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    Clinical Trial Results:
    A Randomized, Single-blind Phase II Study Evaluating the Efficacy, Safety and Pharmacokinetics of Remimazolam in General Anesthesia in Adult Patients Undergoing Cardiac Surgery, Including Follow-up Sedation in the Post-anesthesia Care Unit / Intensive Care Unit

    Summary
    EudraCT number
    		 2013-001113-32
    Trial protocol
    		 DE  
    Global end of trial date
    19 Feb 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 May 2016
    First version publication date
    18 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CNS7056-010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01937767
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PAION UK Limited
    Sponsor organisation address
    Unit D1, Brookmount Court, Kirkwood Road, Cambridge, United Kingdom, CB4 2QH
    Public contact
    Clinical trial information, PAION GmbH, +49 (0)24144530, info@paion.com
    Scientific contact
    Clinical trial information, PAION GmbH, +49 (0)24144530, info@paion.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
    16 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Randomized, single-blind trial to compare 2 doses of remimazolam against each other and against propofol during induction of general anesthesia and to compare remimazolam with the combination of propofol and sevoflurane during maintenance of general anesthesia. Main objectives: efficacy including dose finding for induction, safety
    Protection of trial subjects
    This study was conducted in compliance with the principles of the Declaration of Helsinki and its amendments, the International Conference on Harmonisation (ICH), principles of Good Clinical Practice (GCP), and the applicable regulations in Germany and the European Union. Conduct of the study was approved by the Ethics Committee at the Medical Faculty of the University of Leipzig, an appropriately constituted Independent Ethics Committee.
    Background therapy
    		 - Major elective cardiac surgery, i.e. surgery assumed to require more than 2 hours of maintenance of general anesthesia and the use of extracorporeal circulation. - Fentanyl and remifentanil as opioid narcotics and rocuronium bromide as neuro-muscular blocker - Optionally: further drugs that are used during heart surgery, e.g. catecholamines, heparin
    Evidence for comparator
    		 Remimazolam was compared with the standard regimen for general anesthesia in heart surgery which is the combination of propofol and sevoflurane.
    Actual start date of recruitment
    29 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 90
    Worldwide total number of subjects
    90
    EEA total number of subjects
    90
    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)
    49
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at the Heart Center in Leipzig, Germany. Patients were eligible for the study if they were scheduled for major elective cardiac surgery, i.e. surgery assumed to require >2 hours of maintenance of general anesthesia and extracorporeal circulation, including bypass(es), valve replacement(s), and surgery of the aortic arch.

    Pre-assignment
    Screening details
    		 A total of 125 patients were screened. 10 patients were not eligible so that 115 patients were randomized. Of these 115 patients, 25 patients stopped the study prior to the start of the study medication, mainly due to rescheduling of the surgery or other organisational reasons. Study medication was administered to 90 patients.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Remimazolam 6
    Arm description
    		 Remimazolam 6 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remimazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Remimazolam 6 mg/kg/hr for induction, 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery based on the medical condition of each individual patient. Intravenous administration via syringe pump.

    Arm title
    		 Remimazolam 12
    Arm description
    		 Remimazolam 12 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remimazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Remimazolam 12 mg/kg/hr for induction, 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery based on the medical condition of each individual patient. Intravenous administration via syringe pump.

    Arm title
    		 Remimazolam All
    Arm description
    		 Remimazolam 6 mg/kg/hr or 12 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remimazolam 6
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Remimazolam 6 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery based on the medical condition of each individual patient. intravenous administration via syringe pump.

    Investigational medicinal product name
    Remimazolam 12
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Remimazolam 12 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery based on the medical condition of each individual patient. Intravenous administration via syringe pump.

    Arm title
    		 Propofol/Sevoflurane
    Arm description
    		 Propofol 2 - 2.5 mg/kg for induction, maintenance with sevoflurane 0.8 - 2.5 MAC until start of extracorporeal circulation, afterwards maintenance with propofol 3 - 12 mg/kg/hr, propofol down titration and stop during recovery.
    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 use
    Dosage and administration details
    Propofol for induction: 2.0 - 2.5 mg/kg, manual intravenous administration over approximately 1 minute. Propofol for maintenance: 3 - 12 mg/kg/hr, intravenous administration via syringe pump. Propofol down titration and stop during recovery based on the medical condition of each individual patient, intravenous administration via syringe pump.

