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    Clinical Trial Results:
    A Phase 4 Double-blinded, Randomized, Active Comparator-controlled Clinical Trial to Study the Efficacy, Safety, and Pharmacokinetics of Sugammadex (MK-8616) for Reversal of Neuromuscular Blockade in Pediatric Participants Aged Birth to <2

    Summary
    EudraCT number
    		 2017-000693-11
    Trial protocol
    		 BE   DK   FI   HU   NL   FR  
    Global end of trial date
    21 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2024
    First version publication date
    06 Mar 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    8616-169
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03909165
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, 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 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluated the efficacy, safety, and pharmacokinetics (PK) of sugammadex (MK-8616) for reversal of both moderate and deep neuromuscular blockade (NMB) in pediatric participants aged birth to <2 years. The primary hypothesis of this study was that sugammadex was superior to neostigmine in reversing moderate NMB as measured by time to neuromuscular recovery.
    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
    23 Jul 2019
    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
    Australia: 14
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Malaysia: 14
    Country: Number of subjects enrolled
    Mexico: 11
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    United States: 55
    Worldwide total number of subjects
    145
    EEA total number of subjects
    40
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    29
    Infants and toddlers (28 days-23 months)
    116
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 145 pediatric participants between the ages of birth and <2 years undergoing a procedure requiring a neuromuscular blocking agent (NMBA) for either moderate or deep block were enrolled in this study. Participants were enrolled in 4 age cohorts: birth to 27 days, 28 days to <3 months, 3 months to <6 months, and 6 months to <2 years.

    Pre-assignment
    Screening details
    		 50 participants were allocated to moderate block and reversal (2 mg/kg) or deep block and reversal (4 mg/kg) with sugammadex in Part A. 95 participants were randomized in Part B to moderate block and reversal (2 mg/kg) with sugammadex, deep block and reversal (4 mg/kg) with sugammadex, or moderate block and reversal with neostigmine (50 μg/kg).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: Sugammadex 2 mg/kg
    Arm description
    		 Participants received a single intravenous (IV) bolus of sugammadex at 2 mg/kg for moderate NMB reversal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sugammadex
    Investigational medicinal product code
    Other name
    MK-8616 Bridion
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered per allocation (Part A)/randomization (Part B) in a single IV bolus at 2 mg/kg within 2 minutes of the reappearance of a second twitch (T2) in response to train-of-four (TOF) stimulations for moderate NMB reversal, or in a single IV bolus at 4 mg/kg after final dose of NMBA (rocuronium or vecuronium) within 2 minutes of detection of a target of 1 to 2 post-tetanic counts and no response to TOF stimulations (TOF=0) for deep NMB reversal.

    Arm title
    		 Part A: Sugammadex 4 mg/kg
    Arm description
    		 Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sugammadex
    Investigational medicinal product code
    Other name
    MK-8616 Bridion
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered per allocation (Part A)/randomization (Part B) in a single IV bolus at 2 mg/kg within 2 minutes of the reappearance of a second twitch (T2) in response to train-of-four (TOF) stimulations for moderate NMB reversal, or in a single IV bolus at 4 mg/kg after final dose of NMBA (rocuronium or vecuronium) within 2 minutes of detection of a target of 1 to 2 post-tetanic counts and no response to TOF stimulations (TOF=0) for deep NMB reversal.

    Arm title
    		 Part B: Sugammadex 2 mg/kg
    Arm description
    		 Participants received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sugammadex
    Investigational medicinal product code
    Other name
    MK-8616 Bridion
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered per allocation (Part A)/randomization (Part B) in a single IV bolus at 2 mg/kg within 2 minutes of the reappearance of a second twitch (T2) in response to train-of-four (TOF) stimulations for moderate NMB reversal, or in a single IV bolus at 4 mg/kg after final dose of NMBA (rocuronium or vecuronium) within 2 minutes of detection of a target of 1 to 2 post-tetanic counts and no response to TOF stimulations (TOF=0) for deep NMB reversal.

    Arm title
    		 Part B: Sugammadex 4 mg/kg
    Arm description
    		 Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sugammadex
    Investigational medicinal product code
    Other name
    MK-8616 Bridion
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered per allocation (Part A)/randomization (Part B) in a single IV bolus at 2 mg/kg within 2 minutes of the reappearance of a second twitch (T2) in response to train-of-four (TOF) stimulations for moderate NMB reversal, or in a single IV bolus at 4 mg/kg after final dose of NMBA (rocuronium or vecuronium) within 2 minutes of detection of a target of 1 to 2 post-tetanic counts and no response to TOF stimulations (TOF=0) for deep NMB reversal.

    Arm title
    		 Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Arm description
    		 Participants received a single IV bolus containing neostigmine (50 μg/kg; up to 5 mg maximum dose) in combination with either glycopyrrolate (10 μg/kg) or atropine sulfate (20 μg/kg) based on availability and/or contraindications, for moderate NMB reversal.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Neostigmine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For moderate NMB reversal, a single IV. bolus containing neostigmine (50 μg/kg; up to 5 mg maximum dose) with either glycopyrrolate or atropine was given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of the reappearance of T2 in response to TOF stimulations.

