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    Clinical Trial Results:
    An Open-label, Randomized, Phase IIIB, Multicenter Trial to Evaluate the Pharmacodynamic Parameters of Intubation Bolus, and Bolus and Infusion Maintenance Doses of Zemuron® in Pediatric and Adolescent Subjects

    Summary
    EudraCT number
    		 2005-002926-67
    Trial protocol
    		 DE  
    Global end of trial date
    05 Sep 2007

    Results information
    Results version number
    		 v1
    This version publication date
    05 Mar 2016
    First version publication date
    05 Mar 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    P05797
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00124735
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Registration number: MK-8085-001, Organon Registration number: 021048
    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
    05 Sep 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Sep 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of this study is to determine the dose requirements of Zemuron (rocuronium bromide) when administered as a bolus dose (a single, large dose) for intubation (insertion of a tube through the nose or mouth into the trachea to provide artificial ventilation) and when administered by either continuous infusion or bolus doses for maintenance of muscle relaxation in term neonates (birth to <28 days old), infants (28 days to ≤3 months old), toddlers (>3 months to ≤2 years of age), children (>2 years to ≤11 years of age), and adolescents (>11 years to ≤17 years of age).
    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
    		 Sevoflurane at 2.0-2.5 minimum alveolar concentration (MAC) to up to 7%-8% inspired concentration and nitrous oxide at 0%-70%, or propofol 1-3 mg/kg (may be used in neonates only) for induction of anesthesia; isoflurane 1.0±0.2% expired end-tidal concentration in 0%-70% nitrous oxide and, if needed, propofol as intermittent bolus dose(s) (0.5-2 mg/kg) or infusion (50–150 μg/kg/min) for maintenance of anesthesia.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 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
    Argentina: 9
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    United States: 133
    Worldwide total number of subjects
    149
    EEA total number of subjects
    7
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    12
    Infants and toddlers (28 days-23 months)
    52
    Children (2-11 years)
    49
    Adolescents (12-17 years)
    36
    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
    		 A total of 149 participants were enrolled and randomized in the trial, including 71 participants in the bolus maintenance group and 78 participants in the infusion maintenance group

    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
    		 Zemuron Bolus Maintenance - Neonates
    Arm description
    		 Neonate participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemuron
    Investigational medicinal product code
    Other name
    Esmeron, rocuronium bromide, MK-8085, SCH 900085, Org 9426
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For intubation - 0.6 mg/kg bolus dose, or 1.0 mg/kg bolus dose if had received propofol for anesthesia induction; For maintenance of muscle relaxation – initial 0.15 mg/kg bolus dose at reappearance of T3 (the third twitch of a Train of Four [TOF] stimulation) with additional bolus doses administered at the reappearance of T3 after previous bolus dose

    Arm title
    		 Zemuron Bolus Maintenance – Infants
    Arm description
    		 Infant participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemuron
    Investigational medicinal product code
    Other name
    Esmeron, rocuronium bromide, MK-8085, SCH 900085, Org 9426
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For intubation - 0.6 mg/kg bolus dose; For maintenance of muscle relaxation – initial 0.15 mg/kg bolus dose at reappearance of T3 (the third twitch of a TOF stimulation) with additional bolus doses administered at the reappearance of T3 after previous bolus dose

    Arm title
    		 Zemuron Bolus Maintenance – Toddlers
    Arm description
    		 Toddler participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemuron
    Investigational medicinal product code
    Other name
    Esmeron, rocuronium bromide, MK-8085, SCH 900085, Org 9426
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For intubation - 0.6 mg/kg bolus dose; For maintenance of muscle relaxation – initial 0.15 mg/kg bolus dose at reappearance of T3 (the third twitch of a TOF stimulation) with additional bolus doses administered at the reappearance of T3 after previous bolus dose

    Arm title
    		 Zemuron Bolus Maintenance – Children
    Arm description
    		 Child participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemuron
    Investigational medicinal product code
    Other name
    Esmeron, rocuronium bromide, MK-8085, SCH 900085, Org 9426
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For intubation - 0.6 mg/kg bolus dose; For maintenance of muscle relaxation – initial 0.15 mg/kg bolus dose at reappearance of T3 (the third twitch of a TOF stimulation) with additional bolus doses administered at the reappearance of T3 after previous bolus dose

