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    Clinical Trial Results:
    A randomised, controlled, open-label study to confirm the efficacy and safety of sedation with isoflurane in invasively ventilated ICU patients using the AnaConDa administration system

    Summary
    EudraCT number
    		 2016-004551-67
    Trial protocol
    		 DE   SI  
    Global end of trial date
    11 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Feb 2021
    First version publication date
    27 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SED001
    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, 18232
    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)
    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
    29 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Feb 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that sedation with isoflurane is non-inferior to propofol in terms of maintaining adequate sedation without rescue sedation.
    Protection of trial subjects
    Serious adverse event collection started at signing of the informed consent, adverse event collection started from first administration of IP and continued until the follow-up assessments. Additional safety assessements were safety laboratory, ECG, physical examination, vital signs, ventilator parameters, CAM-ICU, SOFA, SAPS II, SBT, ICU length of stay, ICU-free days, ventilator time, ventilator free days. In case of inadequate sedation or acute agitation which was not controlled by administration of maximum allowed study sedation level, study sedation bolus doses and co-treatment with analgesic agent was allowed. Patient had the right to withdraw consent to participation at any time and without providing reasons. The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference of Harmonization (ICH)/Good Clinical Practice (GCP) E6 (R1), European Union (EU) Clinical Trials Directive, and applicable local regulatory requirements. In accordance with the EU Data Protection Directive (95/46/EC), the data will not identify any persons taking part in the study.
    Background therapy
    		 Apart from study treatments, all subjects in the study was given standard of care treatment in ICU.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jun 2017
    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
    Slovenia: 15
    Country: Number of subjects enrolled
    Germany: 286
    Worldwide total number of subjects
    301
    EEA total number of subjects
    301
    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)
    138
    From 65 to 84 years
    152
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total 26 sites in Germany and three sites in Slovenia were approved for the study; 21 of the German sites and three of the Slovenian sites enrolled patients into the study. First patient in: 2 July 2017. Last patient completed: 11 February 2020.

    Pre-assignment
    Screening details
    		 A pre-screening was done on all mechanically ventilated patients who entered the ICU. The most common main reason for exclusion for participation was "Not clinically likely to need invasive ventilation and sedation ≥24 hours at randomisation“. Patients that passed the pre-screening were then formally screened.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This study was open-label thus no treatment kit blinding was applied for subjects and/or site personnel. Cumulative data, used for example for sample size re-estimation (SSRE) and data safety review, was blinded. Also data analyst and sponsor was blinded to treatment allocation during the trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Isoflurane
    Arm description
    		 Isoflurane administered by inhalation via AnaConDa
    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 AnaConDa device. Dosage was titrated stepwise by increasing/decreasing the infusion rate by 0.5 to 1.0 mL/h as needed up to maximum 1.5 volume % (Vol%) to achieve the prescribed target sedation depth i.e. within RASS -1 to -4.

    Arm title
    		 Propofol
    Arm description
    		 Propofol infusion
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Propofol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection/infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Propofol was given IV continuously during the treatment period. Dosage was titrated stepwise by increasing/decreasing approximately 0.5-0.8 mg/kg/h each time as needed between 0.3 and 4.0 mg/kg/h to achieve the target sedation depth i.e. within RASS -1 to -4.

    Number of subjects in period 1
    		Isoflurane Propofol
    Started
    150
    151
    Completed
    150
    151
    Period 2
    Period 2 title
    Treatment
    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
    		 -
    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 AnaConDa device. Dosage was titrated stepwise by increasing/decreasing the infusion rate by 0.5 to 1.0 mL/h as needed up to maximum 1.5 volume % (Vol%) to achieve the prescribed target sedation depth i.e. within RASS -1 to -4.