    Investigational medicinal product name
    Atropine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atropine (20 ug/kg) administered in a single IV. bolus with neostigmine (50 μg/kg; up to 5 mg maximum dose) after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of the reappearance of T2 in response to TOF stimulations.

    Investigational medicinal product name
    Glycopyrrolate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Glycopyrrolate (10 ug/kg) administered in a single IV. bolus with neostigmine (50 μg/kg; up to 5 mg maximum dose) after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of the reappearance of T2 in response to TOF stimulations.

    Number of subjects in period 1
    		Part A: Sugammadex 2 mg/kg Part A: Sugammadex 4 mg/kg Part B: Sugammadex 2 mg/kg Part B: Sugammadex 4 mg/kg Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Started
    16
    34
    31
    32
    32
    Treated
    15
    32
    29
    31
    31
    Completed
    15
    31
    29
    31
    31
    Not completed
    1
    3
    2
    1
    1
         Physician decision
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    -
    2
    1
    1
    -
         Previous Drug Exposure
    -
    -
    1
    -
    -
         Randomized By Mistake Without Study Treatment
    -
    -
    -
    -
    1
         Early Discharge
    1
    -
    -
    -
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Part A: Sugammadex 2 mg/kg
    Reporting group description
    		 Participants received a single intravenous (IV) bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Reporting group title
    Part A: Sugammadex 4 mg/kg
    Reporting group description
    		 Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Reporting group title
    Part B: Sugammadex 2 mg/kg
    Reporting group description
    		 Participants received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Reporting group title
    Part B: Sugammadex 4 mg/kg
    Reporting group description
    		 Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Reporting group title
    Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Reporting group description
    		 Participants received a single IV bolus containing neostigmine (50 μg/kg; up to 5 mg maximum dose) in combination with either glycopyrrolate (10 μg/kg) or atropine sulfate (20 μg/kg) based on availability and/or contraindications, for moderate NMB reversal.

    Reporting group values
    		 Part A: Sugammadex 2 mg/kg Part A: Sugammadex 4 mg/kg Part B: Sugammadex 2 mg/kg Part B: Sugammadex 4 mg/kg Part B: Neostigmine + (Glycopyrrolate or Atropine) Total
    Number of subjects
    		 16 34 31 32 32 145
    Age Categorical
    Units: Subjects
        Newborns (0-27 days)
    		 4 6 7 6 6 29
        Infants and toddlers (28 days-23 months)
    		 12 28 24 26 26 116
    Age Continuous
    Units: days
        arithmetic mean (standard deviation)
    		 195.9 ( 193.4 ) 140.1 ( 121.7 ) 157.9 ( 171.8 ) 169.1 ( 165.5 ) 174.3 ( 192.7 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 7 13 5 11 12 48
        Male
    		 9 21 26 21 20 97
    Race
    Units: Subjects
        American Indian Or Alaska Native
    		 0 2 4 1 4 11
        Asian
    		 2 4 6 8 8 28
        Black Or African American
    		 0 0 0 2 1 3
        Multiple
    		 0 0 0 1 2 3
        White
    		 14 28 21 20 17 100
    Ethnicity
    Units: Subjects
        Hispanic Or Latino
    		 3 6 10 7 9 35
        Not Hispanic Or Latino
    		 13 28 21 24 23 109
        Not Reported
    		 0 0 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Part A: Sugammadex 2 mg/kg
    Reporting group description
    		 Participants received a single intravenous (IV) bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Reporting group title
    Part A: Sugammadex 4 mg/kg
    Reporting group description
    		 Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Reporting group title
    Part B: Sugammadex 2 mg/kg
    Reporting group description
    		 Participants received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Reporting group title
    Part B: Sugammadex 4 mg/kg
    Reporting group description
    		 Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Reporting group title
    Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Reporting group description
    		 Participants received a single IV bolus containing neostigmine (50 μg/kg; up to 5 mg maximum dose) in combination with either glycopyrrolate (10 μg/kg) or atropine sulfate (20 μg/kg) based on availability and/or contraindications, for moderate NMB reversal.

    Subject analysis set title
    Part A: Sugammadex 2 mg/kg [birth to 27 days]
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged birth to 27 days received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Subject analysis set title
    Part A: Sugammadex 2 mg/kg [28 days to <3 months]
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 28 days to <3 months received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Subject analysis set title
    Part A: Sugammadex 2 mg/kg [3 to < 6 months]
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 3 to < 6 months received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Subject analysis set title
    Part A: Sugammadex 2 mg/kg [6 months to < 2 years]
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 6 months to < 2 years received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Subject analysis set title
    Part A: Sugammadex 4 mg/kg [birth to 27 days]
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged birth to 27 days received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Subject analysis set title
    Part A: Sugammadex 4 mg/kg [28 days to <3 months]
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 28 days to <3 months received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Subject analysis set title
    Part A: Sugammadex 4 mg/kg [3 to < 6 months]
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 3 to < 6 months received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Subject analysis set title
    Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 6 months to < 2 years received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Subject analysis set title
    Parts A + B: Sugammadex 2 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants in Parts A and B received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Subject analysis set title
    Parts A + B: Sugammadex 4 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants in Parts A and B received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Subject analysis set title
    Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received a single IV bolus containing neostigmine (50 μg/kg; up to 5 mg maximum dose) in combination with either glycopyrrolate (10 μg/kg) or atropine sulfate (20 μg/kg) based on availability and/or contraindications, for moderate NMB reversal.