    Arm title
    		 Zemuron Bolus Maintenance – Adolescents
    Arm description
    		 Adolescent participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemuron
    Investigational medicinal product code
    Other name
    Esmeron, rocuronium bromide, MK-8085, SCH 900085, Org 9426
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For intubation - 0.6 mg/kg bolus dose; For maintenance of muscle relaxation – initial 0.15 mg/kg bolus dose at reappearance of T3 (the third twitch of a TOF stimulation) with additional bolus doses administered at the reappearance of T3 after previous bolus dose

    Arm title
    		 Zemuron Continuous Infusion Maintenance - Neonates
    Arm description
    		 Neonate participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemuron
    Investigational medicinal product code
    Other name
    Esmeron, rocuronium bromide, MK-8085, SCH 900085, Org 9426
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For intubation - 0.6 mg/kg bolus dose, or 1.0 mg/kg bolus dose if had received propofol for anesthesia induction; For maintenance of muscle relaxation – continuous infusion of 10 µg/kg/min beginning at reappearance of T2 (the second twitch of a TOF stimulation), infusion was to be adjusted approximately 2.0-5.0 µg/kg/min every 3 minutes until one or two twitches were maintained

    Arm title
    		 Zemuron Continuous Infusion Maintenance - Infants
    Arm description
    		 Infant participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemuron
    Investigational medicinal product code
    Other name
    Esmeron, rocuronium bromide, MK-8085, SCH 900085, Org 9426
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For intubation - 0.6 mg/kg bolus dose; For maintenance of muscle relaxation – continuous infusion of 10 µg/kg/min beginning at reappearance of T2 (the second twitch of a TOF stimulation), infusion was to be adjusted approximately 2.0-5.0 µg/kg/min every 3 minutes until one or two twitches were maintained

    Arm title
    		 Zemuron Continuous Infusion Maintenance - Toddlers
    Arm description
    		 Toddler participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemuron
    Investigational medicinal product code
    Other name
    Esmeron, rocuronium bromide, MK-8085, SCH 900085, Org 9426
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For intubation - 0.6 mg/kg bolus dose; For maintenance of muscle relaxation – continuous infusion of 10 µg/kg/min beginning at reappearance of T2 (the second twitch of a TOF stimulation), infusion was to be adjusted approximately 2.0-5.0 µg/kg/min every 3 minutes until one or two twitches were maintained

    Arm title
    		 Zemuron Continuous Infusion Maintenance - Children
    Arm description
    		 Child participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemuron
    Investigational medicinal product code
    Other name
    Esmeron, rocuronium bromide, MK-8085, SCH 900085, Org 9426
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For intubation - 0.6 mg/kg bolus dose; For maintenance of muscle relaxation – continuous infusion of 10 µg/kg/min beginning at reappearance of T2 (the second twitch of a TOF stimulation), infusion was to be adjusted approximately 2.0-5.0 µg/kg/min every 3 minutes until one or two twitches were maintained

    Arm title
    		 Zemuron Continuous Infusion Maintenance - Adolescents
    Arm description
    		 Adolescent participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zemuron
    Investigational medicinal product code
    Other name
    Esmeron, rocuronium bromide, MK-8085, SCH 900085, Org 9426
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For intubation - 0.6 mg/kg bolus dose; For maintenance of muscle relaxation – continuous infusion of 10 µg/kg/min beginning at reappearance of T2 (the second twitch of a TOF stimulation), infusion was to be adjusted approximately 2.0-5.0 µg/kg/min every 3 minutes until one or two twitches were maintained

