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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled, Multicenter, Crossover Study to Evaluate the Effects of a Single Oral Dose of Montelukast, Compared with Placebo, on Exercise-Induced Bronchoconstriction (EIB) in Pediatric Patients aged 4 to 14 years

    Summary
    EudraCT number
    2007-004879-19
    Trial protocol
    EE  
    Global end of trial date
    26 Mar 2010

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

    Trial information

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    Trial identification
    Sponsor protocol code
    0476-377
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00534976
    WHO universal trial number (UTN)
    -
    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
    26 Mar 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Mar 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will see if there is a change in breathing after exercising when the child receives study drug (montelukast or placebo). Breathing will be measured by a spirometer before exercising and measured again several times after exercising.
    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: rescue with inhaled short-acting beta-agonist.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jan 2008
    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
    Colombia: 9
    Country: Number of subjects enrolled
    Costa Rica: 1
    Country: Number of subjects enrolled
    Estonia: 23
    Country: Number of subjects enrolled
    United States: 33
    Worldwide total number of subjects
    66
    EEA total number of subjects
    23
    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)
    33
    Adolescents (12-17 years)
    33
    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
    Of the 364 participants screened for inclusion, 298 participants were excluded during screening and were not randomized. The remaining 66 participants met inclusion criteria and were randomly allocated to one of the two treatment sequences.

    Period 1
    Period 1 title
    Period 1: Placebo Run-in
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Montelukast/ Placebo
    Arm description
    In Period 1 (screening period/ placebo run-in), participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one montelukast 4-mg chewable tablet (single dose). Period 3 was the crossover to one matching placebo 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one montelukast 5-mg chewable tablet (single dose) in Period 2, crossing over to one matching placebo 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 4-5 years: matching placebo to 4 mg montelukast chewable tablet daily; Participants 6-14 years: matching placebo to 5 mg montelukast chewable tablet daily

    Arm title
    Placebo/ Montelukast
    Arm description
    In Period 1 (screening period/ placebo run-in), participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one placebo 4-mg chewable tablet (single dose). Period 3 was the crossover to one montelukast 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one placebo 5-mg chewable tablet (single dose) in Period 2, crossing over to one montelukast 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 4-5 years: matching placebo to 4 mg montelukast chewable tablet daily; Participants 6-14 years: matching placebo to 5 mg montelukast chewable tablet daily

    Number of subjects in period 1
    Montelukast/ Placebo Placebo/ Montelukast
    Started
    33
    33
    Completed
    33
    33
    Period 2
    Period 2 title
    Period 2: Day 1
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Montelukast/ Placebo
    Arm description
    In Period 1 (screening period/ placebo run-in), participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one montelukast 4-mg chewable tablet (single dose). Period 3 was the crossover to one matching placebo 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one montelukast 5-mg chewable tablet (single dose) in Period 2, crossing over to one matching placebo 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    Montelukast sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 4-5 years: single dose of 4 mg montelukast chewable tablet on Day 1; Participants 6-14 years: single dose of 5 mg montelukast chewable tablet on Day 1

    Arm title
    Placebo/ Montelukast
    Arm description
    In Period 1 (screening period/ placebo run-in) participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one placebo 4-mg chewable tablet (single dose). Period 3 was the crossover to one montelukast 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one placebo 5-mg chewable tablet (single dose) in Period 2, crossing over to one montelukast 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 4-5 years: single dose of matching placebo to 4 mg montelukast chewable tablet daily on Day 1; Participants 6-14 years: single dose of matching placebo to 5 mg montelukast chewable tablet on Day 1

    Number of subjects in period 2
    Montelukast/ Placebo Placebo/ Montelukast
    Started
    33
    33
    Completed
    33
    32
    Not completed
    0
    1
         Protocol deviation
    -
    1
    Period 3
    Period 3 title
    Period 3: Day 5
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Montelukast/ Placebo
    Arm description
    In Period 1 (screening period/ placebo run-in) participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one montelukast 4-mg chewable tablet (single dose). Period 3 was the crossover to one matching placebo 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one montelukast 5-mg chewable tablet (single dose) in Period 2, crossing over to one matching placebo 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 4-5 years: single dose of matching placebo to 4 mg montelukast chewable tablet on Day 5; Participants 6-14 years: single dose of matching placebo to 5 mg montelukast chewable tablet on Day 5