    Investigational medicinal product name
    Sevoflurane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Intrapulmonary use
    Dosage and administration details
    Sevoflurane inhalation gas 0.8 -2.5 MAC for maintenance. Administration by inhalation during mechanical ventilation.

    Number of subjects in period 1
    		Remimazolam 6 Remimazolam 12 Remimazolam All Propofol/Sevoflurane
    Started
    34
    28
    62
    28
    Completed
    34
    28
    62
    28
    Period 2
    Period 2 title
    Induction
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [1]
    Roles blinded
    		 Subject, Assessor
    Blinding implementation details
    Patients were not informed about their treatment allocation. To enable investigators to titrate remimazolam or propofol as effectively and as safely as possible during the induction period, investigators knew about their patients' treatment allocation. An expert assessor who reviewed the Narcotrend data after the end of the general anesthesia was not informed about the patients' treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Remimazolam 6
    Arm description
    		 Remimazolam 6 mg/kg/hr for induction
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remimazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg/kg/hr for induction, intravenous administration via syringe pump.

    Arm title
    		 Remimazolam 12
    Arm description
    		 Remimazolam 12 mg/kg/hr for induction
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remimazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    12 mg/kg/hr for induction, intravenous administration via syringe pump.

    Arm title
    		 Propofol
    Arm description
    		 Propofol 2.0 - 2.5 mg/kg for induction
    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 use
    Dosage and administration details
    Propofol 2.0 - 2.5 mg/kg for induction. Manual intravenous administration over approximately 1 minute.

    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: An expert assessor who reviewed the Narcotrend data after the end of the general anesthesia was not informed about the patients' treatment allocation.
    Number of subjects in period 2
    		Remimazolam 6 Remimazolam 12 Propofol
    Started
    34
    28
    28
    Completed
    34
    28
    28
    Period 3
    Period 3 title
    Maintenance
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [2]
    Roles blinded
    		 Subject, Assessor
    Blinding implementation details
    Patients were not informed about their treatment allocation. To enable investigators to titrate remimazolam or propofol/sevoflurane as effectively and as safely as possible during the maintenance period, investigators knew about their patients' treatment allocation. An expert assessor who reviewed the Narcotrend data after the end of the general anesthesia was not informed about the patients' treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Remimazolam All
    Arm description
    		 Maintenance with remimazolam after induction with remimazolam 6 mg/kg/hr or remimazolam 12 mg/kg/hr
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remimazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Remimazolam 1 mg/kg/hr up to 3 mg/kg/hr intravenously administered via syringe pump according to each individual patient's needs.

    Arm title
    		 Propofol/Sevoflurane
    Arm description
    		 Maintenance with sevoflurane until start of extracorporeal circulation. From start of extracorporeal circulation onwards maintenance with propofol.
    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 use
    Dosage and administration details
    Propofol 3 - 12 mg/kg/hr according to each individual patient's needs. Intravenous administration via syringe pump.

    Investigational medicinal product name
    Sevoflurane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Intrapulmonary use
    Dosage and administration details
    Sevoflurane inhalation gas 0.8 -2.5 MAC according to each individual patient's needs. Administration by inhalation during mechanical ventilation.

    Notes
    [2] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: An expert assessor who reviewed the Narcotrend data after the end of the general anesthesia was not informed about the patients' treatment allocation.
    Number of subjects in period 3
    		Remimazolam All Propofol/Sevoflurane
    Started
    62
    28
    Completed
    62
    28
    Period 4
    Period 4 title
    Recovery
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [3]
    Roles blinded
    		 Subject, Assessor
    Blinding implementation details
    Patients were not informed about their treatment allocation. To enable investigators to titrate remimazolam or propofol as effectively and as safely as possible during the recovery period, investigators knew about their patients' treatment allocation. An expert assessor who reviewed the Narcotrend data after the end of the general anesthesia was not informed about the patients' treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Remimazolam All
    Arm description
    		 Down titration and stop of remimazolam
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remimazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Downtitration of remimazolam from maintenance dosage according to each individual patient's needs. Intravenous administration via syringe pump.