    Number of subjects in period 1
    		Zemuron Bolus Maintenance - Neonates Zemuron Bolus Maintenance – Infants Zemuron Bolus Maintenance – Toddlers Zemuron Bolus Maintenance – Children Zemuron Bolus Maintenance – Adolescents Zemuron Continuous Infusion Maintenance - Neonates Zemuron Continuous Infusion Maintenance - Infants Zemuron Continuous Infusion Maintenance - Toddlers Zemuron Continuous Infusion Maintenance - Children Zemuron Continuous Infusion Maintenance - Adolescents
    Started
    5
    8
    18
    21
    19
    7
    6
    20
    25
    20
    Treated
    5
    6
    18
    18
    17
    5
    6
    19
    23
    20
    Completed
    4
    6
    18
    18
    17
    5
    6
    19
    22
    18
    Not completed
    1
    2
    0
    3
    2
    2
    0
    1
    3
    2
         Physician decision
    1
    -
    -
    -
    -
    -
    -
    -
    -
    -
         Required tourniquet
    -
    -
    -
    -
    -
    -
    -
    -
    -
    2
         Not treated
    -
    2
    -
    3
    2
    2
    -
    1
    2
    -
         Protocol deviation
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zemuron Bolus Maintenance - Neonates
    Reporting group description
    		 Neonate participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Reporting group title
    Zemuron Bolus Maintenance – Infants
    Reporting group description
    		 Infant participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Reporting group title
    Zemuron Bolus Maintenance – Toddlers
    Reporting group description
    		 Toddler participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Reporting group title
    Zemuron Bolus Maintenance – Children
    Reporting group description
    		 Child participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Reporting group title
    Zemuron Bolus Maintenance – Adolescents
    Reporting group description
    		 Adolescent participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Reporting group title
    Zemuron Continuous Infusion Maintenance - Neonates
    Reporting group description
    		 Neonate participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Reporting group title
    Zemuron Continuous Infusion Maintenance - Infants
    Reporting group description
    		 Infant participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Reporting group title
    Zemuron Continuous Infusion Maintenance - Toddlers
    Reporting group description
    		 Toddler participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Reporting group title
    Zemuron Continuous Infusion Maintenance - Children
    Reporting group description
    		 Child participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Reporting group title
    Zemuron Continuous Infusion Maintenance - Adolescents
    Reporting group description
    		 Adolescent participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Reporting group values
    		 Zemuron Bolus Maintenance - Neonates Zemuron Bolus Maintenance – Infants Zemuron Bolus Maintenance – Toddlers Zemuron Bolus Maintenance – Children Zemuron Bolus Maintenance – Adolescents Zemuron Continuous Infusion Maintenance - Neonates Zemuron Continuous Infusion Maintenance - Infants Zemuron Continuous Infusion Maintenance - Toddlers Zemuron Continuous Infusion Maintenance - Children Zemuron Continuous Infusion Maintenance - Adolescents Total
    Number of subjects
    		 5 8 18 21 19 7 6 20 25 20 149
    Age Categorical
    Units: Subjects
        ≤18 years
    		 5 8 18 21 19 7 6 20 25 20 149
        Between 18 and 65 years
    		 0 0 0 0 0 0 0 0 0 0 0
        ≥65 years
    		 0 0 0 0 0 0 0 0 0 0 0
    Gender Categorical
    Units: Subjects
        Female
    		 2 1 1 9 8 2 3 7 11 12 56
        Male
    		 3 7 17 12 11 5 3 13 14 8 93
    Subject analysis sets

    Subject analysis set title
    Zemuron Bolus Maintenance - Neonates
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Neonate participants who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Bolus Maintenance – Infants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Infant participants who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Bolus Maintenance – Toddlers
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Toddler participants who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Bolus Maintenance – Children
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Child participants who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Bolus Maintenance – Adolescents
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Adolescent participants who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Continuous Infusion Maintenance - Neonates
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Neonate participants who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Continuous Infusion Maintenance - Infants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Infant participants who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Continuous Infusion Maintenance - Toddlers
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Toddler participants who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Continuous Infusion Maintenance - Children
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Child participants who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Continuous Infusion Maintenance - Adolescents
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Adolescent participants who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Subject analysis sets values
    		 Zemuron Bolus Maintenance - Neonates Zemuron Bolus Maintenance – Infants Zemuron Bolus Maintenance – Toddlers Zemuron Bolus Maintenance – Children Zemuron Bolus Maintenance – Adolescents Zemuron Continuous Infusion Maintenance - Neonates Zemuron Continuous Infusion Maintenance - Infants Zemuron Continuous Infusion Maintenance - Toddlers Zemuron Continuous Infusion Maintenance - Children Zemuron Continuous Infusion Maintenance - Adolescents
    Number of subjects
    5
    6
    18
    18
    17
    5
    6
    19
    23
    20
    Age Categorical
    Units: Subjects
        ≤18 years
    5
    6
    18
    18
    17
    5
    6
    19
    23
    20
        Between 18 and 65 years
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        ≥65 years
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Age Continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender Categorical
    Units: Subjects
        Female
    2
    1
    1
    8
    6
    2
    3
    6
    11
    12
        Male
    3
    5
    17
    10
    11
    3
    3
    13
    12
    8