    Primary: Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex

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    End point title
    		 Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) for Sugammadex
    End point description
    Pharmacokinetic (PK) blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine AUC0-inf for sugammadex. As pre-specified by the Statistical Analysis Plan (SAP) for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to <28 days, 28 days to <3 months, 3 to <6 months, and 6 to <24 months) for each dose (2 mg and 4 mg). Values of 0000 and 9999 indicate that a 95% confidence interval (CI) was not estimated for n<3 due to insufficient data to support its calculation. All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed. Per protocol, Part B participants were not analyzed for PK.
    End point type
    Primary
    End point timeframe
    Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
    End point values
    		 Part A: Sugammadex 2 mg/kg [birth to 27 days] Part A: Sugammadex 2 mg/kg [28 days to <3 months] Part A: Sugammadex 2 mg/kg [3 to < 6 months] Part A: Sugammadex 2 mg/kg [6 months to < 2 years] Part A: Sugammadex 4 mg/kg [birth to 27 days] Part A: Sugammadex 4 mg/kg [28 days to <3 months] Part A: Sugammadex 4 mg/kg [3 to < 6 months] Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects analysed
    2
    3
    3
    5
    6
    6
    8
    5
    Units: Hour (hr)*ug/mL
        geometric mean (confidence interval 95%)
    13.40 (0000 to 9999)
    16.22 (12.14 to 21.67)
    11.50 (8.61 to 15.37)
    14.07 (11.24 to 17.61)
    39.09 (31.85 to 47.98)
    31.90 (25.99 to 39.16)
    24.75 (20.73 to 29.56)
    27.75 (22.17 to 34.74)
    Statistical analysis title
    		 2 mg/kg AUC0-inf GMR 1
    Statistical analysis description
    2 mg/kg AUC0-inf Geometric Mean Ratio (GMR) = Birth to 27 days AUC0-inf Geometric Mean (GM) / 28 days to < 3 months AUC0-inf GM.
    Comparison groups
    Part A: Sugammadex 2 mg/kg [birth to 27 days] v Part A: Sugammadex 2 mg/kg [28 days to <3 months]
    Number of subjects included in analysis
    5
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.83
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.21
    Statistical analysis title
    		 2 mg/kg AUC0-inf GMR 2
    Statistical analysis description
    2 mg/kg AUC0-inf GMR = 28 days to < 3 months AUC0-inf GM / 3 to < 6 months AUC0-inf GM.
    Comparison groups
    Part A: Sugammadex 2 mg/kg [28 days to <3 months] v Part A: Sugammadex 2 mg/kg [3 to < 6 months]
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    1.41
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.98
    Statistical analysis title
    		 4 mg/kg AUC0-inf GMR 3
    Statistical analysis description
    4 mg/kg AUC0-inf GMR = 3 to < 6 months AUC0-inf GM / 6 months to < 2 years AUC0-inf GM.
    Comparison groups
    Part A: Sugammadex 4 mg/kg [3 to < 6 months] v Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.89
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.13
    Statistical analysis title
    		 4 mg/kg AUC0-inf GMR 1
    Statistical analysis description
    4 mg/kg AUC0-inf GMR = Birth to 27 days AUC0-inf GM / 28 days to < 3 months AUC0-inf GM.
    Comparison groups
    Part A: Sugammadex 4 mg/kg [birth to 27 days] v Part A: Sugammadex 4 mg/kg [28 days to <3 months]
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    1.23
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.56
    Statistical analysis title
    		 4 mg/kg AUC0-inf GMR 2
    Statistical analysis description
    4 mg/kg AUC0-inf GMR = 28 days to < 3 months AUC0-inf GM / 3 to < 6 months AUC0-inf GM.
    Comparison groups
    Part A: Sugammadex 4 mg/kg [28 days to <3 months] v Part A: Sugammadex 4 mg/kg [3 to < 6 months]
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    1.29
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 1.62
    Statistical analysis title
    		 2 mg/kg AUC0-inf GMR 3
    Statistical analysis description
    2 mg/kg AUC0-inf GMR = 3 to < 6 months AUC0-inf GM / 6 months to < 2 years AUC0-inf GM.
    Comparison groups
    Part A: Sugammadex 2 mg/kg [3 to < 6 months] v Part A: Sugammadex 2 mg/kg [6 months to < 2 years]
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.82
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.11

