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    Clinical Trial Results:
    A Worldwide, Randomized, Double Blind, Placebo-Controlled, Parallel Group Clinical Trial to Evaluate the Safety and Efficacy of Rizatriptan for the Acute Treatment of Migraine in Children and Adolescents

    Summary
    EudraCT number
    		 2009-016374-32
    Trial protocol
    		 NL   DE   FI   BE   ES   EE   LV   SE   FR   DK   GB   IT   Outside EU/EEA  
    Global end of trial date
    21 Apr 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2016
    First version publication date
    23 Apr 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-0462-082
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01001234
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Registration Number: 2009_679, CTRI: CTRI/2010/091/000407
    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
    21 Apr 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Apr 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Apr 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To evaluate the efficacy of rizatriptan compared to placebo in the treatment of acute migraine as measured by pain freedom at 2 hours in pediatric migraineurs between 12 and 17 years of age who have not, historically, achieved satisfactory response to treatment with non-steroidal anti-inflammatory drugs (NSAIDS) or acetaminophen (APAP). 2. To evaluate the safety and tolerability of rizatriptan in pediatric migraineurs between 12 and 17 years of age who have not, historically, achieved a satisfactory response to treatment with NSAIDS or APAP.
    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: participants who did not obtain satisfactory relief of migraine pain at 2 hours after administration of Stage 2 study medication could have been treated with usual care at that time or any time thereafter if the headache did not resolve or recurred.
    Background therapy
    		 Rescue therapy and treatments for non-qualifying migraines were limited to the participant’s usual care with the following exception: use of 5-hydroxytryptamine 1 (5-HT1) agonists and ergot derivatives were prohibited for 24 hours following the last dose of any study treatment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Finland: 11
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Norway: 18
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Latvia: 9
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    India: 190
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    United States: 1042
    Worldwide total number of subjects
    1382
    EEA total number of subjects
    141
    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)
    372
    Adolescents (12-17 years)
    1010
    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
    		 Participants randomized to double-blind study medication (Stage 1 - placebo or rizatriptan in a 20:1 ratio) at the Screening visit were given study drug and administration instructions. If a participant had not treated a qualifying migraine attack within up to 2-4 months, he/she may have been discontinued from the study.

    Period 1
    Period 1 title
    All Randomized Participants (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/No Treatment
    Arm description
    		 Stage 1 - Randomized to single placebo oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Responder (mild or no pain 15 minutes after dose), no further study medication was to be administered.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants randomized to placebo in Stage 1: a single placebo oral disintegrating tablet (ODT) was to be taken within 30 minutes of onset of qualifying migraine (defined as a migraine of moderate or intense severity).

    Arm title
    		 Rizatriptan/No Treatment
    Arm description
    		 Stage 1 - Randomized to single rizatriptan 5 or 10 mg oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Responder (mild or no pain 15 minutes after dose), no further study medication was to be administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rizatriptan
    Investigational medicinal product code
    Other name
    Maxalt, MK-0462
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants randomized to rizatriptan in Stage 1: a single 5 or 10 mg rizatriptan ODT was to be taken within 30 minutes of onset of qualifying migraine. Rizatriptan dose administered was based on participant weight at Screening: those <40 kg received 5 mg tablet, those ≥40 kg received 10 mg tablet.

    Arm title
    		 Placebo/Rizatriptan
    Arm description
    		 Stage 1 - Randomized to single placebo oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Non-Responder (moderate or severe pain 15 minutes after dose), Stage 2 randomization was to occur and participants in this reporting group received single rizatriptan 5 or 10 mg oral tablet. Stage 2 dose was administered approximately 15 minutes post Stage 1 dose, to treat same qualifying migraine treated in Stage 1. Stage 2 randomization was in a ratio of 1:1 rizatriptan:placebo.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants randomized to placebo in Stage 1: a single placebo ODT was to be taken within 30 minutes of onset of qualifying migraine.

    Investigational medicinal product name
    Rizatriptan
    Investigational medicinal product code
    Other name
    Maxalt, MK-0462
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants randomized to rizatriptan in Stage 2 (must have taken placebo in Stage 1 and was Non-Responder [moderate or severe pain 15 minutes after dose] to be randomized at Stage 2): a single 5 or 10 mg rizatriptan ODT was to be taken approximately 15 minutes post Stage 1 dose, to treat same qualifying migraine treated in Stage 1. Rizatriptan dose administered was based on participant weight at Screening: those <40 kg received 5 mg tablet, those ≥40 kg received 10 mg tablet.