    End points

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    End points reporting groups
    Reporting group title
    Zemuron Bolus Maintenance - Neonates
    Reporting group description
    		 Neonate participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Reporting group title
    Zemuron Bolus Maintenance – Infants
    Reporting group description
    		 Infant participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Reporting group title
    Zemuron Bolus Maintenance – Toddlers
    Reporting group description
    		 Toddler participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Reporting group title
    Zemuron Bolus Maintenance – Children
    Reporting group description
    		 Child participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Reporting group title
    Zemuron Bolus Maintenance – Adolescents
    Reporting group description
    		 Adolescent participants randomized to receive a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Reporting group title
    Zemuron Continuous Infusion Maintenance - Neonates
    Reporting group description
    		 Neonate participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Reporting group title
    Zemuron Continuous Infusion Maintenance - Infants
    Reporting group description
    		 Infant participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Reporting group title
    Zemuron Continuous Infusion Maintenance - Toddlers
    Reporting group description
    		 Toddler participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Reporting group title
    Zemuron Continuous Infusion Maintenance - Children
    Reporting group description
    		 Child participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Reporting group title
    Zemuron Continuous Infusion Maintenance - Adolescents
    Reporting group description
    		 Adolescent participants randomized to receive a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Bolus Maintenance - Neonates
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Neonate participants who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Bolus Maintenance – Infants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Infant participants who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Bolus Maintenance – Toddlers
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Toddler participants who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Bolus Maintenance – Children
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Child participants who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Bolus Maintenance – Adolescents
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Adolescent participants who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Continuous Infusion Maintenance - Neonates
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Neonate participants who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Continuous Infusion Maintenance - Infants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Infant participants who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Continuous Infusion Maintenance - Toddlers
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Toddler participants who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Continuous Infusion Maintenance - Children
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Child participants who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Subject analysis set title
    Zemuron Continuous Infusion Maintenance - Adolescents
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Adolescent participants who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Primary: Total Dose of Zemuron Administered

