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    Clinical Trial Results:
    A Multicenter, Randomised, Double Blind Study Comparing the Clinical Effects of Intravenous Montelukast With Placebo in Patients With Acute Asthma

    Summary
    EudraCT number
    		 2004-000614-39
    Trial protocol
    		 IT   DK  
    Global end of trial date
    12 Mar 2007

    Results information
    Results version number
    		 v1
    This version publication date
    11 May 2016
    First version publication date
    10 Apr 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    0476-288
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00092989
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharpe & 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)
    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
    12 Mar 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Mar 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the safety and efficacy of montelukast (Singulair™) 7 mg, a leukotriene receptor antagonist, in the treatment of acute exacerbations of asthma when given as an intravenous (IV) bolus dose in addition to a standard care regimen consistent with the Global Initiative for Asthma (GINA) guideline recommendations. During a 60 minute screening period, change from baseline (BL) in lung function was quantified as forced expiratory volume in 1 second (FEV1) before and after the administration of standard care for acute asthma in an emergency department. The primary hypothesis was that in adult patients with acute asthma, the addition of montelukast IV 7 mg to standard therapy will cause a significant improvement in FEV1 within the first 60 minutes after administration (i.e., average change in FEV1 from preallocation baseline over the first 60 minutes after study drug administration) compared with placebo.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The following additional measures for this study were in place for the protection of trial participants: Rescue medication was available for participants that required rescue therapy within 3 hours following the end of study drug administration. Rescue therapy was defined as the administration of any of the following treatments within 30 minutes prior to end of study drug administration, or at least 10 minutes after end of study drug administration and within 3 hours following the end of study drug administration: systemic corticosteroids (prednisone/prednisolone), short-acting β-agonists (albuterol/salbutamol), short-acting anti-cholinergic drugs (ipratropium), magnesium.
    Background therapy
    		 Upon entering the Screening Period (Period 1), standardized treatment for an acute severe asthma episode was initiated and continued throughout the Treatment Period (Period 2) for all participants. Standardized treatment could consist of: (1) β-agonist, (2) oxygen therapy, (3) inhaled ipratropium (optional), and 4) systemic corticosteroids (only administered following completion of study drug in Period 2).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jul 2004
    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
    Peru: 59
    Country: Number of subjects enrolled
    Guatemala: 10
    Country: Number of subjects enrolled
    South Africa: 22
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Mexico: 40
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Colombia: 24
    Country: Number of subjects enrolled
    United States: 318
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    India: 19
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 28
    Country: Number of subjects enrolled
    Italy: 28
    Worldwide total number of subjects
    583
    EEA total number of subjects
    57
    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)
    9
    Adults (18-64 years)
    529
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from 34 sites in the United States and 28 sites in 15 countries.

    Pre-assignment
    Screening details
    		 Screening began at participant arrival at the study site and consisted of the time between the start of urgent treatment (oxygen, short-acting β-agonist) and IV montelukast or placebo, not to exceed 60 minutes

    Pre-assignment period milestones
    Number of subjects started
    		 1147 [1]
    Number of subjects completed
    		 583

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Participant ineligible: 545
    Reason: Number of subjects
    		 Consent withdrawn by subject: 14
    Reason: Number of subjects
    		 Protocol deviation: 5
    Notes
    [1] - The number of subjects reported to have started the pre-assignment 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 worldwide number represents the number of eligible enrolled participants that were treated on study. 1147 participants were screened for inclusion.
    Period 1
    Period 1 title
    Pre-allocation Evaluation and Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Pre-allocation Evaluation and Treatment
    Arm description
    		 Participants admitted to the study site because of an acute exacerbation of asthma entered the screening period (Period 1) and received standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium).
    Arm type
    		 Pre-study Evaluation and Treatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Pre-allocation Evaluation and Treatment
    Started
    583
    Completed
    583
    Period 2
    Period 2 title
    Active Treatment
    Is this the baseline period?
    		 Yes [2]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Montelukast 7 mg + Standard Treatment
    Arm description
    		 During Period 2, randomised participants received IV montelukast 7 mg in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of montelukast.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Montelukast sodium
    Investigational medicinal product code
    Other name
    Singulair™
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Participants received IV montelukast administered in one 7 mg dose after reconstitution of a vial containing montelukast sodium in a lypophilised powder form dissolved in 20 mL of a solution of 3.3% dextrose/0.3% sodium chloride and given as a manual bolus over a period of 2 to 5 minutes.

