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    Clinical Trial Results:
    A Multicenter, Double-Blind, Randomized, Cross-Over Design Study to Evaluate the Effect of Montelukast vs. Salmeterol on the Inhibition of Exercise-Induced Bronchoconstriction in Asthmatic Patients Aged 6-14 Years.

    Summary
    EudraCT number
    2004-004709-53
    Trial protocol
    EE   ES   IT   Outside EU/EEA  
    Global end of trial date
    14 Nov 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    15 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-0476-911
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00127166
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Merck Protocol Number: MK-0476-911
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Nov 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Nov 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine the effect of four weeks of treatment with two investigational drugs (oral versus inhaled administration) plus an inhaled medication in the treatment of airway constriction brought on by exercise in participants with 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: salbutamol was to be used throughout all periods on an “as needed” basis for rescue.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Dec 2005
    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
    Spain: 2
    Country: Number of subjects enrolled
    Estonia: 17
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Brazil: 41
    Country: Number of subjects enrolled
    Colombia: 25
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Peru: 20
    Country: Number of subjects enrolled
    Poland: 14
    Worldwide total number of subjects
    154
    EEA total number of subjects
    60
    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)
    112
    Adolescents (12-17 years)
    42
    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
    For randomization, participants fulfilled the following criteria: 1. Forced Expiratory Volume in one second (FEV1) ≥70% predicted while withholding beta (β)-agonist for at least 6 hours 2. Exercise-induced bronchoconstriction (EIB) showing FEV1 ≥15% reduction from baseline while on inhaled corticosteroids demonstrated twice during the run-in period

    Period 1
    Period 1 title
    Period I
    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
    Montelukast / Salmeterol
    Arm description
    Period I- Montelukast 5 mg oral tablet once daily and salmeterol matching placebo dry powder inhaler (DPI) twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- Montelukast matching placebo oral tablet once daily and salmeterol DPI 50 mcg twice daily for 4 weeks. Inhaled fluticasone 100 mcg twice daily throughout the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Montelukast sodium
    Investigational medicinal product code
    Other name
    MK-0476
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Montelukast 5 mg oral tablet once daily

    Investigational medicinal product name
    Salmeterol matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Matching placebo to salmeterol dry powder for inhalation administered twice daily

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Flixotide Evohaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone (50 mcg per actuation) 100 mcg inhaled twice daily

    Arm title
    Salmeterol / Montelukast
    Arm description
    Period I- Montelukast matching placebo oral tablet once daily and salmeterol DPI 50 mcg twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- Montelukast 5 mg oral tablet once daily and salmeterol matching placebo DPI twice daily for 4 weeks. Inhaled fluticasone 100 mcg twice daily throughout the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Salmeterol xinafoate
    Investigational medicinal product code
    Other name
    Serevent Accuhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Salmeterol 50 mcg dry powder per actuation inhaled twice daily

    Investigational medicinal product name
    Montelukast matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to montelukast oral tablet administered once daily

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Flixotide Evohaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone (50 mcg per actuation) 100 mcg inhaled twice daily

    Number of subjects in period 1
    Montelukast / Salmeterol Salmeterol / Montelukast
    Started
    78
    76
    Completed
    75
    74
    Not completed
    3
    2
         Protocol deviation
             -
             2
         Participant did not meet inclusion criteria
             1
             -
         Consent withdrawn by subject
             2
             -
    Period 2
    Period 2 title
    Washout Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Montelukast / Salmeterol
    Arm description
    Period I- Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily throughout the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Flixotide Evohaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone (50 mcg per actuation) 100 mcg inhaled twice daily

    Investigational medicinal product name
    Salmeterol matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Matching placebo to salmeterol dry powder for inhalation administered twice daily

    Investigational medicinal product name
    Montelukast matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to montelukast oral tablet administered once daily

    Arm title
    Salmeterol / Montelukast
    Arm description
    Period I- Montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily throughout the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Flixotide Evohaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone (50 mcg per actuation) 100 mcg inhaled twice daily

    Investigational medicinal product name
    Salmeterol matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Matching placebo to salmeterol dry powder for inhalation administered twice daily

    Investigational medicinal product name
    Montelukast matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to montelukast oral tablet administered once daily

    Number of subjects in period 2
    Montelukast / Salmeterol Salmeterol / Montelukast
    Started
    75
    74
    Completed
    75
    73
    Not completed
    0
    1
         Participant did not meet inclusion criteria
             -
             1
    Period 3
    Period 3 title
    Period II
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Montelukast / Salmeterol
    Arm description
    Period I- Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily throughout the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Montelukast matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to montelukast oral tablet administered once daily

