined as the average of recorded evening PEF assessments over the 7-day window before randomization.
    End point type
    Secondary
    End point timeframe
    Days -6 to Day 0 (baseline), Day 1 to Week 12
    End point values
    Placebo BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day
    Number of subjects analysed
    106 [23]
    104 [24]
    106 [25]
    106 [26]
    107 [27]
    Units: L/min
        least squares mean (standard error)
    -4.708 ± 2.6503
    4.439 ± 2.6199
    4.462 ± 2.6092
    -0.62 ± 2.6145
    5.594 ± 2.5848
    Notes
    [23] - Full analysis set
    [24] - Full analysis set
    [25] - Full analysis set
    [26] - Full analysis set
    [27] - Full analysis set
    Statistical analysis title
    Change in PM PEF: Placebo to BAI 320 mcg/day
    Statistical analysis description
    The analysis of change from baseline in the weekly average of daily evening PEF over the 12-week treatment period will be performed using a repeated measures mixed model with effects due to baseline weekly average of daily evening PEF, sex, age, treatment, time, and time-by-treatment interaction.
    Comparison groups
    Placebo v BAI 320 mcg/day
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0139 [28]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    9.147
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.866
         upper limit
    16.429
    Notes
    [28] - Statistical significance is <=0.05.
    Statistical analysis title
    Change in PM PEF: Placebo to BAI 640 mc...
    Statistical analysis description
    The analysis of change from baseline in the weekly average of daily evening PEF over the 12-week treatment period will be performed using a repeated measures mixed model with effects due to baseline weekly average of daily evening PEF, sex, age, treatment, time, and time-by-treatment interaction.
    Comparison groups
    Placebo v BAI 640 mcg/day
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0133 [29]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    9.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.914
         upper limit
    16.425
    Notes
    [29] - Statistical significance is <=0.05.
    Statistical analysis title
    Change in PM PEF: Placebo to MDI 320 mc...
    Statistical analysis description
    The analysis of change from baseline in the weekly average of daily evening PEF over the 12-week treatment period will be performed using a repeated measures mixed model with effects due to baseline weekly average of daily evening PEF, sex, age, treatment, time, and time-by-treatment interaction.
    Comparison groups
    Placebo v MDI 320 mcg/day
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2704 [30]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    4.088
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.191
         upper limit
    11.367
    Notes
    [30] - Statistical significance is <=0.05.
    Statistical analysis title
    Change in PM PEF: Placebo to MDI 640 mc...
    Statistical analysis description
    The analysis of change from baseline in the weekly average of daily evening PEF over the 12-week treatment period will be performed using a repeated measures mixed model with effects due to baseline weekly average of daily evening PEF, sex, age, treatment, time, and time-by-treatment interaction.
    Comparison groups
    Placebo v MDI 640 mcg/day
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0053 [31]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    10.301
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.073
         upper limit
    17.53
    Notes
    [31] - Statistical significance is <=0.05.

    Secondary: Change from Baseline in Weekly Average of Total Daily Use of Albuterol/Salbutamol Inhalation Aerosol Over Weeks 1-12

