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    Clinical Trial Results:
    An international, multi-center, randomized, controlled trial evaluating the effect of xenon on post-operative delirium in elderly patients undergoing hip fracture surgery.

    Summary
    EudraCT number
    		 2009-017153-35
    Trial protocol
    		 FR   DE   GB   ES   IT   BE  
    Global end of trial date
    28 Oct 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions
    Summary report(s)
    		 Publication_HIPELD_BJA_2018_120_127-137

    Trial information

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    Trial identification
    Sponsor protocol code
    ALMED-08-C2-020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01199276
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Air Liquide Santé International
    Sponsor organisation address
    75, quai d'Orsay, Paris, France, 75007
    Public contact
    Healthcare Communication, Air Liquide Santé International, fralsi-publicontact@airliquide.com
    Scientific contact
    Clinical Development Physician, Air Liquide Santé International, fralsi-ctpublication@airliquide.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the incidence of Post-Operative Delirium (POD), diagnosed with the Confusion Assessment Method (CAM), in elderly patients undergoing hip fracture surgery under general anaesthesia, with xenon or sevoflurane, for a period of four days post-surgery.
    Protection of trial subjects
    The study was conducted in compliance with Good Clinical Practice (GCP) guidelines, the most recent revised version of the Declaration of Helsinki (Seoul, 2008), and the European Directive 2001/20/EC on 4th April 2001 on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of Good Clinical Practice in the conduct of the clinical trials on medicinal products for human use. The protocol and subsequent substantial amendments were submitted to the local ethics committee and competent authority for approvals in each participating country. The enrolment of the patients in the study started in a given participating country only after the written approvals of the corresponding national ethics committee and competent authority.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Sep 2010
    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
    Spain: 74
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    France: 46
    Country: Number of subjects enrolled
    Germany: 90
    Country: Number of subjects enrolled
    Italy: 31
    Worldwide total number of subjects
    268
    EEA total number of subjects
    268
    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)
    0
    From 65 to 84 years
    144
    85 years and over
    124

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 268 patients were enrolled (256 randomised and treated, plus 1 not randomised but treated) from 12 centres in 6 countries; 1 in Belgium, 5 in France (5 sites out of the 6 initiated sites), 3 in Germany, 1 in Italy, 1 in Spain and 1 in United Kingdom. First Patient Enrolled: 22 September 2010 Last Patient Completed: 28 October 2014

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 268
    Number of subjects completed
    		 256

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 At least one inclusion criterion not fulfilled: 7
    Reason: Number of subjects
    		 Technical issues: 2
    Reason: Number of subjects
    		 Suspected urinary infection: 1
    Reason: Number of subjects
    		 Accidentally used demonstration randomisation env.: 1
    Reason: Number of subjects
    		 Adverse event, non-fatal: 1
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject
    Blinding implementation details
    There were two teams of physicians: - Physicians 1 who performed selection of patients and follow-up visits (including Study End visit) were kept blind regarding the natures and doses of all study treatments. - Physicians 2 who performed the visits including randomisation and surgical procedure under general anaesthesia were unblinded. All information on the study drugs administered was kept confidential by Physicians 2 in separate source documents and specific dedicated Case Report Forms.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Xenon - ITT
    Arm description
    		 Xenon 60% (55%-65%)(1 MAC) in oxygen (FiO2 = 0.35-0.45) ITT – Intent-to-treat, i.e all randomised and treated patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    Xenon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Medicinal gas, liquefied
    Routes of administration
    Inhalation use
    Dosage and administration details
    Xenon 60% (55%-65%) (1 MAC) in oxygen (FiO2 = 0.35-0.45)

    Arm title
    		 Sevoflurane - ITT
    Arm description
    		 sevoflurane 1.1-1.4%(1 MAC) in oxygen (FiO2 = 0.35-0.45) and Medical air ITT – Intent-to-treat, i.e all randomised and treated patients
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sevoflurane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, liquid
    Routes of administration
    Inhalation use
    Dosage and administration details
    1.1-1.4% (1 MAC) in oxygen (FiO2 = 0.35-0.45) and medical air

    Number of subjects in period 1 [1]
    		Xenon - ITT Sevoflurane - ITT
    Started
    124
    132
    Completed
    109
    120
    Not completed
    15
    12
         Early discharge
    13
    6
         Adverse event, serious fatal
    -
    4
         Adverse event, non-fatal
    1
    2
         Lost to follow-up
    1
    -
    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: 268 patients signed an informed consent. 256 patients were randomised and treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Xenon - ITT
    Reporting group description
    		 Xenon 60% (55%-65%)(1 MAC) in oxygen (FiO2 = 0.35-0.45) ITT – Intent-to-treat, i.e all randomised and treated patients

