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    Clinical Trial Results:
    A 12-Week, Randomized, Placebo-Controlled, Dose-Ranging, Efficacy and Safety Study of Mometasone Furoate Metered Dose Inhaler in the Treatment of Children Ages 5 to 11 Years With Persistent Asthma

    Summary
    EudraCT number
    		 2008-007504-28
    Trial protocol
    		 LV   EE   HU   PL   GR   BG  
    Global end of trial date
    29 Jan 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Mar 2016
    First version publication date
    25 Jul 2015
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    P04223
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01502371
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MK-0887-086: Merck protocol number, SCH 032088 P04223: Merck protocol number
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    29 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the dose-related efficacy by evaluating morning lung function at the end of the dosing interval (AM pre-dose percent predicted forced expiratory volume in one second [FEV1]) after 12 weeks of treatment, of three doses (50 mcg, 100 mcg, and 200 mcg) of mometasone furoate (MF) metered dose inhaler (MDI) twice a day (BID) compared with placebo in children 5 to 11 years of age, inclusive, with persistent asthma.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The following additional measure defined for this individual study was in place for the protection of trial subjects: participants were provided with a short-acting ß-agonist (albuterol MDI 90 mcg in the United States [US], salbutamol MDI 100 mcg non-US) as rescue therapy.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jan 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 64
    Country: Number of subjects enrolled
    Bulgaria: 41
    Country: Number of subjects enrolled
    Estonia: 19
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 71
    Country: Number of subjects enrolled
    Latvia: 20
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Colombia: 28
    Country: Number of subjects enrolled
    Croatia: 5
    Country: Number of subjects enrolled
    Guatemala: 92
    Country: Number of subjects enrolled
    Mexico: 20
    Country: Number of subjects enrolled
    South Africa: 14
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    Ukraine: 32
    Country: Number of subjects enrolled
    United States: 91
    Country: Number of subjects enrolled
    Romania: 41
    Country: Number of subjects enrolled
    Russian Federation: 24
    Worldwide total number of subjects
    578
    EEA total number of subjects
    265
    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)
    577
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants aged 5 to 11 years, inclusive, who had persistent asthma were screened for this study.

    Period 1
    Period 1 title
    Treatment Period (12 weeks) (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
    		 MF MDI 50 mcg BID
    Arm description
    		 Participants receive MF MDI 25 mcg X 2 inhalations (50 mcg total dose) BID plus Placebo dry powder inhaler (DPI) X 1 inhalation in the evening for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mometasone furoate metered dose inhaler (MF MDI)
    Investigational medicinal product code
    Other name
    SCH 032088, MK-0887
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    MF MDI 25 mcg, 50 mcg or 100 mcg X 2 inhalations BID for 12 weeks

    Investigational medicinal product name
    Placebo dry powder inhaler (Placebo DPI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo DPI X 1 inhalation in the evening for 12 weeks

    Arm title
    		 MF MDI 100 mcg BID
    Arm description
    		 Participants receive MF MDI 50 mcg X 2 inhalations (100 mcg total dose) BID plus Placebo DPI X 1 inhalation in the evening for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo dry powder inhaler (Placebo DPI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo DPI X 1 inhalation in the evening for 12 weeks

    Investigational medicinal product name
    Mometasone furoate metered dose inhaler (MF MDI)
    Investigational medicinal product code
    Other name
    SCH 032088, MK-0887
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    MF MDI 25 mcg, 50 mcg or 100 mcg X 2 inhalations BID for 12 weeks

    Arm title
    		 MF MDI 200 mcg BID
    Arm description
    		 Participants receive MF MDI 100 mcg X 2 inhalations (200 mcg total dose) BID plus Placebo DPI X 1 inhalation in the evening for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo dry powder inhaler (Placebo DPI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo DPI X 1 inhalation in the evening for 12 weeks

    Investigational medicinal product name
    Mometasone furoate metered dose inhaler (MF MDI)
    Investigational medicinal product code
    Other name
    SCH 032088, MK-0887
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    MF MDI 25 mcg, 50 mcg or 100 mcg X 2 inhalations BID for 12 weeks