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    End point title
    		 Total Dose of Zemuron Administered
    End point description
    Total Zemuron dose from administration of intubating dose to reappearance of T3 (the third twitch of a TOF stimulation) after the last maintenance bolus dose or discontinuation of Zemuron infusion. Analysis population is the Per Protocol group, which is all participants who were randomized after protocol Amendment 5 (major revision to study), received study drug, had at least one efficacy parameter measured and did not have any major protocol violations.
    End point type
    Primary
    End point timeframe
    From administration of intubating dose of Zemuron through reappearance of T3 after last bolus maintenance Zemuron dose or end of continuous infusion maintenance Zemuron dose, an estimated average duration of 107 minutes
    End point values
    		 Zemuron Bolus Maintenance - Neonates Zemuron Bolus Maintenance – Infants Zemuron Bolus Maintenance – Toddlers Zemuron Bolus Maintenance – Children Zemuron Bolus Maintenance – Adolescents Zemuron Continuous Infusion Maintenance - Neonates Zemuron Continuous Infusion Maintenance - Infants Zemuron Continuous Infusion Maintenance - Toddlers Zemuron Continuous Infusion Maintenance - Children Zemuron Continuous Infusion Maintenance - Adolescents
    Number of subjects analysed
    3
    5
    13
    14
    15
    5
    2
    12
    19
    15
    Units: mg/kg
        arithmetic mean (standard deviation)
    0.91 ( 0.17 )
    0.78 ( 0.07 )
    0.86 ( 0.18 )
    0.81 ( 0.1 )
    0.96 ( 0.16 )
    1.01 ( 0.37 )
    0.84 ( 0.15 )
    1 ( 0.25 )
    1.26 ( 0.78 )
    0.99 ( 0.37 )
    Statistical analysis title
    		 Bolus v Infusion Maintenance by Age Group
    Statistical analysis description
    Two-way analysis of variance (ANOVA) model including terms treatment group, site and interaction between treatment and site. Difference in least squares means is bolus minus infusion
    Comparison groups
    Zemuron Bolus Maintenance - Neonates v Zemuron Continuous Infusion Maintenance - Neonates
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.497
    Method
    		 ANOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.175761
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.792979
         upper limit
    		 0.441457
    Statistical analysis title
    		 Bolus v Infusion Maintenance by Age Group
    Statistical analysis description
    Two-way ANOVA model including terms treatment group, site and interaction between treatment and site. Difference in least squares means is bolus minus infusion
    Comparison groups
    Zemuron Bolus Maintenance – Infants v Zemuron Continuous Infusion Maintenance - Infants
    Number of subjects included in analysis
    7
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4433
    Method
    		 ANOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.074936
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.415185
         upper limit
    		 0.265313
    Statistical analysis title
    		 Bolus v Infusion Maintenance by Age Group
    Statistical analysis description
    Two-way ANOVA model including terms treatment group, site and interaction between treatment and site. Difference in least squares means is bolus minus infusion
    Comparison groups
    Zemuron Bolus Maintenance – Toddlers v Zemuron Continuous Infusion Maintenance - Toddlers
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4143
    Method
    		 ANOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.069673
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.246559
         upper limit
    		 0.107213
    Statistical analysis title
    		 Bolus v Infusion Maintenance by Age Group
    Statistical analysis description
    Two-way analysis of variance (ANOVA) model including terms treatment group, site and interaction between treatment and site. Difference in least squares means is bolus minus infusion
    Comparison groups
    Zemuron Bolus Maintenance – Children v Zemuron Continuous Infusion Maintenance - Children
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0303
    Method
    		 ANOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.234979
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.445466
         upper limit
    		 -0.024492
    Statistical analysis title
    		 Bolus v Infusion Maintenance by Age Group
    Statistical analysis description
    Two-way ANOVA model including terms treatment group, site and interaction between treatment and site. Difference in least squares means is bolus minus infusion
    Comparison groups
    Zemuron Bolus Maintenance – Adolescents v Zemuron Continuous Infusion Maintenance - Adolescents
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8208
    Method
    		 ANOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.027891
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.282009
         upper limit
    		 0.226226

    Secondary: Duration of Recovery of T4/T1 (TOF Fourth Twitch to First Twitch) Ratio 70%

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    End point title
    		 Duration of Recovery of T4/T1 (TOF Fourth Twitch to First Twitch) Ratio 70%
    End point description
    The time it takes for the T4 to T1 ratio to reach 70%. The T4/T1 ratio is indicative of recovery. At complete recovery, the T4/T1 ratio is 1.0 (100%). Analysis population is the Per Protocol group, which is all participants who were randomized after protocol Amendment 5 (major revision to study), received study drug, had at least one efficacy parameter measured and did not have any major protocol violations. Also to be included, participant must have an evaluable assessment for this measure.
    End point type
    Secondary
    End point timeframe
    After surgery, from the reappearance of T3 after Zemuron infusion/last bolus dose of Zemuron to T4/T1 ratio of 70%
    End point values
    		 Zemuron Bolus Maintenance - Neonates Zemuron Bolus Maintenance – Infants Zemuron Bolus Maintenance – Toddlers Zemuron Bolus Maintenance – Children Zemuron Bolus Maintenance – Adolescents Zemuron Continuous Infusion Maintenance - Neonates Zemuron Continuous Infusion Maintenance - Infants Zemuron Continuous Infusion Maintenance - Toddlers Zemuron Continuous Infusion Maintenance - Children Zemuron Continuous Infusion Maintenance - Adolescents
    Number of subjects analysed
    2
    4
    10
    12
    11
    3
    1
    9
    14
    13
    Units: minutes
        arithmetic mean (standard deviation)
    29.62 ( 13.6 )
    33.25 ( 16.17 )
    22.65 ( 7.62 )
    16.29 ( 6.98 )
    28.04 ( 13.33 )
    43.42 ( 1.53 )
    33.25 ( 0 )
    23.08 ( 13.4 )
    18.32 ( 13.16 )
    27.59 ( 12.51 )
    No statistical analyses for this end point