    Arm title
    		 Propofol
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Propofol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection/infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Propofol was given IV continuously during the treatment period. Dosage was titrated stepwise by increasing/decreasing approximately 0.5-0.8 mg/kg/h each time as needed between 0.3 and 4.0 mg/kg/h to achieve the target sedation depth i.e. within RASS -1 to -4.

    Number of subjects in period 2
    		Isoflurane Propofol
    Started
    150
    151
    Completed
    146
    146
    Not completed
    4
    5
         Adverse event, serious fatal
    2
    2
         Physician decision
    -
    1
         Adverse event, non-fatal
    1
    -
         NOT APPLICABLE
    1
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Isoflurane
    Reporting group description
    		 Isoflurane administered by inhalation via AnaConDa

    Reporting group title
    Propofol
    Reporting group description
    		 Propofol infusion

    Reporting group values
    		 Isoflurane Propofol Total
    Number of subjects
    		 150 151 301
    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)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 68 70 138
        From 65-84 years
    		 78 74 152
        85 years and over
    		 4 7 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.8 ( 11.82 ) 64.3 ( 12.92 ) -
    Gender categorical
    Units: Subjects
        Female
    		 46 53 99
        Male
    		 104 98 202

    End points

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    End points reporting groups
    Reporting group title
    Isoflurane
    Reporting group description
    		 Isoflurane administered by inhalation via AnaConDa

    Reporting group title
    Propofol
    Reporting group description
    		 Propofol infusion
    Reporting group title
    Isoflurane
    Reporting group description
    		 -

    Reporting group title
    Propofol
    Reporting group description
    		 -

    Subject analysis set title
    Isoflurane Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients in the PP analysis was a subset of the FAS population fulfilling the following criteria; • Meeting all inclusion criteria and none of the exclusion criteria • Receiving study treatments for more than 12 hours • At least 5 scheduled RASS assessments performed during the study treatment for patients sedated more than 14 hours. For patients sedated for less than 14 hours 4 scheduled RASS assessments will be required for PP analysis set inclusion. • No major protocol violations that would impact non-inferiority analysis or ef-ficacy analysis.

    Subject analysis set title
    Propofol Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients in the PP analysis was a subset of the FAS population fulfilling the following criteria; • Meeting all inclusion criteria and none of the exclusion criteria • Receiving study treatments for more than 12 hours • At least 5 scheduled RASS assessments performed during the study treatment for patients sedated more than 14 hours. For patients sedated for less than 14 hours 4 scheduled RASS assessments will be required for PP analysis set inclusion. • No major protocol violations that would impact non-inferiority analysis or ef-ficacy analysis.

    Primary: Percentage of time on adequate sedation depth

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    End point title
    		 Percentage of time on adequate sedation depth
    End point description
    Endpoint measures percentage of time with adequate sedation depth without any rescue medication. Adequate sedation depth is defined as having a Richmond agitation sedation scale (RASS-value) between (-1 to -4). The percentage of time on adequate sedation depth was derived as the total amount of time that the patient remained within the prescribed target RASS range (-1 to -4) without rescue medication divided by the amount of time the patient is receiving the study treatment, multiplied by 100%.
    End point type
    Primary
    End point timeframe
    Minimum sedation time 12 hours maximum sedation time 48 + 6 hours.
    End point values
    		 Isoflurane Per Protocol Population Propofol Per Protocol Population
    Number of subjects analysed
    146
    148
    Units: percent
        least squares mean (confidence interval 95%)
    90.691 (86.770 to 94.612)
    91.143 (87.232 to 95.054)
    Statistical analysis title
    		 Non-inferiority analysis
    Statistical analysis description
    Non-inferiority comparison of isoflurane compared to propofol. Least square means and model-based estimate of the difference between the treatment groups, including a 2-sided 95% confidence interval was reported in the statistical analysis.
    Comparison groups
    Isoflurane Per Protocol Population v Propofol Per Protocol Population
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.452
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.996
         upper limit
    		 2.093
    Notes
    [1] - The non-inferiority criterion was treatment relative difference of less than 15%.