    Arm title
    		 Placebo/Placebo
    Arm description
    		 Stage 1 - Randomized to single placebo oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Non-Responder (moderate or severe pain 15 minutes after dose), Stage 2 randomization was to occur and participants in this reporting group received single placebo oral tablet. Stage 2 dose was administered approximately 15 minutes post Stage 1 dose, to treat same qualifying migraine treated in Stage 1. Stage 2 randomization was in a ratio of 1:1 rizatriptan:placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants randomized to placebo in Stage 1: a single placebo ODT was to be taken within 30 minutes of onset of qualifying migraine. For participants randomized to placebo in Stage 2: a single placebo ODT was to be taken approximately 15 minutes post Stage 1 dose, to treat same qualifying migraine treated in Stage 1.

    Arm title
    		 Rizatriptan/Placebo
    Arm description
    		 Stage 1 - Randomized to single rizatriptan 5 or 10 mg oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Non-Responder (moderate or severe pain 15 minutes after dose), allocated to receive single placebo oral tablet in Stage 2 to treat same qualifying migraine treated in Stage 1 (Stage 2 dose to be administered 15 minutes post Stage 1 dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants allocated to placebo in Stage 2 (took rizatriptan in Stage 1 and was Non-Responder [moderate or severe pain 15 minutes after dose]): a single placebo ODT was to be taken approximately 15 minutes post Stage 1 dose, to treat same qualifying migraine treated in Stage 1.

    Investigational medicinal product name
    Rizatriptan
    Investigational medicinal product code
    Other name
    Maxalt, MK-0462
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants randomized to rizatriptan in Stage 1: a single 5 or 10 mg rizatriptan ODT was to be taken within 30 minutes of onset of qualifying migraine. Rizatriptan dose administered was based on participant weight at Screening: those <40 kg received 5 mg tablet, those ≥40 kg received 10 mg tablet.

    Number of subjects in period 1
    		Placebo/No Treatment Rizatriptan/No Treatment Placebo/Rizatriptan Placebo/Placebo Rizatriptan/Placebo
    Started
    492
    31
    409
    410
    40
    Treated
    124
    8
    400
    405
    40
    Completed
    87
    5
    377
    385
    40
    Not completed
    405
    26
    32
    25
    0
         Not treated: protocol violation
    3
    -
    -
    -
    -
         Consent withdrawn by subject
    2
    -
    3
    -
    -
         Physician decision
    1
    -
    -
    -
    -
         Not treated: adverse event
    1
    -
    -
    -
    -
         Not treated: pregnancy
    3
    -
    -
    -
    -
         Not treated: lost to follow-up
    53
    4
    7
    5
    -
         Lost to follow-up
    -
    -
    1
    2
    -
         Not treated: physician decision
    37
    4
    -
    -
    -
         Protocol deviation
    34
    3
    19
    18
    -
         Not treated: withdrawal by subject
    23
    2
    2
    -
    -
         Not treated: lack of qualifying event
    248
    13
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo/No Treatment
    Reporting group description
    		 Stage 1 - Randomized to single placebo oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Responder (mild or no pain 15 minutes after dose), no further study medication was to be administered.

    Reporting group title
    Rizatriptan/No Treatment
    Reporting group description
    		 Stage 1 - Randomized to single rizatriptan 5 or 10 mg oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Responder (mild or no pain 15 minutes after dose), no further study medication was to be administered.

    Reporting group title
    Placebo/Rizatriptan
    Reporting group description
    		 Stage 1 - Randomized to single placebo oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Non-Responder (moderate or severe pain 15 minutes after dose), Stage 2 randomization was to occur and participants in this reporting group received single rizatriptan 5 or 10 mg oral tablet. Stage 2 dose was administered approximately 15 minutes post Stage 1 dose, to treat same qualifying migraine treated in Stage 1. Stage 2 randomization was in a ratio of 1:1 rizatriptan:placebo.

    Reporting group title
    Placebo/Placebo
    Reporting group description
    		 Stage 1 - Randomized to single placebo oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Non-Responder (moderate or severe pain 15 minutes after dose), Stage 2 randomization was to occur and participants in this reporting group received single placebo oral tablet. Stage 2 dose was administered approximately 15 minutes post Stage 1 dose, to treat same qualifying migraine treated in Stage 1. Stage 2 randomization was in a ratio of 1:1 rizatriptan:placebo.

    Reporting group title
    Rizatriptan/Placebo
    Reporting group description
    		 Stage 1 - Randomized to single rizatriptan 5 or 10 mg oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Non-Responder (moderate or severe pain 15 minutes after dose), allocated to receive single placebo oral tablet in Stage 2 to treat same qualifying migraine treated in Stage 1 (Stage 2 dose to be administered 15 minutes post Stage 1 dose).