    Secondary: Duration of Recovery of T4/T1 (TOF Fourth Twitch to First Twitch) Ratio 80%

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    End point title
    		 Duration of Recovery of T4/T1 (TOF Fourth Twitch to First Twitch) Ratio 80%
    End point description
    The time it takes for the T4 to T1 ratio to reach 80%. The T4/T1 ratio is indicative of recovery. At complete recovery, the T4/T1 ratio is 1.0 (100%). Analysis population is the Per Protocol group, which is all participants who were randomized after protocol Amendment 5 (major revision to study), received study drug, had at least one efficacy parameter measured and did not have any major protocol violations. Also to be included, participant must have an evaluable assessment for this measure.
    End point type
    Secondary
    End point timeframe
    After surgery, from the reappearance of T3 after Zemuron infusion/last bolus dose of Zemuron to T4/T1 ratio of 80%
    End point values
    		 Zemuron Bolus Maintenance - Neonates Zemuron Bolus Maintenance – Infants Zemuron Bolus Maintenance – Toddlers Zemuron Bolus Maintenance – Children Zemuron Bolus Maintenance – Adolescents Zemuron Continuous Infusion Maintenance - Neonates Zemuron Continuous Infusion Maintenance - Infants Zemuron Continuous Infusion Maintenance - Toddlers Zemuron Continuous Infusion Maintenance - Children Zemuron Continuous Infusion Maintenance - Adolescents
    Number of subjects analysed
    2
    3
    9
    11
    10
    3
    1
    9
    14
    11
    Units: minutes
        arithmetic mean (standard deviation)
    36.62 ( 17.14 )
    43.58 ( 21.47 )
    32.39 ( 12.84 )
    20.43 ( 9.79 )
    36.1 ( 20.45 )
    57.83 ( 12.33 )
    44.75 ( 0 )
    29.47 ( 16.65 )
    21.84 ( 15.12 )
    35.45 ( 17.02 )
    No statistical analyses for this end point

    Secondary: Duration of Recovery of T4/T1 (TOF Fourth Twitch to First Twitch) Ratio 90%

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    End point title
    		 Duration of Recovery of T4/T1 (TOF Fourth Twitch to First Twitch) Ratio 90%
    End point description
    The time it takes for the T4 to T1 ratio to reach 90%. The T4/T1 ratio is indicative of recovery. At complete recovery, the T4/T1 ratio is 1.0 (100%). Analysis population is the Per Protocol group, which is all participants who were randomized after protocol Amendment 5 (major revision to study), received study drug, had at least one efficacy parameter measured and did not have any major protocol violations. Also to be included, participant must have an evaluable assessment for this measure.
    End point type
    Secondary
    End point timeframe
    After surgery, from the reappearance of T3 after Zemuron infusion/last bolus dose of Zemuron to T4/T1 ratio of 90%
    End point values
    		 Zemuron Bolus Maintenance - Neonates Zemuron Bolus Maintenance – Infants Zemuron Bolus Maintenance – Toddlers Zemuron Bolus Maintenance – Children Zemuron Bolus Maintenance – Adolescents Zemuron Continuous Infusion Maintenance - Neonates Zemuron Continuous Infusion Maintenance - Infants Zemuron Continuous Infusion Maintenance - Toddlers Zemuron Continuous Infusion Maintenance - Children Zemuron Continuous Infusion Maintenance - Adolescents
    Number of subjects analysed
    1
    3
    8
    8
    6
    1
    1
    9
    12
    10
    Units: minutes
        arithmetic mean (standard deviation)
    28.25 ( 0 )
    53.66 ( 14.58 )
    43.31 ( 18.2 )
    23.09 ( 10.9 )
    51.79 ( 33.97 )
    52.25 ( 0 )
    50.75 ( 0 )
    37.86 ( 18.46 )
    28.46 ( 22.35 )
    38.68 ( 16.08 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For non-serious adverse events (AEs), through in-trial period, which ends at stable neuromuscular recovery (up to 90% of T4/T1 ratio) or administration of another muscle relaxant or a reversal agent. For serious AEs, up to 7 days post-surgery
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Zemuron Continuous Infusion Maintenance
    Reporting group description
    		 Participants in all age groups combined who received a bolus dose of Zemuron for intubation followed by continuous infusion of Zemuron for maintenance of muscle relaxation