    Arm title
    		 Propofol
    Arm description
    		 Down titration and stop of propofol
    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 use
    Dosage and administration details
    Downtitration of propofol from maintenance dosage according to each individual patient's needs. Intravenous administration via syringe pump.

    Notes
    [3] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: An expert assessor who reviewed the Narcotrend data after the end of the general anesthesia was not informed about the patients' treatment allocation.
    Number of subjects in period 4
    		Remimazolam All Propofol
    Started
    62
    28
    Completed
    62
    28
    Period 5
    Period 5 title
    Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    Patients were not informed about their treatment allocation to avoid bias on patients' statements, e.g. regarding adverse events.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Remimazolam All
    Arm description
    		 Study medication-free follow-up
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remimazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    No administration of remimazolam during follow-up.

    Arm title
    		 Propofol/Sevoflurane
    Arm description
    		 Study medication-free follow-up
    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 use
    Dosage and administration details
    No administration of propofol during follow-up.

    Investigational medicinal product name
    Sevoflurane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, liquid
    Routes of administration
    Inhalation use
    Dosage and administration details
    No administration of sevoflurane during follow-up.

    Number of subjects in period 5
    		Remimazolam All Propofol/Sevoflurane
    Started
    62
    28
    Completed
    62
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Remimazolam 6
    Reporting group description
    		 Remimazolam 6 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery.

    Reporting group title
    Remimazolam 12
    Reporting group description
    		 Remimazolam 12 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery.

    Reporting group title
    Remimazolam All
    Reporting group description
    		 Remimazolam 6 mg/kg/hr or 12 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery.

    Reporting group title
    Propofol/Sevoflurane
    Reporting group description
    		 Propofol 2 - 2.5 mg/kg for induction, maintenance with sevoflurane 0.8 - 2.5 MAC until start of extracorporeal circulation, afterwards maintenance with propofol 3 - 12 mg/kg/hr, propofol down titration and stop during recovery.

    Reporting group values
    		 Remimazolam 6 Remimazolam 12 Remimazolam All Propofol/Sevoflurane Total
    Number of subjects
    		 34 28 62 28
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60 ( 11.57 ) 63.9 ( 11.67 ) 61.8 ( 11.68 ) 62.9 ( 10.96 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 5 17 6 23
        Male
    		 22 23 45 22 67
    Planned surgical procedure
    Units: Subjects
        Bypass(es) only
    		 2 3 5 2 7
        Valve replacement(s) only
    		 9 11 20 19 39
        Other or combined procedures
    		 23 14 37 7 44
    Duration of maintenance of anesthesia
    Units: Minutes
        arithmetic mean (standard deviation)
    		 199.14 ( 52.52 ) 209.36 ( 54.1 ) 203.75 ( 53.04 ) 185.27 ( 44.86 ) -

    End points

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    End points reporting groups
    Reporting group title
    Remimazolam 6
    Reporting group description
    		 Remimazolam 6 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery.

    Reporting group title
    Remimazolam 12
    Reporting group description
    		 Remimazolam 12 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery.

    Reporting group title
    Remimazolam All
    Reporting group description
    		 Remimazolam 6 mg/kg/hr or 12 mg/kg/hr for induction, remimazolam 1 - 3 mg/kg/hr for maintenance, remimazolam down titration and stop during recovery.

    Reporting group title
    Propofol/Sevoflurane
    Reporting group description
    		 Propofol 2 - 2.5 mg/kg for induction, maintenance with sevoflurane 0.8 - 2.5 MAC until start of extracorporeal circulation, afterwards maintenance with propofol 3 - 12 mg/kg/hr, propofol down titration and stop during recovery.
    Reporting group title
    Remimazolam 6
    Reporting group description
    		 Remimazolam 6 mg/kg/hr for induction

    Reporting group title
    Remimazolam 12
    Reporting group description
    		 Remimazolam 12 mg/kg/hr for induction

    Reporting group title
    Propofol
    Reporting group description
    		 Propofol 2.0 - 2.5 mg/kg for induction
    Reporting group title
    Remimazolam All
    Reporting group description
    		 Maintenance with remimazolam after induction with remimazolam 6 mg/kg/hr or remimazolam 12 mg/kg/hr