    Reporting group values
    		 Placebo/No Treatment Rizatriptan/No Treatment Placebo/Rizatriptan Placebo/Placebo Rizatriptan/Placebo Total
    Number of subjects
    		 492 31 409 410 40 1382
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 130 6 111 111 14 372
        Adolescents (12-17 years)
    		 362 25 298 299 26 1010
        Adults (18-64 years)
    		 0 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 259 20 233 241 20 773
        Male
    		 233 11 176 169 20 609

    End points

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    End points reporting groups
    Reporting group title
    Placebo/No Treatment
    Reporting group description
    		 Stage 1 - Randomized to single placebo oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Responder (mild or no pain 15 minutes after dose), no further study medication was to be administered.

    Reporting group title
    Rizatriptan/No Treatment
    Reporting group description
    		 Stage 1 - Randomized to single rizatriptan 5 or 10 mg oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Responder (mild or no pain 15 minutes after dose), no further study medication was to be administered.

    Reporting group title
    Placebo/Rizatriptan
    Reporting group description
    		 Stage 1 - Randomized to single placebo oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Non-Responder (moderate or severe pain 15 minutes after dose), Stage 2 randomization was to occur and participants in this reporting group received single rizatriptan 5 or 10 mg oral tablet. Stage 2 dose was administered approximately 15 minutes post Stage 1 dose, to treat same qualifying migraine treated in Stage 1. Stage 2 randomization was in a ratio of 1:1 rizatriptan:placebo.

    Reporting group title
    Placebo/Placebo
    Reporting group description
    		 Stage 1 - Randomized to single placebo oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Non-Responder (moderate or severe pain 15 minutes after dose), Stage 2 randomization was to occur and participants in this reporting group received single placebo oral tablet. Stage 2 dose was administered approximately 15 minutes post Stage 1 dose, to treat same qualifying migraine treated in Stage 1. Stage 2 randomization was in a ratio of 1:1 rizatriptan:placebo.

    Reporting group title
    Rizatriptan/Placebo
    Reporting group description
    		 Stage 1 - Randomized to single rizatriptan 5 or 10 mg oral tablet to be taken within 30 minutes of onset of qualifying migraine / Stage 2 - If Stage 1 dose was taken and participant was Non-Responder (moderate or severe pain 15 minutes after dose), allocated to receive single placebo oral tablet in Stage 2 to treat same qualifying migraine treated in Stage 1 (Stage 2 dose to be administered 15 minutes post Stage 1 dose).

    Subject analysis set title
    Placebo in Stage 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Includes participants who did not respond to placebo in Stage 1, were randomized to and took placebo in Stage 2 and had both Stage 2 baseline migraine severity (moderate or severe) and at least one post Stage 2 dose efficacy measurement prior to or including the 2 hour post dose time point. Those randomized to rizatriptan in Stage 1 were excluded.

    Subject analysis set title
    Rizatriptan in Stage 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Includes participants who did not respond to placebo in Stage 1, were randomized to and took rizatriptan in Stage 2 and had both Stage 2 baseline migraine severity (moderate or severe) and at least one post Stage 2 dose efficacy measurement prior to or including the 2 hour post dose time point. Those randomized to rizatriptan in Stage 1 were excluded.

    Primary: Pain freedom at 2 hours post dose in participants between 12 and 17 years of age

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    End point title
    		 Pain freedom at 2 hours post dose in participants between 12 and 17 years of age
    End point description
    Pain intensity was assessed using a 5-Face Pain Scale ranging from 1=no pain to 5=very bad pain. Pain freedom was defined as a reduction in severity from a rating of 3, 4 or 5 (moderate or severe pain) at the Stage 2 baseline (15 minutes post Stage 1 dose) to a rating of 1 (no pain) at 2 hours post Stage 2 dose. Missing data were imputed by carrying forward the preceding Stage 2 pain intensity values. Missing Stage 2 baseline values were imputed by carrying forward the Stage 1 baseline value, if available.
    End point type
    Primary
    End point timeframe
    2 hours post Stage 2 dose
    End point values
    		 Rizatriptan in Stage 2 Placebo in Stage 2
    Number of subjects analysed
    284 [1]
    286 [2]
    Units: Participants
        2-hour pain freedom
    87
    63
        No 2-hour pain freedom
    197
    223
    Notes
    [1] - Participants between 12 and 17 years of age who received rizatriptan during Stage 2 of the study.
    [2] - Participants between 12 and 17 years of age who received placebo during Stage 2 of the study.
    Statistical analysis title
    		 Pain freedom at 2 hours post dose
    Statistical analysis description
    Pain freedom at 2 hours post dose in participants between 12 and 17 years of age. The comparison of rizatriptan versus placebo with respect to the primary outcome was conducted using a logistic regression model with factors for treatment, Stage 2 baseline pain severity (moderate or severe) and region (United States [US] or ex-US). Model-derived odds ratio and a two-sided p-value were provided. An odds ratio >1 is in favor of the rizatriptan group.
    Comparison groups
    Rizatriptan in Stage 2 v Placebo in Stage 2
    Number of subjects included in analysis
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.025 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 2.26
    Notes
    [3] - Testing of primary endpoint and secondary endpoints was conducted sequentially in a pre-specified order, thus strongly controlling Type I error.
    [4] - The statistical significance level for the primary endpoint was α=0.0477, and had been adjusted to account for the interim sample size adjustment.

