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    Clinical Trial Results:
    MK-476 IV formulation Phase III Open Label Exploratory Comparative Study - Acute Exacerbations of Asthma -

    Summary
    EudraCT number
    		 2014-004749-28
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    01 Aug 2007

    Results information
    Results version number
    		 v2(current)
    This version publication date
    25 Jun 2016
    First version publication date
    19 Jul 2015
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    0476-334
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00442338
    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
    01 Aug 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Aug 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Aug 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study estimates the efficacy and safety of MK-0476 and aminophylline intravenous (IV) administration in adult participants with acute 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 measures defined for this individual study were in place for the protection of trial subjects: as needed administration of beta agonists, IV drip corticosteroids, and oxygen therapy during the treatment period.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2007
    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
    Japan: 91
    Worldwide total number of subjects
    91
    EEA total number of subjects
    0
    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)
    1
    Adults (18-64 years)
    57
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Phase III. Studied period: March 12, 2007 (date study drug was first administered to first participant) to August 1, 2007 (date study drug was last administered to last participant). Study was conducted at 31 clinical sites in Japan.

    Pre-assignment
    Screening details
    		 Participants with acute exacerbation of bronchial asthma received standard treatments of inhaled β-agonist or oxygen inhalation to treat the acute exacerbations during the 60 minutes in the screening period before the study randomization. Additional inclusion and exclusion criteria applied.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Montelukast 7 mg
    Arm description
    		 Montelukast 7 mg IV administration
    Arm type
    		 Experimental

    Investigational medicinal product name
    montelukast sodium
    Investigational medicinal product code
    Other name
    MK-0476
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Montelukast 7 mg single injection (IV bolus administration) over 2-3 minutes

    Arm title
    		 Montelukast 14 mg
    Arm description
    		 Montelukast 14 mg IV administration
    Arm type
    		 Experimental

    Investigational medicinal product name
    montelukast sodium
    Investigational medicinal product code
    Other name
    MK-0476
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Montelukast 14 mg single injection (IV bolus administration) over 5 minutes

    Arm title
    		 Aminophylline 250 mg
    Arm description
    		 Aminophylline 250 mg IV drip administration
    Arm type
    		 Active comparator

    Investigational medicinal product name
    aminophylline hydrate
    Investigational medicinal product code
    Other name
    Kyophyllin® Injection 2.5%, FK05
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Aminophylline 250 mg IV drip infusion over 60 minutes

    Number of subjects in period 1
    		Montelukast 7 mg Montelukast 14 mg Aminophylline 250 mg
    Started
    30
    30
    31
    Completed
    30
    30
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Montelukast 7 mg
    Reporting group description
    		 Montelukast 7 mg IV administration

    Reporting group title
    Montelukast 14 mg
    Reporting group description
    		 Montelukast 14 mg IV administration

    Reporting group title
    Aminophylline 250 mg
    Reporting group description
    		 Aminophylline 250 mg IV drip administration

    Reporting group values
    		 Montelukast 7 mg Montelukast 14 mg Aminophylline 250 mg Total
    Number of subjects
    		 30 30 31 91
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 0 1 0 1
        Adults (18-64 years)
    		 21 16 20 57
        From 65-84 years
    		 9 13 11 33
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56 ( 12.3 ) 56.7 ( 15.2 ) 55.4 ( 14.5 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 22 24 16 62
        Male
    		 8 6 15 29
    Asthma Attack Severity based on Asthma Prevention and Management Guideline 2003, Japan
    Mild (Peak Expiratory Flow >80%), Moderate (Peak Expiratory Flow: 60% ~ 80%), Severe (Peak Expiratory Flow <60%) or Serious (Peak Expiratory Flow: incapable measurement, cyanosis, head trip, disturbed consciousness, incontinence or asphyxia)
    Units: Subjects
        Mild
    		 21 18 26 65
        Moderate
    		 9 12 5 26
        Severe
    		 0 0 0 0
        Serious
    		 0 0 0 0
    Baseline Forced Expiratory Volume in One Second (FEV1)
    Units: Liters
        arithmetic mean (standard deviation)
    		 1.35 ( 0.29 ) 1.18 ( 0.33 ) 1.43 ( 0.53 ) -
    Duration of Asthma
    Units: Years
        arithmetic mean (standard deviation)
    		 14.9 ( 10.4 ) 13.9 ( 11.5 ) 16.7 ( 14.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Montelukast 7 mg
    Reporting group description
    		 Montelukast 7 mg IV administration

