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    Clinical Trial Results:
    A Randomised Active-controlled Study to Compare Efficacy and Safety of Inhaled Isoflurane Delivered by the AnaConDa-S (Anaesthetic Conserving Device) to Intravenous Midazolam for Sedation in Mechanically Ventilated Paediatric Patients 3 to 17 (Less than 18) Years Old

    Summary
    EudraCT number
    2020-000578-31
    Trial protocol
    DE   SE   FR  
    Global end of trial date
    19 Jan 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Nov 2023
    First version publication date
    11 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SED002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sedana Medical AB
    Sponsor organisation address
    Vendevägen 89, Danderyd, Sweden,
    Public contact
    Peter Sackey, MD, PhD, Chief Medical Officer, Sedana Medical AB, peter.sackey@sedanamedical.com
    Scientific contact
    Peter Sackey, MD, PhD, Chief Medical Officer, Sedana Medical AB, peter.sackey@sedanamedical.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002320-PIP01-17
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the percentage of time adequate sedation depth is maintained within the individually prescribed target range in absence of rescue sedation as assessed according to the COMFORT Behavior (COMFORT-B) scale, in isoflurane vs midazolam treated paediatric patients for an expected minimum of 12 hours. (The COMFORT-B scale is a valid and reliable scale measuring distress/sedation of intubated paediatric patients)
    Protection of trial subjects
    Informed consent was obtained from the legal guardian(s) of patients prior to initiation of the study. If appropriate and possible (if the patient was not sedated at the time of recruitment) the patient was approached to provide assent for participation in the study. For patients sedated at the time of recruitment the assent process was completed as appropriate after the patient awakened. If the child was able to understand the information given about the study and after consideration declined participation, this was respected and the child did not enter the study, even if his/her legal guardian(s) had provided informed consent. Rescue sedation (defined as sedative agents other than the investigational medicinal product [IMP]) was allowed in case of inadequate sedation due to e.g. observed acute agitation or immediate risk of extubation which was not controlled by administration of study treatment maintenance dose, bolus doses of study treatment and co-treatment with analgesic agent. Patients (or their legal guardian[s]) had the right to withdraw consent to participation at any time and without providing reasons. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki (2013) that are consistent with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)/Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    Current methods of sedation in mechanically ventilated paediatric patients often involve co-administration of intravenous (IV) midazolam and opioids, and sometimes ketamine and α2-adrenergic agonists. However, midazolam, is associated with relatively long wake up times after discontinuation and, in general, cause severe withdrawal and delirium symptoms after prolonged use.
    Actual start date of recruitment
    14 Jan 2021
    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
    United Kingdom: 4
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Germany: 19
    Worldwide total number of subjects
    96
    EEA total number of subjects
    92
    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)
    77
    Adolescents (12-17 years)
    19
    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
    Patients were children aged 3-17 years who required planned or unplanned mechanical ventilation in the intensive care unit (ICU). Recruitment was monitored to ensure adherence to the target number of patients per age group (3-7, 8-11, 12-17 years).

    Pre-assignment
    Screening details
    Pre-screening was done by sites based on available clinical or chart information to identify potential study patients among patients admitted to the study site. Potential candidates/their legal guardian(s) were invited to formal screening. In total, 111 patients were screened, 96 were randomised (i.e., 15 screen failures), 2 were not treated.

    Period 1
    Period 1 title
    Randomisation
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Isoflurane
    Arm description
    Isoflurane administered by inhalation via Sedaconda ACD-S (old name: AnaConDa-S)
    Arm type
    Experimental

    Investigational medicinal product name
    Isoflurane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, liquid
    Routes of administration
    Inhalation use
    Dosage and administration details
    Isoflurane was given continuously during the treatment period via the Sedaconda ACD-S device. The device was either placed at standard placement or on the inspiratory limb. The Sedaconda ACD-S was primed with 1.2 mL isoflurane and the syringe pump was started at an initial dose-rate of isoflurane (2.0 mL/hour). In case of ongoing sedative treatment, all other sedatives were simultaneously turned off. During initiation and until the prescribed sedation target depth was achieved and considered stable, sedation depth was assessed regularly, and isoflurane dosage was titrated stepwise by increasing/decreasing the infusion rate by 0.5 - 1.0 mL/hour (bolus 0.2 - 0.3 mL). The dose-titration was expected to be completed within 2 hours of initiating study treatment. After the initial dose titration was completed, further titration and bolus doses were allowed to maintain the prescribed sedation target depth. The maintenance dose should not result in exceeding 1.0% end-tidal isoflurane.

