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    Clinical Trial Results:
    A Prospective Randomized Double Blind Multicenter Phase III Study Comparing two Methods of Cardioplegia in Aortic Valve Surgery Custodiol-N versus Custodiol

    Summary
    EudraCT number
    		 2012-003776-40
    Trial protocol
    		 DE  
    Global end of trial date
    06 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2022
    First version publication date
    28 Apr 2022
    Other versions
    Summary report(s)
    		 CSRCustodiol-N_AVS

    Trial information

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    Trial identification
    Sponsor protocol code
    CL-N-CSM-AV-III/05/12
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02098772
    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
    04 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this investigation is to compare the cardioprotective effects and safety of two cardioplegic solutions, Custodiol and Custodiol-N in patients undergoing aortic valve surgery +/- bypass surgery.
    Protection of trial subjects
    Patients were monitored for adverse events. Safety laboratory examinations were performed according to protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2014
    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: 530
    Worldwide total number of subjects
    530
    EEA total number of subjects
    530
    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)
    169
    From 65 to 84 years
    359
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 To obtain a sample for analysis per protocol of 394 patients a total of 530 patients with aortic valve disease was scheduled to be enrolled. One patient included did not receive treatment at all, one other patient received not the treatment randomised to.

    Pre-assignment
    Screening details
    		 The study population was selected from patients of either sex who were to undergo surgery for aortic valve replacement (with or without coronary bypass surgery).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Custodiol
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Custodiol
    Investigational medicinal product code
    B05CX10
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    During aortic valve surgery, after cross clamping of the aorta on cardiopulmonary bypass, the Custodiol® or Custodiol-N solution, was infused into the root of the aorta at a temperature of 4 - 6°C.

    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
    During aortic valve surgery, after cross clamping of the aorta on cardiopulmonary bypass, the Custodiol® or Custodiol-N solution, was infused into the root of the aorta at a temperature of 4 - 6°C.

    Number of subjects in period 1
    		Custodiol Custodiol-N
    Started
    265
    265
    Completed
    265
    263
    Not completed
    0
    2
         Adverse event, serious fatal
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 This reporting group equals the full analysis data set

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 530 530
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 168 168
        From 65-84 years
    		 360 360
        85 years and over
    		 2 2
    Gender categorical
    Units: Subjects
        Female
    		 181 181
        Male
    		 349 349

    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
    		 -

    Subject analysis set title
    Custodiol per protocol analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol analysis set: 205 patients for the Custodiol® group and 206 for the Custodiol-N group.

    Subject analysis set title
    Custodiol-N per protocol analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol analysis set: 205 patients for the Custodiol® group and 206 for the Custodiol-N group.

    Primary: Peak CK-MB value

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    End point title
    		 Peak CK-MB value
    End point description
    End point type
    Primary
    End point timeframe
    CK-MB peak value from 4 to 24 hours (measurements 4, 8, 12, 16, 20, 24 hours ± 30 min) after release of the aortic cross clamp.
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    263
    Units: Units
        arithmetic mean (standard deviation)
    65.1 ( 110.7 )
    58.1 ( 38.2 )
    Statistical analysis title
    		 CK-MB peak value (full analysis set)
    Statistical analysis description
    Primary analysis was performed taking the logarithm of 4h-24h-peak CK-MB values as primary endpoint. The null hypothesis was: “No effect of Custodiol-N over Custodiol® with respect to CKMB peak value”.
    Comparison groups
    Custodiol v Custodiol-N
    Number of subjects included in analysis
    528
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.4815
    Method
    		 likelyhood ratio test (5% level)
    Confidence interval
    Notes
    [1] - Likelihood ratio test +at the 5 per cent level of the treatment group parameter in a linear model. Missing log (CK-MB) values were handled by multiple imputation before deriving peak values.