    Reporting group title
    Sevoflurane - ITT
    Reporting group description
    		 sevoflurane 1.1-1.4%(1 MAC) in oxygen (FiO2 = 0.35-0.45) and Medical air ITT – Intent-to-treat, i.e all randomised and treated patients

    Reporting group values
    		 Xenon - ITT Sevoflurane - ITT Total
    Number of subjects
    		 124 132 256
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 83.83 ( 5.13 ) 84.41 ( 4.55 ) -
    Gender categorical
    Units: Subjects
        Female
    		 90 103 193
        Male
    		 34 29 63
    Body Mass Index
    Units: kg/m²
        arithmetic mean (standard deviation)
    		 23.72 ( 3.78 ) 24.19 ( 4.25 ) -

    End points

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    End points reporting groups
    Reporting group title
    Xenon - ITT
    Reporting group description
    		 Xenon 60% (55%-65%)(1 MAC) in oxygen (FiO2 = 0.35-0.45) ITT – Intent-to-treat, i.e all randomised and treated patients

    Reporting group title
    Sevoflurane - ITT
    Reporting group description
    		 sevoflurane 1.1-1.4%(1 MAC) in oxygen (FiO2 = 0.35-0.45) and Medical air ITT – Intent-to-treat, i.e all randomised and treated patients

    Primary: Post Operative Delirium diagnosed within four days post-surgery

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    End point title
    		 Post Operative Delirium diagnosed within four days post-surgery
    End point description
    Number of patients with Post Operative Delirium (POD) diagnosed with the Confusion Assessment Method within four days post-surgery.
    End point type
    Primary
    End point timeframe
    Four days post-surgery
    End point values
    		 Xenon - ITT Sevoflurane - ITT
    Number of subjects analysed
    124
    132
    Units: Patient
    12
    18
    Statistical analysis title
    		 POD diagnosed within 4 days - ITT
    Statistical analysis description
    POD = Post Operative Delirium ITT – Intent-to-treat, i.e all randomised and treated patients
    Comparison groups
    Xenon - ITT v Sevoflurane - ITT
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.325
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Post Operative Delirium diagnosed from day 5 post surgery to discharge from hospital

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    End point title
    		 Post Operative Delirium diagnosed from day 5 post surgery to discharge from hospital
    End point description
    Number of patients with Post Operative Delirium (POD) diagnosed with the Confusion Assessment Method from day 5 post surgery to discharge from hospital.
    End point type
    Secondary
    End point timeframe
    From day 5 post surgery to discharge from hospital
    End point values
    		 Xenon - ITT Sevoflurane - ITT
    Number of subjects analysed
    124
    132
    Units: Patient
    5
    8
    No statistical analyses for this end point

    Secondary: Sequential Organ Failure Assessment from day 1 to day 4 post-surgery

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    End point title
    		 Sequential Organ Failure Assessment from day 1 to day 4 post-surgery
    End point description
    Total SOFA (Sequential Organ Failure Assessment) score was obtained as the sum of the 6 SOFA domain subscores (i.e., cardiovascular, respiratory, hepatic, haematological, central nervous system and renal components separately).
    End point type
    Secondary
    End point timeframe
    From day 1 to day 4 post-surgery.
    End point values
    		 Xenon - ITT Sevoflurane - ITT
    Number of subjects analysed
    124 [1]
    132 [2]
    Units: Unit in a scale
    arithmetic mean (standard deviation)
        Day 1
    0.87 ( 0.94 )
    1.19 ( 1.49 )
        Day 2
    0.84 ( 1.12 )
    1.12 ( 1.70 )
        Day 3
    0.57 ( 0.84 )
    1.01 ( 1.77 )
        Day 4
    0.53 ( 0.83 )
    0.79 ( 1.81 )
    Notes
    [1] - Day 1=100; Day 2=96; Day 3=90; Day 4=78
    [2] - Day 1=98; Day 2=93; Day 3=85; Day 4=86
    No statistical analyses for this end point

    Secondary: Recovery parameters

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    End point title
    		 Recovery parameters
    End point description
    Time to open eyes; Time to react on verbal command; Time to extubation; Time to spatial orientation; Duration of stay in Post-Anaesthesia Care Unit (PACU). Time calculated in minutes from the end of gas inhalation.
    End point type
    Secondary
    End point timeframe
    Post general anaesthesia.
    End point values
    		 Xenon - ITT Sevoflurane - ITT
    Number of subjects analysed
    124 [3]
    132 [4]
    Units: minute
    median (inter-quartile range (Q1-Q3))
        1) Time to open eyes
    4.0 (2.0 to 8.0)
    8.0 (5.0 to 11.0)
        2) Time to react on verbal command
    5.0 (3.0 to 9.0)
    8.5 (6.0 to 12.0)
        3) Time to extubation
    5.4 (3.2 to 9.1)
    9.1 (6.0 to 12.7)
        4) Time to spatial orientation
    13.0 (6.0 to 21.0)
    15.4 (10.0 to 25.8)
        5) Duration of stay in PACU
    105 (60 to 145)
    112 (75 to 165)
    Notes
    [3] - 1) n=124; 2) n=124; 3) n=124; 4) n=113; 5) n=99
    [4] - 1) n=127; 2) n=128; 3) n=131; 4) n=120; 5) n=102
    No statistical analyses for this end point