    Arm title
    Midazolam
    Arm description
    Intravenously (IV) administered Midazolam
    Arm type
    Active comparator

    Investigational medicinal product name
    Midazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Study treatment started by initiating an IV infusion of midazolam at a start infusion dose rate of 50-100 μg/kg/hour. Other sedatives were simultaneously turned off. The dose was titrated stepwise based on achievement of sedation target depth, by decreasing/increasing 20-50 μg/kg/hour IV (bolus: 50-100 μg/kg). After the initial dose titration was completed (within 2 hours after start of study treatment), further titration and bolus doses were allowed to maintain the prescribed sedation target depth. The maintenance dose should not exceed 300 μg/kg/hour (0.3 mg/kg/hour) midazolam.

    Number of subjects in period 1
    Isoflurane Midazolam
    Started
    63
    33
    Completed
    61
    33
    Not completed
    2
    0
         Protocol deviation
    2
    -
    Period 2
    Period 2 title
    Baseline (BL)
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Isoflurane
    Arm description
    Isoflurane administered by inhalation via Sedaconda ACD-S (old name: AnaConDa-S)
    Arm type
    Experimental

    Investigational medicinal product name
    Isoflurane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, liquid
    Routes of administration
    Inhalation use
    Dosage and administration details
    Isoflurane was given continuously during the treatment period via the Sedaconda ACD-S device. The device was either placed at standard placement or on the inspiratory limb. The Sedaconda ACD-S was primed with 1.2 mL isoflurane and the syringe pump was started at an initial dose-rate of isoflurane (2.0 mL/hour). In case of ongoing sedative treatment, all other sedatives were simultaneously turned off. During initiation and until the prescribed sedation target depth was achieved and considered stable, sedation depth was assessed regularly, and isoflurane dosage was titrated stepwise by increasing/decreasing the infusion rate by 0.5 - 1.0 mL/hour (bolus 0.2 - 0.3 mL). The dose-titration was expected to be completed within 2 hours of initiating study treatment. After the initial dose titration was completed, further titration and bolus doses were allowed to maintain the prescribed sedation target depth. The maintenance dose should not result in exceeding 1.0% end-tidal isoflurane.

    Arm title
    Midazolam
    Arm description
    Intravenously (IV) administered Midazolam
    Arm type
    Active comparator

    Investigational medicinal product name
    Midazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Study treatment started by initiating an IV infusion of midazolam at a start infusion dose rate of 50-100 μg/kg/hour. Other sedatives were simultaneously turned off. The dose was titrated stepwise based on achievement of sedation target depth, by decreasing/increasing 20-50 μg/kg/hour IV (bolus: 50-100 μg/kg). After the initial dose titration was completed (within 2 hours after start of study treatment), further titration and bolus doses were allowed to maintain the prescribed sedation target depth. The maintenance dose should not exceed 300 μg/kg/hour (0.3 mg/kg/hour) midazolam.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: "Randomisation" has been defined as period 1 due to the discrepancy of the number of randomised patients (N=96) and the number of patients with baseline data (N=94). Therefore, the "Baseline" period has been defined as period 2.
    Number of subjects in period 2 [2]
    Isoflurane Midazolam
    Started
    61
    33
    Completed
    61
    33
    Notes
    [2] - 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: 96 patients were enrolled/randomised but data was only collected for 94 patients (included in the safety analysis set) as 2 patients did not start treatment.
    Period 3
    Period 3 title
    Study treatment
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    The study was an open-label study with an assessor-blinded design. At each site, a group assessors were blinded for treatment allocation and prescribed sedation target. The assessors performed the COMFORT-B assessments every 2 h during the study treatment period. Specific measures were taken to ensure treatment allocation was unknown to the blinded assessor upon entry to the room where the patient was being treated, including visually obscuring the Sedaconda ACD-S.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Isoflurane
    Arm description
    Isoflurane administered by inhalation via Sedaconda ACD-S (old name: AnaConDa-S)
    Arm type
    Experimental