    Primary: Peak CK-MB (per protocol set)

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    End point title
    		 Peak CK-MB (per protocol set)
    End point description
    End point type
    Primary
    End point timeframe
    Within 24 h from opening of aortic cross clamp
    End point values
    		 Custodiol per protocol analysis set Custodiol-N per protocol analysis set
    Number of subjects analysed
    205
    206
    Units: U/L
        arithmetic mean (standard deviation)
    59.6 ( 42.7 )
    58.4 ( 38.6 )
    Statistical analysis title
    		 CK-MB 24h peak value (per protocol data set)
    Comparison groups
    Custodiol-N per protocol analysis set v Custodiol per protocol analysis set
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9122
    Method
    		 likelihood ratio test (5% level)
    Confidence interval

    Secondary: Adrenaline requirement on SICU within 24 hours (cumulative dose)

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    End point title
    		 Adrenaline requirement on SICU within 24 hours (cumulative dose)
    End point description
    Values provided for full analysis set
    End point type
    Secondary
    End point timeframe
    Within 24 h after opening of aortic cross clamp
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    263
    262
    Units: µg/kg body mass
        arithmetic mean (standard deviation)
    3.88 ( 35.57 )
    9.04 ( 78.24 )
    No statistical analyses for this end point

    Secondary: Dobutamine requirement on SICU within 24 hours (cumulative dose)

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    End point title
    		 Dobutamine requirement on SICU within 24 hours (cumulative dose)
    End point description
    Data for full analysis set provided.
    End point type
    Secondary
    End point timeframe
    Within 24 h following oopening of aortic cross clamp.
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    263
    262
    Units: µg/kg body mass
        arithmetic mean (standard deviation)
    3.88 ( 35.57 )
    9.04 ( 78.24 )
    No statistical analyses for this end point

    Secondary: Noradrenaline requirement on SICU within 24 hours (cumulative dose)

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    End point title
    		 Noradrenaline requirement on SICU within 24 hours (cumulative dose)
    End point description
    Values for full analysis set provided. Data in the Custodiol-N group were distorted by one single patient for whom a dose of 317 mg per kg body weight were documented.
    End point type
    Secondary
    End point timeframe
    Within 24 h after opening of aortic cross clamp.
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    264
    260
    Units: µg/kg body mass
        arithmetic mean (standard deviation)
    75.81 ( 380.37 )
    842.46 ( 9811.41 )
    No statistical analyses for this end point

    Secondary: 5-day peak value of Troponin-T

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    End point title
    		 5-day peak value of Troponin-T
    End point description
    Due to a confusion of the unit there was one single peak value of 841000 pg/mL in the Custodiol-N group, after removing this single value, the mean value for the remaining group was 1271.3 pg/mL.
    End point type
    Secondary
    End point timeframe
    4, 8, 12, 16, 20, 24 hours ± 30 min and on the days 2, 3, 4 and 5 after release of the aortic cross clamp
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    263
    Units: pg/mL
        arithmetic mean (standard deviation)
    1227.4 ( 1262.7 )
    4465.4 ( 51796.4 )
    No statistical analyses for this end point

    Secondary: CK-MB area under the curve

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    End point title
    		 CK-MB area under the curve
    End point description
    End point type
    Secondary
    End point timeframe
    Between 4 and 24 hours after removal of the aortic cross-clamp
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    263
    Units: area under curve
        arithmetic mean (standard deviation)
    1009.5 ( 1199.6 )
    924.08 ( 593.61 )
    No statistical analyses for this end point

    Secondary: Troponin T area under the curve

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    End point title
    		 Troponin T area under the curve
    End point description
    End point type
    Secondary
    End point timeframe
    Between 4 and 24 hours after removal of the aortic cross-clamp
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    263
    Units: area under the curve
        arithmetic mean (standard deviation)
    16020 ( 14870 )
    64972 ( 796589 )
    No statistical analyses for this end point

    Secondary: Need of defibrillation

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    End point title
    		 Need of defibrillation
    End point description
    End point type
    Secondary
    End point timeframe
    Up to day 5 after opening of aortic cross clamp.
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    261
    Units: patients needing defibrillations
        0 defibrillations needed
    256
    252
        1 defibrillation needed
    7
    7
        2 defibrillations needed
    1
    1
        3 defibrillations needed
    0
    1
        4 defibrillations needed
    1
    0
    No statistical analyses for this end point

    Secondary: Requirement for intraaortic ball pump treatment (IABP)

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    End point title
    		 Requirement for intraaortic ball pump treatment (IABP)
    End point description
    End point type
    Secondary
    End point timeframe
    Within 5 days from surgery
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    263
    Units: patients needing IABP
    1
    2
    No statistical analyses for this end point