    Investigational medicinal product name
    Salmeterol xinafoate
    Investigational medicinal product code
    Other name
    Serevent Accuhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Salmeterol 50 mcg dry powder per actuation inhaled twice daily

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Flixotide Evohaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone (50 mcg per actuation) 100 mcg inhaled twice daily

    Arm title
    Salmeterol / Montelukast
    Arm description
    Period I- Montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily throughout the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Montelukast sodium
    Investigational medicinal product code
    Other name
    MK-0476
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Montelukast 5 mg oral tablet once daily

    Investigational medicinal product name
    Salmeterol matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Matching placebo to salmeterol dry powder inhaler administered twice daily

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Flixotide Evohaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone (50 mcg per actuation) 100 mcg inhaled twice daily

    Number of subjects in period 3
    Montelukast / Salmeterol Salmeterol / Montelukast
    Started
    75
    73
    Completed
    72
    73
    Not completed
    3
    0
         Participant did not perform last visit exercise
             1
             -
         Consent withdrawn by subject
             2
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Montelukast / Salmeterol
    Reporting group description
    Period I- Montelukast 5 mg oral tablet once daily and salmeterol matching placebo dry powder inhaler (DPI) twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- Montelukast matching placebo oral tablet once daily and salmeterol DPI 50 mcg twice daily for 4 weeks. Inhaled fluticasone 100 mcg twice daily throughout the study.

    Reporting group title
    Salmeterol / Montelukast
    Reporting group description
    Period I- Montelukast matching placebo oral tablet once daily and salmeterol DPI 50 mcg twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- Montelukast 5 mg oral tablet once daily and salmeterol matching placebo DPI twice daily for 4 weeks. Inhaled fluticasone 100 mcg twice daily throughout the study.

    Reporting group values
    Montelukast / Salmeterol Salmeterol / Montelukast Total
    Number of subjects
    78 76 154
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.2 ± 2 9.8 ± 2 -
    Gender categorical
    Units: Subjects
        Female
    35 30 65
        Male
    43 46 89
    Race
    Units: Subjects
        Asian
    1 0 1
        Black
    11 7 18
        White
    38 41 79
        Hispanic
    15 18 33
        Multiracial
    13 10 23
    Area under the curve from 0 to 20 minutes (AUC(0-20))
    Area Under the Curve for percent-change from pre-exercise baseline FEV1 in liters, from 0 to 20 minutes (AUC(0-20))
    Units: Percent times minutes
        arithmetic mean (standard deviation)
    320.08 ± 208.62 317.74 ± 165.71 -
    Avg %-change from pre-exercise baseline FEV1 after 1st β-agonist use & Prior to 2nd β-agonist use
    Average (avg) percent (%)-change from pre-exercise baseline FEV1 after 1st β-agonist use & prior to 2nd β-agonist use
    Units: Percent change from baseline
        arithmetic mean (standard deviation)
    1.36 ± 10.99 4.78 ± 10.92 -
    Maximum FEV1 Percent Predicted
    Units: Percent of predicted value
        arithmetic mean (standard deviation)
    99.88 ± 32.45 100.54 ± 15.61 -
    Maximum Percent Fall in FEV1 After Exercise
    Units: Percent change from baseline
        arithmetic mean (standard deviation)
    24.77 ± 10.25 25.42 ± 9.04 -
    Time to recovery
    Population includes participants who returned to within 5% of the baseline FEV1 value. Montelukast / Salmeterol, n=71; Salmeterol / Montelukast, n=70
    Units: Minutes
        arithmetic mean (standard deviation)
    23.53 ± 10.53 21.51 ± 8.3 -

    End points

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    End points reporting groups
    Reporting group title
    Montelukast / Salmeterol
    Reporting group description
    Period I- Montelukast 5 mg oral tablet once daily and salmeterol matching placebo dry powder inhaler (DPI) twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- Montelukast matching placebo oral tablet once daily and salmeterol DPI 50 mcg twice daily for 4 weeks. Inhaled fluticasone 100 mcg twice daily throughout the study.

    Reporting group title
    Salmeterol / Montelukast
    Reporting group description
    Period I- Montelukast matching placebo oral tablet once daily and salmeterol DPI 50 mcg twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- Montelukast 5 mg oral tablet once daily and salmeterol matching placebo DPI twice daily for 4 weeks. Inhaled fluticasone 100 mcg twice daily throughout the study.
    Reporting group title
    Montelukast / Salmeterol
    Reporting group description
    Period I- Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily throughout the study.

    Reporting group title
    Salmeterol / Montelukast
    Reporting group description
    Period I- Montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily throughout the study.
    Reporting group title
    Montelukast / Salmeterol
    Reporting group description
    Period I- Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily throughout the study.

