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    Clinical Trial Results:
    A Phase III, Open-Label Clinical Trial to Study the Safety and Pharmacokinetics of MK-0476 in Japanese Pediatric Subjects Aged 1 to 15 Years Old with Perennial Allergic Rhinitis

    Summary
    EudraCT number
    		 2014-004871-22
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    24 Dec 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    0476-520
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01852812
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MK-0476-520: Merck protocol number
    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
    24 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will evaluate the safety and pharmacokinetics of montelukast (MK-0476) in the treatment of Japanese pediatric participants with perennial allergic rhinitis (PAR). The primary hypothesis of this study is that montelukast oral granules (OG) and chewable tablets (CT) provide appropriate exposure to montelukast in Japanese pediatric participants with PAR.
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jun 2013
    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: 87
    Worldwide total number of subjects
    87
    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)
    81
    Adolescents (12-17 years)
    6
    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
    		 Japanese participants aged 1 to 15 years who had perennial allergic rhinitis (PAR) were screened for this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding was used in this open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Montelukast 4 mg OG/1-5 year olds
    Arm description
    		 Participants receive montelukast 4 mg oral granules (OG) in one sachet orally (PO) once daily (QD) at bed time for 4 weeks with an option to continue for an additional 8 weeks (12 weeks total)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Montelukast Oral Granules
    Investigational medicinal product code
    Other name
    MK-0475
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Montelukast 4 mg oral granules in one sachet once daily at bedtime for up to 12 weeks

    Arm title
    		 Montelukast 5 mg CT/6-9 year olds
    Arm description
    		 Participants receive montelukast 5 mg chewable tablets (CT) in one tablet PO QD at bed time for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Montelukast Chewable Tablets
    Investigational medicinal product code
    Other name
    MK-0476
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Montelukast 5 mg chewable tablets once daily at bedtime for up to 12 weeks

    Arm title
    		 Montelukast 5 mg CT/10-15 year olds
    Arm description
    		 Participants receive montelukast 5 mg CT in one tablet PO QD at bed time for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Montelukast Chewable Tablets
    Investigational medicinal product code
    Other name
    MK-0476
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Montelukast 5 mg chewable tablets once daily at bedtime for up to 12 weeks

    Number of subjects in period 1
    		Montelukast 4 mg OG/1-5 year olds Montelukast 5 mg CT/6-9 year olds Montelukast 5 mg CT/10-15 year olds
    Started
    51
    18
    18
    Completed
    51
    17
    17
    Not completed
    0
    1
    1
         Adverse event, non-fatal
    -
    -
    1
         Non-compliance with study drug
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Montelukast 4 mg OG/1-5 year olds
    Reporting group description
    		 Participants receive montelukast 4 mg oral granules (OG) in one sachet orally (PO) once daily (QD) at bed time for 4 weeks with an option to continue for an additional 8 weeks (12 weeks total)

    Reporting group title
    Montelukast 5 mg CT/6-9 year olds
    Reporting group description
    		 Participants receive montelukast 5 mg chewable tablets (CT) in one tablet PO QD at bed time for 12 weeks

    Reporting group title
    Montelukast 5 mg CT/10-15 year olds
    Reporting group description
    		 Participants receive montelukast 5 mg CT in one tablet PO QD at bed time for 12 weeks

    Reporting group values
    		 Montelukast 4 mg OG/1-5 year olds Montelukast 5 mg CT/6-9 year olds Montelukast 5 mg CT/10-15 year olds Total
    Number of subjects
    		 51 18 18 87
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 51 18 12 81
        Adolescents (12-17 years)
    		 0 0 6 6
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 3.6 ± 1.4 7.8 ± 1.3 11.3 ± 1 -
    Gender, Male/Female
    Units: Participants
        Female
    		 24 8 5 37
        Male
    		 27 10 13 50
    Subject analysis sets

    Subject analysis set title
    Montelukast 5 mg CT/6-15 year olds
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants receive montelukast 5 mg CT in one tablet PO QD at bed time for 12 weeks