    Arm title
    Placebo/ Montelukast
    Arm description
    In Period 1 (screening period/ placebo run-in) participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one placebo 4-mg chewable tablet (single dose). Period 3 was the crossover to one montelukast 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one placebo 5-mg chewable tablet (single dose) in Period 2, crossing over to one montelukast 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    Montelukast sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 4-5 years: single dose of 4 mg montelukast chewable tablet on Day 5; Participants 6-14 years: single dose of 5 mg montelukast chewable tablet on Day 5

    Number of subjects in period 3
    Montelukast/ Placebo Placebo/ Montelukast
    Started
    33
    32
    Completed
    31
    32
    Not completed
    2
    0
         Physician decision
    1
    -
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Montelukast/ Placebo
    Reporting group description
    In Period 1 (screening period/ placebo run-in), participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one montelukast 4-mg chewable tablet (single dose). Period 3 was the crossover to one matching placebo 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one montelukast 5-mg chewable tablet (single dose) in Period 2, crossing over to one matching placebo 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.

    Reporting group title
    Placebo/ Montelukast
    Reporting group description
    In Period 1 (screening period/ placebo run-in), participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one placebo 4-mg chewable tablet (single dose). Period 3 was the crossover to one montelukast 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one placebo 5-mg chewable tablet (single dose) in Period 2, crossing over to one montelukast 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.

    Reporting group values
    Montelukast/ Placebo Placebo/ Montelukast Total
    Number of subjects
    33 33
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    10.9 ± 2.3 11.5 ± 1.8 -
    Gender, Male/Female
    Units: participants
        Female
    14 15 29
        Male
    19 18 37

    End points

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    End points reporting groups
    Reporting group title
    Montelukast/ Placebo
    Reporting group description
    In Period 1 (screening period/ placebo run-in), participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one montelukast 4-mg chewable tablet (single dose). Period 3 was the crossover to one matching placebo 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one montelukast 5-mg chewable tablet (single dose) in Period 2, crossing over to one matching placebo 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.

    Reporting group title
    Placebo/ Montelukast
    Reporting group description
    In Period 1 (screening period/ placebo run-in), participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one placebo 4-mg chewable tablet (single dose). Period 3 was the crossover to one montelukast 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one placebo 5-mg chewable tablet (single dose) in Period 2, crossing over to one montelukast 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.
    Reporting group title
    Montelukast/ Placebo
    Reporting group description
    In Period 1 (screening period/ placebo run-in), participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one montelukast 4-mg chewable tablet (single dose). Period 3 was the crossover to one matching placebo 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one montelukast 5-mg chewable tablet (single dose) in Period 2, crossing over to one matching placebo 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.

    Reporting group title
    Placebo/ Montelukast
    Reporting group description
    In Period 1 (screening period/ placebo run-in) participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one placebo 4-mg chewable tablet (single dose). Period 3 was the crossover to one montelukast 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one placebo 5-mg chewable tablet (single dose) in Period 2, crossing over to one montelukast 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.
    Reporting group title
    Montelukast/ Placebo
    Reporting group description
    In Period 1 (screening period/ placebo run-in) participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one montelukast 4-mg chewable tablet (single dose). Period 3 was the crossover to one matching placebo 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one montelukast 5-mg chewable tablet (single dose) in Period 2, crossing over to one matching placebo 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.

    Reporting group title
    Placebo/ Montelukast
    Reporting group description
    In Period 1 (screening period/ placebo run-in) participants received a single-blind dose of matching-image placebo. In Period 2, participants 4-5 years of age were randomized to receive one placebo 4-mg chewable tablet (single dose). Period 3 was the crossover to one montelukast 4-mg chewable tablet (single dose) after a 3- to 7-day washout period. No participants 4-5 years of age were randomized, so the 4-mg doses were not dispensed. Participants 6-14 years of age were randomized to receive one placebo 5-mg chewable tablet (single dose) in Period 2, crossing over to one montelukast 5-mg chewable tablet (single dose) in Period 3 after a 3- to 7-day washout period.

    Subject analysis set title
    Montelukast
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Completers analysis population included all randomized participants who received the witnessed dose of study drug in both active treatment periods, had at least one post-exercise FEV1 measurement in both active treatment periods, and had to have a baseline pre-exercise challenge FEV1.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Completers analysis population included all randomized participants who received the witnessed dose of study drug in both active treatment periods, had at least one post-exercise FEV1 measurement in both active treatment periods, and had to have a baseline pre-exercise challenge FEV1.

