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    Clinical Trial Results:
    Copenhagen Head Injury Ciclosporin (CHIC) Study: An open-label, uncontrolled Phase II study to investigate pharmacokinetics, safety and biomarkers of efficacy of NeuroSTAT® (ciclosporin) in patients with severe traumatic brain injury (TBI)

    Summary
    EudraCT number
    		 2012-000756-34
    Trial protocol
    		 DK  
    Global end of trial date
    23 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jun 2018
    First version publication date
    07 Jun 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2012.001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01825044
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    NeuroVive Pharmaceutical AB
    Sponsor organisation address
    Medicon Village, Lund, Sweden, SE-223 81
    Public contact
    Dep. Clinical Trials & Reg. Affairs, NeuroVive Pharmaceutical AB, +46 763393147, matilda.hugerth@neurovive.com
    Scientific contact
    Dep. Clinical Trials & Reg. Affairs, NeuroVive Pharmaceutical AB, +46 763393147, matilda.hugerth@neurovive.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
    21 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To establish safety and to characterise the pharmacokinetic profile of two dosing regimens of ciclosporin in severe Traumatic Brain Injury (TBI) patients.
    Protection of trial subjects
    Patients were extensively monitored in the 5 day infusion period. After treatment there was a monitoring period at the intensive care unit of 3 days.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Sep 2012
    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
    Denmark: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Date of first enrollment: 03 June 2013 Date of last patient enrollment: 13 June 2016 Single study site in Denmark.

    Pre-assignment
    Screening details
    		 Male of female patients aged 18 to 75 years (inclusive) with severe TBI, who required intensive care unit admission and monitoring of intracranial pressure via a ventricular catheter. Clinical examination with post-resuscitation GCS of 4-8, inclusive.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ciclosporin 5 mg/kg/day
    Arm description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 5 mg/kg/day ciclosporin for 5 days + 3 days monitoring period, followed by 30 days follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NeuroSTAT® (ciclosporin)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NeuroSTAT® is a sterile intravenous ciclosporin lipid emulsion containing ciclosporin, 5 mg/ml emulsion for infusion. The novel vehicle formulation for ciclosporin is a well-known infusion emulsion, containing e.g. refined soya bean oil and purified structured triglyceride. It is based upon an EU registered and marketed product for parenteral nutrition, manufactured by Fresenius Kabi, Austria (LIPOVENOES® MCT 20%, approved presently in Germany, the Netherlands and Italy). Dosage: 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 5 mg/kg/day ciclosporin for 5 days + 3 days monitoring period, followed by 30 days follow-up period.

    Arm title
    		 Ciclosporin 10 mg/kg/day
    Arm description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 10 mg/kg/day ciclosporin for 5 days (n=10) + 3 days monitoring period, followed by a 30 days follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NeuroSTAT® (ciclosporin)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NeuroSTAT® is a sterile intravenous ciclosporin lipid emulsion containing ciclosporin, 5 mg/ml emulsion for infusion. The novel vehicle formulation for ciclosporin is a well-known infusion emulsion, containing e.g. refined soya bean oil and purified structured triglyceride. It is based upon an EU registered and marketed product for parenteral nutrition, manufactured by Fresenius Kabi, Austria (LIPOVENOES® MCT 20%, approved presently in Germany, the Netherlands and Italy). Dosage: 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 10 mg/kg/day ciclosporin for 5 days + 3 days monitoring period, followed by 30 days follow-up period.