    Reporting group title
    Propofol/Sevoflurane
    Reporting group description
    		 Maintenance with sevoflurane until start of extracorporeal circulation. From start of extracorporeal circulation onwards maintenance with propofol.
    Reporting group title
    Remimazolam All
    Reporting group description
    		 Down titration and stop of remimazolam

    Reporting group title
    Propofol
    Reporting group description
    		 Down titration and stop of propofol
    Reporting group title
    Remimazolam All
    Reporting group description
    		 Study medication-free follow-up

    Reporting group title
    Propofol/Sevoflurane
    Reporting group description
    		 Study medication-free follow-up

    Primary: Success of anesthesia

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    End point title
    		 Success of anesthesia
    End point description
    Success defined as no need for another sedative between start of study medication and end of surgical procedure.
    End point type
    Primary
    End point timeframe
    Between start of study medication and end of surgical procedure, defined as time of completion of last skin suture
    End point values
    		 Remimazolam All Propofol/Sevoflurane
    Number of subjects analysed
    62
    28
    Units: Patients
    61
    27
    Statistical analysis title
    		 CI Remimazolam All vs Propofol/Sevoflurane
    Statistical analysis description
    The difference in the success rate between the group of patients on remimazolam and the group of patients on propofol/sevoflurane was assessed by calculating confidence intervals
    Comparison groups
    Remimazolam All v Propofol/Sevoflurane
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.61
         upper limit
    		 16.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.855

    Secondary: Time to loss of consciousness

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    End point title
    		 Time to loss of consciousness
    End point description
    Loss of consciousness was defined as time by when Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale was found equal or less than 1 for the first time.
    End point type
    Secondary
    End point timeframe
    From start of study medication until loss of consciousness
    End point values
    		 Remimazolam 6 Remimazolam 12 Propofol
    Number of subjects analysed
    34
    28
    28
    Units: seconds
        median (confidence interval 95%)
    75 (63 to 82)
    60.5 (54 to 73)
    56 (51 to 65)
    No statistical analyses for this end point

    Secondary: Time with Narcotrend Index </= 60

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    End point title
    		 Time with Narcotrend Index </= 60
    End point description
    The Narcotrend monitoring system recorded and analyzed the patients' electroencephalogram (EEG). The Narcotrend monitor generated a Narcotrend Index between 100 (fully awake) and 0 (no brain activity) every 5 seconds. During maintenance of general anesthesia, Narcotrend Indices between 50 and 30 were regarded as representing ideal depth of sedation. To allow for minor fluctuations, Narcotrend Indices of 60 and less were regarded as representing appropriate sedation throughout maintenance.
    End point type
    Secondary
    End point timeframe
    General anesthesia, maintenance period
    End point values
    		 Remimazolam All Propofol/Sevoflurane
    Number of subjects analysed
    62
    28
    Units: Percent
        arithmetic mean (standard deviation)
    94.64 ( 5.588 )
    96.91 ( 2.613 )
    No statistical analyses for this end point

    Secondary: Time to extubation

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    End point title
    		 Time to extubation
    End point description
    From arrival at PACU/ICU or first occurrence of normothermia (at least 36 degrees centrigrade), whichever was later, until extubation completed
    End point type
    Secondary
    End point timeframe
    Between completion of last skin suture and discharge from PACU/ICU
    End point values
    		 Remimazolam All Propofol
    Number of subjects analysed
    62
    28
    Units: minute
        median (confidence interval 95%)
    145.5 (111 to 170)
    97 (83 to 140)
    No statistical analyses for this end point

    Secondary: Time to discharge from hospital

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    End point title
    		 Time to discharge from hospital
    End point description
    Number of days from day of surgery to day of discharge from hospital
    End point type
    Secondary
    End point timeframe
    Date of surgery until discharge from hospital
    End point values
    		 Remimazolam All Propofol/Sevoflurane
    Number of subjects analysed
    62
    28
    Units: day
        median (confidence interval 95%)
    9 (8 to 11)
    9.5 (8 to 11)
    No statistical analyses for this end point