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    End point title
    Change from Baseline in Weekly Average of Total Daily Use of Albuterol/Salbutamol Inhalation Aerosol Over Weeks 1-12
    End point description
    Change from baseline in the use of rescue medication, albuterol/salbutamol, during the treatment period offers an indication of asthma control. Baseline was defined as the average of recorded daily usage of albuterol/salbutamol inhalation aerosol over the 7 days prior to the first dose of double-blind study treatment, including the morning usage at the randomization visit.
    End point type
    Secondary
    End point timeframe
    Days -6 to Day 1 (baseline), Day 2 to Week 12
    End point values
    Placebo BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day
    Number of subjects analysed
    101 [32]
    96 [33]
    99 [34]
    97 [35]
    101 [36]
    Units: number of inhalations
        least squares mean (standard error)
    0.478 ± 0.1232
    -0.226 ± 0.1235
    -0.213 ± 0.1221
    -0.173 ± 0.1246
    -0.323 ± 0.1206
    Notes
    [32] - Full analysis set
    [33] - Full analysis set
    [34] - Full analysis set
    [35] - Full analysis set
    [36] - Full analysis set
    Statistical analysis title
    Use of Rescue Med: Placebo to BAI 320 mcg/day
    Statistical analysis description
    LS means, difference of LS means and its 95% confidence interval, and p-value are obtained from the Mixed Model for Repeated Measures analysis with covariate adjustment for baseline, sex, age, treatment, week and treatment by week interaction.
    Comparison groups
    Placebo v BAI 320 mcg/day
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [37]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.703
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.044
         upper limit
    -0.363
    Notes
    [37] - Statistical significance is <=0.05.
    Statistical analysis title
    Use of Rescue Med: Placebo to BAI 640 mcg/day
    Statistical analysis description
    LS means, difference of LS means and its 95% confidence interval, and p-value are obtained from the Mixed Model for Repeated Measures analysis with covariate adjustment for baseline, sex, age, treatment, week and treatment by week interaction.
    Comparison groups
    Placebo v BAI 640 mcg/day
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [38]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.691
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.029
         upper limit
    -0.352
    Notes
    [38] - Statistical significance is <=0.05.
    Statistical analysis title
    Use of Rescue Med: Placebo to MDI 320 mcg/day
    Statistical analysis description
    LS means, difference of LS means and its 95% confidence interval, and p-value are obtained from the Mixed Model for Repeated Measures analysis with covariate adjustment for baseline, sex, age, treatment, week and treatment by week interaction.
    Comparison groups
    Placebo v MDI 320 mcg/day
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [39]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.651
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.994
         upper limit
    -0.309
    Notes
    [39] - Statistical significance is <=0.05.
    Statistical analysis title
    Use of Rescue Med: Placebo to MDI 640 mcg/day
    Statistical analysis description
    LS means, difference of LS means and its 95% confidence interval, and p-value are obtained from the Mixed Model for Repeated Measures analysis with covariate adjustment for baseline, sex, age, treatment, week and treatment by week interaction.
    Comparison groups
    Placebo v MDI 640 mcg/day
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [40]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.801
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.138
         upper limit
    -0.464
    Notes
    [40] - Statistical significance is <=0.05.

    Secondary: Change from Baseline in Weekly Average of Total Daily Asthma Symptom Score over Weeks 1-12