    Secondary: Wake-up test 24H

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    End point title
    		 Wake-up test 24H
    End point description
    Time (in minutes) from start of wake-up test until reaching RASS ≥0
    End point type
    Secondary
    End point timeframe
    Wake-up test performed at 24 hours after start of study sedation
    End point values
    		 Isoflurane Propofol
    Number of subjects analysed
    122
    121
    Units: Minutes
        median (confidence interval 95%)
    15.0 (11.0 to 29.0)
    19.0 (15.0 to 30.0)
    Statistical analysis title
    		 Time to wake-up, Wake-up test 24H
    Statistical analysis description
    The statistical analysis of time to wake-up in the Wake-up test at 24h was conducted using a Cox regression-model.
    Comparison groups
    Isoflurane v Propofol
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.099
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.955
         upper limit
    		 1.717
    Notes
    [2] - Treatment groups were compared using a hazard ratio with corresponding 95 % confidence interval. A hazard ratio above 1 means shorter time to event (in average) in the Isoflurane group.

    Secondary: Wake-up test 48H

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    End point title
    		 Wake-up test 48H
    End point description
    Time (in minutes) from start of wake-up test until reaching RASS ≥0
    End point type
    Secondary
    End point timeframe
    Wake-up test performed at 48 hours after start of study sedation
    End point values
    		 Isoflurane Propofol
    Number of subjects analysed
    75
    65
    Units: Minutes
        median (confidence interval 95%)
    20 (15 to 30)
    30 (15 to 45)
    Statistical analysis title
    		 Time to wake-up, Wake-up test 48H
    Statistical analysis description
    The statistical analysis of time to wake-up in the Wake-up test at 48h was conducted using a Cox regression-model.
    Comparison groups
    Isoflurane v Propofol
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.081
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.339
         upper limit
    		 3.233
    Notes
    [3] - Treatment groups were compared using a hazard ratio with corresponding 95 % confidence interval. A hazard ratio above 1 means shorter time to event (in average) in the Isoflurane group.

    Secondary: Opiate analgesic dose intensity

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    End point title
    		 Opiate analgesic dose intensity
    End point description
    For each patient, opiate analgesic dose intensity was derived.
    End point type
    Secondary
    End point timeframe
    Total sedation period up to 48±6 hours treatment.
    End point values
    		 Isoflurane Propofol
    Number of subjects analysed
    146
    145
    Units: dose intensity
        least squares mean (confidence interval 95%)
    0.228 (0.125 to 0.331)
    0.321 (0.218 to 0.424)
    Statistical analysis title
    		 Opiate dose intensity
    Statistical analysis description
    Opiate analgesic dose intensity adjusted for Behavioral Pain Scale (BPS) was compared between Isoflurane and Propofol.
    Comparison groups
    Isoflurane v Propofol
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.003
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.093
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.154
         upper limit
    		 -0.032
    Notes
    [4] - A negative value on point estimate indicate lower average opiate analgesic dose intensities for patients on Isoflurane adjusted for BPS.

    Secondary: Time to extubation

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    End point title
    		 Time to extubation
    End point description
    Only patients extubated (end of sedation before successful extubation) within 54h(48+6h) from study sedation start are included
    End point type
    Secondary
    End point timeframe
    Time to extubation is the time between final sedation stop prior to a successful extubation
    End point values
    		 Isoflurane Propofol
    Number of subjects analysed
    60
    67
    Units: Hours
        median (inter-quartile range (Q1-Q3))
    0.5 (0.2 to 2.3)
    0.7 (0.3 to 2.1)
    Statistical analysis title
    		 Time to extubation
    Statistical analysis description
    Time to extubation was analysed using a Cox regression model.
    Comparison groups
    Isoflurane v Propofol
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.212
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.864
         upper limit
    		 1.926
    Notes
    [5] - Treatment groups were compared using a hazard ratio with corresponding 95 % confidence interval. A hazard ratio above 1 means shorter time to event (in average) in the Isoflurane group.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAE collection started at signing of the informed consent; adverse event collection started from first administration of IP. Collection of (new) SAEs and AEs ended at the 24h follow-up visit.
    Adverse event reporting additional description
    AEs or SAEs starting after the 24h follow-up was not recorded in the study database.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Isoflurane
    Reporting group description
    		 In the Isoflurane group there were 10 SAEs among 9 patients. None of the SAEs were judged as causally related.

