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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 Low-Dose Inhaled Glucocorticosteroids

    Summary
    EudraCT number
    		 2006-001577-13
    Trial protocol
    		 HU   EE   DK  
    Global end of trial date
    31 Aug 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Feb 2016
    First version publication date
    05 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    P04073
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00383552
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol Number: MK-0887A-081
    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 Sharpe & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharpe & 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
    31 Aug 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a randomized, multi-center, double-blind, double-dummy, placebo-controlled, parallel-group study, evaluating the efficacy of mometasone furoate/formoterol fumarate (MF/F) metered dose inhaler (MDI) versus MF for 26 weeks. Prior to the 26-week double-blind Treatment Period, participants will receive open-label (OL) MF MDI 100 mcg twice daily (BID) for 2 to 3 weeks during the Run-in Period. Efficacy will be measured by the Area Under the Curve from 0 to 12 hours (AUC[0-12 hrs]) of the change from Baseline to the Week 12 Endpoint in Forced Expiratory Volume in One Second (FEV1) and by the time-to-first severe asthma exacerbation across the 26-week treatment period. The primary hypothesis is that MF/F 100/10 mcg BID is significantly more effective than MF 100 mcg BID with respect to change from baseline to week 12 in FEV(0-12 hr) AUC and significantly more effective than F 10 mcg BID in the time-to-first asthma exacerbation over a 26-week treatment period.
    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 participanting in biomedical research. The following additional measures defined for this individual study were in place for the protection of trial subjects: All participants in the current study were carefully monitored for asthma exacerbations and were provided with an asthma action plan with immediate availability of emergency rescue oral steroids (e.g. prednisone) and short-acting beta 2-agonists (SABA), and had access to around-the-clock physician contact. Participants were provided with a SABA Metered Dose Inhaler (MDI) at the Screening Visit for use as rescue medication during the study, and were advised not to take the SABA via an MDI or a nebulizer regularly or in anticipation of asthma symptoms. Rescue medication was recorded in the Patient Diary.
    Background therapy
    		 -
    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
    Bulgaria: 108
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    Croatia: 29
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    Guatemala: 7
    Country: Number of subjects enrolled
    Hungary: 64
    Country: Number of subjects enrolled
    India: 67
    Country: Number of subjects enrolled
    Mexico: 36
    Country: Number of subjects enrolled
    Philippines: 35
    Country: Number of subjects enrolled
    Poland: 106
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    Ukraine: 33
    Country: Number of subjects enrolled
    United States: 356
    Worldwide total number of subjects
    882
    EEA total number of subjects
    315
    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)
    139
    Adults (18-64 years)
    684
    From 65 to 84 years
    59
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 882 participants enrolled in the open-label Run-In Period, of which 746 participants were randomized into 1 of 4 arms. Of 746 randomized participants, 536 participants overall completed the Treatment Period, with 210 participants overall discontinued investigational treatment early. All randomized participants received ≥1 dose of study medication.

    Period 1
    Period 1 title
    Open-Label Run-In Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 OL MF MDI 100 MCG BID
    Arm description
    		 Participants received 2 to 3 weeks (approximately) of open-label, run-in medication with MF MDI 100 mcg BID prior to the 26-week double-blind treatment period.
    Arm type
    		 Run-in

    Investigational medicinal product name
    Mometasone furoate MDI (MF MDI)
    Investigational medicinal product code
    Other name
    MK-0887, SCH 032088
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Open-label MF 100 mcg via metered dose inhaler twice daily for approximately 2 to 3 weeks.