    Arm title
    		 MF DPI 100 mcg QD
    Arm description
    		 Participants receive Placebo MDI X 2 inhalations BID plus MF DPI 100 mcg X 1 inhalation once daily in the evening for 12 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo MDI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo MDI X 2 inhalations BID for 12 weeks

    Investigational medicinal product name
    Mometasone furoate dry powder inhaler (MF DPI)
    Investigational medicinal product code
    Other name
    SCH 032088, MK-0887
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    MF DPI 100 mcg X 1 inhalation once daily in the evening for 12 weeks

    Arm title
    		 Placebo
    Arm description
    		 Participants receive Placebo MDI X 2 inhalations BID plus Placebo DPI X 1 inhalation once daily in the evening for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo dry powder inhaler (Placebo DPI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo DPI X 1 inhalation in the evening for 12 weeks

    Investigational medicinal product name
    Placebo MDI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo MDI X 2 inhalations BID for 12 weeks

    Number of subjects in period 1
    		MF MDI 50 mcg BID MF MDI 100 mcg BID MF MDI 200 mcg BID MF DPI 100 mcg QD Placebo
    Started
    120
    113
    108
    125
    112
    Completed
    79
    81
    83
    88
    60
    Not completed
    41
    32
    25
    37
    52
         Physician decision
    3
    -
    -
    -
    1
         Consent withdrawn by subject
    1
    2
    1
    1
    1
         Treatment failure
    22
    20
    12
    19
    30
         Adverse event, non-fatal
    2
    1
    -
    4
    3
         Technical problems
    1
    -
    2
    4
    1
         Excluded medication
    -
    1
    1
    -
    1
         Noncompliance with study drug
    -
    -
    1
    2
    1
         Lack of efficacy
    3
    3
    2
    2
    4
         Protocol deviation
    9
    5
    6
    5
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MF MDI 50 mcg BID
    Reporting group description
    		 Participants receive MF MDI 25 mcg X 2 inhalations (50 mcg total dose) BID plus Placebo dry powder inhaler (DPI) X 1 inhalation in the evening for 12 weeks.

    Reporting group title
    MF MDI 100 mcg BID
    Reporting group description
    		 Participants receive MF MDI 50 mcg X 2 inhalations (100 mcg total dose) BID plus Placebo DPI X 1 inhalation in the evening for 12 weeks.

    Reporting group title
    MF MDI 200 mcg BID
    Reporting group description
    		 Participants receive MF MDI 100 mcg X 2 inhalations (200 mcg total dose) BID plus Placebo DPI X 1 inhalation in the evening for 12 weeks.

    Reporting group title
    MF DPI 100 mcg QD
    Reporting group description
    		 Participants receive Placebo MDI X 2 inhalations BID plus MF DPI 100 mcg X 1 inhalation once daily in the evening for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants receive Placebo MDI X 2 inhalations BID plus Placebo DPI X 1 inhalation once daily in the evening for 12 weeks.

    Reporting group values
    		 MF MDI 50 mcg BID MF MDI 100 mcg BID MF MDI 200 mcg BID MF DPI 100 mcg QD Placebo Total
    Number of subjects
    		 120 113 108 125 112 578
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 120 113 108 125 111 577
        Adolescents (12-17 years)
    		 0 0 0 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.7 ± 1.7 8.6 ± 1.9 8.7 ± 1.7 8.7 ± 1.7 9 ± 1.7 -
    Gender categorical
    Units: Subjects
        Female
    		 51 44 59 48 30 232
        Male
    		 69 69 49 77 82 346

    End points

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    End points reporting groups
    Reporting group title
    MF MDI 50 mcg BID
    Reporting group description
    		 Participants receive MF MDI 25 mcg X 2 inhalations (50 mcg total dose) BID plus Placebo dry powder inhaler (DPI) X 1 inhalation in the evening for 12 weeks.

    Reporting group title
    MF MDI 100 mcg BID
    Reporting group description
    		 Participants receive MF MDI 50 mcg X 2 inhalations (100 mcg total dose) BID plus Placebo DPI X 1 inhalation in the evening for 12 weeks.

    Reporting group title
    MF MDI 200 mcg BID
    Reporting group description
    		 Participants receive MF MDI 100 mcg X 2 inhalations (200 mcg total dose) BID plus Placebo DPI X 1 inhalation in the evening for 12 weeks.

