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    Clinical Trial Results:
    The effect of intravenous ketamine on the MAC of sevoflurane – a randomized, placebo controlled, double blinded clinical trial

    Summary
    EudraCT number
    		 2012-001908-38
    Trial protocol
    		 AT  
    Global end of trial date
    31 Mar 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    08042012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Spitalgasse 23, Vienna, Austria, 1090
    Public contact
    Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, 0043 14040041000, thomas.hamp@meduniwien.ac.at
    Scientific contact
    Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, 0043 14040041000, thomas.hamp@meduniwien.ac.at
    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
    31 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does intravenous s-ketamine reduce the MAC value of Sevoflurane
    Protection of trial subjects
    Adequate anaesthesia was confirmed using clinical findings and BIS monitoring.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2014
    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
    Austria: 61
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    61
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Adult patients with an American Society of Anaesthesia (ASA) physical status of I to III who were scheduled for elective surgery requiring a skin incision of at least 3 cm at the trunk were eligible for enrolment in the study. Patients were screened in the pre-anesthesia clinic.

    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
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 High Dose S-Ketamine Group
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S-Ketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    s-ketamine was administered as a bolus of 1 mg kg−1 S-ketamine in saline, followed by continuous infusion of 1 mg kg−1 h−1 S-ketamine in saline

    Arm title
    		 Low Dose S-Ketamine Group
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S-Ketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    s-ketamine was administered as a bolus of 0.5 mg kg−1 S-ketamine in saline, followed by continuous infusion of 0.5 mg kg−1 h−1 S-ketamine in saline

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium Chloride 0.9%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The placebo group received a bolus of 0.9% saline, followed by continuous infusion of 0.9% saline.

    Number of subjects in period 1
    		High Dose S-Ketamine Group Low Dose S-Ketamine Group Placebo
    Started
    20
    20
    21
    Completed
    20
    20
    20
    Not completed
    0
    0
    1
         Protocol deviation
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 61 61
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        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)
    		 61 61
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 61 61
        Male
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    High Dose S-Ketamine Group
    Reporting group description
    		 -

    Reporting group title
    Low Dose S-Ketamine Group
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Minimum alveolar concentration of Sevoflurane (MAC)

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    End point title
    		 Minimum alveolar concentration of Sevoflurane (MAC)
    End point description
    The MAC was determined by evaluating the motor response to the initial skin incision. Investigators blinded to both the study group and the ET sevoflurane concentration were positioned at the patient’s head and arms and at the patient’s legs to assess motor response to the skin incision. Reaction to skin incision was classified as movement or no movement. Response to the skin incision was deemed “movement” if a gross, purposeful movement of the head or at least 1 extremity was observed within 1 minute after the skin incision.4 Coughing, bucking, and straining were not considered movement.
    End point type
    Primary
    End point timeframe
    at time of skin incision
    End point values
    		 High Dose S-Ketamine Group Low Dose S-Ketamine Group Placebo
    Number of subjects analysed
    20
    20
    20
    Units: percent volume/volume
        number (confidence interval 95%)
    0.5 (0.4 to 0.8)
    0.9 (0.8 to 1.1)
    2.2 (2 to 2.4)
    Statistical analysis title
    		 Primary outcome
    Statistical analysis description
    Choi´s method was used for the calculation of the MAC estimators of sevoflurane, as this method has been shown to perform well relative to other estimators for up-and-down designs. We also calculated the corresponding bootstrap estimates and confidence intervals. Bootstrap estimates were calculated using 5000 bootstrap samples.
    Comparison groups
    High Dose S-Ketamine Group v Low Dose S-Ketamine Group v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05 [1]
    Method
    		 Choi´s Method
    Parameter type
    		 MAC of Sevoflurane using Choi´s Method
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Notes
    [1] - As there is no statistical test using Choi´s method for calculation of the primary outcome providing a P-value available for comparison of the MAC estimates, 95% confidence intervals were used for the interpretation of statistical significance.

    Secondary: Plasma concentration of lidocaine

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    End point title
    		 Plasma concentration of lidocaine
    End point description
    An arterial blood sample was taken at the time the skin incision was performed to determine the blood concentrations of S-ketamine.
    End point type
    Secondary
    End point timeframe
    at the time of skin incision
    End point values
    		 High Dose S-Ketamine Group Low Dose S-Ketamine Group Placebo
    Number of subjects analysed
    20
    20
    21
    Units: microgram(s)/millilitre
        arithmetic mean (standard deviation)
    1.1 ( 1 )
    0.5 ( 0.2 )
    0 ( 0 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study period
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    High Dose S-Ketamine Group
    Reporting group description
    		 -

    Reporting group title
    Low Dose S-Ketamine Group
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 High Dose S-Ketamine Group Low Dose S-Ketamine Group Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 High Dose S-Ketamine Group Low Dose S-Ketamine Group Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    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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    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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