    Subject analysis set title
    Montelukast
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Completers analysis population included all randomized participants who received the witnessed dose of study drug in both active treatment periods, had at least one post-exercise FEV1 measurement in both active treatment periods, and had to have a baseline pre-exercise challenge FEV1.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Completers analysis population included all randomized participants who received the witnessed dose of study drug in both active treatment periods, had at least one post-exercise FEV1 measurement in both active treatment periods, and had to have a baseline pre-exercise challenge FEV1.

    Primary: Maximum Percent Fall in FEV1 After Exercise Challenge at 2 Hours Postdose

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    End point title
    Maximum Percent Fall in FEV1 After Exercise Challenge at 2 Hours Postdose
    End point description
    Maximum Percent Fall in FEV1 was defined as the % change from pre-exercise baseline FEV1 to the lowest FEV1 within 60 mins (minutes) after exercise. Spirometry measurements were taken 5 mins prior to each exercise challenge and immediately, 5, 10, 15, 30, 45, & 60 mins after each exercise challenge. The 2-hour exercise challenges occurred 2 hours after the witnessed dose of study medication. The calculation used to produce the results was [100*(1-(X/Y))] where X= the lowest FEV1 within 60 mins after exercise & Y= pre-exercise baseline FEV1. Smaller values mean greater response to therapy. The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized participants who received the witnessed dose of study drug in both active treatment periods, had at least one post-exercise FEV1 measurement in both active treatment periods, and had to have a baseline pre-exercise challenge FEV1.
    End point type
    Primary
    End point timeframe
    Pre-exercise baseline and 0-60 minutes after the exercise challenge performed 2 hours post-dose
    End point values
    Montelukast Placebo
    Number of subjects analysed
    64
    64
    Units: Percent fall in FEV1
        arithmetic mean (standard deviation)
    15.35 ± 9.47
    20 ± 15.75
    Statistical analysis title
    Comparison between montelukast vs. placebo
    Statistical analysis description
    There were a total of 64 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02
    Method
    ANOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -4.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.55
         upper limit
    -0.75

    Secondary: Maximum percent fall in FEV1 after exercise challenge at 24 hours post-dose

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    End point title
    Maximum percent fall in FEV1 after exercise challenge at 24 hours post-dose
    End point description
    Maximum Percent Fall in FEV1 was defined as the % change from pre-exercise baseline FEV1 to the lowest FEV1 within 60 mins after exercise. Spirometry measurements were taken 5 mins prior to each exercise challenge and immediately, 5, 10, 15, 30, 45, & 60 mins after each exercise challenge. The 24-hour exercise challenges occurred 20-24 hours after the witnessed dose of study medication. The calculation used to produce the resulted results was [100*(1-(X/Y))] where X= the lowest FEV1 within 60 mins after exercise & Y= pre-exercise baseline FEV1. Smaller values mean greater response to therapy. The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized participants who received the witnessed dose of study drug in both active treatment periods, had at least one post-exercise FEV1 measurement in both active treatment periods, and had to have a baseline pre-exercise challenge FEV1.
    End point type
    Secondary
    End point timeframe
    Pre-exercise baseline and 0-60 minutes after the exercise challenge performed 24 hours post-dose
    End point values
    Montelukast Placebo
    Number of subjects analysed
    62
    62
    Units: percent fall in FEV1
        arithmetic mean (standard deviation)
    12.96 ± 10.38
    17.22 ± 12.06
    Statistical analysis title
    Comparison between montelukast vs. placebo
    Statistical analysis description
    There were a total of 62 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Placebo
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.005
    Method
    ANOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -4.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.31
         upper limit
    -1.34

    Secondary: Area Under the Curve for FEV1 percent fall from pre-exercise baseline to 60 minutes following exercise challenge (AUC0-60 min) at 2 hours post-dose

