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    Clinical Trial Results:
    Exploratory Propofol Dose Finding Study In Neonates receiving a single intravenous propofol bolus for endotracheal intubation during (semi-) elective INSURE (intubation-surfactant-extubation) procedure (preterm neonates) and (semi-)elective non-INSURE procedures (term-preterm neonates). NEOPROP.

    Summary
    EudraCT number
    		 2012-002648-26
    Trial protocol
    		 BE  
    Global end of trial date
    17 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Dec 2024
    First version publication date
    19 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    S54472
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01621373
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospitals Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Liesbeth Thewissen, University Hospitals Leuven, +32 16343211, Liesbeth.thewissen@uzleuven.be
    Scientific contact
    Liesbeth Thewissen, University Hospitals Leuven, +32 16343211, Liesbeth.thewissen@uzleuven.be
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -What is the most effective intravenously (iv) administered single propofol dose for successful INSURE prodecure in neonates? INSURE-procedure is defined as (semi-)elective intubation, intratracheal administration of surfactant and extubation within 60 minutes after propofol administration. -What is the most effective intravenously (iv) administered single propofol dose for successful (semi-)elective intubation of neonates during non-INSURE conditions (e.g. surgery)?
    Protection of trial subjects
    Neonates of the University Hospitals Leuven needing preintubation sedation were included after consent from their parents was obtained. Patients had to be hemodynamically stable and not receiving sedatives or analgesics (except acetaminophen) in the previous 24 hours.
    Background therapy
    		 It is standard of care to give premedication before (semi-)elective intubation in neonates. Drug selection and dosing for this procedure is highly variable and not yet evidence-based. One of the compounds used is propofol, a short-acting anesthetic. Postmenstrual age (PMA) and postnatal age (PNA) have been shown to affect propofol clearance,4 but pharmacodynamic (PD) data in neonates are limited. Because optimal propofol dosing and its PD effects in newborns are lacking, we combined a prospective dose-finding approach with PD assessment in neonates receiving propofol as intravenous bolus for preintubation sedation (The Exploratory Propofol Dose-Finding Study In Neonates [NEOPROP] study). The primary objective was to define the ED50 (ie, effective dose for 50% of patients) for successful intubation and to determine the rate of successful extubation in those patients with planned intubation, surfactant administration, and immediate extubation12,13 (INSURE procedure).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2012
    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
    Belgium: 47
    Worldwide total number of subjects
    47
    EEA total number of subjects
    47
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    47
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    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

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    Recruitment
    Recruitment details
    		 Neonates of the University Hospitals Leuven needing preintubation sedation were included after consent from their parents was obtained.

    Pre-assignment
    Screening details
    		 Patients had to be hemodynamically stable and not receiving sedatives or analgesics (except acetaminophen) in the previous 24 hours.

    Period 1
    Period 1 title
    ED 50 calculation propofol (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Stratum 1
    Arm description
    		 Postmenstrual age < 28 w Postnatal age < 10 days
    Arm type
    		 Stratum 1

    Investigational medicinal product name
    Propofol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for emulsion for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    up and down dose-response design

    Arm title
    		 Stratum 3
    Arm description
    		 Postmenstrual age 28 to <32 w Postnatal age < 10 days
    Arm type
    		 Stratum 3

    Investigational medicinal product name
    Propofol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Up-)and-down dose-response design

    Arm title
    		 Stratum 5
    Arm description
    		 Postmenstrual age 32 to <37 w Postnatal age < 10 days
    Arm type
    		 Stratum 5

    Investigational medicinal product name
    Propofol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Up-and-down dose-response design

    Number of subjects in period 1
    		Stratum 1 Stratum 3 Stratum 5
    Started
    12
    23
    12
    Completed
    12
    23
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ED 50 calculation propofol
    Reporting group description
    		 -

    Reporting group values
    		 ED 50 calculation propofol Total
    Number of subjects
    		 47 47
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 47 47
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 18 18
        Male
    		 29 29

    End points

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    End points reporting groups
    Reporting group title
    Stratum 1
    Reporting group description
    		 Postmenstrual age < 28 w Postnatal age < 10 days

    Reporting group title
    Stratum 3
    Reporting group description
    		 Postmenstrual age 28 to <32 w Postnatal age < 10 days

    Reporting group title
    Stratum 5
    Reporting group description
    		 Postmenstrual age 32 to <37 w Postnatal age < 10 days

    Primary: Effective dose for 50% of patients for Succesful intubation and subsequent extubation in case of planned extubation after INSURE procedure

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    End point title
    		 Effective dose for 50% of patients for Succesful intubation and subsequent extubation in case of planned extubation after INSURE procedure
    End point description
    An up-and-down dose-response design was used to calculate ED50 (mg/kg) in strata with effective sampling size of at least 6, by use of the Dixon-Massey method for small samples.
    End point type
    Primary
    End point timeframe
    1 hour after propofol administration
    End point values
    		 Stratum 1 Stratum 3 Stratum 5
    Number of subjects analysed
    12
    23
    12
    Units: mg/kg
        arithmetic mean (confidence interval 95%)
    0.792 (0.392 to 1.192)
    0.713 (0.424 to 1.002)
    1.350 (0.932 to 1.767)
    Statistical analysis title
    		 Propofol ED50 Calculation
    Statistical analysis description
    An up-and-down dose-response design was used to calculate ED50 (mg/kg) in strata with an effective sampling size (N) of at least 6, by use of the Dixon-Massey method14 for small samples. N is the number of trials reduced by 1 less than the number of similar responses at the beginning. ED50 = ∑Xi/ N + d(A + C)/N, with Xi: initial dose, d: interval between dose levels (0.5 mg/kg) and A, C: tabulated values provided by Dixon.14 SAS 9.2 for Windows (SAS Institute, Inc, Cary, North Carolina)
    Comparison groups
    Stratum 1 v Stratum 3 v Stratum 5
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05
    Method
    		 up-and-down dose response
    Parameter type
    		 ED50
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 4
    Variability estimate
    Standard deviation
    Dispersion value
    0.5
    Notes
    [1] - An up-and-down dose-response design was used to calculate ED50 (mg/kg) in strata with an effective sampling size (N) of at least 6, by use of the Dixon-Massey method14 for small samples. N is the number of trials reduced by 1 less than the number of similar responses at the beginning. ED50 = ∑Xi/ N + d(A + C)/N, with Xi: initial dose, d: interval between dose levels (0.5 mg/kg) and A, C: tabulated values provided by Dixon.14 SAS 9.2 for Windows (SAS Institute, Inc, Cary, North Carolina)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    not specified
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 neonatal
    Dictionary version
    1
    Reporting groups
    Reporting group title
    ED50
    Reporting group description
    		 -

    Serious adverse events
    		 ED50
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 47 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ED50
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 47 (40.43%)
    General disorders and administration site conditions
    permissive hypotension
    Additional description: Permissive hypotension was noted with a duration of blood pressure decrease at least 120-200 minutes after propofol administration.
         subjects affected / exposed
    19 / 47 (40.43%)
         occurrences all number
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27597733
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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