    Investigational medicinal product name
    Isoflurane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, liquid
    Routes of administration
    Inhalation use
    Dosage and administration details
    Isoflurane was given continuously during the treatment period via the Sedaconda ACD-S device. The device was either placed at standard placement or on the inspiratory limb. The Sedaconda ACD-S was primed with 1.2 mL isoflurane and the syringe pump was started at an initial dose-rate of isoflurane (2.0 mL/hour). In case of ongoing sedative treatment, all other sedatives were simultaneously turned off. During initiation and until the prescribed sedation target depth was achieved and considered stable, sedation depth was assessed regularly, and isoflurane dosage was titrated stepwise by increasing/decreasing the infusion rate by 0.5 - 1.0 mL/hour (bolus 0.2 - 0.3 mL). The dose-titration was expected to be completed within 2 hours of initiating study treatment. After the initial dose titration was completed, further titration and bolus doses were allowed to maintain the prescribed sedation target depth. The maintenance dose should not result in exceeding 1.0% end-tidal isoflurane.

    Arm title
    Midazolam
    Arm description
    Intravenously (IV) administered Midazolam
    Arm type
    Active comparator

    Investigational medicinal product name
    Midazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Study treatment started by initiating an IV infusion of midazolam at a start infusion dose rate of 50-100 μg/kg/hour. Other sedatives were simultaneously turned off. The dose was titrated stepwise based on achievement of sedation target depth, by decreasing/increasing 20-50 μg/kg/hour IV (bolus: 50-100 μg/kg). After the initial dose titration was completed (within 2 hours after start of study treatment), further titration and bolus doses were allowed to maintain the prescribed sedation target depth. The maintenance dose should not exceed 300 μg/kg/hour (0.3 mg/kg/hour) midazolam.

    Number of subjects in period 3
    Isoflurane Midazolam
    Started
    61
    33
    Completed
    52
    27
    Not completed
    9
    6
         Lack of efficacy/treatment failure
    1
    3
         Patient required continuous neuromuscular blockade
    2
    1
         Consent withdrawn by subject
    1
    -
         Medical emergency
    1
    -
         Worsening bronchospasm
    1
    -
         Sudden wake-up
    1
    -
         Accidental extubation
    1
    -
         Midazolam bottle was empty and not renewed
    -
    1
         Accidently received non-study drug midazolam
    -
    1
         New risk to the patient
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Isoflurane
    Reporting group description
    Isoflurane administered by inhalation via Sedaconda ACD-S (old name: AnaConDa-S)

    Reporting group title
    Midazolam
    Reporting group description
    Intravenously (IV) administered Midazolam

    Reporting group values
    Isoflurane Midazolam Total
    Number of subjects
    61 33 94
    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)
    47 28 75
        Adolescents (12-17 years)
    14 5 19
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.0 ( 4.2 ) 7.0 ( 3.9 ) -
    Gender categorical
    Units: Subjects
        Female
    23 13 36
        Male
    38 20 58
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety analysis set was defined as all patients who received any dose of the IMP.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS included all randomised patients who received IMP and had at least a 6-hour sedation period and at least 3 blinded COMFORT-B-assessments. The FAS followed the intention-to-treat (ITT) principle, i.e., patients were analysed according to the treatment group they were assigned to at randomisation. The main statistical analysis was performed on this population.