    Secondary: Successful intubation

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    End point title
    		 Successful intubation
    End point description
    End point type
    Secondary
    End point timeframe
    Between start of study medication and departure from induction room
    End point values
    		 Remimazolam 6 Remimazolam 12 Propofol
    Number of subjects analysed
    34
    28
    28
    Units: patients
        Successful
    34
    28
    28
        Not successful
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Time to intubation completed

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    End point title
    		 Time to intubation completed
    End point description
    Time between start of administration of study drug and intubation completed
    End point type
    Secondary
    End point timeframe
    Between start of study medication and departure from induction room
    End point values
    		 Remimazolam 6 Remimazolam 12 Propofol
    Number of subjects analysed
    34
    28
    28
    Units: seconds
        median (confidence interval 95%)
    293 (260 to 328)
    284.5 (253 to 323)
    286.5 (265 to 301)
    No statistical analyses for this end point

    Post-hoc: Use of norepinephrine

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    End point title
    		 Use of norepinephrine
    End point description
    Vasopressors were used to treat hemodynamic instability. Norepinephrine was the first-line vasopressor. Low use of norepinephrine was regarded as indicating high hemodynamic stability.
    End point type
    Post-hoc
    End point timeframe
    From start of study medication until end of PiCCO (system of invasive hemodynamic monitoring) recording. PiCCO recording was stopped after end of surgery and before discharge from Post-anesthesia Care Unit / Intensive Care Unit
    End point values
    		 Remimazolam All Propofol/Sevoflurane
    Number of subjects analysed
    60 [1]
    28
    Units: ng/kg/min
        arithmetic mean (standard deviation)
    23.676 ( 20.3064 )
    43.171 ( 38.7774 )
    Notes
    [1] - 2 patients did not get any amount of norepinephrine
    Statistical analysis title
    		 Test for difference in use of norepinephrine
    Statistical analysis description
    To investigate whether the use of norepinephrine is lower under remimazolam compared with the use of norepinephrine under the combination of propofol and sevoflurane
    Comparison groups
    Remimazolam All v Propofol/Sevoflurane
    Number of subjects included in analysis
    88
    Analysis specification
    Post-hoc
    Analysis type
    		 other [2]
    P-value
    		 = 0.0172
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - Test for difference

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signature of informed consent until discharge from hospital
    Adverse event reporting additional description
    Treatment-emergent adverse events were defined as AEs reported during treatment, i.e. at or after the start of the treatment Administration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Safety Population Remimazolam 6 mg
    Reporting group description
    		 All patients who received any amount of study drug and who actually received remimazolam 6 mg/kg/hr for induction. For maintenance, remimazolam 1 - 3 mg/kg/hr was administered. Down titration and stop of remimazolam during recovery.

    Reporting group title
    Safety Population Remimazolam 12 mg
    Reporting group description
    		 All patients who received any amount of study drug and who actually received remimazolam 12 mg/kg/hr for induction. For maintenance, remimazolam 1 - 3 mg/kg/hr was administered. Down titration and stop of remimazolam during recovery.

    Reporting group title
    Safety Population Remimazolam All
    Reporting group description
    		 All patients on remimazolam, i.e. patients with induction with remimazolam 6 mg/kg/hr AND patients with induction with remimazolam 12 mg/kg/hr. For maintenance, remimazolam 1 - 3 mg/kg/hr was administered. Down titration and stop of remimazolam during recovery.

    Reporting group title
    Safety Population Propofol/Sevoflurane
    Reporting group description
    		 All patients who received any amount of study drug and who got propofol for induction. For maintenance, sevoflurane 0.8 - 2.5 MAC was administered until start of extracorporeal circulation. From start of extracorporeal circulation, propofol 3 -12 mg/kg/hr was administered. Down titration and stop of propofol during recovery.