    Number of subjects in period 1
    		Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Started
    10
    6
    Completed
    10
    6
    Period 2
    Period 2 title
    Treatment and Follow up
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ciclosporin 5 mg/kg/day
    Arm description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 5 mg/kg/day ciclosporin for 5 days + 3 days monitoring period, followed by 30 days follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NeuroSTAT®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    NeuroSTAT® is a sterile intravenous ciclosporin lipid emulsion containing ciclosporin, 5 mg/ml emulsion for infusion. The novel vehicle formulation for ciclosporin is a well-known infusion emulsion, containing e.g. refined soya bean oil and purified structured triglyceride. It is based upon an EU registered and marketed product for parenteral nutrition, manufactured by Fresenius Kabi, Austria (LIPOVENOES® MCT 20%, approved presently in Germany, the Netherlands and Italy). Dosage: 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 5 mg/kg/day ciclosporin for 5 days + 3 days monitoring period, followed by 30 days follow-up period.

    Arm title
    		 Ciclosporin 10 mg/kg/day
    Arm description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 10 mg/kg/day ciclosporin for 5 days (n=10) + 3 days monitoring period, followed by a 30 days follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NeuroSTAT®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    NeuroSTAT® is a sterile intravenous ciclosporin lipid emulsion containing ciclosporin, 5 mg/ml emulsion for infusion. The novel vehicle formulation for ciclosporin is a well-known infusion emulsion, containing e.g. refined soya bean oil and purified structured triglyceride. It is based upon an EU registered and marketed product for parenteral nutrition, manufactured by Fresenius Kabi, Austria (LIPOVENOES® MCT 20%, approved presently in Germany, the Netherlands and Italy). Dosage: 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 10 mg/kg/day ciclosporin for 5 days + 3 days monitoring period, followed by 30 days follow-up period.

    Number of subjects in period 2
    		Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Started
    10
    6
    Completed
    10
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ciclosporin 5 mg/kg/day
    Reporting group description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 5 mg/kg/day ciclosporin for 5 days + 3 days monitoring period, followed by 30 days follow-up period.

    Reporting group title
    Ciclosporin 10 mg/kg/day
    Reporting group description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 10 mg/kg/day ciclosporin for 5 days (n=10) + 3 days monitoring period, followed by a 30 days follow-up period.

    Reporting group values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day Total
    Number of subjects
    		 10 6 16
    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)
    		 10 6 16
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.50 ( 14.42 ) 37.33 ( 14.38 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 1 4
        Male
    		 7 5 12

    End points

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    End points reporting groups
    Reporting group title
    Ciclosporin 5 mg/kg/day
    Reporting group description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 5 mg/kg/day ciclosporin for 5 days + 3 days monitoring period, followed by 30 days follow-up period.

    Reporting group title
    Ciclosporin 10 mg/kg/day
    Reporting group description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 10 mg/kg/day ciclosporin for 5 days (n=10) + 3 days monitoring period, followed by a 30 days follow-up period.
    Reporting group title
    Ciclosporin 5 mg/kg/day
    Reporting group description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 5 mg/kg/day ciclosporin for 5 days + 3 days monitoring period, followed by 30 days follow-up period.

    Reporting group title
    Ciclosporin 10 mg/kg/day
    Reporting group description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 10 mg/kg/day ciclosporin for 5 days (n=10) + 3 days monitoring period, followed by a 30 days follow-up period.

    Primary: Adverse Events

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    End point title
    		 Adverse Events [1]
    End point description
    Total number of adverse events during treatment and after end of study drug administration (follow-up).
    End point type
    Primary
    End point timeframe
    During treatment and after end of study drug administration (follow-up).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Adverse Events
        Total No. of AEs
    69
    47
        Total No. of unique AEs
    65
    47
        Total No. of patients with at least 1 AE
    10
    6
        Total No. of unique related AEs
    8
    13
        Total No. of related AEs
    8
    13
        Total No. patients with at least 1 related AE
    4
    5
        Total No. of SAEs
    0
    1
        Total No. of patients with at least 1 SAE
    0
    1
        Total No. of patients with AE leading to discont.
    0
    1
    No statistical analyses for this end point