    Subject analysis sets values
    		 Montelukast 5 mg CT/6-15 year olds
    Number of subjects
    36
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    30
        Adolescents (12-17 years)
    6
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    ±
    Gender, Male/Female
    Units: Participants
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Montelukast 4 mg OG/1-5 year olds
    Reporting group description
    		 Participants receive montelukast 4 mg oral granules (OG) in one sachet orally (PO) once daily (QD) at bed time for 4 weeks with an option to continue for an additional 8 weeks (12 weeks total)

    Reporting group title
    Montelukast 5 mg CT/6-9 year olds
    Reporting group description
    		 Participants receive montelukast 5 mg chewable tablets (CT) in one tablet PO QD at bed time for 12 weeks

    Reporting group title
    Montelukast 5 mg CT/10-15 year olds
    Reporting group description
    		 Participants receive montelukast 5 mg CT in one tablet PO QD at bed time for 12 weeks

    Subject analysis set title
    Montelukast 5 mg CT/6-15 year olds
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants receive montelukast 5 mg CT in one tablet PO QD at bed time for 12 weeks

    Primary: Percentage of Participants Who Experience at Least One Adverse Event (AE)

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    End point title
    		 Percentage of Participants Who Experience at Least One Adverse Event (AE) [1] [2]
    End point description
    An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of study drug or protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a pre-existing condition that is temporally associated with the use of study drug is also an AE. Participants were monitored for the occurrence of AEs for up to 14 days after last dose of study drug (up to a total of 14 weeks). AEs were reported based on the dose of study drug participants received.
    End point type
    Primary
    End point timeframe
    Up to 14 days after last dose of study drug (Up to 14 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this end point.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Safety data from the two montelukast 5 mg CT groups (6-9 year olds and 10-15 year olds) were pooled for safety analyses.
    End point values
    		 Montelukast 4 mg OG/1-5 year olds Montelukast 5 mg CT/6-15 year olds
    Number of subjects analysed
    51 [3]
    36 [4]
    Units: Percentage of participants
        number (not applicable)
    74.5
    55.6
    Notes
    [3] - All randomized participants who received ≥1 dose of study drug.
    [4] - All randomized participants who received ≥1 dose of study drug.
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Discontinue Study Drug Due to an AE

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    End point title
    		 Percentage of Participants Who Discontinue Study Drug Due to an AE [5] [6]
    End point description
    An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of study drug or protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a pre-existing condition that is temporally associated with the use of study drug is also an AE. Discontinuations due to an AE were reported based on the dose of study drug participants received.
    End point type
    Primary
    End point timeframe
    Up to 12 weeks
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this end point.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Safety data from the two montelukast 5 mg CT groups (6-9 year olds and 10-15 year olds) were pooled for safety analyses.
    End point values
    		 Montelukast 4 mg OG/1-5 year olds Montelukast 5 mg CT/6-15 year olds
    Number of subjects analysed
    51 [7]
    36 [8]
    Units: Percentage of participants
        number (not applicable)
    0
    2.8
    Notes
    [7] - All randomized participants who received ≥1 dose of study drug.
    [8] - All randomized participants who received ≥1 dose of study drug.
    No statistical analyses for this end point

    Primary: Area Under the Time-Concentration Curve (AUC 0-∞) of Montelukast CT and Montelukast OG

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    End point title
    		 Area Under the Time-Concentration Curve (AUC 0-∞) of Montelukast CT and Montelukast OG [9]
    End point description
    Blood samples for pharmacokinetic (PK) assessments were collected at either 1 hour (h) or 3 h post-dose on Day 1 and at either 14 h or 22 h post-dose on Day 28.
    End point type
    Primary
    End point timeframe
    Up to Day 28 after first dose of study drug
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this end point.
    End point values
    		 Montelukast 4 mg OG/1-5 year olds Montelukast 5 mg CT/6-9 year olds Montelukast 5 mg CT/10-15 year olds
    Number of subjects analysed
    51 [10]
    18 [11]
    18 [12]
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    4300 ± 890
    4350 ± 760
    3500 ± 620
    Notes
    [10] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    [11] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    [12] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    No statistical analyses for this end point

    Primary: Maximum Plasma Concentration (Cmax) of Montelukast CT and Montelukast OG