    Number of subjects in period 1
    		OL MF MDI 100 MCG BID
    Started
    882
    Completed
    746
    Not completed
    136
         Did not meet protocol eligibility
    84
         Administrative
    2
         Adverse event, non-fatal
    6
         Subject did not wish to continue, reason related
    1
         Treatment Failure
    2
         Subject did not wish to continue, reason unrelated
    20
         Non-compliance with protocol
    12
         Lost to follow-up
    9
    Period 2
    Period 2 title
    Double-Blind Treatment Period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MF/F MDI 100/10 mcg BID
    Arm description
    		 Participants received mometasone furoate 100 mcg and formoterol 10 mcg fixed dose combination taken twice daily for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mometasone furoate 100 mcg/formoterol 10 mcg (MF/F) combination
    Investigational medicinal product code
    Other name
    MK-0887A, SCH 418131
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    MF/F 100/10 mcg via a metered dose inhaler (MDI) twice daily for 26 weeks

    Arm title
    		 MF MDI 100 mcg BID
    Arm description
    		 Participants received mometasone furoate 100 mcg taken twice daily for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mometasone furoate MDI (MF MDI)
    Investigational medicinal product code
    Other name
    SCH 032088
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    MF 100 mcg via metered dose inhaler twice daily for 26 weeks

    Arm title
    		 F MDI 10 mcg BID
    Arm description
    		 Participants received formoterol fumarate (F) 10 mcg taken twice daily for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (F)
    Investigational medicinal product code
    Other name
    Foradil®, MK-5571
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    F 10 mcg via a metered dose inhaler (MDI) twice daily for 26 weeks

    Arm title
    		 Placebo BID
    Arm description
    		 Participants received placebo taken twice daily for 26 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo twice daily for 26 weeks

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 represents an open-label run-in to standardize treatment - not all of these subjects participated in the trial. Period 2 (baseline period) represents the randomized double-blind treatment phase. This is the primary study period of interest, thus baseline characteristics are reported for this period.
    Number of subjects in period 2 [2]
    		MF/F MDI 100/10 mcg BID MF MDI 100 mcg BID F MDI 10 mcg BID Placebo BID
    Started
    182
    188
    188
    188
    Completed
    146
    147
    127
    116
    Not completed
    36
    41
    61
    72
         Did not meet protocol eligibility
    8
    6
    2
    3
         Did not wish to continue (unrelated)
    4
    9
    5
    6
         Administrative
    1
    -
    1
    1
         Adverse event, non-fatal
    7
    6
    9
    6
         Did not wish to continue (related)
    1
    -
    2
    3
         Non-compliance with protocol
    11
    6
    8
    10
         Lost to follow-up
    -
    1
    5
    1
         Lack of efficacy
    4
    13
    29
    42
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects in the baseline period represent those who were randomized to treatment on study; this is the primary population of interest. The worldwide number represents all enrolled subjects who entered an open-label run-in to standardize treatment - not all of these subjects participated in trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MF/F MDI 100/10 mcg BID
    Reporting group description
    		 Participants received mometasone furoate 100 mcg and formoterol 10 mcg fixed dose combination taken twice daily for 26 weeks.

    Reporting group title
    MF MDI 100 mcg BID
    Reporting group description
    		 Participants received mometasone furoate 100 mcg taken twice daily for 26 weeks.

    Reporting group title
    F MDI 10 mcg BID
    Reporting group description
    		 Participants received formoterol fumarate (F) 10 mcg taken twice daily for 26 weeks.

    Reporting group title
    Placebo BID
    Reporting group description
    		 Participants received placebo taken twice daily for 26 weeks.

    Reporting group values
    		 MF/F MDI 100/10 mcg BID MF MDI 100 mcg BID F MDI 10 mcg BID Placebo BID Total
    Number of subjects
    		 182 188 188 188 746
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.1 ( 16.9 ) 39.4 ( 16.7 ) 38.5 ( 15.6 ) 38.1 ( 17.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 99 105 103 106 413
        Male
    		 83 83 85 82 333

    End points

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    End points reporting groups
    Reporting group title
    OL MF MDI 100 MCG BID
    Reporting group description
    		 Participants received 2 to 3 weeks (approximately) of open-label, run-in medication with MF MDI 100 mcg BID prior to the 26-week double-blind treatment period.
    Reporting group title
    MF/F MDI 100/10 mcg BID
    Reporting group description
    		 Participants received mometasone furoate 100 mcg and formoterol 10 mcg fixed dose combination taken twice daily for 26 weeks.