    Reporting group title
    MF DPI 100 mcg QD
    Reporting group description
    		 Participants receive Placebo MDI X 2 inhalations BID plus MF DPI 100 mcg X 1 inhalation once daily in the evening for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants receive Placebo MDI X 2 inhalations BID plus Placebo DPI X 1 inhalation once daily in the evening for 12 weeks.

    Primary: Change from Baseline in Percent Predicted Morning (AM) Forced Expiratory Volume in 1 Second (FEV1)

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    End point title
    		 Change from Baseline in Percent Predicted Morning (AM) Forced Expiratory Volume in 1 Second (FEV1)
    End point description
    FEV1 is the amount of air, measured in liters, forcibly exhaled in 1 second. Pulmonary function tests were to be performed by participants in the morning before dosing. The percent predicted FEV1 equals the participant's observed FEV1 divided by the participant's predicted FEV1 (determined by height and race) and converted to a percentage by multiplying by 100%.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MF MDI 50 mcg BID MF MDI 100 mcg BID MF MDI 200 mcg BID MF DPI 100 mcg QD Placebo
    Number of subjects analysed
    114 [1]
    109 [2]
    105 [3]
    122 [4]
    111 [5]
    Units: Percentage of Predicted FEV1
        least squares mean (confidence interval 95%)
    4.52 (2.32 to 6.72)
    6.95 (4.73 to 9.16)
    6 (3.74 to 8.25)
    3.13 (1.01 to 5.25)
    0.66 (-1.72 to 3.03)
    Notes
    [1] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [2] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [3] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [4] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [5] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    Statistical analysis title
    		 MF MDI 50 mcg BID vs. Placebo
    Statistical analysis description
    Change from Baseline in percent predicted FEV1 at Week 12 - MF MDI 50 mcg BID vs. Placebo. Constrained longitudinal data analysis (cLDA) model method proposed by Liang and Zeger includes terms for treatment, time in weeks, age strata (ages 5-6, 7-11), treatment by time interaction and region (North America, Latin America and the European Union)
    Comparison groups
    MF MDI 50 mcg BID v Placebo
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019
    Method
    		 cLDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 7.09
    Statistical analysis title
    		 MF MDI 100 mcg BID vs. Placebo
    Statistical analysis description
    Change from Baseline in percent predicted FEV1 at Week 12 - MF MDI 100 mcg BID vs. Placebo. cLDA model method proposed by Liang and Zeger includes terms for treatment, time in weeks, age strata (ages 5-6, 7-11), treatment by time interaction and region (North America, Latin America and the European Union)
    Comparison groups
    MF MDI 100 mcg BID v Placebo
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.05
         upper limit
    		 9.53
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. Placebo
    Statistical analysis description
    Change from Baseline in percent predicted FEV1 at Week 12 - MF MDI 200 mcg BID vs. Placebo. cLDA model method proposed by Liang and Zeger includes terms for treatment, time in weeks, age strata (ages 5-6, 7-11), treatment by time interaction and region (North America, Latin America and the European Union)
    Comparison groups
    MF MDI 200 mcg BID v Placebo
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 cLDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.07
         upper limit
    		 8.61
    Statistical analysis title
    		 MF MDI 50 mcg BID vs. MF DPI 100 mcg QD
    Statistical analysis description
    Change from Baseline in percent predicted FEV1 at Week 12 - MF MDI 50 mcg BID vs. MF DPI 100 mcg QD. cLDA model method proposed by Liang and Zeger includes terms for treatment, time in weeks, age strata (ages 5-6, 7-11), treatment by time interaction and region (North America, Latin America and the European Union)
    Comparison groups
    MF MDI 50 mcg BID v MF DPI 100 mcg QD
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.368
    Method
    		 cLDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.65
         upper limit
    		 4.44

    Secondary: Change from Baseline in Morning (AM) Peak Expiratory Flow (PEF)