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Montelukast CT and Montelukast OG [13]
    End point description
    Blood samples for PK assessments were collected at either 1 h or 3 h post-dose on Day 1 and at either 14 h or 22 h post-dose on Day 28.
    End point type
    Primary
    End point timeframe
    Up to Day 28 after first dose of study drug
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this end point.
    End point values
    		 Montelukast 4 mg OG/1-5 year olds Montelukast 5 mg CT/6-9 year olds Montelukast 5 mg CT/10-15 year olds
    Number of subjects analysed
    51 [14]
    18 [15]
    18 [16]
    Units: ng/mL
        arithmetic mean (standard deviation)
    510 ± 84
    438 ± 82
    344 ± 61
    Notes
    [14] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    [15] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    [16] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    No statistical analyses for this end point

    Primary: Time to Cmax (Tmax) of Montelukast CT and Montelukast OG

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    End point title
    		 Time to Cmax (Tmax) of Montelukast CT and Montelukast OG [17]
    End point description
    Blood samples for PK assessments were collected at either 1 h or 3 h post-dose on Day 1 and at either 14 h or 22 h post-dose on Day 28.
    End point type
    Primary
    End point timeframe
    Up to Day 28 after first dose of study drug
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this end point.
    End point values
    		 Montelukast 4 mg OG/1-5 year olds Montelukast 5 mg CT/6-9 year olds Montelukast 5 mg CT/10-15 year olds
    Number of subjects analysed
    51 [18]
    18 [19]
    18 [20]
    Units: Hours
        arithmetic mean (standard deviation)
    2.74 ± 0.6
    3.55 ± 0.71
    3.65 ± 0.6
    Notes
    [18] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    [19] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    [20] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    No statistical analyses for this end point

    Primary: Apparent Elimination Half-life (t1/2) of Montelukast CT and Montelukast OG

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    End point title
    		 Apparent Elimination Half-life (t1/2) of Montelukast CT and Montelukast OG [21]
    End point description
    Blood samples for PK assessments were collected at either 1 h or 3 h post-dose on Day 1 and at either 14 h or 22 h post-dose on Day 28.
    End point type
    Primary
    End point timeframe
    Up to Day 28 after first dose of study drug
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this end point.
    End point values
    		 Montelukast 4 mg OG/1-5 year olds Montelukast 5 mg CT/6-9 year olds Montelukast 5 mg CT/10-15 year olds
    Number of subjects analysed
    51 [22]
    18 [23]
    18 [24]
    Units: Hours
        arithmetic mean (standard deviation)
    1.27 ± 0.56
    2.01 ± 0.75
    2.08 ± 0.66
    Notes
    [22] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    [23] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    [24] - All participants who received ≥1 dose of study drug, had ≥1 PK assessment & no protocol violations.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 14 days after last dose of study drug (Up to 14 weeks)
    Adverse event reporting additional description
    The safety population consisted of all participants who received at least one dose of study drug. AEs were reported based on the dose of study drug participants received. Data from the two montelukast 5 mg CT groups (6-9 year olds and 10-15 year olds) were pooled for safety analyses.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Montelukast 5 mg CT/6-15 year olds
    Reporting group description
    		 Participants receive montelukast 5 mg CT in one tablet PO QD at bed time for 12 weeks

    Reporting group title
    Montelukast 4 mg OG/1-5 year olds
    Reporting group description
    		 Participants receive montelukast 4 mg OG in one sachet PO QD at bed time for 4 weeks with an option to continue for an additional 8 weeks (12 weeks total)

    Serious adverse events
    		 Montelukast 5 mg CT/6-15 year olds Montelukast 4 mg OG/1-5 year olds
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 51 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Montelukast 5 mg CT/6-15 year olds Montelukast 4 mg OG/1-5 year olds
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 36 (50.00%)
    37 / 51 (72.55%)
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 51 (3.92%)
         occurrences all number
    4
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 36 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Miliaria
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 36 (0.00%)
    6 / 51 (11.76%)
         occurrences all number
    0
    8
    Bronchitis
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 51 (5.88%)
         occurrences all number
    3
    4
    Gastroenteritis
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    12 / 36 (33.33%)
    22 / 51 (43.14%)
         occurrences all number
    15
    32
    Otitis media
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 51 (7.84%)
         occurrences all number
    1
    4
    Otitis media acute
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    4
    Pharyngitis
         subjects affected / exposed
    3 / 36 (8.33%)
    9 / 51 (17.65%)
         occurrences all number
    4
    14

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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