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    Clinical Trial Results:
    A Prospective, randomized, single blind, multicenter Phase III study of organ perfusion with Custodiol-N solution compared with Custodiol solution in Heart transplantation

    Summary
    EudraCT number
    		 2012-001112-29
    Trial protocol
    		 DE   AT  
    Global end of trial date
    02 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2022
    First version publication date
    28 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL-N-HTX-CSM-III/04/12
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02869022
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dr. Franz Köhler Chemie GmbH
    Sponsor organisation address
    Werner-von – Siemens-Str. 14-28, Bensheim, Germany, 64625
    Public contact
    Dr. Roman Petrov, Dr. Franz Köhler Chemie GmbH, +49 625110830, r.petrov@koehler-chemie.de
    Scientific contact
    Dr. Roman Petrov, Dr. Franz Köhler Chemie GmbH, +49 625110830, r.petrov@koehler-chemie.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this investigation is to demonstrate non-inferiority in outcome of Custodiol-N against Custodiol in heart transplantation. CK-MB peak value from 4 to 168 hours after release of the aortic cross clamp (day 1: measurements 4, 8, 12, 16, 20, 24 hours ± 30 min; day 2-3: measurements 8, 16 and 24 hours ± 2 hours; day 4-7 one time/day).
    Protection of trial subjects
    Adverse events were documented systematically.
    Background therapy
    		 -
    Evidence for comparator
    		 Custodiol is in use in many cardiac centres throughout the world for the indication heart transplantation.
    Actual start date of recruitment
    01 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 60
    Country: Number of subjects enrolled
    Germany: 45
    Worldwide total number of subjects
    105
    EEA total number of subjects
    105
    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)
    104
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study population was recruited patients on the waiting list for heart transplantation.

    Pre-assignment
    Screening details
    		 Patients (organ recipients) were screened for inclusion and exclusion criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Custodiol ®
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Custodiol ®
    Investigational medicinal product code
    B05XA16
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The perfusion of the donor heart with 2° - 8° C cold Custodiol-N / Custodiol ® was be performed for a minimum of 7 minutes. After mobilisation and appropriate preparation of heart and blood vessels and clamping of the aorta, perfusion with 4 litres of Custodiol-N / Custodiol ® was started via aorta. In case of donor lung explantation, separate perfusion of the lungs was ensured to avoid the perfusion of the lungs with the study medication.

    Arm title
    		 Custodiol-N
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Custodiol-N
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The perfusion of the donor heart with 2° - 8° C cold Custodiol-N / Custodiol ® was be performed for a minimum of 7 minutes. After mobilisation and appropriate preparation of heart and blood vessels and clamping of the aorta, perfusion with 4 litres of Custodiol-N / Custodiol ® was started via aorta. In case of donor lung explantation, separate perfusion of the lungs was ensured to avoid the perfusion of the lungs with the study medication.

    Number of subjects in period 1
    		Custodiol ® Custodiol-N
    Started
    52
    53
    Completed
    52
    52
    Not completed
    0
    1
         Adverse event, serious fatal
    -
    1

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Custodiol ®
    Reporting group description
    		 -

    Reporting group title
    Custodiol-N
    Reporting group description
    		 -

    Primary: CK-MB peak value (FAS)

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    End point title
    		 CK-MB peak value (FAS)
    End point description
    Full analysis set
    End point type
    Primary
    End point timeframe
    4 to 168 hours after release of the aortic cross clamp (day 1: measurements 4, 8, 12, 16, 20, 24 hours ± 30 min; day 2-3: measurements 8, 16 and 24 hours ± 2 hours; day 4-7 one time/day)
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    52
    53
    Units: U/L
        arithmetic mean (standard deviation)
    176.94 ( 189.61 )
    130.51 ( 69.60 )
    Statistical analysis title
    		 CK-MB peak value (FAS)
    Comparison groups
    Custodiol ® v Custodiol-N
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 log-linear
    Confidence interval
    Notes
    [1] - The main analysis of 24h peak value was done as quasi-Poisson regression (log-linear family) with treatment group, age and study site as explanatory factors.
    [2] - Noninferiority of Custodiol-N by 30%. Overall treatment effect in the FAS was 0.764 (95% confidence interval of a treatment effect [0.672; 0.931]).

    Primary: CK-MB peak value (PP)

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    End point title
    		 CK-MB peak value (PP)
    End point description
    End point type
    Primary
    End point timeframe
    4 to 168 hours after release of the aortic cross clamp (day 1: measurements 4, 8, 12, 16, 20, 24 hours ± 30 min; day 2-3: measurements 8, 16 and 24 hours ± 2 hours; day 4-7 one time/day)
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    45
    41
    Units: U/L
        arithmetic mean (standard deviation)
    178.17 ( 202.41 )
    136.29 ( 70.72 )
    Statistical analysis title
    		 CK-MB peak value
    Statistical analysis description
    CK-MB peak value within 168 h from opening of acortic cross clamp
    Comparison groups
    Custodiol ® v Custodiol-N
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001 [3]
    Method
    		 log-linear model
    Confidence interval
    Notes
    [3] - 1-sided p-value for noninferiority to 30 per cent

    Secondary: Catecholamine requirement, defined as “yes” or “no”

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    End point title
    		 Catecholamine requirement, defined as “yes” or “no”
    End point description
    End point type
    Secondary
    End point timeframe
    4 - 168 h after opening of aortic cross clamp
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    52
    53
    Units: Patients
        Catecholamins 'yes'
    52
    53
        Catecholamins 'no'
    0
    0
    No statistical analyses for this end point

