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    Clinical Trial Results:
    A 26-Week Placebo-Controlled Efficacy and Safety Study of Mometasone Furoate/Formoterol Fumarate Combination Formulation Compared With Mometasone Furoate and Formoterol Monotherapy in Subjects with Persistent Asthma Previously Treated With Medium-Dose Inhaled Glucocorticosteroids

    Summary
    EudraCT number
    		 2006-001578-25
    Trial protocol
    		 HU   EE   DK  
    Global end of trial date
    23 Sep 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Apr 2016
    First version publication date
    09 May 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    P04334
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00383240
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MK-0887A-092: 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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000025-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Sep 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To determine the efficacy of mometasone furoate/formoterol (MF/F) metered-dose inhaler (MDI) 200/10 mcg twice each day (BID) compared with mometasone furoate (MF MDI 200 mcg BID), in order to assess the added benefit of formoterol (F MDI 10 mcg BID) to the combination. 2. To determine the efficiacy of MF/F MDI 200/10 mcg BID compared with F MDI 10 mcg BID, in order to assess the benefit of the steroid component of the combination.
    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 measures defined for this individual study were in place for the protection of trial subjects: subjects were provided with locally purchased short-acting ß-agonist (SABA: albuterol MDI 90 mcg in the United States; salbutamol MDI 100 mcg outside of the United States) to treat asthma symptoms and were also provided with locally purchased oral prednisone/prednisolone for acute self-administration.
    Background therapy
    		 Subjects were provided with locally purchased SABA (albuterol MDI 90 mcg in the United States; salbutamol MDI 100 mcg outside of the United States) to treat asthma symptoms and were also provided with locally purchased oral prednisone/prednisolone for acute self-administration.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Sep 2006
    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
    Denmark: 1
    Country: Number of subjects enrolled
    Estonia: 5
    Country: Number of subjects enrolled
    Hungary: 86
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Colombia: 4
    Country: Number of subjects enrolled
    Costa Rica: 22
    Country: Number of subjects enrolled
    Croatia: 6
    Country: Number of subjects enrolled
    Ecuador: 7
    Country: Number of subjects enrolled
    Guatemala: 17
    Country: Number of subjects enrolled
    India: 58
    Country: Number of subjects enrolled
    Mexico: 45
    Country: Number of subjects enrolled
    Philippines: 47
    Country: Number of subjects enrolled
    Poland: 113
    Country: Number of subjects enrolled
    Russian Federation: 41
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    Ukraine: 53
    Country: Number of subjects enrolled
    United States: 264
    Worldwide total number of subjects
    781
    EEA total number of subjects
    211
    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)
    63
    Adults (18-64 years)
    677
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants screened for this study were 12 years of age or older, had a diagnosis of asthma of at least 12 months duration, were using a medium daily dose of inhaled coticosteroids (ICS) for at least 12 weeks and were on a stable ICS regimen for at least 2 weeks prior to Screening.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MF/F MDI 200/10 mcg BID
    Arm description
    		 Participants receive MF/F MDI 200/10 mcg BID for up to 26 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    mometasone furoate/formoterol fumarate
    Investigational medicinal product code
    Other name
    MK-0887A, SCH 418131
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    MF/F MDI 200/10 mcg BID for up to 26 weeks

    Arm title
    		 MF MDI 200 mcg BID
    Arm description
    		 Participants receive MF MDI 200 mcg BID for up to 26 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    mometasone furoate
    Investigational medicinal product code
    Other name
    MK-0887, SCH 032088
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    MF MDI 200 mcg BID for up to 26 weeks

    Arm title
    		 F MDI 10 mcg BID
    Arm description
    		 Participants receive F MDI 10 mcg BID for up to 26 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    formoterol fumarate
    Investigational medicinal product code
    Other name
    Foradil®, MK-5571
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    F MDI 10 mcg BID for up to 26 weeks

    Arm title
    		 Placebo MDI BID
    Arm description
    		 Participants receive placebo MDI BID for up to 26 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo MDI BID for up to 26 weeks

    Number of subjects in period 1
    		MF/F MDI 200/10 mcg BID MF MDI 200 mcg BID F MDI 10 mcg BID Placebo MDI BID
    Started
    191
    192
    202
    196
    Treated
    191
    192
    202
    195
    Completed
    156
    159
    117
    119
    Not completed
    35
    33
    85
    77
         Consent withdrawn by subject
    6
    4
    11
    13
         Administrative
    1
    1
    -
    -
         Adverse event, non-fatal
    4
    6
    9
    7
         Non-compliance with protocol
    4
    5
    9
    6
         Lost to follow-up
    3
    -
    -
    2
         Lack of efficacy
    8
    13
    47
    46
         Protocol deviation
    9
    4
    9
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MF/F MDI 200/10 mcg BID
    Reporting group description
    		 Participants receive MF/F MDI 200/10 mcg BID for up to 26 weeks