    Primary: Number of subjects with positive infectious symptom abnormalities

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    End point title
    		 Number of subjects with positive infectious symptom abnormalities [2]
    End point description
    Assessment of infections: abnormality assessed as Yes/No according to standard procedures at intensive care unit.
    End point type
    Primary
    End point timeframe
    From screening until Day 8.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Number of Subjects
        Screening/Enrolment
    0
    1
        Treatment, Day 2
    0
    0
        Treatment, Day 3
    0
    1
        Treatment, Day 4
    1
    2
        Treatment, Day 5
    0
    1
        Monitoring, Day 1
    0
    3
        Monitoring, Day 2
    2
    1
        Monitoring, Day 3
    1
    0
    No statistical analyses for this end point

    Primary: Intracranial pressure

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    End point title
    		 Intracranial pressure [3]
    End point description
    For intracranial pressure (ICP), several measurements were made each day. Post-baseline values within each patient were averaged within day before summary statistics were derived.
    End point type
    Primary
    End point timeframe
    From baseline (last observation before bolus dose).
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Observed values (mmHg)
    median (full range (min-max))
        Baseline
    8.0 (-1 to 22)
    16.0 (13 to 18)
        Treatment Day 1
    12.3 (2 to 18)
    14.8 (7 to 16)
        Treatment Day 2
    13.9 (2 to 19)
    13.5 (8 to 15)
        Treatment Day 3
    12.8 (1 to 23)
    12.1 (8 to 16)
        Treatment Day 4
    12.0 (4 to 19)
    15.0 (8 to 19)
        Treatment Day 5
    13.6 (10 to 19)
    11.6 (7 to 21)
        Monitoring Day 1
    14.6 (10 to 18)
    12.0 (1 to 17)
        Monitoring Day 2
    12.8 (3 to 21)
    12.8 (2 to 15)
        Monitoring Day 3
    12.7 (3 to 23)
    13.9 (12 to 15)
    No statistical analyses for this end point

    Primary: Markers of hepatic function-Alanine Aminotransferase

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    End point title
    		 Markers of hepatic function-Alanine Aminotransferase [4]
    End point description
    Blood samples were taken at protocol specified time points and alanine aminotransferase was assessed as a marker of hepatic function.
    End point type
    Primary
    End point timeframe
    Measurements made at, baseline, during the five days of treatment and until Day 3 following completion of treatment.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Observed Values (U/L)
    median (full range (min-max))
        Baseline
    89.0 (14 to 252)
    32.0 (18 to 83)
        Treatment Day 1
    41.0 (16 to 215)
    28.0 (17 to 47)
        Treatment Day 2
    36.0 (15 to 261)
    26.0 (15 to 43)
        Treatment Day 3
    46.5 (17 to 224)
    41.0 (15 to 63)
        Treatment Day 4
    48.5 (22 to 171)
    43 (21 to 81)
        Treatment Day 5
    67.0 (24 to 165)
    35.0 (21 to 78)
        Monitoring Day 1
    65.1 (26 to 145)
    34.0 (16 to 78)
        Monitoring Day 2
    64.0 (30 to 183)
    58.0 (26 to 110)
        Monitoring Day 3
    69.0 (28 to 159)
    66.5 (23 to 128)
    No statistical analyses for this end point

    Primary: Markers of hepatic function-Aspartate Aminotransferase

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    End point title
    		 Markers of hepatic function-Aspartate Aminotransferase [5]
    End point description
    Blood samples were taken at protocol specified time points and Aspartate Aminotransferase was assessed as a marker of hepatic function.
    End point type
    Primary
    End point timeframe
    Measurements made at, baseline, during the five days of treatment and until Day 3 following completion of treatment.
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Observed values (U/L)
    median (full range (min-max))
        Baseline
    143 (27 to 264)
    50.0 (22 to 89)
        Treatment Day 1
    42 (24 to 190)
    37.0 (32 to 75)
        Treatment Day 2
    31.5 (24 to 245)
    43.0 (30 to 76)
        Treatment Day 3
    35.5 (17 to 184)
    64.5 (42 to 109)
        Treatment Day 4
    51.5 (25 to 151)
    46.0 (28 to 99)
        Treatment Day 5
    73 (37 to 123)
    58.0 (20 to 128)
        Monitoring Day 1
    55.5 (32 to 134)
    50.0 (16 to 79)
        Monitoring Day 2
    66.5 (35 to 162)
    64.0 (33 to 124)
        Monitoring Day 3
    54.5 (26 to 163)
    56.0 (29 to 147)
    No statistical analyses for this end point