    Subject analysis set title
    Per protocol (PP) analysis set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PP analysis set included all patients in the FAS without any major protocol deviation affecting the primary analysis. To be included in the PP analysis set patients had to have been sedated for at least 12 h (which was interpreted as 12 h of study sedative treatment from start of IMP), with at least 50% of the planned COMFORT-B assessments performed. Furthermore, if two or more changes in prescribed target sedation depth occurred (one change was allowed), the patient was excluded from the PP analysis set.

    Subject analysis sets values
    Safety analysis set Full analysis set (FAS) Per protocol (PP) analysis set
    Number of subjects
    94
    92
    85
    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)
    75
    73
    68
        Adolescents (12-17 years)
    19
    19
    17
        Adults (18-64 years)
    0
    0
    0
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    7.6 ( 4.1 )
    7.7 ( 4.1 )
    7.8 ( 4.1 )
    Gender categorical
    Units: Subjects
        Female
    36
    35
    30
        Male
    58
    57
    55

    End points

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    End points reporting groups
    Reporting group title
    Isoflurane
    Reporting group description
    Isoflurane administered by inhalation via Sedaconda ACD-S (old name: AnaConDa-S)

    Reporting group title
    Midazolam
    Reporting group description
    Intravenously (IV) administered Midazolam
    Reporting group title
    Isoflurane
    Reporting group description
    Isoflurane administered by inhalation via Sedaconda ACD-S (old name: AnaConDa-S)

    Reporting group title
    Midazolam
    Reporting group description
    Intravenously (IV) administered Midazolam
    Reporting group title
    Isoflurane
    Reporting group description
    Isoflurane administered by inhalation via Sedaconda ACD-S (old name: AnaConDa-S)

    Reporting group title
    Midazolam
    Reporting group description
    Intravenously (IV) administered Midazolam

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety analysis set was defined as all patients who received any dose of the IMP.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS included all randomised patients who received IMP and had at least a 6-hour sedation period and at least 3 blinded COMFORT-B-assessments. The FAS followed the intention-to-treat (ITT) principle, i.e., patients were analysed according to the treatment group they were assigned to at randomisation. The main statistical analysis was performed on this population.

    Subject analysis set title
    Per protocol (PP) analysis set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PP analysis set included all patients in the FAS without any major protocol deviation affecting the primary analysis. To be included in the PP analysis set patients had to have been sedated for at least 12 h (which was interpreted as 12 h of study sedative treatment from start of IMP), with at least 50% of the planned COMFORT-B assessments performed. Furthermore, if two or more changes in prescribed target sedation depth occurred (one change was allowed), the patient was excluded from the PP analysis set.

    Primary: Percentage of time of adequately maintained sedation within the COMFORT-B interval (light, moderate or deep sedation) prescribed at randomisation, monitored every 2 h for a minimum of 12 h (up to 48 h ± 6 h) - FAS

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    End point title
    Percentage of time of adequately maintained sedation within the COMFORT-B interval (light, moderate or deep sedation) prescribed at randomisation, monitored every 2 h for a minimum of 12 h (up to 48 h ± 6 h) - FAS
    End point description
    End point type
    Primary
    End point timeframe
    From start of study treatment until end of study treatment
    End point values
    Isoflurane Midazolam
    Number of subjects analysed
    59 [1]
    33 [2]
    Units: percent
        least squares mean (confidence interval 95%)
    68.94 (52.83 to 85.05)
    62.37 (44.70 to 80.04)
    Notes
    [1] - FAS
    [2] - FAS
    Statistical analysis title
    Percent time of adequately maintained sedation
    Statistical analysis description
    Least square means of the difference between the treatment groups, including a 2-sided 95% confidence interval was reported in the statistical analysis. The noninferiority criterion was a relative difference of less than 15% between treatment groups.
    Comparison groups
    Isoflurane v Midazolam
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.403 [4]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    6.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.99
         upper limit
    22.13
    Notes
    [3] - Superiority was not met, as the entire 95% CI was not above 0. Noninferiority was met as the entire 95% CI for the difference was above the noninferiority margin for the relative difference of -15% (corresponding to a margin of -9.36% units).
    [4] - Testing the hypothesis of no difference between isoflurane and midazolam.