    Primary: Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex

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    End point title
    		 Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 1 Hour Post Dose (AUC0-1hr) for Sugammadex
    End point description
    PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine AUC0-1hr for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to <28 days, 28 days to <3 months, 3 to <6 months, and 6 to <24 months) for each dose (2 mg and 4 mg). All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed. Per protocol, Part B participants were not analyzed for PK.
    End point type
    Primary
    End point timeframe
    Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
    End point values
    		 Part A: Sugammadex 2 mg/kg [birth to 27 days] Part A: Sugammadex 2 mg/kg [28 days to <3 months] Part A: Sugammadex 2 mg/kg [3 to < 6 months] Part A: Sugammadex 2 mg/kg [6 months to < 2 years] Part A: Sugammadex 4 mg/kg [birth to 27 days] Part A: Sugammadex 4 mg/kg [28 days to <3 months] Part A: Sugammadex 4 mg/kg [3 to < 6 months] Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects analysed
    3
    3
    3
    6
    6
    7
    9
    7
    Units: hr*ug/mL
        geometric mean (confidence interval 95%)
    6.95 (5.38 to 8.99)
    7.63 (5.90 to 9.87)
    6.10 (4.72 to 7.88)
    7.31 (6.09 to 8.76)
    12.38 (10.33 to 14.85)
    14.39 (12.16 to 17.02)
    13.46 (11.61 to 15.61)
    13.92 (11.76 to 16.46)
    Statistical analysis title
    		 2 mg/kg AUC0-1hr GMR 1
    Statistical analysis description
    2 mg/kg AUC0-1hr GMR = Birth to 27 days AUC0-1hr GM / 28 days to < 3 months AUC0-1hr GM.
    Comparison groups
    Part A: Sugammadex 2 mg/kg [birth to 27 days] v Part A: Sugammadex 2 mg/kg [28 days to <3 months]
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.91
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.23
    Statistical analysis title
    		 2 mg/kg AUC0-1hr GMR 2
    Statistical analysis description
    2 mg/kg AUC0-1hr GMR = 28 days to < 3 months AUC0-1hr GM / 3 to < 6 months AUC0-1hr GM.
    Comparison groups
    Part A: Sugammadex 2 mg/kg [28 days to <3 months] v Part A: Sugammadex 2 mg/kg [3 to < 6 months]
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    1.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.69
    Statistical analysis title
    		 4 mg/kg AUC0-1hr GMR 2
    Statistical analysis description
    4 mg/kg AUC0-1hr GMR = 28 days to < 3 months AUC0-1hr GM / 3 to < 6 months AUC0-1hr GM.
    Comparison groups
    Part A: Sugammadex 4 mg/kg [28 days to <3 months] v Part A: Sugammadex 4 mg/kg [3 to < 6 months]
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    1.07
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.29
    Statistical analysis title
    		 4 mg/kg AUC0-1hr GMR 1
    Statistical analysis description
    4 mg/kg AUC0-1hr GMR = Birth to 27 days AUC0-1hr GM / 28 days to < 3 months AUC0-1hr GM.
    Comparison groups
    Part A: Sugammadex 4 mg/kg [birth to 27 days] v Part A: Sugammadex 4 mg/kg [28 days to <3 months]
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.86
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.06
    Statistical analysis title
    		 4 mg/kg AUC0-1hr GMR 3
    Statistical analysis description
    4 mg/kg AUC0-1hr GMR = 3 to < 6 months AUC0-1hr GM / 6 months to < 2 years AUC0-1hr GM.
    Comparison groups
    Part A: Sugammadex 4 mg/kg [3 to < 6 months] v Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.17
    Statistical analysis title
    		 2 mg/kg AUC0-1hr GMR 3
    Statistical analysis description
    2 mg/kg AUC0-1hr GMR = 3 to < 6 months AUC0-1hr GM / 6 months to < 2 years AUC0-1hr GM.
    Comparison groups
    Part A: Sugammadex 2 mg/kg [3 to < 6 months] v Part A: Sugammadex 2 mg/kg [6 months to < 2 years]
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.83
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.08

    Primary: Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex

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    End point title
    		 Part A: Area Under the Plasma Concentration Time Curve up to the Interpolated Concentration at 4 Hours Post Dose (AUC0-4hr) for Sugammadex [1]
    End point description
    PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine AUC0-4hr for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to <28 days, 28 days to <3 months, 3 to <6 months, and 6 to <24 months) for each dose (2 mg and 4 mg). Values of 0000 and 9999 indicate that a 95% CI was not estimated for n<3 due to insufficient data to support its calculation. All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed. Per protocol, Part B participants were not analyzed for PK.
    End point type
    Primary
    End point timeframe
    Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
    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 endpoint.
    End point values
    		 Part A: Sugammadex 2 mg/kg [birth to 27 days] Part A: Sugammadex 2 mg/kg [28 days to <3 months] Part A: Sugammadex 2 mg/kg [3 to < 6 months] Part A: Sugammadex 2 mg/kg [6 months to < 2 years] Part A: Sugammadex 4 mg/kg [birth to 27 days] Part A: Sugammadex 4 mg/kg [28 days to <3 months] Part A: Sugammadex 4 mg/kg [3 to < 6 months] Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects analysed
    2
    3
    3
    5
    6
    6
    8
    6
    Units: hr*ug/mL
        geometric mean (confidence interval 95%)
    10.68 (0000 to 9999)
    13.99 (10.67 to 18.33)
    10.13 (7.73 to 13.27)
    12.57 (10.19 to 15.50)
    27.79 (22.95 to 33.64)
    27.16 (22.43 to 32.89)
    21.51 (18.23 to 25.39)
    22.43 (18.52 to 27.15)
    No statistical analyses for this end point