    Primary: Markers of hepatic function-Bilirubin

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    End point title
    		 Markers of hepatic function-Bilirubin [6]
    End point description
    Blood samples were taken at protocol specified time points and bilirubin was assessed as a marker of hepatic function.
    End point type
    Primary
    End point timeframe
    Measurements made at, baseline, during the five days of treatment and until Day 3 following completion of treatment.
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Observed values (umol/L)
    median (full range (min-max))
        Baseline
    8.0 (3 to 14)
    4.5 (3 to 22)
        Treatment Day 1
    11.0 (5 to 34)
    11.5 (7 to 24)
        Treatment Day 2
    14.5 (4 to 31)
    17.5 (8 to 36)
        Treatment Day 3
    16 (4 to 48)
    23.5 (9 to 101)
        Treatment Day 4
    20.0 (3 to 42)
    51.0 (8 to 106)
        Treatment Day 5
    15.0 (4 to 42)
    47.0 (6 to 117)
        Monitoring Day 1
    13.5 (3 to 35)
    55.0 (4 to 70)
        Monitoring Day 2
    10.0 (3 to 23)
    24.5 (3 to 36)
        Monitoring Day 3
    8.0 (4 to 19)
    16.5 (4 to 28)
    No statistical analyses for this end point

    Primary: Markers of hepatic function- Prothrombin INR

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    End point title
    		 Markers of hepatic function- Prothrombin INR [7]
    End point description
    Blood samples were taken at protocol specified time points and assessed for Prothrombin INR as a marker of hepatic function.
    End point type
    Primary
    End point timeframe
    Measurements made at, baseline, during the five days of treatment and until Day 3 following completion of treatment.
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Observed values
    median (full range (min-max))
        Baseline
    1.15 (1.0 to 1.5)
    1.15 (1.0 to 1.5)
        Treatment Day 1
    1.30 (1.1 to 1.5)
    1.15 (1.1 to 1.4)
        Treatment Day 2
    1.20 (1.1 to 1.3)
    1.15 (1.0 to 1.6)
        Treatment Day 3
    1.20 (1.1 to 1.3)
    1.25 (1.0 to 1.5)
        Treatment Day 4
    1.20 (1.1 to 1.4)
    1.20 (0.9 to 1.4)
        Treatment Day 5
    1.10 (1.0 to 1.2)
    1.20 (0.9 to 1.3)
        Monitoring Day 1
    1.10 (1.0 to 1.1)
    1.10 (0.9 to 1.3)
        Monitoring Day 2
    1.00 (1.0 to 1.2)
    1.10 (1.0 to 1.2)
        Monitoring Day 3
    1.00 (0.9 to 1.1)
    1.00 (1.0 to 1.0)
    No statistical analyses for this end point