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    End point title
    		 Change from Baseline in Morning (AM) Peak Expiratory Flow (PEF)
    End point description
    PEF, measured in liters, is the highest flow during exhalation. Participants recorded diary entries for PEF twice daily (in the AM upon rising and in the PM at bedtime).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MF MDI 50 mcg BID MF MDI 100 mcg BID MF MDI 200 mcg BID MF DPI 100 mcg QD Placebo
    Number of subjects analysed
    118 [6]
    112 [7]
    108 [8]
    123 [9]
    111 [10]
    Units: liters per minute
        least squares mean (confidence interval 95%)
    17.83 (5.35 to 30.3)
    26.03 (13.55 to 38.51)
    16.68 (4.5 to 28.86)
    -0.92 (-12.82 to 10.99)
    -1.32 (-15.49 to 12.85)
    Notes
    [6] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [7] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [8] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [9] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [10] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    Statistical analysis title
    		 MF MDI 50 mcg BID vs. Placebo
    Statistical analysis description
    Change from Baseline in AM PEF - MF MDI 50 mcg BID vs. Placebo. cLDA model includes terms for treatment, time in weeks, age strata (ages 5-6,7-11), treatment by time interaction and region (North America, Latin America, and the European Union).
    Comparison groups
    MF MDI 50 mcg BID v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045
    Method
    		 cLDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    19.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 37.87
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. Placebo
    Statistical analysis description
    Change from Baseline in AM PEF - MF MDI 200 mcg BID vs. Placebo. cLDA model includes terms for treatment, time in weeks, age strata (ages 5-6,7-11), treatment by time interaction and region (North America, Latin America, and the European Union).
    Comparison groups
    MF MDI 200 mcg BID v Placebo
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.057
    Method
    		 cLDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    18.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 36.53
    Statistical analysis title
    		 MF MDI 100 mcg BID vs. Placebo
    Statistical analysis description
    Change from Baseline in AM PEF - MF MDI 100 mcg BID vs. Placebo. cLDA model includes terms for treatment, time in weeks, age strata (ages 5-6,7-11), treatment by time interaction and region (North America, Latin America, and the European Union).
    Comparison groups
    MF MDI 100 mcg BID v Placebo
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 cLDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    27.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.63
         upper limit
    		 46.08

    Secondary: Change from Baseline in Standardized Paediatric Asthma Quality of Life Questionnaire Score (PAQLQ[S]) Total Score

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    End point title
    		 Change from Baseline in Standardized Paediatric Asthma Quality of Life Questionnaire Score (PAQLQ[S]) Total Score
    End point description
    The PAQLQ(S) consists of 23 questions in 3 categories: Symptoms (10 items), Activity Limitations (5 items) and Emotional Function (8 items). Responses are based on a 7-point scale (7=not bothered at all to 1=extremely bothered). The PAQLQ(S) included only participants in participating countries in which a validated translated questionnaire was available.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MF MDI 50 mcg BID MF MDI 100 mcg BID MF MDI 200 mcg BID MF DPI 100 mcg QD Placebo
    Number of subjects analysed
    111 [11]
    105 [12]
    101 [13]
    115 [14]
    102 [15]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    0.35 (0.23 to 0.48)
    0.38 (0.25 to 0.5)
    0.44 (0.31 to 0.56)
    0.47 (0.35 to 0.59)
    0.26 (0.12 to 0.39)
    Notes
    [11] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [12] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [13] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [14] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    [15] - All participants who received ≥1 study drug dose & had a baseline or ≥1 post-randomization value.
    Statistical analysis title
    		 MF MDI 50 mcg BID vs. Placebo
    Statistical analysis description
    Change from Baseline in PAQLQ(S) Total Score - MF MDI 50 mcg BID vs. Placebo. cLDA model includes terms for treatment, time in weeks, age strata (ages 5-6,7-11), treatment by time interaction and region (North America, Latin America, and the European Union).
    Comparison groups
    MF MDI 50 mcg BID v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 cLDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.27
    Statistical analysis title
    		 MF MDI 100 mcg BID vs. Placebo
    Statistical analysis description
    Change from Baseline in PAQLQ(S) Total Score - MF MDI 100 mcg BID vs. Placebo. cLDA model includes terms for treatment, time in weeks, age strata (ages 5-6,7-11), treatment by time interaction and region (North America, Latin America, and the European Union).
    Comparison groups
    MF MDI 100 mcg BID v Placebo
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.178
    Method
    		 cLDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.3
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. Placebo
    Statistical analysis description
    Change from Baseline in PAQLQ(S) Total Score - MF MDI 200 mcg BID vs. Placebo. cLDA model includes terms for treatment, time in weeks, age strata (ages 5-6,7-11), treatment by time interaction and region (North America, Latin America, and the European Union).
    Comparison groups
    MF MDI 200 mcg BID v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045
    Method
    		 cLDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.36