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    End point title
    Change from Baseline in Weekly Average of Total Daily Asthma Symptom Score over Weeks 1-12
    End point description
    The daily asthma score is the average of the daytime and nighttime scores over weeks 1-12. Asthma symptom scores are recorded in the patient’s diary each morning and each evening before determining PEF and before administration of study or rescue medications. The Daytime Symptom Score (determined in the evening) has a range from 0=No symptoms during the day to 5=Symptoms so severe that I could not go to work or perform normal daily activities. The Nighttime Symptom Score (determined in the morning) has a range from 0=No symptoms during the night to 4=Symptoms so severe that I did not sleep at all. The scale for the daily asthma score is therefore 0 (no symptoms) to 9 (severe symptoms). Baseline was defined as the average of recorded daily asthma symptom scores over the 7 days prior to the first dose of double-blind study treatment, including the morning score at the randomization visit.
    End point type
    Secondary
    End point timeframe
    Days -6 to Day 1 (baseline), Week 1 to Week 12
    End point values
    Placebo BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day
    Number of subjects analysed
    106 [41]
    104 [42]
    106 [43]
    106 [44]
    107 [45]
    Units: units on a scale
        least squares mean (standard error)
    -0.058 ± 0.0425
    -0.207 ± 0.0417
    -0.159 ± 0.0415
    -0.247 ± 0.0417
    -0.274 ± 0.0411
    Notes
    [41] - Full analysis set
    [42] - Full analysis set
    [43] - Full analysis set
    [44] - Full analysis set
    [45] - Full analysis set
    Statistical analysis title
    Asthma Symptoms: Placebo to BAI 320 mcg/day
    Statistical analysis description
    LS means, difference of LS means and its 95% confidence interval, and p-value are obtained from the Mixed Model for Repeated Measures analysis with covariate adjustment for baseline, sex, age, treatment, week and treatment by week interaction.
    Comparison groups
    Placebo v BAI 320 mcg/day
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0119 [46]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.149
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.265
         upper limit
    -0.033
    Notes
    [46] - Statistical significance is <=0.05.
    Statistical analysis title
    Asthma Symptoms: Placebo to BAI 640 mcg/day
    Statistical analysis description
    LS means, difference of LS means and its 95% confidence interval, and p-value are obtained from the Mixed Model for Repeated Measures analysis with covariate adjustment for baseline, sex, age, treatment, week and treatment by week interaction.
    Comparison groups
    Placebo v BAI 640 mcg/day
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0854 [47]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.102
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.217
         upper limit
    0.014
    Notes
    [47] - Statistical significance is <=0.05.
    Statistical analysis title
    Asthma Symptoms: Placebo to MDI 320 mcg/day
    Statistical analysis description
    LS means, difference of LS means and its 95% confidence interval, and p-value are obtained from the Mixed Model for Repeated Measures analysis with covariate adjustment for baseline, sex, age, treatment, week and treatment by week interaction.
    Comparison groups
    Placebo v MDI 320 mcg/day
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0016 [48]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.189
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.306
         upper limit
    -0.072
    Notes
    [48] - Statistical significance is <=0.05.
    Statistical analysis title
    Asthma Symptoms: Placebo to MDI 640 mcg/day
    Statistical analysis description
    LS means, difference of LS means and its 95% confidence interval, and p-value are obtained from the Mixed Model for Repeated Measures analysis with covariate adjustment for baseline, sex, age, treatment, week and treatment by week interaction.
    Comparison groups
    Placebo v MDI 640 mcg/day
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003 [49]
    Method
    repeated measures mixed model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.216
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.332
         upper limit
    -0.101
    Notes
    [49] - Statistical significance is <=0.05.

    Secondary: Time to Withdrawal from the Study Treatment Due to Meeting Stopping Criteria for Worsening Asthma

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    End point title
    Time to Withdrawal from the Study Treatment Due to Meeting Stopping Criteria for Worsening Asthma
    End point description
    Time to withdrawal due to meeting stopping criteria is defined as number of days elapsed from the date of the first dose of double-blind study treatment to the date of withdrawal due to meeting stopping criteria. Stopping criteria are: - FEV1 as measured at the study center is below the FEV1 stability limit value calculated at RV. - Based upon review of patient diary data, the patient has experienced any of the following during any 7-day period: - 4+ days in which the highest (of 3 efforts) am PEF fall below the PEF stability limit calculated when randomized. The patient meets with the investigator who determines whether the FEV1 is consistent with worsening asthma; - 3+ days in which 12+ inhalations/day of rescue medication were used - 2+ days in which the patient experienced a nighttime asthma symptom score of more than 2 - Clinical asthma exacerbation requiring (for example) the use of systemic corticosteroids, or the emergency room or hospitalization.
    End point type
    Secondary
    End point timeframe
    Day 1 – Week 12
    End point values
    Placebo BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day
    Number of subjects analysed
    106 [50]
    104 [51]
    106 [52]
    106 [53]
    107 [54]
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [50] - Full analysis set 9999=not able to calculate as few patients met stopping criteria
    [51] - Full analysis set 9999=not able to calculate as few patients met stopping criteria
    [52] - Full analysis set 9999=not able to calculate as few patients met stopping criteria
    [53] - Full analysis set 9999=not able to calculate as few patients met stopping criteria
    [54] - Full analysis set 9999=not able to calculate as few patients met stopping criteria
    No statistical analyses for this end point