    Primary: Markers of renal function - Creatinine

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    End point title
    		 Markers of renal function - Creatinine [8]
    End point description
    Blood samples were taken at protocol specified time points and assessed for creatinine as a marker of renal function.
    End point type
    Primary
    End point timeframe
    Measurements made at, baseline, during the five days of treatment and until Day 3 following completion of treatment.
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Observed values (umol/L)
    median (full range (min-max))
        Baseline
    62.0 (52 to 84)
    69.0 (38 to 108)
        Treatment Day 1
    68.0 (49 to 119)
    72.0 (54 to 100)
        Treatment Day 2
    69.5 (53 to 163)
    80.0 (61 to 104)
        Treatment Day 3
    70.5 (56 to 215)
    80.5 (52 to 192)
        Treatment Day 4
    70.5 (54 to 277)
    104.5 (51 to 296)
        Treatment Day 5
    67.5 (53 to 258)
    92.0 (47 to 267)
        Monitoring Day 1
    65.0 (50 to 250)
    105.0 (39 to 424)
        Monitoring Day 2
    54.5 (45 to 186)
    90.0 (40 to 327)
        Monitoring Day 3
    53.5 (37 to 108)
    65.5 (38 to 350)
    No statistical analyses for this end point

    Primary: Markers of renal function - Cystatin C

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    End point title
    		 Markers of renal function - Cystatin C [9]
    End point description
    Blood samples were taken at protocol specified time points and assessed for cystatin C as a marker of renal function.
    End point type
    Primary
    End point timeframe
    Measurements made at, baseline, during the five days of treatment and until Day 3 following completion of treatment.
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Observed values (mg/L)
    median (full range (min-max))
        Baseline
    0.66 (0.5 to 1.1)
    0.88 (0.8 to 1.4)
        Treatment Day 1
    0.90 (0.6 to 1.2)
    0.83 (0.6 to 1.5)
        Treatment Day 2
    0.86 (0.6 to 1.6)
    0.93 (0.8 to 1.2)
        Treatment Day 3
    0.86 (0.6 to 1.6)
    1.20 (1.0 to 1.7)
        Treatment Day 4
    0.96 (0.7 to 2.0)
    1.40 (1.1 to 2.6)
        Treatment Day 5
    1.00 (0.7 to 1.9)
    1.50 (1.0 to 2.9)
        Monitoring Day 1
    1.00 (0.7 to 2.1)
    1.40 (1.0 to 1.8)
        Monitoring Day 2
    1.00 (0.8 to 1.7)
    1.40 (1.4 to 1.4)
        Monitoring Day 3
    0.8 (0.7 to 1.7)
    1.10 (1.0 to 1.3)
    No statistical analyses for this end point

    Primary: Markers of renal function - Urea Nitrogen

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    End point title
    		 Markers of renal function - Urea Nitrogen [10]
    End point description
    Blood samples were taken at protocol specified time points and assessed for urea nitrogen as a marker of renal function.
    End point type
    Primary
    End point timeframe
    Measurements made at, baseline, during the five days of treatment and until Day 3 following completion of treatment.
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Observed values (mmol/L)
    median (full range (min-max))
        Baseline
    2.70 (2.1 to 4.6)
    4.10 (2.0 to 10.9)
        Treatment Day 1
    3.10 (1.5 to 5.2)
    3.80 (2.5 to 7.4)
        Treatment Day 2
    4.05 (2.5 to 7.4)
    5.10 (2.8 to 9.5)
        Treatment Day 3
    5.40 (3.3 to 9.0)
    8.00 (5.4 to 9.9)
        Treatment Day 4
    6.95 (3.8 to 13.1)
    11.00 (6.9 to 12.3)
        Treatment Day 5
    8.65 (5.3 to 18.1)
    11.90 (7.2 to 15.9)
        Monitoring Day 1
    9.40 (6.6 to 21.4)
    15.95 (7.4 to 24.6)
        Monitoring Day 2
    7.40 (4.6 to 16.7)
    13.60 (7.2 to 22.6)
        Monitoring Day 3
    5.95 (4.3 to 9.4)
    10.20 (6.6 to 27.2)
    No statistical analyses for this end point

    Primary: Clearance

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    End point title
    		 Clearance [11]
    End point description
    PK paramters were based on ciclosporin levels in blood. Clearance (CL), primary pharmacokinetic parameter of population pharmacokinetic analysis
    End point type
    Primary
    End point timeframe
    From start of bolus infusion to end of monitoring period (Day 8).
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: L/h
        arithmetic mean (standard deviation)
    24.3 ( 5.82 )
    24.6 ( 4.52 )
    No statistical analyses for this end point