    Primary: Percentage of time of adequately maintained sedation within the COMFORT-B interval (light, moderate or deep sedation) prescribed at randomisation, monitored every 2 h for a minimum of 12 h (up to 48 h ± 6 h) - PP analysis set

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    End point title
    Percentage of time of adequately maintained sedation within the COMFORT-B interval (light, moderate or deep sedation) prescribed at randomisation, monitored every 2 h for a minimum of 12 h (up to 48 h ± 6 h) - PP analysis set
    End point description
    End point type
    Primary
    End point timeframe
    From start of study treatment until end of study treatment
    End point values
    Isoflurane Midazolam
    Number of subjects analysed
    56 [5]
    29 [6]
    Units: percent
        least squares mean (confidence interval 95%)
    70.91 (50.75 to 91.07)
    65.57 (44.03 to 87.11)
    Notes
    [5] - PP analysis set
    [6] - PP analysis set
    Statistical analysis title
    Supplementary analysis 1
    Comparison groups
    Midazolam v Isoflurane
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.504 [8]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    5.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.48
         upper limit
    21.17
    Notes
    [7] - Superiority was not met, as the entire 95% CI was not above 0. Noninferiority was not met, as the entire 95% CI for the difference was not above the noninferiority margin for the relative difference of -15%.
    [8] - Testing the hypothesis of no difference between isoflurane and midazolam

    Secondary: Dose of opioids from first blinded COMFORT-B assessment (at +2 h) to end of study treatment period

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    End point title
    Dose of opioids from first blinded COMFORT-B assessment (at +2 h) to end of study treatment period
    End point description
    This was a key secondary efficacy endpoint. Dose of opioids was expressed as fentanyl IV equivalents.
    End point type
    Secondary
    End point timeframe
    From first blinded COMFORT-B assessment to end of the study treatment period
    End point values
    Isoflurane Midazolam
    Number of subjects analysed
    59 [9]
    33 [10]
    Units: µg/kg/h
        least squares mean (confidence interval 95%)
    2.1 (1.3 to 2.9)
    4.6 (3.5 to 5.6)
    Notes
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    Dose of opioids (total study treatment period)
    Comparison groups
    Isoflurane v Midazolam
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    -1.1

    Secondary: Dose of opioids during the last 4 h of study treatment, as compared to the first 4 h of study treatment after first blinded COMFORT-B assessment

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    End point title
    Dose of opioids during the last 4 h of study treatment, as compared to the first 4 h of study treatment after first blinded COMFORT-B assessment
    End point description
    This was a key secondary efficacy endpoint. Dose of opioids is expressed as fentanyl IV equivalents.
    End point type
    Secondary
    End point timeframe
    Last 4 hours of study treatment compared to first 4 hours of study treatment after first blinded COMFORT-B assessment.
    End point values
    Isoflurane Midazolam
    Number of subjects analysed
    57 [11]
    31 [12]
    Units: µg/kg/h
        least squares mean (confidence interval 95%)
    -0.19 (-0.74 to 0.35)
    0.58 (-0.16 to 1.32)
    Notes
    [11] - FAS; 2 patients with <8 hours on study treatment from first blinded COMFORT-B assessment excluded
    [12] - FAS; 2 patients with <8 hours on study treatment from first blinded COMFORT-B assessment excluded
    Statistical analysis title
    Change in dose of opioids
    Statistical analysis description
    Results display comparison between isoflurane and midazolam and are based on an analysis of variance model with treatment group as fixed effect and baseline opioid dose as covariate.
    Comparison groups
    Isoflurane v Midazolam
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.096
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.69
         upper limit
    0.14

    Secondary: Time from end of study drug administration to extubation if study drug was terminated for extubation