    Reporting group title
    Propofol
    Reporting group description
    		 In the Propofol group there were 7 SAEs among 6 patients. None of the SAEs were judged as causally related.

    Serious adverse events
    		 Isoflurane Propofol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 150 (6.00%)
    6 / 151 (3.97%)
         number of deaths (all causes)
    3
    3
         number of deaths resulting from adverse events
    3
    3
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Low cardiac output syndrome
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (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
    Cerebral infarction
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Laryngeal oedema
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (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
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Metabolic acidosis
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Isoflurane Propofol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 150 (42.00%)
    50 / 151 (33.11%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 150 (6.67%)
    2 / 151 (1.32%)
         occurrences all number
    15
    2
    Hypotension
         subjects affected / exposed
    3 / 150 (2.00%)
    3 / 151 (1.99%)
         occurrences all number
    3
    3
    Hypertensive crisis
         subjects affected / exposed
    1 / 150 (0.67%)
    3 / 151 (1.99%)
         occurrences all number
    1
    3
    Haemodynamic instability
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Peripheral venous disease
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Thrombosis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Orchidopexy
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Debridement
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Withdrawal syndrome
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Hyperthermia malignant
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 150 (0.00%)
    2 / 151 (1.32%)
         occurrences all number
    0
    2
    Bronchospasm
         subjects affected / exposed
    0 / 150 (0.00%)
    2 / 151 (1.32%)
         occurrences all number
    0
    2
    Haemoptysis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Pulmonary congestion
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Pleural disorder
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Mediastinal haemorrhage
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Respiratory failure
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Hypercapnia
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Respiration Abnormal
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    8 / 150 (5.33%)
    7 / 151 (4.64%)
         occurrences all number
    8
    7
    Agitation
         subjects affected / exposed
    3 / 150 (2.00%)
    6 / 151 (3.97%)
         occurrences all number
    3
    6
    Anxiety
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 151 (0.00%)
         occurrences all number
    2
    0
    Insomnia
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Restlessness
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Red blood cell count decreased
         subjects affected / exposed
    1 / 150 (0.67%)
    4 / 151 (2.65%)
         occurrences all number
    1
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 150 (1.33%)
    2 / 151 (1.32%)
         occurrences all number
    2
    2
    Blood pressure increased
         subjects affected / exposed
    2 / 150 (1.33%)
    1 / 151 (0.66%)
         occurrences all number
    2
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 151 (0.66%)
         occurrences all number
    1
    1
    Body temperature increased
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Blood calcium decreased
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Blood albumin decreased
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Postoperative delirium
         subjects affected / exposed
    2 / 150 (1.33%)
    1 / 151 (0.66%)
         occurrences all number
    2
    1
    Endotracheal Intubation Complication
         subjects affected / exposed
    0 / 150 (0.00%)
    2 / 151 (1.32%)
         occurrences all number
    0
    2
    Procedural pneumothorax
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Post procedural complication
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    5 / 150 (3.33%)
    4 / 151 (2.65%)
         occurrences all number
    5
    5
    Tachycardia
         subjects affected / exposed
    4 / 150 (2.67%)
    3 / 151 (1.99%)
         occurrences all number
    4
    3
    Sinus tachycardia
         subjects affected / exposed
    3 / 150 (2.00%)
    0 / 151 (0.00%)
         occurrences all number
    3
    0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 151 (0.66%)
         occurrences all number
    1
    1
    Tachyarrhythmia
         subjects affected / exposed
    0 / 150 (0.00%)
    2 / 151 (1.32%)
         occurrences all number
    0
    2
    Bradycardia
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 151 (0.66%)
         occurrences all number