    Reporting group title
    Montelukast 14 mg
    Reporting group description
    		 Montelukast 14 mg IV administration

    Reporting group title
    Aminophylline 250 mg
    Reporting group description
    		 Aminophylline 250 mg IV drip administration

    Primary: Change from Baseline in forced expiratory volume in one second (FEV1) within the first 60 minutes after administration

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    End point title
    		 Change from Baseline in forced expiratory volume in one second (FEV1) within the first 60 minutes after administration
    End point description
    The time weighted average change from Baseline in Forced Expiratory Volume in One Second (FEV1) over the first 60 minutes after study drug administration (average change FEV1 (0-60 min)). Baseline (pre-allocation) was the last measurement obtained during the screening period. Analysis was performed on data obtained from the Per Protocol Set, which is the subset of participants who comply with the protocol sufficiently to ensure that these data will be likely to exhibit the effects of treatment, according to the underlying scientific model.
    End point type
    Primary
    End point timeframe
    Baseline and 60 minutes after study drug administration
    End point values
    		 Montelukast 7 mg Montelukast 14 mg Aminophylline 250 mg
    Number of subjects analysed
    27
    30
    29 [1]
    Units: Liters
        least squares mean (confidence interval 95%)
    0.07 (0.02 to 0.12)
    0.05 (0 to 0.11)
    0.06 (0.01 to 0.12)
    Notes
    [1] - 1 patient with no FEV1 data at 60 minutes was excluded from the analysis.
    Statistical analysis title
    		 Montelukast 7 mg vs. Aminophylline 250 mg
    Statistical analysis description
    Treatment difference in change from Baseline in FEV1 within the first 60 minutes after study drug administration was assessed as the difference in the least square (LS) means of time weighted average change FEV1 (0-60 min) using an Analysis of Covariance (ANCOVA) model. The model included a factor for treatment and used the baseline FEV1 as a covariate.
    Comparison groups
    Montelukast 7 mg v Aminophylline 250 mg
    Number of subjects included in analysis
    56
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.871
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.08
    Statistical analysis title
    		 Montelukast 14 mg vs. Aminophylline 250 mg
    Statistical analysis description
    Treatment difference in change from Baseline in FEV1 within the first 60 minutes after study drug administration was assessed as the difference in the LS means of time weighted average change FEV1 (0-60 min) using an ANCOVA model. The model included a factor for treatment and used the baseline FEV1 as a covariate.
    Comparison groups
    Montelukast 14 mg v Aminophylline 250 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.794
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.06
    Statistical analysis title
    		 Montelukast 7 mg vs. Montelukast 14 mg
    Statistical analysis description
    Treatment difference in change from Baseline in FEV1 within the first 60 minutes after study drug administration was assessed as the difference in the LS means of time weighted average change FEV1 (0-60 min) using an ANCOVA model. The model included a factor for treatment and used the baseline FEV1 as a covariate.
    Comparison groups
    Montelukast 14 mg v Aminophylline 250 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.675
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.09

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Screening through post-trial visit (up to 14 days)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Montelukast 7 mg
    Reporting group description
    		 Montelukast 7 mg IV administration

    Reporting group title
    Aminophylline 250 mg
    Reporting group description
    		 Aminophylline 250 mg IV drip administration

    Reporting group title
    Montelukast 14 mg
    Reporting group description
    		 Montelukast 14 mg IV administration

    Serious adverse events
    		 Montelukast 7 mg Aminophylline 250 mg Montelukast 14 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    White blood cell count increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Montelukast 7 mg Aminophylline 250 mg Montelukast 14 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 30 (16.67%)
    3 / 31 (9.68%)
    1 / 30 (3.33%)
    Investigations
    Glucose urine present
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    0
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0

    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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