    Secondary: Vital status at 28 days post-surgery

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    End point title
    		 Vital status at 28 days post-surgery
    End point description
    Number of patients who died within the 28 days post-surgery
    End point type
    Secondary
    End point timeframe
    28 days post-surgery
    End point values
    		 Xenon - ITT Sevoflurane - ITT
    Number of subjects analysed
    103
    110
    Units: Patient
    0
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events observed from the start of study treatment up to 30 days.
    Adverse event reporting additional description
    Participants at risk are the patients from the safety set, i.e. patients treated. Multiple occurrences of a same adverse event (i.e. same preferred term) for a given patient are counted only once.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Xenon
    Reporting group description
    		 xenon 60% (55%-65%)(1 MAC) in oxygen (FiO2 = 0.35-0.45) Safety population, i.e all treated patients (including one non-randomised patient)

    Reporting group title
    Sevoflurane
    Reporting group description
    		 sevoflurane 1.1-1.4%(1 MAC) in oxygen (FiO2 = 0.35-0.45) and Medical air Safety population, i.e all treated patients

    Serious adverse events
    		 Xenon Sevoflurane
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 125 (8.00%)
    21 / 132 (15.91%)
         number of deaths (all causes)
    0
    5
         number of deaths resulting from adverse events
    0
    5
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device dislocation
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombosis in device
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bradypnoea
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 125 (0.00%)
    3 / 132 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cardiac function disturbance postoperative
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site haematoma
         subjects affected / exposed
    2 / 125 (1.60%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 125 (0.80%)
    3 / 132 (2.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 125 (1.60%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Anticholinergic syndrome
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 125 (0.00%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary retention
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint effusion
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bone abscess
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 125 (0.00%)
    4 / 132 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Sepsis
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 125 (0.00%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         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
    108 / 125 (86.40%)
    115 / 132 (87.12%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 125 (4.80%)
    9 / 132 (6.82%)
         occurrences all number
    6
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 125 (8.00%)
    10 / 132 (7.58%)
         occurrences all number
    10
    10
    C-reactive protein increased
         subjects affected / exposed
    24 / 125 (19.20%)
    23 / 132 (17.42%)
         occurrences all number
    24
    23
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    8 / 125 (6.40%)
    11 / 132 (8.33%)
         occurrences all number
    8
    11
    Haemoglobin decreased
         subjects affected / exposed
    7 / 125 (5.60%)
    8 / 132 (6.06%)
         occurrences all number
    7
    8
    Troponin T increased
         subjects affected / exposed
    10 / 125 (8.00%)
    7 / 132 (5.30%)
         occurrences all number
    10
    7
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    10 / 125 (8.00%)
    12 / 132 (9.09%)
         occurrences all number
    10
    12
    Hypertension
         subjects affected / exposed
    16 / 125 (12.80%)
    15 / 132 (11.36%)
         occurrences all number
    16
    15
    Hypotension
         subjects affected / exposed
    32 / 125 (25.60%)
    41 / 132 (31.06%)
         occurrences all number
    32
    41
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    9 / 125 (7.20%)
    4 / 132 (3.03%)
         occurrences all number
    9
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    45 / 125 (36.00%)
    57 / 132 (43.18%)
         occurrences all number
    45
    57
    Thrombocytopenia
         subjects affected / exposed
    3 / 125 (2.40%)
    7 / 132 (5.30%)
         occurrences all number
    3
    7
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 125 (3.20%)
    8 / 132 (6.06%)
         occurrences all number
    4
    8
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    9 / 125 (7.20%)
    10 / 132 (7.58%)
         occurrences all number
    9
    10
    Nausea
         subjects affected / exposed
    11 / 125 (8.80%)
    10 / 132 (7.58%)
         occurrences all number
    11
    10
    Retching
         subjects affected / exposed
    15 / 125 (12.00%)
    11 / 132 (8.33%)
         occurrences all number
    15
    11
    Vomiting
         subjects affected / exposed
    15 / 125 (12.00%)
    14 / 132 (10.61%)
         occurrences all number
    15
    14
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    5 / 125 (4.00%)
    9 / 132 (6.82%)