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    End point title
    Time from end of study drug administration to extubation if study drug was terminated for extubation
    End point description
    This was a key secondary safety endpoint.
    End point type
    Secondary
    End point timeframe
    From end of study drug administration to extubation
    End point values
    Isoflurane Midazolam
    Number of subjects analysed
    35 [13]
    20 [14]
    Units: hour
        median (inter-quartile range (Q1-Q3))
    0.75 (0.25 to 1.5)
    1.09 (0.49 to 5.50)
    Notes
    [13] - Subgroup of patients with endotracheal tube where wake-up was initiated at end of study treatment
    [14] - Subgroup of patients with endotracheal tube where wake-up was initiated at end of study treatment
    Statistical analysis title
    Time to extubation
    Statistical analysis description
    This analysis evaluated a treatment difference between isoflurane and midazolam.
    Comparison groups
    Isoflurane v Midazolam
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    3.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.54
         upper limit
    7.07

    Secondary: Proportion of observations with spontaneous breathing efforts during study treatment

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    End point title
    Proportion of observations with spontaneous breathing efforts during study treatment
    End point description
    This was a key secondary safety endpoint.
    End point type
    Secondary
    End point timeframe
    From the first blinded COMFORT-B assessment to end of study treatment period
    End point values
    Isoflurane Midazolam
    Number of subjects analysed
    59 [15]
    33 [16]
    Units: percent
        least squares mean (confidence interval 95%)
    0.48 (0.36 to 0.60)
    0.44 (0.28 to 0.59)
    Notes
    [15] - FAS
    [16] - FAS
    Statistical analysis title
    Spontaneous breathing efforts
    Statistical analysis description
    Results display a comparison between isoflurane and midazolam and are based on a mixed effects analysis of variance model with treatment group as fixed effect.
    Comparison groups
    Isoflurane v Midazolam
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.636
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    0.25

    Secondary: Need for additional inotropic/vasopressor agent defined by change in vasoactive-inotropic score (VIS) during study treatment period compared to baseline

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    End point title
    Need for additional inotropic/vasopressor agent defined by change in vasoactive-inotropic score (VIS) during study treatment period compared to baseline
    End point description
    Change from baseline in VIS was assessed a ≤24 hours and >24 hours.
    End point type
    Secondary
    End point timeframe
    From start of study treatment to end of study treatment
    End point values
    Isoflurane Midazolam
    Number of subjects analysed
    61 [17]
    33 [18]
    Units: change from baseline in VIS
    arithmetic mean (standard deviation)
        ≤24 hours
    3.4 ( 19.9 )
    5.4 ( 19.3 )
        >24 hours
    8.8 ( 44.4 )
    1.9 ( 9.7 )
    Notes
    [17] - Safety analysis set; data available for 26 patients at >24 hours
    [18] - Safety analysis set; data available for 32 patients at ≤24 hours and 10 patients at >24 hours
    Statistical analysis title
    Need for inotropic/vasopressor agent at ≤24 hours
    Statistical analysis description
    At ≤24 hours, data was only available for 32 patients in the Midazolam group.
    Comparison groups
    Isoflurane v Midazolam
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.55
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [19] - Results display comparison between isoflurane and midazolam and are based on a Wilcoxon rank-sum test.
    Statistical analysis title
    Need for inotropic/vasopressor agent at >24 hours
    Statistical analysis description
    At >24 hours, data was only available for 26 patients in the Isoflurane group and 10 patients in the Midazolam group.
    Comparison groups
    Isoflurane v Midazolam
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.637
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Ventilator-free days at 30 days from start of study treatment period

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    End point title
    Ventilator-free days at 30 days from start of study treatment period
    End point description
    This was a secondary safety endpoint. Patients that were withdrawn prior to day 30 were excluded from the analysis. Patients who died before day 30 were not considered withdrawals. For these patients, the days up to day 30 were considered ventilator days.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until day 30.
    End point values
    Isoflurane Midazolam
    Number of subjects analysed
    60 [20]
    33 [21]
    Units: Number of ventilator-free days
        arithmetic mean (standard deviation)
    25.00 ( 6.74 )
    22.55 ( 10.62 )
    Notes
    [20] - Safety analysis set (only patients not withdrawn prior to day 30)
    [21] - Safety analysis set (only patients not withdrawn prior to day 30)
    No statistical analyses for this end point