    Reporting group title
    Salmeterol / Montelukast
    Reporting group description
    Period I- Montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks followed by a 2-week washout period (salmeterol matching placebo + montelukast matching placebo). Period II- Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily throughout the study.

    Subject analysis set title
    Montelukast
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The primary efficacy analysis was based on the full analysis set (FAS) population which included all randomized participants who took at least one dose of post randomization study drug and had a measurement for analysis available in both treatment periods of the cross-over design.

    Subject analysis set title
    Salmeterol
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The primary efficacy analysis was based on the full analysis set (FAS) population which included all randomized participants who took at least one dose of post randomization study drug and had a measurement for analysis available in both treatment periods of the cross-over design.

    Primary: Maximum post-exercise percent fall in FEV1

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    End point title
    Maximum post-exercise percent fall in FEV1
    End point description
    The effect of four weeks of treatment with oral montelukast plus inhaled fluticasone, and inhaled salmeterol plus inhaled fluticasone on EIB as measured by the maximum post-exercise percent fall (relative to pre-exercise baseline) in FEV1.
    End point type
    Primary
    End point timeframe
    4 weeks (Weeks 0 to 4 or Weeks 6 to 10)
    End point values
    Montelukast Salmeterol
    Number of subjects analysed
    144
    144
    Units: Percent change from baseline
        least squares mean (confidence interval 95%)
    10.57 (8.86 to 12.27)
    13.82 (12.11 to 15.52)
    Statistical analysis title
    Difference in least squares mean
    Statistical analysis description
    There were a total of 144 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Salmeterol
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.009 [1]
    Method
    ANOVA
    Parameter type
    Least squares mean difference
    Point estimate
    -3.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.66
         upper limit
    -0.84
    Notes
    [1] - Model terms: participant, treatment and period. The treatment test is adjusted for period.

    Secondary: Area under the curve for percent-change from pre-exercise baseline FEV1 in liters, from 0 to 20 Minutes (AUC(0-20))

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    End point title
    Area under the curve for percent-change from pre-exercise baseline FEV1 in liters, from 0 to 20 Minutes (AUC(0-20))
    End point description
    The effect of a four-week treatment course of oral montelukast plus inhaled fluticasone, compared to inhaled salmeterol plus inhaled fluticasone, on the extent and severity of EIB as measured by the area under the curve from 0 to 20 minutes (AUC0-20) for FEV1 percent change from pre-exercise baseline.
    End point type
    Secondary
    End point timeframe
    4 weeks (Weeks 0 to 4 or Weeks 6 to 10)
    End point values
    Montelukast Salmeterol
    Number of subjects analysed
    144
    144
    Units: Percent times minutes
        least squares mean (confidence interval 95%)
    116.04 (89.95 to 142.24)
    168.75 (142.56 to 194.95)
    Statistical analysis title
    Difference in least squares mean
    Statistical analysis description
    There were a total of 144 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Salmeterol
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.006 [2]
    Method
    ANOVA
    Parameter type
    Least squares mean difference
    Point estimate
    -52.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -89.76
         upper limit
    -15.66
    Notes
    [2] - Model terms: participant, treatment and period. The treatment test is adjusted for period.

    Secondary: Maximum FEV1 percent predicted following first β-agonist use

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    End point title
    Maximum FEV1 percent predicted following first β-agonist use
    End point description
    The effect of a four-week treatment course of oral montelukast plus inhaled fluticasone, compared to inhaled salmeterol plus inhaled fluticasone, on short-acting β-agonist bronchodilation as measured by the maximum FEV1 percent predicted following first β-agonist use.
    End point type
    Secondary
    End point timeframe
    4 weeks (Weeks 0 to 4 or Weeks 6 to 10)
    End point values
    Montelukast Salmeterol
    Number of subjects analysed
    144
    144
    Units: Percent of predicted value
        least squares mean (confidence interval 95%)
    104.03 (102.83 to 105.23)
    99.92 (98.72 to 101.12)
    Statistical analysis title
    Difference in least squares mean
    Statistical analysis description
    There were a total of 144 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Salmeterol
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [3]
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    4.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.58
         upper limit
    5.64
    Notes
    [3] - Terms: participant, treatment, period & covariate for FEV1 %-predicted at pre-exercise baseline.