    Reporting group title
    MF MDI 100 mcg BID
    Reporting group description
    		 Participants received mometasone furoate 100 mcg taken twice daily for 26 weeks.

    Reporting group title
    F MDI 10 mcg BID
    Reporting group description
    		 Participants received formoterol fumarate (F) 10 mcg taken twice daily for 26 weeks.

    Reporting group title
    Placebo BID
    Reporting group description
    		 Participants received placebo taken twice daily for 26 weeks.

    Primary: Mean area under the time curve from 0 to 12 hours (AUC [0-12 hours]) of change from Baseline to Week 12 in forced expiratory volume (liters) in 1 second (FEV1)

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    End point title
    		 Mean area under the time curve from 0 to 12 hours (AUC [0-12 hours]) of change from Baseline to Week 12 in forced expiratory volume (liters) in 1 second (FEV1)
    End point description
    The average of the two predose FEV1 measurements (30 minutes prior to dosing and 0 hour, immediately prior to dosing) at the Baseline Visit were subtracted from each of the serial measurements over the 12-hour period. The AUC was calculated based on these changes from Baseline evaluations. The comparison was for MF/F vs MF. Standard deviation was pooled.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    		 MF/F MDI 100/10 mcg BID MF MDI 100 mcg BID F MDI 10 mcg BID Placebo BID
    Number of subjects analysed
    155
    156
    146
    129
    Units: liters x hours
        least squares mean (standard deviation)
    4 ( 3.71 )
    2.53 ( 3.71 )
    3.83 ( 3.71 )
    1.11 ( 3.71 )
    Statistical analysis title
    		 MF/F MDI 100/10 mcg BID vs. MF MDI 100 mcg BID
    Statistical analysis description
    Least Squares (LS) Means and pooled standard deviations (Pstd) for post-baseline evaluations were obtained from the ANCOVA model with treatment, site effects, and the baseline FEV1 (liters) as a covariate. BL was the mean of two pre-dose measurements (30 minutes before dosing and 0 hour, immediately before dosing) on Day 1. The last post-BL non-missing FEV1 AUC(0-12 hr) result carried forward was used.
    Comparison groups
    MF/F MDI 100/10 mcg BID v MF MDI 100 mcg BID
    Number of subjects included in analysis
    311
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Confidence interval

    Primary: Median Time-to-first severe asthma exacerbation over the 26-week Treatment Period

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    End point title
    		 Median Time-to-first severe asthma exacerbation over the 26-week Treatment Period [1]
    End point description
    Severe asthma exacerbation refers to an occurrence of a decrease below 80% of Baseline in FEV1, a decrease below 70% of Baseline in peak expiratory flow (PEF) on 2 consecutive days or a clinical deterioration of asthma resulting in emergency treatment, hospitalization or treatment with asthma medication. Medians for time-to-event outcomes are estimated for those who had events.
    End point type
    Primary
    End point timeframe
    Across the 26 week treatment period
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed on this endpoint.
    End point values
    		 MF/F MDI 100/10 mcg BID MF MDI 100 mcg BID F MDI 10 mcg BID Placebo BID
    Number of subjects analysed
    30 [2]
    53 [3]
    84 [4]
    86 [5]
    Units: days
        median (inter-quartile range (Q1-Q3))
    45.5 (11 to 101)
    54 (12 to 98)
    51.5 (16.5 to 125.5)
    27.5 (8 to 87)
    Notes
    [2] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [3] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [4] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [5] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    No statistical analyses for this end point

    Primary: Number of Participants with at least one severe asthma exacerbation at week 26