    Secondary: Pain relief at 2 hours post dose in participants between 12 and 17 years of age

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    End point title
    		 Pain relief at 2 hours post dose in participants between 12 and 17 years of age
    End point description
    Pain intensity was assessed using a 5-Face Pain Scale ranging from 1=no pain to 5=very bad pain. Pain relief was defined as a reduction in severity from a rating of 3, 4 or 5 (moderate or severe pain) at the Stage 2 baseline (15 minutes post Stage 1 dose) to a rating of 2 or 1 (mild or no pain) at 2 hours post Stage 2 dose. Missing data were imputed by carrying forward the preceding Stage 2 pain intensity values. Missing Stage 2 baseline values were imputed by carrying forward the Stage 1 baseline value, if available.
    End point type
    Secondary
    End point timeframe
    2 hours post Stage 2 dose
    End point values
    		 Rizatriptan in Stage 2 Placebo in Stage 2
    Number of subjects analysed
    284 [5]
    286 [6]
    Units: Participants
        2-hour pain relief
    167
    147
        No 2-hr pain relief
    117
    139
    Notes
    [5] - Participants between 12 and 17 years of age who received rizatriptan during Stage 2 of the study.
    [6] - Participants between 12 and 17 years of age who received placebo during Stage 2 of the study.
    Statistical analysis title
    		 Pain Relief at 2 Hours Post Dose
    Statistical analysis description
    Pain relief at 2 hours post dose in participants between 12 and 17 years of age. The comparison of rizatriptan vs placebo with respect to pain relief at 2 hrs post Stage 2 dose for participants between 12 and 17 years of age was conducted using a logistic regression model with factors for treatment, Stage 2 baseline pain severity (moderate or severe) and region (US or ex-US). Model-derived odds ratio and a two-sided p-value were provided. An odds ratio >1 is in favor of the rizatriptan group.
    Comparison groups
    Rizatriptan in Stage 2 v Placebo in Stage 2
    Number of subjects included in analysis
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.9
    Notes
    [7] - Secondary endpoints were to be formally tested only if the test of the primary endpoint was statistically significant at the α=0.0477 level. The secondary endpoints were then tested sequentially in a pre-specified order, each at the α=0.05 level.

    Secondary: Pain freedom at 2 hours post dose in participants between 6 and 17 years of age

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    End point title
    		 Pain freedom at 2 hours post dose in participants between 6 and 17 years of age
    End point description
    Pain intensity was assessed using a 5-Face Pain Scale ranging from 1=no pain to 5=very bad pain. Pain freedom was defined as a reduction in severity from a rating of 3, 4 or 5 (moderate or severe pain) at the Stage 2 baseline (15 minutes post Stage 1 dose) to a rating of 1 (no pain) at 2 hours post Stage 2 dose. Missing data were imputed by carrying forward the preceding Stage 2 pain intensity values. Missing Stage 2 baseline values were imputed by carrying forward the Stage 1 baseline value, if available.
    End point type
    Secondary
    End point timeframe
    2 hours post Stage 2 dose
    End point values
    		 Rizatriptan in Stage 2 Placebo in Stage 2
    Number of subjects analysed
    382 [8]
    388 [9]
    Units: Participants
        2-hour pain freedom
    126
    94
        No 2-hour pain freedom
    256
    294
    Notes
    [8] - Participants between 6 and 17 years of age who received rizatriptan during Stage 2 of the study.
    [9] - Participants between 6 and 17 years of age who received placebo during Stage 2 of the study.
    Statistical analysis title
    		 Pain freedom at 2 hours post dose
    Statistical analysis description
    The comparison of rizatriptan versus placebo with respect to pain freedom at 2 hours post Stage 2 dose for participants between 6 and 17 years of age was conducted using a logistic regression model with factors for treatment, Stage 2 baseline pain severity (moderate or severe), age (6 to 11 years old or 12 to 17 years old), and region (US or ex-US). Model-derived odds ratio and a two-sided p-value were provided. An odds ratio >1 is in favor of the rizatriptan group.
    Comparison groups
    Rizatriptan in Stage 2 v Placebo in Stage 2
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 2.1
    Notes
    [10] - This second secondary hypothesis was not formally tested since the first secondary was not statistically significant.