    Secondary: Time in ICU at 30 days from start of study treatment period

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    End point title
    Time in ICU at 30 days from start of study treatment period
    End point description
    This was a secondary safety endpoint. Patients that were withdrawn prior to day 30 were excluded from the analysis. Patients who died before day 30 were not considered withdrawals. For these patients, the days in ICU until day of death were considered ICU days.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until day 30.
    End point values
    Isoflurane Midazolam
    Number of subjects analysed
    60 [22]
    33 [23]
    Units: Number of ICU days
        arithmetic mean (standard deviation)
    9.65 ( 7.87 )
    10.21 ( 9.13 )
    Notes
    [22] - Safety analysis set (only patients not withdrawn prior to day 30)
    [23] - Safety analysis set (only patients not withdrawn prior to day 30)
    No statistical analyses for this end point

    Secondary: Days alive and not in the ICU at day 30 from start of study treatment period

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    End point title
    Days alive and not in the ICU at day 30 from start of study treatment period
    End point description
    This was a secondary safety endpoint. Patients that were withdrawn prior to day 30 were excluded from the analysis. Patients who died before day 30 were not considered withdrawals. For these patients, the days in ICU until day of death were considered ICU days.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until day 30.
    End point values
    Isoflurane Midazolam
    Number of subjects analysed
    60 [24]
    33 [25]
    Units: Number of days alive and not in the ICU
        arithmetic mean (standard deviation)
    20.35 ( 7.87 )
    18.58 ( 10.26 )
    Notes
    [24] - Safety analysis set (only patients not withdrawn prior to day 30)
    [25] - Safety analysis set (only patients not withdrawn prior to day 30)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were recorded from start of IMP until the end of the 48-hour post-study treatment monitoring.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Isoflurane
    Reporting group description
    -

