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    Clinical Trial Results:
    Xenon as an adjuvant to sevoflurane anaesthesia in children undergoing interventional or diagnostic cardiac catheterization: a randomized controlled clinical trial

    Summary
    EudraCT number
    2014-002510-23
    Trial protocol
    BE  
    Global end of trial date
    12 Dec 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SR062014
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University Hospitals Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Anesthesia research, University Hospitals Leuven, 0032 16344620, christel.huygens@uzleuven.be
    Scientific contact
    Anesthesia research, University Hospitals Leuven, 0032 16344620, christel.huygens@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
    08 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    As a primary study aim we hypothesized that the administration of 50% Xenon as an adjuvant to general anesthesia with sevoflurane is safe and feasible.
    Protection of trial subjects
    The interventional treatment was administered to patients with standard haemodynamic monitoring in the setting of a fully equipped cardiac catheterization room. This enabled immediate detection and treatment of adverse events. Xenon inhalation was to be immediately stopped in case that the study patient would show a life-threatening deterioration. Also after leaving the operation room, all patients were closely monitored by the study team for the occurrence of eventual (S)AE’s, first on the PACU, later on the normal ward. Moreover, the inclusion of each individual patient into the study was indicated in the electronic hospital information system and hence visible to all physicians and nurses involved in the care of this patient. This facilitated reporting of (S)AE’s to the principal investigator.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Sep 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Scientific research
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 62
    Worldwide total number of subjects
    62
    EEA total number of subjects
    62
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    62
    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
    From November 2014 to November 2016, 40 children aged between 4 and 12 years old were included in this trial and random- ized to receive either xenon‐augmented sevoflurane or mono‐sevoflurane for the maintenance of the anesthesia. 22 age‐ and gender‐matched healthy and nonhospitalized children underwent the at comparable time intervals.

    Pre-assignment
    Screening details
    72 children were assessed for eligibility. A screening failure occurred in 32 children (7 refused, 14 met exclusion criteria, 11 had other reasons for exclusion).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject
    Blinding implementation details
    Subjects were allocated based on a closed envelope method [1:1 ratio, stratified by age (stratum I: age 4‐7 years; stratum II: 8‐12 years)]. 2 types of investigators conducted the trial. Inves- tigator I accomplished the enrollment on the day before the inter- vention and performed all postoperative visits. He was, as the patient and his parents, blinded to treatment allocation. Investigator II conducted the GA and was necessarily unblinded to the treatment due to the treatment conditions.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Xenon
    Arm description
    General anesthesia with 50%‐65% xenon (LENOXeTM, AirLiquide Santé International, Paris, France) in oxygen (FiO2 = 0.25‐0.4) as an adjuvant to sevoflurane
    Arm type
    Experimental

    Investigational medicinal product name
    Xenon
    Investigational medicinal product code
    N01AX15
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    50%‐65% xenon in oxygen (FiO2 = 0.25‐0.4) as an adjuvant to sevoflurane applied via inhalation by means of an endotracheal tube

    Investigational medicinal product name
    Sevoflurane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    EEG-titrated dosing, application via inhalation via endotracheal tube

    Arm title
    Sevoflurane
    Arm description
    Sevoflurane (Sevorane, AbbVie, Wavre, Belgium) alone (FiO2 = 0.25‐0.4)
    Arm type
    Active comparator

    Investigational medicinal product name
    Sevoflurane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    EEG-titrated dosing, application via inhalation via endotracheal tube

    Number of subjects in period 1 [1]
    Xenon Sevoflurane
    Started
    20
    20
    Completed
    20
    20
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: We included 62 children in total. 40 of them were randomized to receive general anesthesia. Twenty‐two additional healthy children matched for age and gender were included as control group for the neurocognitive assessments but received no treatment, neither with the IMP nor the active comparator.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Xenon
    Reporting group description
    General anesthesia with 50%‐65% xenon (LENOXeTM, AirLiquide Santé International, Paris, France) in oxygen (FiO2 = 0.25‐0.4) as an adjuvant to sevoflurane

    Reporting group title
    Sevoflurane
    Reporting group description
    Sevoflurane (Sevorane, AbbVie, Wavre, Belgium) alone (FiO2 = 0.25‐0.4)

    Reporting group values
    Xenon Sevoflurane Total
    Number of subjects
    20 20 40
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    20 20 40
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    8 9 17
        Male
    12 11 23

    End points

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    End points reporting groups
    Reporting group title
    Xenon
    Reporting group description
    General anesthesia with 50%‐65% xenon (LENOXeTM, AirLiquide Santé International, Paris, France) in oxygen (FiO2 = 0.25‐0.4) as an adjuvant to sevoflurane

    Reporting group title
    Sevoflurane
    Reporting group description
    Sevoflurane (Sevorane, AbbVie, Wavre, Belgium) alone (FiO2 = 0.25‐0.4)

    Primary: Hemodynamic instability

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    End point title
    Hemodynamic instability
    End point description
    Incidence of intraprocedural hemody- namic adverse events (not caused by obvious interventional manipulation), defined by a > 20% change from baseline for HR or MAP or by the need for fluid boluses, vasopressors, inotropes, or chronotropes.
    End point type
    Primary
    End point timeframe
    During administration of IMP
    End point values
    Xenon Sevoflurane
    Number of subjects analysed
    20
    20
    Units: Counts
    19
    20
    Statistical analysis title
    Categorical endpoints
    Statistical analysis description
    Statistical analysis was performed using SPSS 24 software (SPSS Statistics version 24 for Windows, IBM, Armonk, New York, United states) according to the intention‐to‐treat principle. Categorical data are summa- rized by observed frequencies and percentages and compared using Fisher's exact test.
    Comparison groups
    Xenon v Sevoflurane
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 1
    Method
    Fisher exact
    Confidence interval

    Primary: Anesthetic depth

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    End point title
    Anesthetic depth
    End point description
    End point type
    Primary
    End point timeframe
    During administration of IMP
    End point values
    Xenon Sevoflurane
    Number of subjects analysed
    20
    20
    Units: Bispectral index
        median (inter-quartile range (Q1-Q3))
    48 (42 to 57)
    44 (36 to 49)
    Statistical analysis title
    Continuous variables
    Statistical analysis description
    Continuous variables are reported using median and interquartile range (IQR) and were com- pared using the Mann‐Whitney U test.
    Comparison groups
    Sevoflurane v Xenon
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.0001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - Continuous variables are reported using median and interquartile range (IQR) and were compared using the Mann‐Whitney U test.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From enrollment (the day before the intervention) until the first post-interventional day.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Xenon
    Reporting group description
    General anesthesia with 50%‐65% xenon (LENOXeTM, AirLiquide Santé International, Paris, France) in oxygen (FiO2 = 0.25‐0.4) as an adjuvant to sevoflurane

    Reporting group title
    Sevoflurane
    Reporting group description
    Sevoflurane (Sevorane, AbbVie, Wavre, Belgium) alone (FiO2 = 0.25‐0.4)

    Serious adverse events
    Xenon Sevoflurane
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 20 (10.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Device embolization
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Xenon Sevoflurane
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 20 (65.00%)
    7 / 20 (35.00%)
    Gastrointestinal disorders
    PONV
         subjects affected / exposed
    7 / 20 (35.00%)
    6 / 20 (30.00%)
         occurrences all number
    7
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2015
    20 healthy children will undergo the neuropsychological testing on three consecutive days in order to evaluate the effect of repeated testing.

    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/30004615
    http://www.ncbi.nlm.nih.gov/pubmed/31287192
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