    Secondary: Pain relief at 2 hours post dose in participants between 6 and 17 years of age

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    End point title
    		 Pain relief at 2 hours post dose in participants between 6 and 17 years of age
    End point description
    Pain intensity was assessed using a 5-Face Pain Scale ranging from 1=no pain to 5=very bad pain. Pain relief was defined as a reduction in severity from a rating of 3, 4 or 5 (moderate or severe pain) at the Stage 2 baseline (15 minutes post Stage 1 dose) to a rating of 2 or 1 (mild or no pain) at 2 hours post Stage 2 dose. Missing data were imputed by carrying forward the preceding Stage 2 pain intensity values. Missing Stage 2 baseline values were imputed by carrying forward the Stage 1 baseline value, if available.
    End point type
    Secondary
    End point timeframe
    2 hours post Stage 2 dose
    End point values
    		 Rizatriptan in Stage 2 Placebo in Stage 2
    Number of subjects analysed
    382 [11]
    388 [12]
    Units: participants
        2-hour pain relief
    220
    204
        No 2-hour pain relief
    162
    184
    Notes
    [11] - Participants between 6 and 17 years of age who received rizatriptan during Stage 2 of the study.
    [12] - Participants between 6 and 17 years of age who received placebo during Stage 2 of the study.
    Statistical analysis title
    		 Pain relief at 2 hours post dose
    Statistical analysis description
    The comparison of rizatriptan versus placebo with respect to pain relief at 2 hours post Stage 2 dose for participants between 6 and 17 years of age was conducted using a logistic regression model with factors for treatment, Stage 2 baseline pain severity (moderate or severe), age (6 to 11 years old or 12 to 17 years old), and region (US or ex-US). Model-derived odds ratio and a two-sided p-value were provided. An odds ratio >1 is in favor of the rizatriptan group.
    Comparison groups
    Rizatriptan in Stage 2 v Placebo in Stage 2
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.178 [13]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.63
    Notes
    [13] - This third secondary hypothesis was not formally tested since the first secondary was not statistically significant.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to 14 days post dose
    Adverse event reporting additional description
    Includes all randomized participants who received at least one dose of study drug (i.e., participants who only took study drug in Stage 1 were also included). Participants were included in the treatment group corresponding to the study treatment they actually received, with active treatment taking precedence over placebo treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Rizatriptan
    Reporting group description
    		 Participants who took any rizatriptan during the study (Stage 1 or 2)

    Reporting group title
    Placebo
    Reporting group description
    		 Participants who took only placebo during the study

    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 exceeded the 5% threshold for any treatment group.
    Serious adverse events
    		 Rizatriptan Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 462 (0.00%)
    2 / 515 (0.39%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 462 (0.00%)
    1 / 515 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Enterobacter bacteremia
         subjects affected / exposed
    0 / 462 (0.00%)
    1 / 515 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Rizatriptan Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 462 (0.00%)
    0 / 515 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2010
    Amendment 2: Primary reasons for amendment were (1) to indicate that approximately 900 participants between 12 and 17 years of age will be needed to enter the study in Stage 1 to yield approximately 548 evaluable adolescent participants in Stage 2 to demonstrate the primary hypothesis regarding pain freedom at 2 hours post Stage 2 dose; and (2) to indicate that text has been changed from a maximum of 362 participants aged 6 to 11 years will be enrolled in Stage 1 to state that a minimum of 135 participants to a maximum of 165 participants aged 6 to 11 years will be enrolled in Stage 1 which is expected to yield ~ 80 to 100 evaluable participants in Stage 2 under the same assumptions as the 12 – 17 year old group.
    13 Nov 2010
    Amendment 4: Primary reason for amendment was to indicate that approximately 265 participants aged 6 to 11 years old will be enrolled in Stage 1 which is expected to yield approximately 160 evaluable participants (80/arm) in Stage 2 under the same evaluability assumptions as for the 12-17 year olds.
    24 Jan 2011
    Amendment 6: Primary reason for amendment was to indicate that approximately 340 participants aged 6 to 11 years old will be enrolled in Stage 1 which is expected to yield approximately 160 evaluable participants (80 rizatriptan/80 placebo) in Stage 2.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/22711898
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