    Arm title
    		 Placebo + Standard Treatment
    Arm description
    		 During Period 2, randomised participants received IV placebo for montelukast in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of IV placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for montelukast
    Investigational medicinal product code
    Other name
    Singulair™
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Participants received matching placebo for montelukast supplied as a lyophilised powder in light-protected vials. Placebo powder was reconstituted in 20 mL of a solution of 3.3% dextrose/0.3% sodium chloride and given as a manual bolus infusion over 2 to 5 minutes.

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 was a screening period to determine eligibility for randomization in Period 2. For the purpose of reporting baseline characteristics by reporting arm, Period 2 has been designated the baseline period.
    Number of subjects in period 2
    		Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
    Started
    291
    292
    Completed
    288
    285
    Not completed
    3
    7
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    -
    1
         Infusion complications
    3
    1
         Protocol deviation
    -
    1
         Lack of efficacy
    -
    3
    Period 3
    Period 3 title
    Post-study (14 Days)
    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 7 mg + Standard Treatment: Post-Study
    Arm description
    		 During the follow-up period, montelukast-treated participants received a telephone call approximately 14 days after the participant had completed Period 2 to review information on subsequent asthma-related healthcare contacts (doctor visits, emergency visits, and/or hospitalizations), asthma-related medication usage, impact on work, concomitant therapies, adverse experiences, and procedures that may have been performed within the 14 ± 3 days.
    Arm type
    		 Follow-up

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo + Standard Treatment: Post-Study
    Arm description
    		 During the follow-up period, placebo-treated participants received a telephone call approximately 14 days after the participant had completed Period 2 to review information on subsequent asthma-related healthcare contacts (doctor visits, emergency visits, and/or hospitalizations), asthma-related medication usage, impact on work, concomitant therapies, adverse experiences, and procedures that may have been performed within the 14 ± 3 days.
    Arm type
    		 Follow-up

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Montelukast 7 mg + Standard Treatment: Post-Study Placebo + Standard Treatment: Post-Study
    Started
    288
    285
    Completed
    291
    292
    Joined
    3
    7
         Follow-up call, though did not complete Period 2
    3
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Montelukast 7 mg + Standard Treatment
    Reporting group description
    		 During Period 2, randomised participants received IV montelukast 7 mg in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of montelukast.

    Reporting group title
    Placebo + Standard Treatment
    Reporting group description
    		 During Period 2, randomised participants received IV placebo for montelukast in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of IV placebo.

    Reporting group values
    		 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment Total
    Number of subjects
    		 291 292 583
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.1 ± 15 41 ± 15.3 -
    Gender categorical
    Units: Subjects
        Female
    		 153 175 328
        Male
    		 138 117 255
    Baseline FEV1
    Baseline FEV1 was defined as last measurement obtained prior to the administration of study drug. Data were available for 287 in the Montelukast 7 mg group and 284 in the Placebo group.
    Units: Liters
        arithmetic mean (standard deviation)
    		 1.3 ± 0.4 1.2 ± 0.4 -

    End points

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    End points reporting groups
    Reporting group title
    Pre-allocation Evaluation and Treatment
    Reporting group description
    		 Participants admitted to the study site because of an acute exacerbation of asthma entered the screening period (Period 1) and received standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium).
    Reporting group title
    Montelukast 7 mg + Standard Treatment
    Reporting group description
    		 During Period 2, randomised participants received IV montelukast 7 mg in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of montelukast.

    Reporting group title
    Placebo + Standard Treatment
    Reporting group description
    		 During Period 2, randomised participants received IV placebo for montelukast in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of IV placebo.
    Reporting group title
    Montelukast 7 mg + Standard Treatment: Post-Study
    Reporting group description
    		 During the follow-up period, montelukast-treated participants received a telephone call approximately 14 days after the participant had completed Period 2 to review information on subsequent asthma-related healthcare contacts (doctor visits, emergency visits, and/or hospitalizations), asthma-related medication usage, impact on work, concomitant therapies, adverse experiences, and procedures that may have been performed within the 14 ± 3 days.