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    End point title
    Area Under the Curve for FEV1 percent fall from pre-exercise baseline to 60 minutes following exercise challenge (AUC0-60 min) at 2 hours post-dose
    End point description
    AUC0-60min was defined as the Area Under the Curve for FEV1 percent change from pre-exercise baseline to the 60 mins following exercise challenge. The area was computed by applying the trapezoidal rule, and including only the area below the pre-exercise baseline. If a participant received β-agonist during the 60 mins after the exercise challenge, the FEV1 measurements obtained after β-agonist administration were excluded and the last pre-rescue FEV1 measurement was carried forward to the 60 mins time point in the calculation of the AUC0-60 min. Smaller values mean greater response to therapy. The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized participants who received the witnessed dose of study drug in both active treatment periods, had at least one post-exercise FEV1 measurement in both active treatment periods, and had to have a baseline pre-exercise challenge FEV1.
    End point type
    Secondary
    End point timeframe
    Pre-exercise baseline to 60 minutes after the exercise challenge performed 2 hours post-dose
    End point values
    Montelukast Placebo
    Number of subjects analysed
    64
    64
    Units: percent fall * minute
        arithmetic mean (standard deviation)
    294.5 ± 278.46
    415.37 ± 375.94
    Statistical analysis title
    Comparison between montelukast vs. placebo
    Statistical analysis description
    There were a total of 64 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.022
    Method
    ANOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -120.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -223.77
         upper limit
    -17.95

    Secondary: Area Under the Curve for FEV1 percent fall from pre-exercise baseline to 60 minutes following exercise challenge (AUC0-60 min) at 24 hours post-dose

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    End point title
    Area Under the Curve for FEV1 percent fall from pre-exercise baseline to 60 minutes following exercise challenge (AUC0-60 min) at 24 hours post-dose
    End point description
    AUC0-60min was defined as the Area Under the Curve for FEV1 percent change from pre-exercise baseline to the 60 mins following exercise challenge. The area was computed by applying the trapezoidal rule, and including only the area below the pre-exercise baseline. If a participant received β-agonist during the 60 mins after the exercise challenge, the FEV1 measurements obtained after β-agonist administration were excluded and the last pre-rescue FEV1 measurement was carried forward to the 60 mins time point in the calculation of the AUC0-60 min. Smaller values mean greater response to therapy. The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized participants who received the witnessed dose of study drug in both active treatment periods, had at least one post-exercise FEV1 measurement in both active treatment periods, and had to have a baseline pre-exercise challenge FEV1.
    End point type
    Secondary
    End point timeframe
    Pre-exercise baseline to 60 minutes after the exercise challenge performed 24 hours post-dose
    End point values
    Montelukast Placebo
    Number of subjects analysed
    62
    62
    Units: percent fall * minute
        arithmetic mean (standard deviation)
    229.19 ± 233.93
    349.59 ± 315.29
    Statistical analysis title
    Comparison between montelukast vs. placebo
    Statistical analysis description
    There were a total of 62 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Placebo
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.013
    Method
    ANOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -122.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -218.36
         upper limit
    -27.29

    Secondary: Time to recovery from Maximum Percent Fall in FEV1 at 2 hours post-dose

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    End point title
    Time to recovery from Maximum Percent Fall in FEV1 at 2 hours post-dose
    End point description
    This endpoint was defined as the duration between the time at which the maximum percent fall in FEV1 occurred & the time when the percent fall in FEV1 returned to within 5% of the pre-exercise baseline for the first time. Spirometry measurements were taken 5 mins prior to each exercise challenge & immediately, 5, 10, 15, 30, 45, & 60 mins after each exercise challenge. If participant had not returned to within 5% of the pre-exercise FEV1 value by 60 mins, then measurements were obtained at 75 & 90 mins. The 2-hour exercise challenges occurred 2 hours after the witnessed dose of medication. The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized participants who received the witnessed dose of study drug in both active treatment periods, had at least one post-exercise FEV1 measurement in both active treatment periods, and had to have a baseline pre-exercise challenge FEV1.
    End point type
    Secondary
    End point timeframe
    0-60 minutes and 0-90 minutes after the exercise challenge at 2 hours postdose
    End point values
    Montelukast Placebo
    Number of subjects analysed
    64
    64
    Units: Minutes
        arithmetic mean (standard deviation)
    16.21 ± 22.01
    24.48 ± 27.91
    Statistical analysis title
    Comparison between montelukast vs. placebo
    Statistical analysis description
    There were a total of 64 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.064
    Method
    ANOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -8.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.04
         upper limit
    0.51

    Secondary: Time to recovery from maximum percent fall in FEV1 at 24 hours post-dose