    1
    1
    Ventricular tachycardia
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Left ventricular failure
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Bundle branch block right
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Cardiovascular disorder
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Nervous system disorders
    Myoclonus
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Seizure
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    3 / 150 (2.00%)
    1 / 151 (0.66%)
         occurrences all number
    3
    1
    Leukocytosis
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Anaemia
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 150 (2.67%)
    2 / 151 (1.32%)
         occurrences all number
    4
    2
    Vomiting
         subjects affected / exposed
    3 / 150 (2.00%)
    1 / 151 (0.66%)
         occurrences all number
    3
    1
    Tongue haematoma
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Tooth disorder
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Small intestinal perforation
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Swelling face
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    7 / 150 (4.67%)
    6 / 151 (3.97%)
         occurrences all number
    7
    6
    Renal failure
         subjects affected / exposed
    4 / 150 (2.67%)
    0 / 151 (0.00%)
         occurrences all number
    4
    0
    Renal impairment
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Anuria
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Chronic kidney disease
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Acute kidney injury
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 150 (0.00%)
    3 / 151 (1.99%)
         occurrences all number
    0
    3
    Pneumonia
         subjects affected / exposed
    0 / 150 (0.00%)
    2 / 151 (1.32%)
         occurrences all number
    0
    2
    Peritonitis
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Intervertebral discitis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Septic encephalopathy
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Diverticulitis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0
    Abdominal infection
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    0
    1
    Hypernatraemia
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 151 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Mar 2017
    BfArM and EC requested the following clarifications were made : • Use of gas monitor and elimination system with AnaConDa • That warnings, contraindications and interactions in SmPC for applicable investigational product must be followed • ICF procedure • Randomisation stratified by site • Adding creatine kinase lab test • Adding an independent data safety monitoring board
    19 May 2017
    The following changes were made due to clarifications, change of details and removal of inconsistencies: • Adding methodology section in synopsis • Change of biostatistician • Clarification of wordings of objectives and endpoints • Administrative changes to clarify inconsistencies and order of study procedures • Clarification of wordings of incl/excl criteria • Clarification on replacement for withdrawn subjects • Clarification on blinding procedures • Clarification of rescue sedation and sedation failure • Modification of procedure after surgery or anaestesia • Corrections/clarifications on vital signs, ventilator parameters and concomitant meds to be collected • Modification of SBT procedure • Adding collection of data for extubation • Change of follow-up adverse event and concomitant medication data collection • Clarifications in statistical methods
    24 Jun 2018
    The following changes were made: • Extending safety follow-up to include seven days of organ systems function and 30 days mortality and health economy in terms of days in ICU and days with invasive ventilation. • Adding secondary objectives and endpoints related to the extended follow-up of organ function, mortality and health economy • Clarifying informed consent procedure and the emergency situation • Adding the AnaConDa-S device to be used for isoflurane administration • Changing sponsor representative • Correcting errors and clarifying inconsistencies
    27 Mar 2019
    To reduce number of secondary objectives and endpoints and for clarifications and removal of inconsistencies the following changes were made: • Re-structuring of objectives and endpoints • Clarifications in Table 1, Study plan • Clarification of exclusion criteria 5, 6 and 13 • Clarification of concomitant medication/prohibited medication section. • Clarification of AE collection timeframes • Adding written consent or putative consent for collection of 30 day f/u data for subjects included before amendment 3 • Changing Last Subject completed to Q1 2020
    09 Dec 2019
    For clarification the following updates were made: • Restructuring of objectives • Ordering of secondary safety endpoints • Repositioning of endpoints

    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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