    Reporting group title
    MF MDI 200 mcg BID
    Reporting group description
    		 Participants receive MF MDI 200 mcg BID for up to 26 weeks

    Reporting group title
    F MDI 10 mcg BID
    Reporting group description
    		 Participants receive F MDI 10 mcg BID for up to 26 weeks

    Reporting group title
    Placebo MDI BID
    Reporting group description
    		 Participants receive placebo MDI BID for up to 26 weeks

    Reporting group values
    		 MF/F MDI 200/10 mcg BID MF MDI 200 mcg BID F MDI 10 mcg BID Placebo MDI BID Total
    Number of subjects
    		 191 192 202 196 781
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 19 10 18 16 63
        Adults (18-64 years)
    		 161 173 174 169 677
        From 65-84 years
    		 11 9 10 11 41
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.9 ± 16.3 42.8 ± 14.9 41.9 ± 15.3 41.9 ± 15.3 -
    Gender categorical
    Units: Subjects
        Female
    		 97 112 129 122 460
        Male
    		 94 80 73 74 321

    End points

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    End points reporting groups
    Reporting group title
    MF/F MDI 200/10 mcg BID
    Reporting group description
    		 Participants receive MF/F MDI 200/10 mcg BID for up to 26 weeks

    Reporting group title
    MF MDI 200 mcg BID
    Reporting group description
    		 Participants receive MF MDI 200 mcg BID for up to 26 weeks

    Reporting group title
    F MDI 10 mcg BID
    Reporting group description
    		 Participants receive F MDI 10 mcg BID for up to 26 weeks

    Reporting group title
    Placebo MDI BID
    Reporting group description
    		 Participants receive placebo MDI BID for up to 26 weeks

    Primary: Mean Area Under the Time Curve From 0 to 12 Hours (AUC[0-12h]) of Change From Baseline to Week 12 in Forced Expiratory Volume in One Second (FEV1)

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    End point title
    		 Mean Area Under the Time Curve From 0 to 12 Hours (AUC[0-12h]) of Change From Baseline to Week 12 in Forced Expiratory Volume in One Second (FEV1)
    End point description
    Baseline was the mean of two pre-dose FEV1 measurements on Day 1. Endpoint was the last post-Baseline non-missing FEV1 AUC(0-12h) result carried forward. Post-Baseline least squares (LS) means and pooled standard deviations were obtained from the analysis of covariance (ANCOVA) model with treatment, site effects and the Baseline FEV1 (liters) as a covariate.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12 End Point
    End point values
    		 MF/F MDI 200/10 mcg BID MF MDI 200 mcg BID F MDI 10 mcg BID Placebo MDI BID
    Number of subjects analysed
    190 [1]
    190 [2]
    202 [3]
    193 [4]
    Units: liters x hours
        least squares mean (standard deviation)
    3.19 ± 3.98
    1.31 ± 3.98
    1.6 ± 3.98
    0.51 ± 3.98
    Notes
    [1] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [2] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [3] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [4] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. MF MDI 200 mcg BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. MF MDI 200 mcg BID pairwise comparison P-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v MF MDI 200 mcg BID
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. F MDI 10 mcg BID pairwise comparison P-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF MDI 200 mcg BID vs. F MDI 10 mcg BID pairwise comparison P-value
    Comparison groups
    MF MDI 200 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.491
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    MF MDI 200 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    MF MDI 200 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.055
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 F MDI 10 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    F MDI 10 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    F MDI 10 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    395
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 ANCOVA
    Confidence interval