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    End point title
    		 Number of Participants with at least one severe asthma exacerbation at week 26
    End point description
    Severe asthma exacerbation refers to an occurrence of a decrease below 80% of Baseline in FEV1, a decrease below 70% of Baseline in PEF on 2 consecutive days and or a clinical deterioration of asthma resulting in emergency treatment, hospitalization or treatment with asthma medication.
    End point type
    Primary
    End point timeframe
    Week 26
    End point values
    		 MF/F MDI 100/10 mcg BID MF MDI 100 mcg BID F MDI 10 mcg BID Placebo BID
    Number of subjects analysed
    182 [6]
    188 [7]
    188 [8]
    188 [9]
    Units: Participants
        number (not applicable)
    30
    53
    84
    86
    Notes
    [6] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [7] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [8] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [9] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    Statistical analysis title
    		 MF/F MDI 100/10 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    MF/F MDI 100/10 mcg BID vs. F MDI 10 mcg BID pairwise comparison P-value
    Comparison groups
    MF/F MDI 100/10 mcg BID v F MDI 10 mcg BID
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Logrank
    Confidence interval

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

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    End point title
    		 Change from Baseline to Week 26 in the Asthma Control Questionnaire (ACQ) Total Score
    End point description
    ACQ consists of seven questions each scaled from 0 (best case) to 6 (worst case). The comparison was for MF/F vs placebo. Standard deviation was pooled.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 MF/F MDI 100/10 mcg BID MF MDI 100 mcg BID F MDI 10 mcg BID Placebo BID
    Number of subjects analysed
    143 [10]
    145 [11]
    129 [12]
    116 [13]
    Units: units on a scale
    least squares mean (standard deviation)
        Baseline
    1.34 ( 0.71 )
    1.29 ( 0.6 )
    1.38 ( 0.76 )
    1.23 ( 0.71 )
        Change from Baseline
    -0.4 ( 0.65 )
    -0.32 ( 0.65 )
    -0.12 ( 0.65 )
    -0.11 ( 0.65 )
    Notes
    [10] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [11] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [12] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [13] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    Statistical analysis title
    		 MF/F MDI 100/10 mcg BID vs. Placebo BID
    Statistical analysis description
    Post-Baseline LS Means and Pstd (pooled standard deviations) were obtained from the ANCOVA model with treatment (trt), site effects, and the Baseline (Base) as a covariate. Baseline LS Means excluded the covariate. The last post-BL non-missing ACQ result carried forward was used.
    Comparison groups
    MF/F MDI 100/10 mcg BID v Placebo BID
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Confidence interval

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

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    End point title
    		 Change from Baseline to Week 26 in Asthma Quality of Life Questionnaire with Standarized Activities (AQLQ[S]) Total Score
    End point description
    AQLQ(S) consists of 32 questions each scaled from 1 (worst case) to 7 (best case). The comparison was for MF/F vs placebo. Standard deviation was pooled.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 MF/F MDI 100/10 mcg BID MF MDI 100 mcg BID F MDI 10 mcg BID Placebo BID
    Number of subjects analysed
    144 [14]
    147 [15]
    129 [16]
    117 [17]
    Units: units on a scale
    least squares mean (standard deviation)
        Baseline
    5.6 ( 0.93 )
    5.65 ( 1 )
    5.6 ( 0.98 )
    5.76 ( 1.02 )
        Change from Baseline
    0.44 ( 0.73 )
    0.39 ( 0.73 )
    0.15 ( 0.73 )
    0.06 ( 0.73 )
    Notes
    [14] - All Randomized Partcipants with BL and any post-BL data (intent-to-treat principle).
    [15] - All Randomized Partcipants with BL and any post-BL data (intent-to-treat principle).
    [16] - All Randomized Partcipants with BL and any post-BL data (intent-to-treat principle).
    [17] - All Randomized Partcipants with BL and any post-BL data (intent-to-treat principle).
    Statistical analysis title
    		 MF/F MDI 100/10 mcg BID vs. Placebo BID
    Statistical analysis description
    Post-Baseline LS Means and Pstd (pooled standard deviations) are obtained from the ANCOVA model with treatment, site effects and the baseline as a covariate. The last post-Baseline non-missing AQLQ result carried forward.
    Comparison groups
    MF/F MDI 100/10 mcg BID v Placebo BID
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from Baseline in proportion of nights across the treatment period with nocturnal awakenings due to asthma which require use of short-acting beta agonists (SABA)