    Secondary: Time to recovery to within 5 percent of baseline FEV1

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    End point title
    Time to recovery to within 5 percent of baseline FEV1
    End point description
    The effect of a four-week treatment course of oral montelukast plus inhaled fluticasone, compared to inhaled salmeterol plus inhaled fluticasone, on the extent and severity of EIB as measured by the time to recovery (to within 5 percent of the pre-exercise baseline FEV1) following a standardized exercise challenge.
    End point type
    Secondary
    End point timeframe
    4 weeks (Weeks 0 to 4 or Weeks 6 to 10)
    End point values
    Montelukast Salmeterol
    Number of subjects analysed
    144
    144
    Units: minutes
        median (inter-quartile range (Q1-Q3))
    5.9 (0 to 19.12)
    11.1 (0.065 to 22.94)
    Statistical analysis title
    Comparison between montelukast vs. salmeterol
    Statistical analysis description
    There were a total of 144 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Salmeterol
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    P-value
    = 0.035 [5]
    Method
    Cox proportional hazard model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.02
         upper limit
    1.55
    Notes
    [4] - A robust estimate of the variance of the treatment effect was calculated using the marginal approach introduced by Wei, Lin and Weissfeld (WLW model).
    [5] - Model terms: treatment and period.

    Secondary: Average percent-change in FEV1 after first β-agonist use and prior to second β-agonist use

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    End point title
    Average percent-change in FEV1 after first β-agonist use and prior to second β-agonist use
    End point description
    The effect of a four-week treatment course of oral montelukast plus inhaled fluticasone, compared to inhaled salmeterol plus inhaled fluticasone, on the extent and severity of EIB as measured by the average percent change in FEV1 after first β-agonist intake and prior to second β-agonist use.
    End point type
    Secondary
    End point timeframe
    4 weeks (Weeks 0 to 4 or Weeks 6 to 10)
    End point values
    Montelukast Salmeterol
    Number of subjects analysed
    144
    144
    Units: Percent change from baseline
        least squares mean (confidence interval 95%)
    6.51 (5.44 to 7.59)
    2.72 (1.64 to 3.79)
    Statistical analysis title
    Difference in least squares mean
    Statistical analysis description
    There were a total of 144 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Salmeterol
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [6]
    Method
    ANOVA
    Parameter type
    Least squares mean difference
    Point estimate
    3.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.28
         upper limit
    5.32
    Notes
    [6] - Model terms: participant, treatment and period. The treatment test is adjusted for period.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 12 weeks (including 2 weeks following last dose of study drug)
    Adverse event reporting additional description
    Of 154 participants enrolled, only 150 took at least 1 dose of each treatment (tx); 78 were in Montelukast (M) /Salmeterol (S) sequence (seq) and 76 in S/M seq. 4 participants in M/S seq only took 1st tx; so 78 took M & 74 took S. 4 different participants in S/M seq only took 1st tx; so 76 took S & 72 took M. Total 150 pts took M and 150 took S.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Montelukast
    Reporting group description
    Period I- Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks. Period II- Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily throughout the study.

    Reporting group title
    Salmeterol
    Reporting group description
    Period I- Montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks. Period II- Montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily throughout the study.

    Serious adverse events
    Montelukast Salmeterol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 150 (0.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Montelukast Salmeterol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 150 (18.00%)
    21 / 150 (14.00%)
    Injury, poisoning and procedural complications
    Ear injury
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 150 (0.67%)
         occurrences all number
    1
    1
    Skin injury
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Wound
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 150 (2.67%)
    4 / 150 (2.67%)
         occurrences all number
    4
    4
    Bronchospasm
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Allergy to plants
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 150 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 150 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 150 (0.00%)
         occurrences all number
    2
    0
    Toothache
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Menstruation delayed
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Eczema
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 150 (0.67%)
         occurrences all number
    1
    1
    Skin lesion
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    Infections and infestations
    Candidiasis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 150 (0.67%)
         occurrences all number
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 150 (1.33%)
    1 / 150 (0.67%)
         occurrences all number
    2
    1
    Pertussis
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 150 (0.00%)
         occurrences all number
    2
    0
    Pharyngitis
         subjects affected / exposed
    5 / 150 (3.33%)
    3 / 150 (2.00%)
         occurrences all number
    5
    3
    Pneumonia
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    3 / 150 (2.00%)
    2 / 150 (1.33%)
         occurrences all number
    3
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 150 (0.67%)
         occurrences all number
    1
    1
    Viral infection
         subjects affected / exposed
    0 / 150 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    0
    2
    Viral pharyngitis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    Viral rhinitis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2005
    Amendment 1: Primary reason for the amendment was to update the salmeterol dosage to salmeterol/matching placebo drug powder inhaler (DPI) formulation 50 mcg/puff, one puff twice daily, total dose of 100 mcg/day. Use of spacer device with salmeterol was deleted.
    16 Jan 2007
    Amendment 2: Primary reason for the amendment was that participants must demonstrate exercise induced bronchoconstriction with post-exercise decline in FEV1 of 15 % (change from 20 %).

    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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