    Primary: Number of Participants With At Least One Severe Asthma Exacerbation

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    End point title
    		 Number of Participants With At Least One Severe Asthma Exacerbation
    End point description
    A severe asthma exacerbation was defined as a clinically judged deterioration of asthma or a meaningful reduction in lung function based on any one of the following criteria during the Treatment Period: 1) A decrease in FEV1 (absolute value) below the Treatment Period stability limit at any visit during the Treatment Period. The Treatment Period stability limit was defined as 80% of the average of the two predose FEV1 measurements just prior to the first dose of randomized study medication. 2) A decrease in AM or PM peak flow of 30% or more on 2 consecutive days of treatment during the Treatment Period. The Treatment Period stability limit was defined as 70% of the respective mean AM or PM PEF obtained over the last 7 days immediately prior to receiving randomized study medication. 3) An occurrence of any clinical deterioration of asthma (i.e., asthma attack) that resulted in emergency treatment, hospitalization due to asthma or treatment with additional, excluded asthma medication.
    End point type
    Primary
    End point timeframe
    26 weeks
    End point values
    		 MF/F MDI 200/10 mcg BID MF MDI 200 mcg BID F MDI 10 mcg BID Placebo MDI BID
    Number of subjects analysed
    191 [5]
    192 [6]
    202 [7]
    196 [8]
    Units: participants
    58
    65
    109
    109
    Notes
    [5] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [6] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [7] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [8] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. MF MDI 200 mcg BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. MF MDI 200 mcg BID pairwise comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v MF MDI 200 mcg BID
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.565
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. F MDI 10 mcg BID pairwise comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. Placebo MDI BID pairwise comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF MDI 200 mcg BID vs. F MDI 10 mcg BID pairwise comparison P-value
    Comparison groups
    MF MDI 200 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    394
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    MF MDI 200 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    MF MDI 200 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 F MDI 10 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    F MDI 10 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    F MDI 10 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.967
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from Baseline to Week 26 in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ[S]) Score

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    End point title
    		 Change from Baseline to Week 26 in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ[S]) Score
    End point description
    The AQLQ(S) consists of 32 questions covering 4 domains: symptoms, emotional functioning, impact of environmental stimuli and activity limitation. Responses to each question were to reflect participant experience over the previous 2 weeks and were scaled from 1 (worst case) to 7 (best case). End point was the last post-Baseline non-missing AQLQ(S) result carried forward. Post-Baseline LS means and pooled standard deviations were obtained from the ANCOVA model with treatment, site effects and the Baseline AQLQ(S) score as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26 End Point
    End point values
    		 MF/F MDI 200/10 mcg BID MF MDI 200 mcg BID F MDI 10 mcg BID Placebo MDI BID
    Number of subjects analysed
    183 [9]
    189 [10]
    187 [11]
    189 [12]
    Units: score on a scale
        least squares mean (standard deviation)
    0.49 ± 0.85
    0.37 ± 0.85
    0.05 ± 0.85
    -0.01 ± 0.85
    Notes
    [9] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [10] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [11] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [12] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. MF MDI 200 mcg BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. MF MDI 200 mcg BID pairwiase comparison p-value
    Comparison groups
    MF MDI 200 mcg BID v MF/F MDI 200/10 mcg BID
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.174
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. F MDI 10 mcg BID pairwiase comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. Placebo MDI BID pairwiase comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF MDI 200 mcg BID vs. F MDI 10 mcg BID pairwise comparison P-value
    Comparison groups
    MF MDI 200 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    MF MDI 200 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    MF MDI 200 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    378
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 F MDI 10 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    F MDI 10 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    F MDI 10 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.521
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from Baseline to Week 26 in Asthma Control Questionnaire (ACQ) Score

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    End point title
    		 Change from Baseline to Week 26 in Asthma Control Questionnaire (ACQ) Score
    End point description
    The ACQ consists of 7 questions covering awakenings due to asthma, symptoms when awoken, activity limitations, shortness of breath, wheezing, number of puffs of SABA used and FEV1 % predicted. Responses to questions were to reflect participant experience over the previous week and were each scaled from 0 (best case) to 6 (worst case). End point was the last post-Baseline non-missing ACQ result carried forward. Post-Baseline LS means and pooled standard deviations were obtaines from the ANCOVA model with treatment, site effects and the Baseline ACQ score as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26 End Point
    End point values
    		 MF/F MDI 200/10 mcg BID MF MDI 200 mcg BID F MDI 10 mcg BID Placebo MDI BID
    Number of subjects analysed
    179 [13]
    186 [14]
    184 [15]
    187 [16]
    Units: score on a scale
        least squares mean (standard deviation)
    -0.4 ± 0.74
    -0.23 ± 0.74
    0.11 ± 0.74
    0.14 ± 0.74
    Notes
    [13] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [14] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [15] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [16] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. MF MDI 200 mcg BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. MF MDI 200 mcg BID pairwise comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v MF MDI 200 mcg BID
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. F MDI 10 mcg BID pairwise comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. Placebo MDI BID pairwise comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF MDI 200 mcg BID vs. F MDI 10 mcg BID pairwise comparison P-value
    Comparison groups
    MF MDI 200 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF MDI 200 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    MF MDI 200 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    MF MDI 200 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 F MDI 10 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    F MDI 10 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    F MDI 10 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.738
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from Baseline Across the Treatment Period in Percentage of Nights With Nocturnal Awakenings Due to Asthma that Require Use of SABA