    Serious adverse events
    		 Safety Population Remimazolam 6 mg Safety Population Remimazolam 12 mg Safety Population Remimazolam All Safety Population Propofol/Sevoflurane
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 34 (26.47%)
    8 / 28 (28.57%)
    17 / 62 (27.42%)
    7 / 28 (25.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 28 (3.57%)
    1 / 62 (1.61%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac valve rupture
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 28 (0.00%)
    0 / 62 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative thoracic procedure complication
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 28 (0.00%)
    0 / 62 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 28 (3.57%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 28 (10.71%)
    3 / 62 (4.84%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 28 (0.00%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 28 (0.00%)
    0 / 62 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 28 (3.57%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 28 (0.00%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial hemorrhage
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 28 (0.00%)
    0 / 62 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 28 (0.00%)
    0 / 62 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinoatrial block
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 28 (0.00%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 28 (0.00%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 28 (0.00%)
    0 / 62 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 28 (0.00%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal adhesions
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 28 (3.57%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 28 (3.57%)
    2 / 62 (3.23%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 28 (3.57%)
    2 / 62 (3.23%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 28 (0.00%)
    2 / 62 (3.23%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory depression
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 28 (0.00%)
    0 / 62 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 28 (0.00%)
    1 / 62 (1.61%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient psychosis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 28 (0.00%)
    0 / 62 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 28 (0.00%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Postoperative wound infection
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 28 (0.00%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 28 (0.00%)
    0 / 62 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection fungal
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 28 (3.57%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 28 (0.00%)
    1 / 62 (1.61%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Population Remimazolam 6 mg Safety Population Remimazolam 12 mg Safety Population Remimazolam All Safety Population Propofol/Sevoflurane
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 34 (100.00%)
    28 / 28 (100.00%)
    62 / 62 (100.00%)
    28 / 28 (100.00%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 34 (8.82%)
    3 / 28 (10.71%)
    6 / 62 (9.68%)
    4 / 28 (14.29%)
         occurrences all number
    3
    3
    6
    4
    Bilirubin conjugated increased
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 28 (7.14%)
    5 / 62 (8.06%)
    0 / 28 (0.00%)
         occurrences all number
    3
    2
    5
    0
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    18 / 34 (52.94%)
    14 / 28 (50.00%)
    32 / 62 (51.61%)
    12 / 28 (42.86%)
         occurrences all number
    18
    14
    32
    12
    Procedural nausea
         subjects affected / exposed
    18 / 34 (52.94%)
    13 / 28 (46.43%)
    31 / 62 (50.00%)
    10 / 28 (35.71%)
         occurrences all number
    18
    13
    31
    10
    Vascular disorders
    Haematoma
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 28 (14.29%)
    9 / 62 (14.52%)
    0 / 28 (0.00%)
         occurrences all number
    5
    4
    9
    0
    Hypertension
         subjects affected / exposed
    7 / 34 (20.59%)
    9 / 28 (32.14%)
    16 / 62 (25.81%)
    8 / 28 (28.57%)
         occurrences all number
    7
    9
    16
    8
    Hypotension
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 28 (3.57%)
    5 / 62 (8.06%)
    1 / 28 (3.57%)
         occurrences all number
    4
    1
    5
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    9 / 34 (26.47%)
    4 / 28 (14.29%)
    13 / 62 (20.97%)
    9 / 28 (32.14%)
         occurrences all number
    9
    4
    13
    10
    Bradycardia
         subjects affected / exposed
    5 / 34 (14.71%)
    3 / 28 (10.71%)
    8 / 62 (12.90%)
    4 / 28 (14.29%)
         occurrences all number
    5
    3
    8
    4
    Pericardial effusion
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 28 (7.14%)