         occurrences all number
    5
    9
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    7 / 125 (5.60%)
    5 / 132 (3.79%)
         occurrences all number
    7
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 May 2010
    Amendment for France: adjustment of study period, rocuronium allowed as a muscle relaxant
    20 May 2010
    Amendment for Spain: adjustment of study period, Exclusion criteria added, change of contact detail of Pharmacovigilance department
    06 Aug 2010
    Amendment for Italy: adjustment of study period, exclusion criteria added, calculation of SOFA subscore, change of contact detail of Pharmacovigilance department
    24 Aug 2010
    Amendment for United Kingdom: PI change in UK, Study period, calculation of SOFA subscore
    02 Sep 2010
    Amendment for Germany: to correct the SAE contacts, new PI in UK, Study period, calculation of SOFA subscore
    16 Mar 2011
    Amendment for France: 2 new sites in Germany and 3 in France, Troponin T test could be used in place of Troponin I, Calculation of SOFA subscore, updated timelines
    10 Jun 2011
    Amendment for Germany: 2 new sites in Germany and 3 in France, Troponin T test could be used in place of Troponin I, updated timelines
    05 Aug 2011
    Amendment for Spain: new PI in UK, 2 new sites in Germany and 3 in France, Troponin T test could be used in place of Troponin I, Calculation of SOFA subscore, updated timelines
    23 Aug 2011
    Amendment for Italy: new PI in UK, 2 new sites in Germany and 3 in France, Troponin T test could be used in place of Troponin I, updated timelines
    25 Aug 2011
    Amendment for United Kingdom: 2 new sites in Germany and 3 in France, Troponin T test could be used in place of Troponin I, updated timelines
    10 Aug 2012
    Amendment for France: recruitment extension (Nov 2013), three new sites added, use of blood test results obtained before ICF at hospital's patient admission are allowed, detail of AE definition and reporting of SAE. Use of triplicate ICF
    07 Jan 2013
    Amendment for Germany: recruitment extension (Nov 2013), 3 new sites added, detail of AE definition and reporting of SAE, use of blood test results obtained before ICF at hospital's patient admission are allowed, two original ICF to be signed instead of three
    10 Jan 2013
    Amendment for United Kingdom: recruitment extension (Nov 2013), two new sites added, detail of AE definition and reporting of SAE, use of blood test results obtained before ICF at hospital's patient admission are allowed
    15 Jan 2013
    Amendment for Italy: recruitment extension (Nov 2013), 3 new sites added, detail of AE definition and reporting of SAE, use of blood test results obtained before ICF at hospital's patient admission are allowed
    18 Jan 2013
    Amendment for Spain: Recruitment extension (Nov 2013), three new sites added, detail of AE definition and reporting of SAE, use of blood test results obtained before ICF at hospital's patient admission are allowed
    30 Oct 2013
    Amendment for United Kingdom: recruitment extension (May 2014), to avoid exams repetition (ECG, MMSE, …) the use of test results within 24 h before ICF signature are allowed, CAM assessment by physician 1 or trained designee, all investigators can present the study to the patient, clarified that patient data could be transferred outside European Union
    05 Nov 2013
    Amendment for Germany and Belgium: recruitment extension (May 2014), to avoid exams repetition (ECG, MMSE, …) the use of test results within 24 h before ICF signature are allowed, CAM assessment by physician 1 or trained designee, all investigators can present the study to the patient, clarified that patient data could be transferred outside European Union
    12 Nov 2013
    Amendment for Italy: recruitment extension (May 2014), to avoid exams repetition (ECG, MMSE, …) the use of test results within 24 h before ICF signature are allowed, CAM assessment by physician 1 or trained designee, all investigators can present the study to the patient, two original ICF to be signed instead of three
    14 Nov 2013
    Amendment for France: recruitment extension (May 2014), to avoid exams repetition (ECG, MMSE, …) the use of test results within 24 h before ICF signature are allowed, CAM assessment by physician 1 or trained designee, all investigators can present the study to the patient, clarified that patient data could be transferred outside European Union
    24 Mar 2014
    Amendment for France, Germany, United Kingdom, Italy and Belgium: recruitment extension (Dec 2014), vital status to be collected 28 days post-surgery, Information letter for patients who signed ICF before clarification that patient data could be transferred outside European Union
    16 Apr 2014
    Amendment for Spain: recruitment extension (Dec 2014), to avoid exams repetition (ECG, MMSE, …) the use of test results within 24 h before ICF signature are allowed, CAM assessment by physician 1 or trained designee, all investigators can present the study to the patient, Vital status to be collected 28 days post-surgery, Information letter for patients who signed ICF without information that patient data could be transferred outside European Union

    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/29397119
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