    Reporting group title
    Placebo + Standard Treatment: Post-Study
    Reporting group description
    		 During the follow-up period, placebo-treated participants received a telephone call approximately 14 days after the participant had completed Period 2 to review information on subsequent asthma-related healthcare contacts (doctor visits, emergency visits, and/or hospitalizations), asthma-related medication usage, impact on work, concomitant therapies, adverse experiences, and procedures that may have been performed within the 14 ± 3 days.

    Primary: Time-weighted Average Change from Baseline in FEV1 (0 to 60 minutes)

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    End point title
    		 Time-weighted Average Change from Baseline in FEV1 (0 to 60 minutes)
    End point description
    Time-weighted average change from baseline in FEV1 over the first 60 minutes after IV montelukast or placebo administration. Changes from baseline in FEV1 were computed at 10, 20, 40 and 60 minutes post study drug administration and then used to calculate a time-weighted average for 0-60 minutes, with the time interval between any measurement and the measurement prior to it being used as the weighting factor. The Full Analysis Set (FAS), comprised of all participants who started study drug and had efficacy measurements (FEV1) both at BL and at least one time point over the time interval considered, was used for this analysis.
    End point type
    Primary
    End point timeframe
    0 minutes (baseline), 10, 20, 40, and 60 minutes after IV bolus infusion of montelukast 7 mg or placebo.
    End point values
    		 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    287 [1]
    284 [2]
    Units: Liters
        least squares mean (confidence interval 95%)
    0.32 (0.27 to 0.37)
    0.22 (0.17 to 0.27)
    Notes
    [1] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    [2] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    Statistical analysis title
    		 Time-weighted Average ΔFEV1 (0-60 min)
    Statistical analysis description
    Time-weighted average change from baseline (BL) in FEV1, computed in the interval 0-60 minutes, was analysed using an analysis of covariance (ANCOVA) model with the baseline FEV1 as a covariate and including treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene (yes or no), and region (US or non-US) as factors. The ANCOVA model was used to estimate the least squares mean (LS mean) for treatment, between-treatment difference, and 95% CI.
    Comparison groups
    Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
    Number of subjects included in analysis
    571
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.001 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.16
    Notes
    [3] - P-value for LS mean difference between treatments, montelukast 7 mg versus placebo.

    Secondary: Percentage of Participants with Treatment Failure

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    End point title
    		 Percentage of Participants with Treatment Failure
    End point description
    The percentage of participants with treatment failure was summarized. Treatment failure was defined as: (1) participants that required hospitalization; or (2) participants for whom a decision to discharge home had not been reached by 3 hours following the end of study drug administration. The FAS was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Up to ≥ 3 hours after IV manual bolus infusion of montelukast 7 mg or placebo.
    End point values
    		 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    287 [4]
    284 [5]
    Units: Percentage of Participants
        number (not applicable)
    26.8
    29.9
    Notes
    [4] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    [5] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    Statistical analysis title
    		 Percentage of Participants With Treatment Failure
    Statistical analysis description
    A logistic regression model was used for analysis of the FAS population to compare the percentage of treatment failures between treatment groups. Factors in the model included treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene, and baseline FEV1 was used as a covariate. Descriptive statistics by treatment group provided by definition of treatment failure: participants requiring hospitalization or participants for whom decision to discharge home not reached by 3 hours.
    Comparison groups
    Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
    Number of subjects included in analysis
    571
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.654 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.34
    Notes
    [6] - Treatment differences were summarized by the odds ratio (OR) derived from the logistic regression model and the 95% CI.
    [7] - Percentage of treatment failures in the IV montelukast 7 mg group compared to the placebo treatment group.

    Secondary: Time-weighted Average Change from Baseline in FEV1 (0 to 40 minutes)