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    End point title
    		 Change from Baseline in proportion of nights across the treatment period with nocturnal awakenings due to asthma which require use of short-acting beta agonists (SABA)
    End point description
    Baseline is the proportion of nights of the last week (Days -7 to 1) prior to first dose with nocturnal awakenings. Scale is measured as 0 to 1 with 0=no awakenings to 1=awakenings every night. The comparison was for MF/F vs placebo. Standard deviation was pooled.
    End point type
    Secondary
    End point timeframe
    Baseline to Endpoint
    End point values
    		 MF/F MDI 100/10 mcg BID MF MDI 100 mcg BID F MDI 10 mcg BID Placebo BID
    Number of subjects analysed
    181 [18]
    185 [19]
    185 [20]
    188 [21]
    Units: Proportion of Nights
    least squares mean (standard deviation)
        Baseline
    0.13 ( 0.12 )
    0.12 ( 0.12 )
    0.15 ( 0.15 )
    0.13 ( 0.14 )
        Change from Baseline
    -0.06 ( 0.16 )
    -0.03 ( 0.16 )
    -0.03 ( 0.16 )
    0.02 ( 0.16 )
    Notes
    [18] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [19] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [20] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [21] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    Statistical analysis title
    		 MF/F MDI 100/10 mcg BID vs. Placebo BID
    Statistical analysis description
    Post-Baseline LS Means and Pstd (pooled standard deviations) were obtained from the ANCOVA model with treatment (Trt), site effects, and the Baseline (Base) as a covariate. Baseline LS Means excluded the covariate.
    Comparison groups
    MF/F MDI 100/10 mcg BID v Placebo BID
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from Baseline in AM FEV1 pre-dose assessment, or trough FEV1, at Week 12

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    End point title
    		 Change from Baseline in AM FEV1 pre-dose assessment, or trough FEV1, at Week 12
    End point description
    Trough FEV1 is a measure of the end-of-dosing interval. The comparison was for MF/F vs F. Standard deviation was pooled.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 MF/F MDI 100/10 mcg BID MF MDI 100 mcg BID F MDI 10 mcg BID Placebo BID
    Number of subjects analysed
    160 [22]
    163 [23]
    160 [24]
    137 [25]
    Units: liters
    least squares mean (standard deviation)
        Baseline
    2.5 ( 2.56 )
    2.41 ( 2.46 )
    2.47 ( 2.52 )
    2.46 ( 2.5 )
        Change from Baseline
    0.18 ( 0.21 )
    0.16 ( 0.21 )
    0.11 ( 0.21 )
    0.04 ( 0.21 )
    Notes
    [22] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [23] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [24] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [25] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    Statistical analysis title
    		 MF/F MDI 100/10 mcg BID vs. F MDI 10 mcg BID
    Statistical analysis description
    Post-Baseline LS Means and Model Effects were obtained from a longitudinal model with treatment (Trt), participant, visit, and visit-by-treatment as fixed effects, Baseline (Base) as a covariate, and random intercept. Screening/Baseline LS Means were obtained from an ANOVA model with treatment and site fixed effects.
    Comparison groups
    F MDI 10 mcg BID v MF/F MDI 100/10 mcg BID
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.073
    Method
    		 Longitudinal Model
    Confidence interval

    Secondary: AUC(0-12 hour) of the change from Baseline to Week 12 in FEV1 for each body mass index (BMI) subgroup