    Primary: Volume of distribution of the central compartment

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    End point title
    		 Volume of distribution of the central compartment [12]
    End point description
    PK parameters based on ciclosporin levels in blood. Volume of distribution of the central compartment (Vc), primary pharmacokinetic parameter of population pharmacokinetic analysis.
    End point type
    Primary
    End point timeframe
    From start of bolus infusion to end of monitoring period (Day 8).
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Litres
        arithmetic mean (standard deviation)
    29.1 ( 46.3 )
    21.5 ( 7.19 )
    No statistical analyses for this end point

    Primary: The volume of distribution of the peripheral compartments

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    End point title
    		 The volume of distribution of the peripheral compartments [13]
    End point description
    PK parameters based on ciclosporin levels in blood. Volume of distribution of the peripheral compartment (Vp), primary pharmacokinetic parameter of population pharmacokinetic analysis. Vp1 is the first peripheral volume of distribution, Vp2 is the second peripheral volume of distribution
    End point type
    Primary
    End point timeframe
    From start of bolus infusion to end of monitoring period (Day 8).
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Litres
    arithmetic mean (standard deviation)
        Vp1
    46.9 ( 7.65 )
    50.5 ( 5.68 )
        Vp2
    373 ( 81.1 )
    398 ( 66.2 )
    No statistical analyses for this end point

    Primary: Mean concentration at steady state

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    End point title
    		 Mean concentration at steady state [14]
    End point description
    PK parameters based on ciclosporin levels in blood. Mean concentration at steady state Cav,ss = Dose rate/CL
    End point type
    Primary
    End point timeframe
    From start of bolus infusion to end of monitoring period (Day 8).
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: ng/mL
        arithmetic mean (standard deviation)
    665 ( 117 )
    1320 ( 279 )
    No statistical analyses for this end point

    Primary: The observed maximum plasma concentration after single dose administration

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    End point title
    		 The observed maximum plasma concentration after single dose administration [15]
    End point description
    PK parameters based on ciclosporin levels in blood: The observed maximum plasma concentration (Cmax) after single dose administration.
    End point type
    Primary
    End point timeframe
    From start of bolus infusion to end of monitoring period (Day 8).
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: ng/mL
        arithmetic mean (standard deviation)
    4420 ( 2350 )
    4930 ( 511 )
    No statistical analyses for this end point

    Primary: The time to reach Cmax

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    End point title
    		 The time to reach Cmax [16]
    End point description
    PK parameters based on ciclosporin levels in blood: Tmax, the time to reach Cmax.
    End point type
    Primary
    End point timeframe
    From start of bolus infusion to end of monitoring period (Day 8).
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Hours
        median (full range (min-max))
    0.250 (0.250 to 0.417)
    0.308 (0.250 to 0.417)
    No statistical analyses for this end point

    Primary: The area under the concentration vs. time curve

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    End point title
    		 The area under the concentration vs. time curve [17]
    End point description
    PK parameters based on ciclosporin levels in blood: Total area under the concentration curve vs. time curve (AUC) to infinity.
    End point type
    Primary
    End point timeframe
    From start of bolus infusion to end of monitoring period (Day 8).
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: mg.h/L
        arithmetic mean (standard deviation)
    87.5 ( 15.3 )
    155 ( 30.2 )
    No statistical analyses for this end point

    Primary: AUC to the last quantifiable concentration

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    End point title
    		 AUC to the last quantifiable concentration [18]
    End point description
    PK parameters based on ciclosporin levels in blood: AUC0-t, the area under the concentration vs. time curve from time zero to the last quantifiable concentration (Clast, obs).
    End point type
    Primary
    End point timeframe
    From start of bolus infusion to end of monitoring period (Day 8).
    Notes
    [18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: mg.h/L
        arithmetic mean (standard deviation)
    82.5 ( 12.6 )
    146 ( 29.2 )
    No statistical analyses for this end point