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    End point title
    		 Time-weighted Average Change from Baseline in FEV1 (0 to 40 minutes)
    End point description
    Time-weighted average change from baseline in FEV1 over the first 40 minutes after IV montelukast or placebo administration. Changes from baseline in FEV1 were computed at 10, 20, and 40 minutes post study drug administration and then used to calculate a time-weighted average for 0-40 minutes, with the time interval between any measurement and the measurement prior to it being used as the weighting factor. The FAS was used for this analysis.
    End point type
    Secondary
    End point timeframe
    0 minutes (BL), 10, 20, and 40 minutes after IV bolus infusion of montelukast 7 mg or placebo.
    End point values
    		 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    287 [8]
    283 [9]
    Units: Liters
        least squares mean (confidence interval 95%)
    0.28 (0.23 to 0.33)
    0.18 (0.13 to 0.23)
    Notes
    [8] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    [9] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    Statistical analysis title
    		 Time-weighted Average ΔFEV1 (0-40 min)
    Statistical analysis description
    The time weighted average change from baseline in FEV1, computed in the interval 0-40 minutes, was analysed with an ANCOVA model using the baseline FEV1 as a covariate and including treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene (yes/no), and region (US/Non-US) as factors. This ANCOVA model was used to estimate the least squares mean (LS-mean) for each treatment, between-treatment difference, and 95% CI.
    Comparison groups
    Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
    Number of subjects included in analysis
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.001 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.15
    Notes
    [10] - P-value for LS mean difference between treatments, montelukast 7 mg versus placebo.

    Secondary: Time-weighted Average Change From Baseline in FEV1 (0 to 20 minutes)

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    End point title
    		 Time-weighted Average Change From Baseline in FEV1 (0 to 20 minutes)
    End point description
    Time-weighted average change from baseline in FEV1 over the first 20 minutes after IV montelukast or placebo administration. Changes from baseline in FEV1 were computed at 10 and 20 minutes post study drug administration and then used to calculate a time-weighted average for 0-20 minutes, with the time interval between any measurement and the measurement prior to it being used as the weighting factor. The FAS was used for this analysis.
    End point type
    Secondary
    End point timeframe
    0 minutes (BL), 10, and 20 minutes after IV bolus infusion of montelukast 7 mg or placebo.
    End point values
    		 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    287 [11]
    282 [12]
    Units: Liters
        least squares mean (confidence interval 95%)
    0.23 (0.19 to 0.28)
    0.15 (0.1 to 0.2)
    Notes
    [11] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    [12] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    Statistical analysis title
    		 Time-weighted Average ΔFEV1 (0-20 min)
    Statistical analysis description
    The time weighted average change from baseline in FEV1, computed in the interval 0-20 minutes, was analysed with an ANCOVA model using the baseline FEV1 as a covariate and including treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene (yes/no), and region (US/Non-US) as factors. This ANCOVA model was used to estimate the least squares mean (LS-mean) for each treatment, between-treatment difference, and 95% CI.
    Comparison groups
    Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [13]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.14
    Notes
    [13] - P-value for LS mean difference between treatments, i.e., montelukast 7 mg versus placebo.

    Secondary: Average Change from Baseline in FEV1 at 10 minutes

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    End point title
    		 Average Change from Baseline in FEV1 at 10 minutes
    End point description
    Average change from baseline in FEV1 at 10 minutes after IV montelukast or placebo. The FAS was used for this analysis.
    End point type
    Secondary
    End point timeframe
    0 minutes (baseline), 10 minutes after IV manual bolus infusion of montelukast 7 mg or placebo.
    End point values
    		 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    269 [14]
    260 [15]
    Units: Liters
        least squares mean (confidence interval 95%)
    0.2 (0.15 to 0.26)
    0.12 (0.06 to 0.17)
    Notes
    [14] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    [15] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    Statistical analysis title
    		 Average ΔFEV1 at 10 min
    Statistical analysis description
    The average change from baseline in FEV1, computed at 10 minutes, was analysed with an ANCOVA model using the baseline FEV1 as a covariate and including treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene (yes/no), and region (US/Non-US) as factors. This ANCOVA model was used to estimate the least squares mean (LS-mean) for each treatment, between treatment difference, and 95% CI.
    Comparison groups
    Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
    Number of subjects included in analysis
    529
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008 [16]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.15
    Notes
    [16] - P-value for LS mean difference between treatments, i.e., montelukast 7 mg versus placebo.