    Reporting group title
    Zemuron Bolus Maintenance
    Reporting group description
    		 Participants in all age groups combined who received a bolus dose of Zemuron for intubation followed by bolus doses for maintenance of muscle relaxation

    Serious adverse events
    		 Zemuron Continuous Infusion Maintenance Zemuron Bolus Maintenance
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 64 (1.56%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    postoperative wound infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 64 (1.56%)
         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
    		 Zemuron Continuous Infusion Maintenance Zemuron Bolus Maintenance
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 73 (12.33%)
    10 / 64 (15.63%)
    Injury, poisoning and procedural complications
    procedural pain
         subjects affected / exposed
    9 / 73 (12.33%)
    10 / 64 (15.63%)
         occurrences all number
    9
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2004
    Amendment 01: Primary reason for amendment was to add a secondary objective, revise trial assessments to include electrocardiograms (ECGs), revise clinical trial design and statistical methods to comply with United States Food and Drug Administration (US FDA) Pediatric Written Request (PWR) and revise the exclusion criteria.
    27 Sep 2004
    Amendment 02: Primary reason for amendment was to revise the hazards and precautions section to include indications and possible complications of rapid sequence intubation.
    27 Sep 2004
    Amendment 03: Primary reason for amendment was to revise the exclusion criteria, standardize start time of administration of the intubating dose of Zemuron, and standardize reporting of fraction of inspired oxygen (FiO2).
    27 Sep 2004
    Amendment 04: Primary reason for amendment was to revise demographic data collected to comply with US FDA directive regarding collection of race and ethnicity data in clinical trials.
    20 Jan 2005
    Amendment 08: Primary reason for amendment was to indicate that non-US sites would not be conducting the trial under the US Investigational New Drug (IND) authorization and specify criteria for vital signs and ECG findings that are considered to be adverse events.
    09 Aug 2005
    Amendment 05: Primary reason for amendment was to exclude use of intravenous lidocaine and glycopyrrolate, define use of fentanyl for induction/maintenance of anesthesia, redefine the age groups for study participants, permit direct measurements of ventilatory parameters, include measurement of central body temperature, revise directions for induction with sevoflurane and description of boundary conditions for arterial oxygen percent saturation (SAO2) and end-tidal carbon dioxide (ETCO2), clarify description of reduction of sevoflurane after intubation and revise the blood sampling schedules.
    15 Sep 2005
    Amendment 06: Primary reason for amendment was to include reporting of Medical Device Reporting (MDR) reportable events.
    09 Dec 2005
    Amendment 07: Primary reason for amendment was to define use of local anesthetics for premedication and during surgery, define duration of induction of anesthesia, revise directions for administration of Zemuron for intubation, revise directions for measuring ventilatory parameters, revise the description of boundary conditions for SAO2 and include a requirement for obtaining acceptable practice neuromuscular recordings before neuromuscular transmission evaluation.
    28 Sep 2006
    Amendment 09: Primary reason for amendment was to indicate that sites from Argentina were to be involved in the clinical trial and add the use of epidural/caudal anesthesia to general anesthesia.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Jul 2005
    The P05797 protocol was performed under an FDA PWR. The protocol was amended several times in response to PWR amendments, FDA’s comments on the protocol, changing FDA directives regarding the collection of data in clinical trials (e.g., FDA directive for collecting ethnicity data) or in response to requests from the trial site Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs). The major revisions to the protocol introduced in Protocol Amendments 5, 6 and 7 substantially altered trial conditions and assessment parameters. The trial was temporarily suspended during this period, and re-initiated after Protocol Amendment 8.
    15 Mar 2006

    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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