    Primary: Part A: Maximum Plasma Concentration (Cmax) of Sugammadex

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    End point title
    		 Part A: Maximum Plasma Concentration (Cmax) of Sugammadex
    End point description
    PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine Cmax for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to <28 days, 28 days to <3 months, 3 to <6 months, and 6 to <24 months) for each dose (2 mg and 4 mg). All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed. Per protocol, Part B participants were not analyzed for PK.
    End point type
    Primary
    End point timeframe
    Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
    End point values
    		 Part A: Sugammadex 2 mg/kg [birth to 27 days] Part A: Sugammadex 2 mg/kg [28 days to <3 months] Part A: Sugammadex 2 mg/kg [3 to < 6 months] Part A: Sugammadex 2 mg/kg [6 months to < 2 years] Part A: Sugammadex 4 mg/kg [birth to 27 days] Part A: Sugammadex 4 mg/kg [28 days to <3 months] Part A: Sugammadex 4 mg/kg [3 to < 6 months] Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects analysed
    4
    3
    3
    6
    6
    8
    9
    7
    Units: ug/mL
        geometric mean (confidence interval 95%)
    19.59 (14.15 to 27.13)
    21.18 (14.55 to 30.84)
    19.39 (13.32 to 28.23)
    20.99 (16.09 to 27.38)
    28.56 (21.89 to 37.25)
    30.38 (24.13 to 38.24)
    44.51 (35.83 to 55.29)
    40.86 (31.95 to 52.25)
    Statistical analysis title
    		 2 mg/kg Cmax GMR 1
    Statistical analysis description
    2 mg/kg Cmax GMR = Birth to 27 days Cmax GM / 28 days to < 3 months Cmax GM.
    Comparison groups
    Part A: Sugammadex 2 mg/kg [birth to 27 days] v Part A: Sugammadex 2 mg/kg [28 days to <3 months]
    Number of subjects included in analysis
    7
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.92
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.4
    Statistical analysis title
    		 2 mg/kg Cmax GMR 2
    Statistical analysis description
    2 mg/kg Cmax GMR = 28 days to < 3 months Cmax GM / 3 to < 6 months Cmax GM.
    Comparison groups
    Part A: Sugammadex 2 mg/kg [28 days to <3 months] v Part A: Sugammadex 2 mg/kg [3 to < 6 months]
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    1.09
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.7
    Statistical analysis title
    		 4 mg/kg Cmax GMR 3
    Statistical analysis description
    4 mg/kg AUC0-1hr GMR = 3 to < 6 months Cmax GM / 6 months to < 2 years Cmax GM.
    Comparison groups
    Part A: Sugammadex 4 mg/kg [3 to < 6 months] v Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    1.09
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.43
    Statistical analysis title
    		 4 mg/kg Cmax GMR 1
    Statistical analysis description
    4 mg/kg Cmax GMR = Birth to 27 days Cmax GM / 28 days to < 3 months Cmax GM.
    Comparison groups
    Part A: Sugammadex 4 mg/kg [birth to 27 days] v Part A: Sugammadex 4 mg/kg [28 days to <3 months]
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.94
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.26
    Statistical analysis title
    		 4 mg/kg Cmax GMR 2
    Statistical analysis description
    4 mg/kg Cmax GMR = 28 days to < 3 months Cmax GM / 3 to < 6 months Cmax GM.
    Comparison groups
    Part A: Sugammadex 4 mg/kg [28 days to <3 months] v Part A: Sugammadex 4 mg/kg [3 to < 6 months]
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.68
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.89
    Statistical analysis title
    		 2 mg/kg Cmax GMR 3
    Statistical analysis description
    2 mg/kg Cmax GMR = 3 to < 6 months Cmax GM / 6 months to < 2 years Cmax GM.
    Comparison groups
    Part A: Sugammadex 2 mg/kg [3 to < 6 months] v Part A: Sugammadex 2 mg/kg [6 months to < 2 years]
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio (GMR)
    Point estimate
    0.92
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.36