    5 / 62 (8.06%)
    1 / 28 (3.57%)
         occurrences all number
    3
    2
    5
    1
    Atrioventricular block complete
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 28 (10.71%)
    3 / 62 (4.84%)
    2 / 28 (7.14%)
         occurrences all number
    0
    3
    3
    2
    General disorders and administration site conditions
    Drug effect prolonged
         subjects affected / exposed
    5 / 34 (14.71%)
    7 / 28 (25.00%)
    12 / 62 (19.35%)
    6 / 28 (21.43%)
         occurrences all number
    5
    7
    12
    6
    Chills
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 28 (14.29%)
    9 / 62 (14.52%)
    3 / 28 (10.71%)
         occurrences all number
    5
    4
    9
    3
    Oedema
         subjects affected / exposed
    4 / 34 (11.76%)
    3 / 28 (10.71%)
    7 / 62 (11.29%)
    5 / 28 (17.86%)
         occurrences all number
    4
    3
    7
    5
    Blood and lymphatic system disorders
    Haemorrhagic anaemia
         subjects affected / exposed
    5 / 34 (14.71%)
    8 / 28 (28.57%)
    13 / 62 (20.97%)
    4 / 28 (14.29%)
         occurrences all number
    5
    8
    13
    4
    Thrombocytopenia
         subjects affected / exposed
    4 / 34 (11.76%)
    6 / 28 (21.43%)
    10 / 62 (16.13%)
    5 / 28 (17.86%)
         occurrences all number
    4
    6
    10
    5
    Coagulopathy
         subjects affected / exposed
    3 / 34 (8.82%)
    4 / 28 (14.29%)
    7 / 62 (11.29%)
    2 / 28 (7.14%)
         occurrences all number
    3
    4
    7
    2
    Leukocytosis
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 28 (0.00%)
    3 / 62 (4.84%)
    2 / 28 (7.14%)
         occurrences all number
    3
    0
    3
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 34 (17.65%)
    4 / 28 (14.29%)
    10 / 62 (16.13%)
    3 / 28 (10.71%)
         occurrences all number
    6
    4
    10
    3
    Flatulence
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 28 (3.57%)
    3 / 62 (4.84%)
    2 / 28 (7.14%)
         occurrences all number
    2
    1
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    28 / 34 (82.35%)
    27 / 28 (96.43%)
    55 / 62 (88.71%)
    23 / 28 (82.14%)
         occurrences all number
    28
    27
    55
    23
    Cough
         subjects affected / exposed
    13 / 34 (38.24%)
    6 / 28 (21.43%)
    19 / 62 (30.65%)
    3 / 28 (10.71%)
         occurrences all number
    13
    6
    19
    3
    Respiratory failure
         subjects affected / exposed
    5 / 34 (14.71%)
    7 / 28 (25.00%)
    12 / 62 (19.35%)
    4 / 28 (14.29%)
         occurrences all number
    5
    7
    12
    4
    Bronchospasm
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 28 (14.29%)
    9 / 62 (14.52%)
    4 / 28 (14.29%)
         occurrences all number
    5
    4
    9
    4
    Pneumothorax
         subjects affected / exposed
    4 / 34 (11.76%)
    3 / 28 (10.71%)
    7 / 62 (11.29%)
    2 / 28 (7.14%)
         occurrences all number
    4
    3
    7
    2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    18 / 34 (52.94%)
    13 / 28 (46.43%)
    31 / 62 (50.00%)
    7 / 28 (25.00%)
         occurrences all number
    18
    13
    31
    7
    Sleep disorder
         subjects affected / exposed
    14 / 34 (41.18%)
    11 / 28 (39.29%)
    25 / 62 (40.32%)
    12 / 28 (42.86%)
         occurrences all number
    14
    11
    25
    12
    Delirium
         subjects affected / exposed
    4 / 34 (11.76%)
    6 / 28 (21.43%)
    10 / 62 (16.13%)
    4 / 28 (14.29%)
         occurrences all number
    4
    6
    10
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 34 (11.76%)
    6 / 28 (21.43%)
    10 / 62 (16.13%)
    1 / 28 (3.57%)
         occurrences all number
    4
    6
    10
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 28 (10.71%)
    4 / 62 (6.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    3
    4
    1
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    12 / 34 (35.29%)
    8 / 28 (28.57%)
    20 / 62 (32.26%)
    4 / 28 (14.29%)
         occurrences all number
    12
    8
    20
    4
    Hyperglycaemia
         subjects affected / exposed
    2 / 34 (5.88%)
    5 / 28 (17.86%)
    7 / 62 (11.29%)
    5 / 28 (17.86%)
         occurrences all number
    2
    5
    7
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2013
    1.) Remimazolam dosage for maintenance increased from 1 - 2 mg/kg/hr to 1 - 3 mg/kg/hr 2.) post-operative bleedings were to be reported as AEs only if administration of at least one transfusion or at least one unit of products that support blood coagulation was required or if re-surgery was required 3.) cardiac arrhythmias did not need to be reported as AEs if they occurred within 5 minutes before or after cardioplegia that was induced for extracorporeal circulation of if they stopped within 30 seconds 4.) plus further minor corrections and clarifications of the protocol

    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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