    Secondary: Participants with Adverse Events

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    End point title
    Participants with Adverse Events
    End point description
    An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. Treatment-emergent AEs (TEAE) started during the treatment timeframe.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 13
    End point values
    Placebo BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day
    Number of subjects analysed
    106 [55]
    106 [56]
    106 [57]
    107 [58]
    107 [59]
    Units: participants
        At least 1 AE
    29
    31
    37
    33
    45
        At least 1 severe TEAE
    1
    2
    1
    0
    2
        At least 1 treatment-related TEAE
    2
    5
    16
    6
    13
        At least 1 serious AE
    0
    1
    1
    1
    2
        At least 1 AE causing discontinuation
    0
    0
    2
    0
    0
    Notes
    [55] - Safety population
    [56] - Safety population
    [57] - Safety population
    [58] - Safety population
    [59] - Safety population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 13
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    BAI 320 mcg/day
    Reporting group description
    Patients took 4 inhalations of 40 mcg of beclomethasone dipropionate per inhalation delivered via breath actuated inhaler (BAI) (twice daily) totaling 320 mcg/day. Plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.

    Reporting group title
    BAI 640 mcg/day
    Reporting group description
    Patients took 4 inhalations of 80 mcg of beclomethasone dipropionate per inhalation delivered via breath actuated inhaler (BAI) (twice daily) totaling 640 mcg/day. Plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.

    Reporting group title
    MDI 320 mcg/day
    Reporting group description
    Patients took 4 inhalations of 40 mcg of beclomethasone dipropionate per inhalation delivered via metered-dose inhaler (MDI) (twice daily) totaling 320 mcg/day. Plus 4 inhalations of placebo breath-actuated inhaler (BAI) (twice daily) for 12 weeks.

    Reporting group title
    MDI 640 mcg/day
    Reporting group description
    Patients took 4 inhalations of 80 mcg of beclomethasone dipropionate per inhalation delivered via metered dose inhaler (MDI) (twice daily) totaling 640 mcg/day. Plus 4 inhalations of placebo breath actuated inhaler (BAI) (twice daily) for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Patients took 4 inhalations of matching placebo breath actuated inhaler (BAI) (twice daily) plus 4 inhalations of placebo metered dose inhaler (MDI) (twice daily) for 12 weeks.

    Serious adverse events
    BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 106 (0.94%)
    1 / 107 (0.93%)
    2 / 107 (1.87%)
    0 / 106 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric disorder
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 106 (0.00%)
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 106 (0.00%)
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 106 (0.00%)
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 106 (0.00%)
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pharyngeal abscess
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BAI 320 mcg/day BAI 640 mcg/day MDI 320 mcg/day MDI 640 mcg/day Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 106 (8.49%)
    11 / 106 (10.38%)
    9 / 107 (8.41%)
    12 / 107 (11.21%)
    2 / 106 (1.89%)
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    5 / 106 (4.72%)
    10 / 106 (9.43%)
    3 / 107 (2.80%)
    9 / 107 (8.41%)
    0 / 106 (0.00%)
         occurrences all number
    7
    12
    3
    11
    0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 106 (3.77%)
    1 / 106 (0.94%)
    7 / 107 (6.54%)
    4 / 107 (3.74%)
    2 / 106 (1.89%)
         occurrences all number
    4
    1
    7
    4
    2

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Apr 2014
    Amendment 1 (dated 24 April 2014) to the protocol was issued after 140 patients were enrolled into the study. The primary reasons for the amendment were removal of prohibited medications and clarification of study procedure. The following major procedural changes (not all-inclusive) were made to the protocol: • Clarified minimum age requirements for certain countries where local regulations exclude participation by minors • Specified, as part of inclusion criteria, that historical spirometry data need only include the expiratory tracings • Edited allowed medications to include aqueous formulations of intranasal steroids and included nonsteroidal anti inflammatory drug use as standard of care • Corrected minor discrepancies and made changed to wording in the protocol for added clarity.

    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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