    Secondary: Patient survival at 7 days and 1, 3 and 12 months

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    End point title
    		 Patient survival at 7 days and 1, 3 and 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    at 7 days and 1, 3 and 12 months from surgery
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    52
    53
    Units: Patients
        7 days
    51
    53
        1 month
    51
    53
        3 months
    50
    53
        12 months
    47
    47
    No statistical analyses for this end point

    Secondary: Complications

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    End point title
    		 Complications
    End point description
    Retransplantation was reported under the endpoint 'primary poor function', procedural complications were reported under 'adverse events'.
    End point type
    Secondary
    End point timeframe
    From transplantation to day 7 after surgery
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    52
    53
    Units: Patients with complications
    42
    39
    No statistical analyses for this end point

    Secondary: Length of ICU stay

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    End point title
    		 Length of ICU stay
    End point description
    Duration in days as difference between end and start date.
    End point type
    Secondary
    End point timeframe
    After surgery until end of ICU stay
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    50
    52
    Units: days
        median (inter-quartile range (Q1-Q3))
    10.0 (6 to 19)
    8.0 (5 to 11.5)
    No statistical analyses for this end point

    Secondary: Requirement of IABP

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    End point title
    		 Requirement of IABP
    End point description
    End point type
    Secondary
    End point timeframe
    From end of surgery to day 7 after surgery
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    52
    53
    Units: Patients
    5
    3
    No statistical analyses for this end point

    Secondary: Ejection fraction

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    End point title
    		 Ejection fraction
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 and day 7 after transplantation
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    41 [4]
    41 [5]
    Units: percent volume/volume
    arithmetic mean (standard deviation)
        Day 1
    52.61 ( 11.82 )
    55.40 ( 11.19 )
        Day 7
    53.76 ( 14.46 )
    53.71 ( 9.85 )
    Notes
    [4] - day 1 n=41 day7 n=38
    [5] - day 1 n=40 day 7 n=41
    No statistical analyses for this end point

    Secondary: Cardiac index

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    End point title
    		 Cardiac index
    End point description
    End point type
    Secondary
    End point timeframe
    6h/12h/18h/24h after opening of the aortic cross clamp
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    34 [6]
    40 [7]
    Units: liter/min/m²
    arithmetic mean (standard deviation)
        6h
    2.70 ( 0.73 )
    3.11 ( 1.01 )
        12h
    2.61 ( 0.84 )
    3.27 ( 0.82 )
        18h
    2.69 ( 0.76 )
    3.16 ( 0.85 )
        24h
    2.87 ( 0.77 )
    3.05 ( 0.74 )
    Notes
    [6] - 6h n=26 12h n=28 18h n=33 24h n=34
    [7] - 6h n=32 12h n=39 18h n=38 24h n=40
    No statistical analyses for this end point

    Secondary: Enddiastolic ventricle volumes

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    End point title
    		 Enddiastolic ventricle volumes
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 and day 7 after transplantation
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    30 [8]
    29 [9]
    Units: mL
    arithmetic mean (standard deviation)
        Day 1
    78.10 ( 39.93 )
    81.21 ( 29.75 )
        Day 7
    82.15 ( 37.88 )
    92.74 ( 31.57 )
    Notes
    [8] - Number of subjects: Day 1 n = 30, day 7 n = 27
    [9] - Number of subjects: Day 1 n=29 Day 7 n= 27
    No statistical analyses for this end point

    Secondary: Endsystolic ventricle volumes

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    End point title
    		 Endsystolic ventricle volumes
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 and day 7 after transplantation
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    28
    30
    Units: mL
    arithmetic mean (standard deviation)
        Day 1
    37.27 ( 18.93 )
    38.79 ( 19.86 )
        Day 7
    40.15 ( 23.40 )
    43.56 ( 17.07 )
    No statistical analyses for this end point

    Secondary: Primary poor function

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    End point title
    		 Primary poor function
    End point description
    Need for assist device and retransplantation
    End point type
    Secondary
    End point timeframe
    Until day 7 after transplantation
    End point values
    		 Custodiol ® Custodiol-N
    Number of subjects analysed
    52
    53
    Units: Patients with primary poor function
        Need for assist device
    11
    5
        retransplantation
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From transplantation to day 7
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Custodiol® safety data set
    Reporting group description
    		 -

    Reporting group title
    Custodiol-N safety data set
    Reporting group description
    		 -

    Serious adverse events
    		 Custodiol® safety data set Custodiol-N safety data set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 52 (40.38%)
    15 / 53 (28.30%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Investigations
    Investigations
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    7 / 52 (13.46%)
    5 / 53 (9.43%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    5 / 52 (9.62%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    4 / 52 (7.69%)
    8 / 53 (15.09%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    1 / 52 (1.92%)
    5 / 53 (9.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Custodiol® safety data set Custodiol-N safety data set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 52 (88.46%)
    46 / 53 (86.79%)
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    8 / 52 (15.38%)
    3 / 53 (5.66%)
         occurrences all number
    8
    3
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    5 / 52 (9.62%)
    8 / 53 (15.09%)
         occurrences all number
    7
    11
    Blood and lymphatic system disorders
    Blood and lymphatic disorders
         subjects affected / exposed
    15 / 52 (28.85%)
    18 / 53 (33.96%)
         occurrences all number
    24
    23
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    7 / 52 (13.46%)
    9 / 53 (16.98%)
         occurrences all number
    7
    10
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    12 / 52 (23.08%)
    12 / 53 (22.64%)
         occurrences all number
    12
    12
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    11 / 52 (21.15%)
    7 / 53 (13.21%)
         occurrences all number
    11
    7
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    2 / 52 (3.85%)
    5 / 53 (9.43%)
         occurrences all number
    2
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Feb 2019
    Patient number increased from 90 to 105

    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
    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
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