    Primary: Part A: Plasma Clearance (CL) of Sugammadex

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    End point title
    		 Part A: Plasma Clearance (CL) of Sugammadex [2]
    End point description
    PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine CL for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to <28 days, 28 days to <3 months, 3 to <6 months, and 6 to <24 months) for each dose (2 mg and 4 mg). Values of 0000 and 9999 indicate that a 95% CI was not estimated for n<3 due to insufficient data to support its calculation. All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed. Per protocol, Part B participants were not analyzed for PK.
    End point type
    Primary
    End point timeframe
    Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
    Notes
    [2] - 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 endpoint.
    End point values
    		 Part A: Sugammadex 2 mg/kg [birth to 27 days] Part A: Sugammadex 2 mg/kg [28 days to <3 months] Part A: Sugammadex 2 mg/kg [3 to < 6 months] Part A: Sugammadex 2 mg/kg [6 months to < 2 years] Part A: Sugammadex 4 mg/kg [birth to 27 days] Part A: Sugammadex 4 mg/kg [28 days to <3 months] Part A: Sugammadex 4 mg/kg [3 to < 6 months] Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects analysed
    2
    3
    3
    5
    6
    6
    8
    5
    Units: Liters/hour
        geometric mean (confidence interval 95%)
    0.43 (0000 to 9999)
    0.66 (0.47 to 0.92)
    1.28 (0.91 to 1.80)
    1.34 (1.03 to 1.74)
    0.35 (0.28 to 0.45)
    0.61 (0.48 to 0.78)
    0.97 (0.79 to 1.19)
    1.27 (0.98 to 1.65)
    No statistical analyses for this end point

    Primary: Part A: Apparent Volume of Distribution (Vd) for Sugammadex

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    End point title
    		 Part A: Apparent Volume of Distribution (Vd) for Sugammadex [3]
    End point description
    PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine Vd for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to <28 days, 28 days to <3 months, 3 to <6 months, and 6 to <24 months) for each dose (2 mg and 4 mg). Values of 0000 and 9999 indicate that a 95% CI was not estimated for n<3 due to insufficient data to support its calculation. All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed. Per protocol, Part B participants were not analyzed for PK.
    End point type
    Primary
    End point timeframe
    Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
    Notes
    [3] - 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 endpoint.
    End point values
    		 Part A: Sugammadex 2 mg/kg [birth to 27 days] Part A: Sugammadex 2 mg/kg [28 days to <3 months] Part A: Sugammadex 2 mg/kg [3 to < 6 months] Part A: Sugammadex 2 mg/kg [6 months to < 2 years] Part A: Sugammadex 4 mg/kg [birth to 27 days] Part A: Sugammadex 4 mg/kg [28 days to <3 months] Part A: Sugammadex 4 mg/kg [3 to < 6 months] Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects analysed
    2
    3
    3
    5
    6
    6
    8
    5
    Units: Liters (L)
        geometric mean (confidence interval 95%)
    1.14 (0000 to 9999)
    1.45 (1.06 to 1.98)
    2.68 (1.96 to 3.67)
    2.70 (2.11 to 3.44)
    1.22 (0.98 to 1.52)
    1.35 (1.08 to 1.68)
    2.16 (1.78 to 2.62)
    2.77 (2.17 to 3.53)
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution at Steady State (Vss) for Sugammadex

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    End point title
    		 Apparent Volume of Distribution at Steady State (Vss) for Sugammadex [4]
    End point description
    PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine Vss for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to <28 days, 28 days to <3 months, 3 to <6 months, and 6 to <24 months) for each dose (2 mg and 4 mg). Values of 0000 and 9999 indicate that a 95% CI was not estimated for n<3 due to insufficient data to support its calculation. All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed. Per protocol, Part B participants were not analyzed for PK.
    End point type
    Primary
    End point timeframe
    Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
    Notes
    [4] - 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 endpoint.
    End point values
    		 Part A: Sugammadex 2 mg/kg [birth to 27 days] Part A: Sugammadex 2 mg/kg [28 days to <3 months] Part A: Sugammadex 2 mg/kg [3 to < 6 months] Part A: Sugammadex 2 mg/kg [6 months to < 2 years] Part A: Sugammadex 4 mg/kg [birth to 27 days] Part A: Sugammadex 4 mg/kg [28 days to <3 months] Part A: Sugammadex 4 mg/kg [3 to < 6 months] Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects analysed
    2
    3
    3
    5
    6
    6
    8
    5
    Units: Liters (L)
        geometric mean (confidence interval 95%)
    1.04 (0000 to 9999)
    1.23 (0.94 to 1.60)
    2.07 (1.59 to 2.70)
    2.14 (1.74 to 2.63)
    1.11 (0.92 to 1.34)
    1.18 (0.98 to 1.43)
    1.69 (1.43 to 1.98)
    2.18 (1.77 to 2.68)
    No statistical analyses for this end point