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    End point title
    		 AUC(0-12 hour) of the change from Baseline to Week 12 in FEV1 for each body mass index (BMI) subgroup
    End point description
    The average of the two predose FEV1 measurements (30 minutes prior to dosing and 0 hour, immediately prior to dosing) at the Baseline Visit were subtracted from each of the serial measurements over the 12-hour period. The AUC was calculated based on these changes from Baseline evaluations. BMI is a number calculated from a person's weight and height. The higher the number, the higher the amount of fat. The comparison was for MF/F vs placebo. Standard deviation was pooled.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 MF/F MDI 100/10 mcg BID MF MDI 100 mcg BID F MDI 10 mcg BID Placebo BID
    Number of subjects analysed
    155 [26]
    156 [27]
    146 [28]
    128 [29]
    Units: Liter x hour
    least squares mean (standard deviation)
        Less than 25
    5.24 ( 4.42 )
    3.19 ( 4.42 )
    4.34 ( 4.42 )
    2.22 ( 4.42 )
        25 to less than 30
    3.36 ( 4.14 )
    3.23 ( 4.14 )
    4.26 ( 4.14 )
    1.22 ( 4.14 )
        30 or more
    3.35 ( 3.68 )
    1.69 ( 3.68 )
    3.13 ( 3.68 )
    -0.73 ( 3.68 )
    Notes
    [26] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [27] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [28] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    [29] - All Randomized Participants with BL and any post-BL data (intent-to-treat principle).
    Statistical analysis title
    		 MF/F MDI 100/10 mcg BID v. Placebo BID
    Statistical analysis description
    Least Squares (LS) Means and Pstd for post-baseline evaluations were obtained from the ANCOVA model with treatment, site effects, and the baseline FEV1 (liters) as a covariate. BL was the mean of two pre-dose measurements (30 minutes before dosing and 0 hour, immediately before dosing) on Day 1. The last post-BL non-missing FEV1 AUC(0-12 hr) result carried forward was used.
    Comparison groups
    MF/F MDI 100/10 mcg BID v Placebo BID
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015 [30]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [30] - BMI 25 to less than 30
    Statistical analysis title
    		 MF/F MDI 100/10 mcg BID vs. Placebo BID
    Statistical analysis description
    Least Squares (LS) Means and Pstd for post-baseline evaluations were obtained from the ANCOVA model with treatment, site effects, and the baseline FEV1 (liters) as a covariate. BL was the mean of two pre-dose measurements (30 minutes before dosing and 0 hour, immediately before dosing) on Day 1. The last post-BL non-missing FEV1 AUC(0-12 hr) result carried forward was used.
    Comparison groups
    MF/F MDI 100/10 mcg BID v Placebo BID
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [31]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [31] - BMI less than 25
    Statistical analysis title
    		 MF/F MDI 100/10 mcg BID vs. Placebo BID
    Statistical analysis description
    Least Squares (LS) Means and Pstd for post-baseline evaluations were obtained from the ANCOVA model with treatment, site effects, and the baseline FEV1 (liters) as a covariate. BL was the mean of two pre-dose measurements (30 minutes before dosing and 0 hour, immediately before dosing) on Day 1. The last post-BL non-missing FEV1 AUC(0-12 hr) result carried forward was used.
    Comparison groups
    MF/F MDI 100/10 mcg BID v Placebo BID
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [32]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [32] - BMI greater than or equal to 30

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Open Label Run-In + DB Treatment Period (Day -21 to Week 26)
    Adverse event reporting additional description
    All participants treated with OL MF MDI and/or double-blind study medication are included in the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    OL MF MDI 100 MCG BID
    Reporting group description
    		 Participants received 2 to 3 weeks (approximately) of open-label, run-in medication with MF MDI 100 mcg BID prior to the 26-week double-blind treatment period.

    Reporting group title
    MF/F MDI 100/10 MCG BID
    Reporting group description
    		 Participants received mometasone furoate 100 mcg and formoterol 10 mcg fixed dose combination taken twice daily for 26 weeks.

    Reporting group title
    MF MDI 100 MCG BID
    Reporting group description
    		 Participants received mometasone furoate 100 mcg taken twice daily for 26 weeks.

    Reporting group title
    F MDI 10 MCG BID'
    Reporting group description
    		 Participants received formoterol fumarate (F) 10 mcg taken twice daily for 26 weeks.

    Reporting group title
    PLACEBO
    Reporting group description
    		 Participants received placebo taken twice daily for 26 weeks.