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 12 weeks
    Adverse event reporting additional description
    The safety population consisted of all participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    MF MDI 50 mcg BID
    Reporting group description
    		 Participants receive MF MDI 25 mcg X 2 inhalations (50 mcg total dose) BID plus Placebo DPI X 1inhalation in the evening for 12 weeks.

    Reporting group title
    MF MDI 100 mcg BID
    Reporting group description
    		 Participants receive MF MDI 50 mcg X 2 inhalations (100 mcg total dose) BID plus Placebo DPI X 1inhalation in the evening for 12 weeks.

    Reporting group title
    MF MDI 200 mcg BID
    Reporting group description
    		 Participants receive MF MDI 100 mcg X 2 inhalations (200 mcg total dose) BID plus Placebo DPI X 1 inhalation in the evening for 12 weeks.

    Reporting group title
    MF DPI 100 mcg QD PM
    Reporting group description
    		 Participants receive Placebo MDI X 2 inhalations BID plus MF DPI 100 mcg X 1 inhalation once daily in the evening for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants receive Placebo MDI X 2 inhalations BID plus Placebo DPI X 1 inhalation once daily in the evening for 12 weeks.

    Serious adverse events
    		 MF MDI 50 mcg BID MF MDI 100 mcg BID MF MDI 200 mcg BID MF DPI 100 mcg QD PM Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 113 (0.88%)
    2 / 108 (1.85%)
    4 / 125 (3.20%)
    2 / 112 (1.79%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 113 (0.00%)
    0 / 108 (0.00%)
    1 / 125 (0.80%)
    0 / 112 (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
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 113 (0.88%)
    0 / 108 (0.00%)
    0 / 125 (0.00%)
    0 / 112 (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
    Enteritis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 113 (0.00%)
    0 / 108 (0.00%)
    1 / 125 (0.80%)
    0 / 112 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 113 (0.00%)
    0 / 108 (0.00%)
    0 / 125 (0.00%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 113 (0.00%)
    1 / 108 (0.93%)
    0 / 125 (0.00%)
    0 / 112 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 113 (0.00%)
    0 / 108 (0.00%)
    1 / 125 (0.80%)
    0 / 112 (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
    0 / 120 (0.00%)
    0 / 113 (0.00%)
    0 / 108 (0.00%)
    1 / 125 (0.80%)
    0 / 112 (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
    Otitis media
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 113 (0.00%)
    1 / 108 (0.93%)
    0 / 125 (0.00%)
    0 / 112 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MF MDI 50 mcg BID MF MDI 100 mcg BID MF MDI 200 mcg BID MF DPI 100 mcg QD PM Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 120 (15.83%)
    18 / 113 (15.93%)
    18 / 108 (16.67%)
    16 / 125 (12.80%)
    19 / 112 (16.96%)
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    13 / 120 (10.83%)
    13 / 113 (11.50%)
    12 / 108 (11.11%)
    10 / 125 (8.00%)
    13 / 112 (11.61%)
         occurrences all number
    18
    19
    19
    14
    19
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 120 (6.67%)
    5 / 113 (4.42%)
    7 / 108 (6.48%)
    8 / 125 (6.40%)
    8 / 112 (7.14%)
         occurrences all number
    9
    6
    9
    8
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2011
    Amendment 02: Amendment 02 was developed prior to any participant being randomized. The primary reason for the protocol amendment was to remove the Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) from the study and to clarify Events of Clinical Interest.
    30 Mar 2012
    Amendment 01: Amendment 01 was developed prior to any participant being randomized. The primary reason for the protocol amendment was to clarify text and update the protocol template.
    13 Sep 2013
    Amendment 03: The primary reason for Amendment 03 was to clarify and align sections throughout the protocol and to remove an analysis of covariance (ANCOVA) analysis originally proposed as a confirmatory analysis.

    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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