    Primary: Part A: Half-Life (t1/2) of Sugammadex in Plasma

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    End point title
    		 Part A: Half-Life (t1/2) of Sugammadex in Plasma [5]
    End point description
    PK blood samples were collected in Part A from pediatric participants at multiple collection times post administration of sugammadex using a sparse sampling approach and used to determine t½ for sugammadex. As pre-specified by the SAP for the PK analysis, all PK parameters were analyzed and reported by Part A age cohort (birth to <28 days, 28 days to <3 months, 3 to <6 months, and 6 to <24 months) for each dose (2 mg and 4 mg). Values of 0000 and 9999 indicate that a 95% CI was not estimated for n<3 due to insufficient data to support its calculation. All pediatric participants in Part A who received at least 1 dose of sugammadex and had at least 5 samples at the time points of interest were analyzed. Per protocol, Part B participants were not analyzed for PK.
    End point type
    Primary
    End point timeframe
    Day 1: 2, 15, 30, 60, 240 to 360, and 600 to 720 minutes post-dose
    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 endpoint.
    End point values
    		 Part A: Sugammadex 2 mg/kg [birth to 27 days] Part A: Sugammadex 2 mg/kg [28 days to <3 months] Part A: Sugammadex 2 mg/kg [3 to < 6 months] Part A: Sugammadex 2 mg/kg [6 months to < 2 years] Part A: Sugammadex 4 mg/kg [birth to 27 days] Part A: Sugammadex 4 mg/kg [28 days to <3 months] Part A: Sugammadex 4 mg/kg [3 to < 6 months] Part A: Sugammadex 4 mg/kg [6 months to < 2 years]
    Number of subjects analysed
    2
    3
    3
    5
    6
    6
    9
    5
    Units: Hours (h)
        geometric mean (geometric coefficient of variation)
    1.84 ( 9999 )
    1.52 ( 20.21 )
    1.45 ( 28.57 )
    1.40 ( 24.25 )
    2.39 ( 27.34 )
    1.53 ( 16.42 )
    1.51 ( 28.79 )
    1.51 ( 19.46 )
    No statistical analyses for this end point

    Primary: Part B: Time to Neuromuscular Recovery (TTNMR)

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    End point title
    		 Part B: Time to Neuromuscular Recovery (TTNMR)
    End point description
    Time to neuromuscular recovery was defined as the interval from administration of reversal agent to time to neuromuscular recovery. TTNMR could be assessed by 1 of 4 methods selected by the investigator, based on their judgment of what was technically feasible and clinically appropriate for the participant’s procedure. These methods were inclusive of both clinical signs (head lift or hip flexion) and neuromuscular transmission monitoring using either a standard peripheral nerve stimulator or the technically challenging quantitative neuromuscular monitoring to train-of-four (TOF) ratio ≥0.9. As pre-specified by the protocol and SAP, TTNMR was analyzed only in Part B participants under the setting of moderate block for comparison of sugammadex 2 mg to neostigmine. All participants in Part B who received either sugammadex 2 mg/kg or neostigmine and with available TTNMR data were analyzed.
    End point type
    Primary
    End point timeframe
    Within Day 1
    End point values
    		 Part A: Sugammadex 2 mg/kg Part A: Sugammadex 4 mg/kg Part B: Sugammadex 2 mg/kg Part B: Sugammadex 4 mg/kg Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Number of subjects analysed
    0 [6]
    0 [7]
    29
    0 [8]
    31
    Units: Minutes
        median (confidence interval 95%)
    ( to )
    ( to )
    1.4 (1.1 to 2.0)
    ( to )
    4.4 (2.7 to 7.9)
    Notes
    [6] - TTNMR was analyzed only in Part B under setting of moderate block.
    [7] - TTNMR was analyzed only in Part B under setting of moderate block.
    [8] - TTNMR was analyzed only in Part B under setting of moderate block.
    Statistical analysis title
    		 Part B TTNMR
    Statistical analysis description
    The Hazard Ratio (HR) for the pairwise comparison of Sugammadex 2 mg/kg vs. Neostigmine + (Glycopyrrolate or Atropine) was based on a Cox regression model with Efron’s method of tie handling with covariates of treatment, age (continuous) and stratified by neuromuscular blocking agent.
    Comparison groups
    Part B: Sugammadex 2 mg/kg v Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [9]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.37
         upper limit
    		 4.18
    Notes
    [9] - Two-sided p-value based on log-rank test stratified by neuromuscular blocking agent and age groups.

    Primary: Parts A and B: Percentage of Participants with Adverse Events (AEs) Up To 7 Days Post Administration of Study Medication

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    End point title
    		 Parts A and B: Percentage of Participants with Adverse Events (AEs) Up To 7 Days Post Administration of Study Medication
    End point description
    An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. As pre-specified by the protocol and SAP, the primary analysis of safety combined data across Part A and Part B (and across age cohorts) and included all AEs that occurred up to 7 days post administration of study medication. All enrolled/randomized participants from both Part A and Part B (combined) who received at least 1 dose of study treatment were analyzed and the percentage of participants with an AE was reported.
    End point type
    Primary
    End point timeframe
    Up to Day 7
    End point values
    		 Parts A + B: Sugammadex 2 mg/kg Parts A + B: Sugammadex 4 mg/kg Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Number of subjects analysed
    44
    63
    31
    Units: Percentage of Participants
        number (not applicable)
    68.2
    68.3
    61.3
    Statistical analysis title
    		 Sugammadex 2 mg/kg vs. Neostigmine
    Statistical analysis description
    The difference in percentage of sugammadex versus Neostigmine +plus (Glycopyrrolate or Atropine) was based on the Miettinen and Nurminen method stratified by neuromuscular blocking agent and age group.
    Comparison groups
    Parts A + B: Sugammadex 2 mg/kg v Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.2
         upper limit
    		 29.5
    Statistical analysis title
    		 Sugammadex 4 mg/kg vs. Neostigmine
    Statistical analysis description
    The difference in percentage of sugammadex versus Neostigmine +plus (Glycopyrrolate or Atropine) was based on the Miettinen and Nurminen method stratified by neuromuscular blocking agent and age group.
    Comparison groups
    Parts A + B: Sugammadex 4 mg/kg v Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    5.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.5
         upper limit
    		 26.7