    Serious adverse events
    		 OL MF MDI 100 MCG BID MF/F MDI 100/10 MCG BID MF MDI 100 MCG BID F MDI 10 MCG BID' PLACEBO
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 882 (0.23%)
    4 / 182 (2.20%)
    5 / 188 (2.66%)
    1 / 188 (0.53%)
    1 / 188 (0.53%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 882 (0.00%)
    1 / 182 (0.55%)
    0 / 188 (0.00%)
    0 / 188 (0.00%)
    0 / 188 (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
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 882 (0.00%)
    0 / 182 (0.00%)
    0 / 188 (0.00%)
    1 / 188 (0.53%)
    0 / 188 (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
    Cardiac disorders
    Pulmonary Valve Stenosis
         subjects affected / exposed
    0 / 882 (0.00%)
    1 / 182 (0.55%)
    0 / 188 (0.00%)
    0 / 188 (0.00%)
    0 / 188 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 882 (0.00%)
    0 / 182 (0.00%)
    1 / 188 (0.53%)
    0 / 188 (0.00%)
    0 / 188 (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
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 882 (0.00%)
    0 / 182 (0.00%)
    1 / 188 (0.53%)
    0 / 188 (0.00%)
    0 / 188 (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
    Gastrointestinal disorders
    Duodenal Ulcer
         subjects affected / exposed
    0 / 882 (0.00%)
    0 / 182 (0.00%)
    1 / 188 (0.53%)
    0 / 188 (0.00%)
    0 / 188 (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
    Reproductive system and breast disorders
    Dysfunctional Uterine Bleeding
         subjects affected / exposed
    0 / 882 (0.00%)
    1 / 182 (0.55%)
    0 / 188 (0.00%)
    0 / 188 (0.00%)
    0 / 188 (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
    Fallopian Tube Cyst
         subjects affected / exposed
    1 / 882 (0.11%)
    0 / 182 (0.00%)
    0 / 188 (0.00%)
    0 / 188 (0.00%)
    0 / 188 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 882 (0.11%)
    0 / 182 (0.00%)
    0 / 188 (0.00%)
    0 / 188 (0.00%)
    0 / 188 (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
    Pneumothorax
         subjects affected / exposed
    0 / 882 (0.00%)
    1 / 182 (0.55%)
    0 / 188 (0.00%)
    0 / 188 (0.00%)
    0 / 188 (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
    Pulmonary Embolism
         subjects affected / exposed
    0 / 882 (0.00%)
    0 / 182 (0.00%)
    0 / 188 (0.00%)
    0 / 188 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 882 (0.00%)
    0 / 182 (0.00%)
    1 / 188 (0.53%)
    0 / 188 (0.00%)
    0 / 188 (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
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 882 (0.00%)
    1 / 182 (0.55%)
    0 / 188 (0.00%)
    0 / 188 (0.00%)
    0 / 188 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 882 (0.00%)
    0 / 182 (0.00%)
    1 / 188 (0.53%)
    0 / 188 (0.00%)
    0 / 188 (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
    Viral Pericarditis
         subjects affected / exposed
    0 / 882 (0.00%)
    0 / 182 (0.00%)
    1 / 188 (0.53%)
    0 / 188 (0.00%)
    0 / 188 (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
    		 OL MF MDI 100 MCG BID MF/F MDI 100/10 MCG BID MF MDI 100 MCG BID F MDI 10 MCG BID' PLACEBO
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 882 (2.49%)
    33 / 182 (18.13%)
    37 / 188 (19.68%)
    32 / 188 (17.02%)
    24 / 188 (12.77%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 882 (1.70%)
    12 / 182 (6.59%)
    11 / 188 (5.85%)
    9 / 188 (4.79%)
    7 / 188 (3.72%)
         occurrences all number
    18
    17
    18
    9
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 882 (0.34%)
    17 / 182 (9.34%)
    13 / 188 (6.91%)
    7 / 188 (3.72%)
    5 / 188 (2.66%)
         occurrences all number
    3
    19
    15
    7
    5
    Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 882 (0.57%)
    10 / 182 (5.49%)
    17 / 188 (9.04%)
    20 / 188 (10.64%)
    12 / 188 (6.38%)
         occurrences all number
    5
    11
    19
    26
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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