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    Clinical Trial Results:
    Xenon as an adjuvant to propofol anaesthesia in patients undergoing off-pump coronary artery bypass graft surgery: a randomized controlled trial

    Summary
    EudraCT number
    2013-000485-11
    Trial protocol
    BE  
    Global end of trial date
    01 Dec 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    SR022013
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01948765
    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 of the KU Leuven, 0032 16344620, christel.huygens@uzleuven.be
    Scientific contact
    Anesthesia Research, University Hospitals of the KU 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
    01 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to assess whether the administration of xenon as an adjuvant to propofol anesthesia is superior to anesthesia with propofol alone in patients undergoing off-pump coronary artery bypass surgery.
    Protection of trial subjects
    The interventional treatment was administered to patients under advanced hemodynamic monitoring in the setting of a fully equipped cardiac surgical operating room. This enables immediate detection and treatment of adverse events. Xenon inhalation was immediately stopped in case that the study patient shows a life-threatening deterioration. After leaving the operation room, all patients were closely monitored by the study team for the occurrence of eventual adverse or serious adverse events (S) AE’s during the whole postoperative period until hospital discharge. 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 facilitates reporting of (S)AE’s to the principal investigator. Finally, suspected unexpected serious adverse reactions were reported by the principal investigator to the federal health authorities.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 May 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    18
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    After obtaining written informed consent, 50 patients scheduled for elective OPCAB surgery were enrolled in this prospective, single-centre, randomized, single-blinded controlled trial. Patients assessed for eligibility; (n = 86) Patients did not meet inclusion criteria; (n = 25) Patients decline to participate; (n= 11)

    Pre-assignment
    Screening details
    Eighty-six patients planned for elective coronary artery surgery in off-pump technique were screened from June 2013 to February 2014. A total of 50 patients were allocated randomly to receive either propofol-TCI alone (n = 25) or xenon 30%+propofol-TCI (n = 25). All patients received the allocated intervention, and no patient was lost to follow-up.

    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
    Randomization was performed using a software-generated allocation sequence (QuickCalcs; GraphPad Software, La Jolla, CA). To avoid selection bias, we used a masked randomization process in which group assignments were hidden in closed, consecutively numbered envelopes that were only opened on arrival of the participant into the operation room. Two separate and independent investigators performed the study. Investigator I performed enrolment and the assessment of postoperative outcomes.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Xenon+propofol
    Arm description
    30%Xenon with Propofol-TCI (n = 25).
    Arm type
    Experimental

    Investigational medicinal product name
    Xenon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    30% xenon bases on EEG monitoring and clinical and hemodynamic signs.

    Investigational medicinal product name
    Propofol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection/infusion in pre-filled syringe
    Routes of administration
    Intravenous drip use , Intravenous bolus use
    Dosage and administration details
    Propofol target-controlled infusion; doses were adjusted based on EEG-monitoring

    Arm title
    Propofol alone
    Arm description
    propofol-TCI (n = 25)
    Arm type
    Active comparator

    Investigational medicinal product name
    Propofol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection/infusion
    Routes of administration
    Intravenous drip use , Intravenous bolus use
    Dosage and administration details
    propofol target-controlled infusion titrated based on EEG-monitoring and clinical signs of light anaesthesia (n = 25)

    Number of subjects in period 1
    Xenon+propofol Propofol alone
    Started
    25
    25
    Completed
    25
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Xenon+propofol
    Reporting group description
    30%Xenon with Propofol-TCI (n = 25).

    Reporting group title
    Propofol alone
    Reporting group description
    propofol-TCI (n = 25)

    Reporting group values
    Xenon+propofol Propofol alone Total
    Number of subjects
    25 25 50
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    8 10 18
        From 65-84 years
    17 15 32
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    68 ± 9 66 ± 7 -
    Gender categorical
    Units: Subjects
        Female
    2 3 5
        Male
    23 22 45

    End points

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    End points reporting groups
    Reporting group title
    Xenon+propofol
    Reporting group description
    30%Xenon with Propofol-TCI (n = 25).

    Reporting group title
    Propofol alone
    Reporting group description
    propofol-TCI (n = 25)

    Primary: norepinephrine doses

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    End point title
    norepinephrine doses
    End point description
    The primary outcome was intraoperative hemodynamic stability, which was quantified with the doses of norepinephrine required intraoperatively to accomplish the predefined hemodynamic targets (MAP > 70 mmHg).
    End point type
    Primary
    End point timeframe
    Start of anaesthesia induction to end surgery (Intraoperatively)
    End point values
    Xenon+propofol Propofol alone
    Number of subjects analysed
    25
    25
    Units: µg/kg/min
        median (inter-quartile range (Q1-Q3))
    0.01 (0.006 to 0.02)
    0.04 (0.02 to 0.06)
    Statistical analysis title
    Primary outcome
    Statistical analysis description
    This trial was designed to demonstrate that the application of 30% xenon in addition to general anaesthesia with a TCI of propofol results in superior hemodynamics when compared to equipotent general anaesthesia with propofol alone.
    Comparison groups
    Xenon+propofol v Propofol alone
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Median difference (final values)
    Confidence interval
         level
    95%

    Secondary: Anesthesia depth (BIS)

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    End point title
    Anesthesia depth (BIS)
    End point description
    Depth of anaesthesia as assessed by the bispectral index (BIS) monitoring
    End point type
    Secondary
    End point timeframe
    Intraoperative
    End point values
    Xenon+propofol Propofol alone
    Number of subjects analysed
    25
    25
    Units: value
        arithmetic mean (standard deviation)
    36 ± 5
    35 ± 6
    No statistical analyses for this end point

    Secondary: Postoperatve delirium

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    End point title
    Postoperatve delirium
    End point description
    End point type
    Secondary
    End point timeframe
    In the first 5 postoperative days.
    End point values
    Xenon+propofol Propofol alone
    Number of subjects analysed
    25
    25
    Units: n (%)
    7
    2
    Statistical analysis title
    Postoperative delirium
    Comparison groups
    Propofol alone v Xenon+propofol
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.05 [1]
    Method
    Fisher exact
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Notes
    [1] - The incidence of postoperative delirium (pod) was similar between the groups; POD, n (%)= xenon-propofol 7 (28%) vs propofol alone 2 (8%); p = 0.138

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From enrollment until patient's discharge.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Xenon+propofol
    Reporting group description
    30%Xenon with Propofol-TCI (n = 25).

    Reporting group title
    Propofol alone
    Reporting group description
    propofol-TCI (n = 25)

    Serious adverse events
    Xenon+propofol Propofol alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Ventricular arrhythmia
    Additional description: In-hospital (postoperatively) ventricular fibrillation/tachycardia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CVA
    Additional description: Postoperative cerebrovascular accident
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Xenon+propofol Propofol alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 25 (36.00%)
    9 / 25 (36.00%)
    Cardiac disorders
    Arrhythmia supraventricular
    Additional description: Postoperative atrial fibrillation
         subjects affected / exposed
    4 / 25 (16.00%)
    5 / 25 (20.00%)
         occurrences all number
    4
    5
    Angina pectoris
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Pericarditis
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    Infections and infestations
    Wound infection
    Additional description: Surgical wound infection
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0

    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
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