    Reporting group title
    Midazolam
    Reporting group description
    -

    Serious adverse events
    Isoflurane Midazolam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 61 (31.15%)
    8 / 33 (24.24%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    2
    Investigations
    Magnetic resonance imaging head abnormal
    Additional description: Preferred term: Magnetic resonance imaging brain abnormal
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anaesthetic complication neurological
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complications of transplanted liver
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrostomy tube site complication
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative thoracic procedure complication
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpericardiotomy syndrome
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
    Additional description: The patient who had this serious adverse event (SAE) also had two additional SAEs (Preferred terms "Acute kidney injury" and "Acute respiratory distress syndrome") which were considered to have led to death of the patient.
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Complication associated with device
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Urinary tract infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
    Additional description: The patient who had this serious adverse event (SAE) also had two additional SAEs (Preferred terms "Acute kidney injury" and "Hypoxic-ischaemic encephalopathy") which were considered to have led to death of the patient.
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chylothorax
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (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 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: One of the patients who had this serious adverse event (SAE) also had two additional SAEs (Preferred terms "Hypoxic-ischaemic encephalopathy" and "Acute respiratory distress syndrome") which were considered to have led to death of the patient.
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (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: 0%
    Non-serious adverse events
    Isoflurane Midazolam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 61 (83.61%)
    21 / 33 (63.64%)
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    9 / 61 (14.75%)
    1 / 33 (3.03%)
         occurrences all number
    20
    1
    Hypotension
         subjects affected / exposed
    15 / 61 (24.59%)
    5 / 33 (15.15%)
         occurrences all number
    33
    11
    Superior vena cava stenosis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Endotracheal intubation
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hyperthermia
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Hypothermia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    8 / 61 (13.11%)
    2 / 33 (6.06%)
         occurrences all number
    13
    2
    Withdrawal syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Graft versus host disease
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Transplant rejection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Aphonia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Atelectasis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Bradypnoea
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Bronchospasm
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Chylothorax
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Haemoptysis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Hypoxia
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 33 (3.03%)
         occurrences all number
    12
    3
    Pleural effusion
         subjects affected / exposed
    5 / 61 (8.20%)
    1 / 33 (3.03%)
         occurrences all number
    6
    2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Anger
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Delirium
         subjects affected / exposed
    5 / 61 (8.20%)
    1 / 33 (3.03%)
         occurrences all number
    5
    1
    Hallucination
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Hallucination, visual
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Mood swings
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Blood lactic acid increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Blood pressure decreased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Blood prolactin increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Inflammatory marker increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 33 (3.03%)
         occurrences all number
    3
    2
    Urine output decreased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Endotracheal intubation complication
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Fall
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Vasoplegia syndrome
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Atrial flutter
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Atrioventricular block
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Bradycardia
         subjects affected / exposed
    3 / 61 (4.92%)
    3 / 33 (9.09%)
         occurrences all number
    12
    10
    Cardiac arrest
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Nodal rhythm
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 33 (0.00%)
         occurrences all number
    8
    0
    Nervous system disorders
    Extrapyramidal disorder
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Poor quality sleep
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Seizure
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Tremor
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    12 / 61 (19.67%)
    4 / 33 (12.12%)
         occurrences all number
    12
    4
    Ileus paralytic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic artery stenosis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Oliguria
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Renal failure
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Postoperative wound infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Viral myositis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Septic shock
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Food intolerance
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2020
    Clinical study protocol (CSP) amendment 1: Updates included addition of an exclusion criterion, clarification of the pregnancy test procedure and addition of a section on study stopping criteria. Also, the future use of biological samples and reporting procedures for serious events were clarified as well as an addition of an adverse event of special interest (AESI). In addition, a few of the defined study assessments were re-evaluated which triggered minor updates in their definition to provide further clarification or minor adjustments in the data collection. One planned supplementary analysis was re-defined to be considered an additional analysis, to support a future filing in the US. This was a global amendment submitted to the Competent Authorities (CAs) and Ethics Committees (EC) in all involved countries except for the German EC. A local amendment (CSP Version 2.1 [DEU] dated 15-Dec-2020) was submitted to the German EC and CA where the use of highly effective contraception methods was added as inclusion criteria in Section 9.3.1 as requested by the leading EC in Germany.
    04 Oct 2022
    CSP amendment 2 (non-substantial): The main changes included revision of inconsistencies regarding how the structured recruitment was specified in the previous version of the CSP, to clarify rules for when to stop randomisation per age group. To ensure enough patients across all age groups for the safety evaluation, the structured recruitment was adjusted to include more adolescent patients ‘12 to less than 18 years of age’. Furthermore, country specific updates in Germany (CSP Version 2.1 [DEU], 15-Dec-2020, and the United Kingdom (CSP Version 2.2 [UK], 13-Jan-2022), were included in this version to have one global CSP version. In addition, some administrative changes were made and the planned "last patient completed date" was updated in line with the increase of the study duration. This amendment was not submitted in Sweden as the EC confirmed that they did not want to receive non-substantial updates.
    30 Dec 2022
    CSP amendment 3: The Sponsor’s rationale and justification for the amendment was: Alignment with a modified Paediatric Investigation Plan supported by the Paediatric Committee (PDCO) on 16-Dec-2022 (EMA/PDCO/773923/2022). Given a low recruitment rate despite efforts to stimulate recruitment, and the view of the PDCO to not extend the study further, it was agreed to a switch of the statistical approach, i.e., a change from superiority ambition to non-inferiority ambition. The protocol already had a pre-defined non-inferiority margin. A switch of the statistical approach would solve the recruitment problems identified to finalise the study. An adequate number of patients, i.e., a minimum of 90 evaluable patients, would be available for a non-inferior efficacy evaluation as well as safety evaluations by strata, and thus the study could be finalised and still provide data for the safe and efficacious use in the paediatric population. This was a global amendment submitted to the CAs and ECs in all involved countries.

    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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