    Secondary: Part B: Time to Extubation

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    End point title
    		 Part B: Time to Extubation
    End point description
    Time to extubation was defined as the interval from administration of reversal agent to removal of the endotracheal tube. Monitoring of time to extubation was achieved using the Extubation Readiness Assessment, which evaluated and documented clinically relevant elements including neuromuscular recovery, mental status, return of spontaneous ventilation, adequate oxygenation, hemodynamically stabile, and core body temperature with “Yes”/”No” answers (no overall score or direction attributed). The Operating Room anesthesiologist or other trained personnel were responsible for assessing extubation readiness beginning about 1 minute after study treatment administration and reassessing every 60 seconds until time of extubation readiness was achieved.
    End point type
    Secondary
    End point timeframe
    Within Day 1
    End point values
    		 Part A: Sugammadex 2 mg/kg Part A: Sugammadex 4 mg/kg Part B: Sugammadex 2 mg/kg Part B: Sugammadex 4 mg/kg Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Number of subjects analysed
    0 [10]
    0 [11]
    29
    0 [12]
    31
    Units: Minutes
        median (confidence interval 95%)
    ( to )
    ( to )
    7.9 (5.7 to 11.6)
    ( to )
    10.5 (7.9 to 13.5)
    Notes
    [10] - Time to Extubation was analyzed only in Part B under setting of moderate block.
    [11] - Time to Extubation was analyzed only in Part B under setting of moderate block.
    [12] - Time to Extubation was analyzed only in Part B under setting of moderate block.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 14
    Adverse event reporting additional description
    All-Cause Mortality includes all randomized participants. Serious adverse events (SAEs) and Nonserious AEs include all randomized participants who received ≥1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Part A: Sugammadex 2 mg/kg
    Reporting group description
    		 Participants received a single intravenous (IV) bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Reporting group title
    Part B: Neostigmine + (Glycopyrrolate or Atropine)
    Reporting group description
    		 Participants received a single IV bolus containing neostigmine (50 μg/kg; up to 5 mg maximum dose) in combination with either glycopyrrolate (10 μg/kg) or atropine sulfate (20 μg/kg) based on availability and/or contraindications, for moderate NMB reversal.

    Reporting group title
    Part B: Sugammadex 4 mg/kg
    Reporting group description
    		 Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Reporting group title
    Part A: Sugammadex 4 mg/kg
    Reporting group description
    		 Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal.

    Reporting group title
    Part B: Sugammadex 2 mg/kg
    Reporting group description
    		 Participants received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal.

    Serious adverse events
    		 Part A: Sugammadex 2 mg/kg Part B: Neostigmine + (Glycopyrrolate or Atropine) Part B: Sugammadex 4 mg/kg Part A: Sugammadex 4 mg/kg Part B: Sugammadex 2 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    3 / 29 (10.34%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Anaesthetic complication
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinoma
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device mechanical issue
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A: Sugammadex 2 mg/kg Part B: Neostigmine + (Glycopyrrolate or Atropine) Part B: Sugammadex 4 mg/kg Part A: Sugammadex 4 mg/kg Part B: Sugammadex 2 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 15 (73.33%)
    16 / 31 (51.61%)
    17 / 31 (54.84%)
    22 / 32 (68.75%)
    19 / 29 (65.52%)
    Injury, poisoning and procedural complications
    Post procedural oedema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Procedural vomiting
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    1 / 29 (3.45%)
         occurrences all number
    2
    0
    0
    1
    1
    Procedural pain
         subjects affected / exposed
    7 / 15 (46.67%)
    10 / 31 (32.26%)
    13 / 31 (41.94%)
    21 / 32 (65.63%)
    11 / 29 (37.93%)
         occurrences all number
    7
    10
    13
    21
    12
    Procedural nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    0
    1
    2
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 31 (9.68%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    0
    0
    0
    2
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    0 / 32 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    1
    2
    0
    2
    Pyrexia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    1 / 32 (3.13%)
    2 / 29 (6.90%)
         occurrences all number
    3
    1
    2
    1
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    0 / 32 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    2
    1
    2
    0
    3
    Teething
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Bradypnoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Respiratory depression
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Irregular breathing
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    Device related sepsis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Postoperative wound infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2020
    Major changes of Amendment (AM) 1 included allowing the use of deep endotracheal extubation in addition to awake extubation, moving “time to neuromuscular recovery” from a secondary endpoint to a primary efficacy endpoint and moving “time to extubation” from a primary endpoint to a secondary endpoint, and adding a hypothesis for “time to neuromuscular recovery”.
    10 Jan 2023
    Major changes of AM 2 included a Sponsor entity name and address change and changes to the collection of “core temperature” after assessing the ERA question.

    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
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