    Secondary: Total Dose of β-agonist Administered Within 3 Hours

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    End point title
    		 Total Dose of β-agonist Administered Within 3 Hours
    End point description
    Total dose of β-agonist in mg administered per participant within 3 hours following end of study drug administration or placebo. Participants hospitalised prior to 3 hours post IV montelukast or placebo administration were assigned the largest total dose of β-agonist observed over all randomised participants plus 1 mg, or 5 mg plus 1 mg, whichever is larger.
    End point type
    Secondary
    End point timeframe
    Up to 3 hours following end of IV manual bolus infusion of montelukast 7 mg or placebo.
    End point values
    		 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    287 [17]
    284 [18]
    Units: mg
        median (inter-quartile range (Q1-Q3))
    5 (1 to 10)
    5 (0.9 to 10)
    Notes
    [17] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    [18] - Participants starting study drug with FEV1 both at BL and at least 1 time point over interval (FAS).
    Statistical analysis title
    		 Total Dose of β-Agonist
    Statistical analysis description
    A non-parametric ANCOVA model based on Tukey’s normalised ranks was used with factors for treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene, region, and rank of BL FEV1 as covariate. Total dose of β-agonist administered per participant over a period of 3 hours following end of study drug administration was compared between treatment groups. Within-treatment effect was described using medians. Difference between medians were computed by the Hodges-Lehmann estimation.
    Comparison groups
    Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
    Number of subjects included in analysis
    571
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.952 [20]
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [19] - Distribution-free confidence interval was based on the rank-sum test.
    [20] - P-value for comparison between treatment groups, IV montelukast 7 mg versus placebo treatment.

    Secondary: Number of Doses of β-agonist Administered Within 3 Hours

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    End point title
    		 Number of Doses of β-agonist Administered Within 3 Hours
    End point description
    Number of times a dose of a β-agonist was administered per participant within 3 hours following end of study drug or placebo administration. Participants hospitalised prior to 3 hours post study drug or placebo administration were assigned the largest number of β-agonist doses administered as observed over all randomised patients.
    End point type
    Secondary
    End point timeframe
    Up to 3 hours after IV manual bolus infusion of montelukast 7 mg or placebo.
    End point values
    		 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    287
    284
    Units: Doses
        median (inter-quartile range (Q1-Q3))
    2 (1 to 3)
    2 (1 to 4)
    Statistical analysis title
    		 Number of Doses of β-agonist
    Statistical analysis description
    A non-parametric ANCOVA model based on Tukey’s normalised ranks was used with factors for treatment, prior therapy with systemic corticosteroids and/or anti-leukotriene, region, and rank of BL FEV1 as covariate. Number of doses of β-agonist administered per participant over a period of 3 hours following end of study drug administration was compared between treatment groups. Within-treatment effect was described using medians. Difference of medians was computed by the Hodges-Lehmann estimation.
    Comparison groups
    Montelukast 7 mg + Standard Treatment v Placebo + Standard Treatment
    Number of subjects included in analysis
    571
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.265 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [21] - Distribution-free confidence interval was based on the rank-sum test.
    [22] - P-value for comparison between treatment groups, IV montelukast 7 mg versus placebo treatment.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    During the treatment period after IV montelukast or placebo administration until permanent discontinuation (end of Period 2) plus 14 days (Post-study, Period 3).
    Adverse event reporting additional description
    All randomised patients who started study drug were included in the All-Participants-as-Treated (APaT) set for the safety analyses. The participant’s treatment group was determined by the actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Montelukast 7 mg + Standard Treatment
    Reporting group description
    		 During Period 2, randomised participants received IV montelukast 7 mg in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of montelukast.

    Reporting group title
    Placebo + Standard Treatment
    Reporting group description
    		 During Period 2, randomised participants received IV placebo for montelukast in addition to a standard therapy regimen recommended by international guidelines for an acute severe asthma episode (e.g. oxygen, short-acting β-agonist, corticosteroid, ipratropium). Time-weighted change in FEV1 as a measure of lung function was determined for up to 120 minutes post-infusion of IV placebo.

    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 nonserious adverse events reaching the cut-off of >5% on at least one treatment arm were reported.
    Serious adverse events
    		 Montelukast 7 mg + Standard Treatment Placebo + Standard Treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 291 (9.62%)
    26 / 292 (8.90%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Drug Toxicity
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    23 / 291 (7.90%)
    23 / 292 (7.88%)
         occurrences causally related to treatment / all
    0 / 24
    1 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 291 (0.69%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Varicella
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 292 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 292 (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 7 mg + Standard Treatment Placebo + Standard Treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 291 (0.00%)
    0 / 292 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Mar 2005
    Amendment 01: Primary reasons for the amendment were to incorporate revisions to the inclusion and exclusion criteria, add language that removes the requirement to report hospitalisation due to worsening asthma (which is also a study endpoint) as a serious adverse experience, and include an updated montelukast sodium product circular that includes new in vitro data regarding CYP2C8.

    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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