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    End point title
    		 Change from Baseline Across the Treatment Period in Percentage of Nights With Nocturnal Awakenings Due to Asthma that Require Use of SABA
    End point description
    Baseline percentage of nights with nocturnal awakenings that required use of SABA included data from the last week before first dose of randomized study drug. End point percentage included data from the entire 26-week Treatment Period. Post-Baseline LS means and pooled standard deviations were obtained from the ANCOVA model with treatment, site effects and the Baseline percentage as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and 26-week Treatment Period End Point
    End point values
    		 MF/F MDI 200/10 mcg BID MF MDI 200 mcg BID F MDI 10 mcg BID Placebo MDI BID
    Number of subjects analysed
    186 [17]
    191 [18]
    199 [19]
    194 [20]
    Units: percentage of nocturnal awakenings
        least squares mean (standard deviation)
    -0.08 ± 0.17
    -0.05 ± 0.17
    0.01 ± 0.17
    0 ± 0.17
    Notes
    [17] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [18] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [19] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    [20] - All randomized participants who took ≥1 study drug dose and were evaluable for this end point.
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. MF MDI 200 mcg BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. MF MDI 200 mcg BID pairwise comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v MF MDI 200 mcg BID
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.063
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. F MDI 10 mcg BID pairwise comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF/F MDI 200/10 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    MF/F MDI 200/10 mcg BID vs. Placebo MDI BID pairwise comparison p-value
    Comparison groups
    MF/F MDI 200/10 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF MDi 200 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF MDi 200 mcg BID vs. F MDI 10 mcg BID pairwise comparison P-value
    Comparison groups
    MF MDI 200 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 MF MDi 200 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    MF MDi 200 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    MF MDI 200 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 F MDI 10 mcg BID vs. Placebo MDI BID
    Statistical analysis description
    F MDI 10 mcg BID vs. Placebo MDI BID pairwise comparison P-value
    Comparison groups
    F MDI 10 mcg BID v Placebo MDI BID
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.601
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 26 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    MF/F MDI 200/10 mcg BID
    Reporting group description
    		 Participants receive MF/F MDI 200/10 mcg BID for up to 26 weeks

    Reporting group title
    Placebo MDI BID
    Reporting group description
    		 Participants receive placebo MDI BID for up to 26 weeks

    Reporting group title
    F MDI 10 mcg BID
    Reporting group description
    		 Participants receive F MDI 10 mcg BID for up to 26 weeks

    Reporting group title
    MF MDI 200 mcg BID
    Reporting group description
    		 Participants receive MF MDI 200 mcg BID for up to 26 weeks

    Serious adverse events
    		 MF/F MDI 200/10 mcg BID Placebo MDI BID F MDI 10 mcg BID MF MDI 200 mcg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 191 (2.62%)
    3 / 196 (1.53%)
    3 / 202 (1.49%)
    3 / 192 (1.56%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine Leiomyosarcoma
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 196 (0.00%)
    0 / 202 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 196 (0.00%)
    1 / 202 (0.50%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus Fracture
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 196 (0.51%)
    0 / 202 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Spinal Decompression
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 196 (0.51%)
    0 / 202 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 196 (0.00%)
    0 / 202 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 196 (0.00%)
    0 / 202 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 196 (0.00%)
    0 / 202 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal Haemorrhage
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 196 (0.00%)
    0 / 202 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 196 (0.00%)
    1 / 202 (0.50%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis Atopic
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 196 (0.51%)
    0 / 202 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 196 (0.00%)
    0 / 202 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 196 (0.00%)
    0 / 202 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 196 (0.00%)
    0 / 202 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 196 (0.00%)
    1 / 202 (0.50%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MF/F MDI 200/10 mcg BID Placebo MDI BID F MDI 10 mcg BID MF MDI 200 mcg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 191 (16.23%)
    30 / 196 (15.31%)
    29 / 202 (14.36%)
    35 / 192 (18.23%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 191 (4.71%)
    7 / 196 (3.57%)
    6 / 202 (2.97%)
    10 / 192 (5.21%)
         occurrences all number
    10
    10
    8
    17
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 191 (6.28%)
    7 / 196 (3.57%)
    13 / 202 (6.44%)
    15 / 192 (7.81%)
         occurrences all number
    13
    8
    14
    22
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 191 (5.76%)
    17 / 196 (8.67%)
    12 / 202 (5.94%)
    16 / 192 (8.33%)
         occurrences all number
    13
    17
    16
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2007
    Amendment 01: The main reasons for Amendment 01 were 1) to clarify that open-label run-in medication was to be dispensed at Visit 1, but that participants were NOT to start taking open-label MF MDI (run-in medication) until after the laboratory results were available and found to be clinically acceptable, 2) to clarify inclusion and exclusion criteria and 3) to modify the age of participants for countries such as Russia where minors are not permitted in clinical studies and therefore only adults (participants ≥18 years of age) so as to reflect various Ethics Committees and Competent Authorities requirements.

    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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