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    End point title
    Time to recovery from maximum percent fall in FEV1 at 24 hours post-dose
    End point description
    This endpoint was defined as the duration between the time at which the maximum percent fall in FEV1 occurred & the time when the percent fall in FEV1 returned to within 5% of the pre-exercise baseline for the first time. Spirometry measurements were taken 5 mins prior to each exercise challenge & immediately, 5, 10, 15, 30, 45 & 60 mins after each exercise challenge. If participant had not returned to within 5% of the pre-exercise FEV1 value by 60 mins, then measurements were obtained at 75 & 90 mins. The 24-hour exercise challenges occurred 20-24 hours after the witnessed dose of medication. The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized participants who received the witnessed dose of study drug in both active treatment periods, had at least one post-exercise FEV1 measurement in both active treatment periods, and had to have a baseline pre-exercise challenge FEV1.
    End point type
    Secondary
    End point timeframe
    0-60 minutes and 0-90 minutes after the exercise challenge at 24 hours postdose
    End point values
    Montelukast Placebo
    Number of subjects analysed
    62
    62
    Units: Minutes
        arithmetic mean (standard deviation)
    11.58 ± 16.51
    18.46 ± 22.66
    Statistical analysis title
    Comparison between montelukast vs. placebo
    Statistical analysis description
    There were a total of 62 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Placebo
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.054
    Method
    ANOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -7.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.23
         upper limit
    0.11

    Secondary: Number of participants requiring rescue medication at 2 hours postdose

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    End point title
    Number of participants requiring rescue medication at 2 hours postdose
    End point description
    This endpoint was defined as the number of participants requiring rescue medication with β-agonist within the 90 mins following exercise challenge. The 2-hour exercise challenges occurred 2 hours after the witnessed dose of study medication. The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized participants who received the witnessed dose of study drug in both active treatment periods and had at least one post-exercise FEV1 measurement in both active treatment periods.
    End point type
    Secondary
    End point timeframe
    0-90 minutes after the exercise challenge at 2 hours postdose
    End point values
    Montelukast Placebo
    Number of subjects analysed
    64
    64
    Units: participants
        number (not applicable)
    1
    2
    Statistical analysis title
    Comparison between montelukast vs. placebo
    Statistical analysis description
    There were a total of 64 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 1 [1]
    Method
    Mcnemar
    Parameter type
    Difference in proportions
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.27
         upper limit
    5.63
    Notes
    [1] - P-value provided is for comparison between the two proportions: Montelukast versus placebo.

    Secondary: Number of participants requiring rescue medication at 24 hours postdose

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    End point title
    Number of participants requiring rescue medication at 24 hours postdose
    End point description
    This endpoint was defined as the number of participants requiring rescue medication with β-agonist within the 90 mins following exercise challenge. The 24-hour exercise challenges occurred 20-24 hours after the witnessed dose of study medication. The analysis of efficacy data was carried out using a completers analysis population. This population included all randomized participants who received the witnessed dose of study drug in both active treatment periods and had at least one post-exercise FEV1 measurement in both active treatment periods.
    End point type
    Secondary
    End point timeframe
    0-90 minutes after the exercise challenge at 24 hours postdose
    End point values
    Montelukast Placebo
    Number of subjects analysed
    62
    62
    Units: Participants
        number (not applicable)
    0
    2
    Statistical analysis title
    Comparison between montelukast vs. placebo
    Statistical analysis description
    There were a total of 62 participants included in this analysis (cross-over design).
    Comparison groups
    Montelukast v Placebo
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in proportions
    Point estimate
    -3.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.02
         upper limit
    3.06

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to 24 days (including 14 days following the last dose of study drug)
    Adverse event reporting additional description
    The analysis of safety data was carried out using an all participants as treated (APaT) population. This population included all randomized participants who received at least one dose of study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Montelukast
    Reporting group description
    In Period 1 (screening period/ placebo run-in) participants received a single-blind dose of matching-image placebo. Participants 6-14 years of age were randomized to receive one montelukast 5-mg chewable tablet (single dose) in Period 2 or Period 3, according to the randomized treatment sequence assigned. Period 2 and Period 3 were separated by a washout period of 3-7 days.

    Reporting group title
    Placebo
    Reporting group description
    In Period 1 (screening period/ placebo run-in) participants received a single-blind dose of matching-image placebo. Participants 6-14 years of age were randomized to receive one matching placebo 5-mg chewable tablet (single dose) in Period 2 or Period 3, according to the randomized treatment sequence assigned. Period 2 and Period 3 were separated by a washout period of 3-7 days.

    Serious adverse events
    Montelukast Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 66 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Montelukast Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 66 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events occurred in greater than 5% of participants in any reporting group.

    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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