    Primary: Extrapolated area under the curve from t last to infinity

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    End point title
    		 Extrapolated area under the curve from t last to infinity [19]
    End point description
    PK parameters based on ciclosporin levels in blood: AUCextr, extrapolated area under the curve from t last to infinity.
    End point type
    Primary
    End point timeframe
    From start of bolus infusion to end of monitoring period (Day 8).
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Percent (%)
        arithmetic mean (standard deviation)
    5.10 ( 2.75 )
    5.88 ( 2.60 )
    No statistical analyses for this end point

    Primary: The apparent elimination half-life

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    End point title
    		 The apparent elimination half-life [20]
    End point description
    PK parameters based on ciclosporin levels in blood: t½ the apparent elimination half-life, calculated based on CL, Vc, Q, and Vp
    End point type
    Primary
    End point timeframe
    From start of bolus infusion to end of monitoring period (Day 8).
    Notes
    [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis for this endpoint. Only summary statistics are presented.
    End point values
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Number of subjects analysed
    10
    6
    Units: Hours
        arithmetic mean (standard deviation)
    43.5 ( 11.3 )
    46.0 ( 8.06 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the time of infusion start through end of Day 8.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Ciclosporin 5 mg/kg/day
    Reporting group description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 5 mg/kg/day ciclosporin for 5 days + 3 days monitoring period, followed by 30 days follow-up period.

    Reporting group title
    Ciclosporin 10 mg/kg/day
    Reporting group description
    		 2.5 mg/kg ciclosporin intravenous bolus dose infusion (given between 10 to 15 minutes) + continuous intravenous infusion of 10 mg/kg/day ciclosporin for 5 days (n=10) + 3 days monitoring period, followed by a 30 days follow-up period.

    Serious adverse events
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Renal and urinary disorders
    Renal tubular necrosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ciclosporin 5 mg/kg/day Ciclosporin 10 mg/kg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    6 / 6 (100.00%)
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Blood albumin decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine abnormal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    2
    Blood magnesium decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Blood phosphorus decreased
         subjects affected / exposed
    4 / 10 (40.00%)
    3 / 6 (50.00%)
         occurrences all number
    4
    3
    Blood potassium increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Blood urea increased
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    2
    Blood zinc decreased
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 6 (50.00%)
         occurrences all number
    3
    3
    Body temperature increased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Cystatin C increased
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 6 (33.33%)
         occurrences all number
    3
    2
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Myoglobin blood increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pupillary light reflex tests abnormal
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    1
    Platelet count increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 6 (66.67%)
         occurrences all number
    0
    4
    Blood calcium decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Intracranial pressure increased
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    1
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Face oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    8 / 10 (80.00%)
    5 / 6 (83.33%)
         occurrences all number
    9
    5
    Impaired gastric emptying
         subjects affected / exposed
    6 / 10 (60.00%)
    2 / 6 (33.33%)
         occurrences all number
    6
    2
    Subileus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 6 (83.33%)
         occurrences all number
    0
    5
    Renal tubular necrosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Candida infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 6 (50.00%)
         occurrences all number
    3
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Hypervolaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Nov 2013
    Change in inclusion criterion no 4: requirement to conduct a wake-up call to assess GCS score was removed.
    28 Aug 2014
    Change in inclusion criterion no 5 and change in study assessments.
    24 Sep 2015
    Change in inclusion criterion no 1, upper age limited increased from 65 to 75 years. Addition of exclusion criterion no 15.
    25 Jan 2016
    Microdialysis measurements of metabolic biomarkers and brain tissue oxygen measurements were made optional.

    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.
    It had been planned to include ten patients in the higher dose group but the study was prematurely closed due to slow recruitment.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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