    Secondary: Blood pressure

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    End point title
    		 Blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Within 5 days from surgery
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    263
    Units: mmHg
    arithmetic mean (standard deviation)
        systolic
    135.8 ( 18.8 )
    136.5 ( 19.4 )
        diastolic
    77.0 ( 11.3 )
    77.2 ( 10.9 )
    No statistical analyses for this end point

    Secondary: Length of surgical intensive care unit (SICU) stay

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    End point title
    		 Length of surgical intensive care unit (SICU) stay
    End point description
    End point type
    Secondary
    End point timeframe
    Following surgery
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    262
    Units: days
        arithmetic mean (standard deviation)
    2.6 ( 3.8 )
    2.4 ( 4.2 )
    No statistical analyses for this end point

    Secondary: Duration of mechanical ventilation (intubation to extubation)

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    End point title
    		 Duration of mechanical ventilation (intubation to extubation)
    End point description
    The duration 24 h and 4 min was displayed as 24.67h; 27 h 55 min as 27.92h.
    End point type
    Secondary
    End point timeframe
    Following surgery
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    264
    261
    Units: hours
        arithmetic mean (standard deviation)
    24.67 ( 31.7 )
    27.92 ( 54.52 )
    No statistical analyses for this end point

    Secondary: Occurrence of cardiac arrhythmias

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    End point title
    		 Occurrence of cardiac arrhythmias
    End point description
    End point type
    Secondary
    End point timeframe
    Within 5 days after surgery
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    263
    Units: arrhythmias
        no arrhythmia
    168
    159
        1 episode of arhythmia
    72
    73
        2 episodes
    17
    20
        3 episodes
    4
    4
        4 episodes
    2
    5
        5 episodes
    2
    2
    No statistical analyses for this end point

    Secondary: Repeated patient transfer to intensive care unit

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    End point title
    		 Repeated patient transfer to intensive care unit
    End point description
    End point type
    Secondary
    End point timeframe
    Within 6 days after surgery
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    263
    Units: number of patients
    2
    5
    No statistical analyses for this end point

    Secondary: Mortality

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    End point title
    		 Mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Within 30 days from surgery
    End point values
    		 Custodiol Custodiol-N
    Number of subjects analysed
    265
    263
    Units: number of fatalities
    4
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    30 days from surgery
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Custodiol saftey data set
    Reporting group description
    		 One patient randomised to Custodiol-N received Custodiol instead and was excluded from efficacy analysis. However, for safety analysis, this patient was analysed in the Custodiol-group

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

    Serious adverse events
    		 Custodiol saftey data set Custodiol-N safety data set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    34 / 266 (12.78%)
    28 / 263 (10.65%)
         number of deaths (all causes)
    4
    3
         number of deaths resulting from adverse events
    2
    1
    Investigations
    Investigations
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    4 / 266 (1.50%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 266 (0.38%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    9 / 266 (3.38%)
    12 / 263 (4.56%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
    Additional description: One fatality in the Cutodiol-N group was documented as cerebral infarction.
         subjects affected / exposed
    3 / 266 (1.13%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    3 / 266 (1.13%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Custodiol saftey data set Custodiol-N safety data set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    241 / 266 (90.60%)
    248 / 263 (94.30%)
    Investigations
    Investigations
         subjects affected / exposed
    79 / 266 (29.70%)
    83 / 263 (31.56%)
         occurrences all number
    162
    151
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    70 / 266 (26.32%)
    67 / 263 (25.48%)
         occurrences all number
    88
    85
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    56 / 266 (21.05%)
    41 / 263 (15.59%)
         occurrences all number
    63
    43
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    114 / 266 (42.86%)
    136 / 263 (51.71%)
         occurrences all number
    168
    194
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    91 / 266 (34.21%)
    91 / 263 (34.60%)
         occurrences all number
    124
    128
    General disorders and administration site conditions
    General disorders and administrations site conditions
         subjects affected / exposed
    42 / 266 (15.79%)
    41 / 263 (15.59%)
         occurrences all number
    51
    47
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    45 / 266 (16.92%)
    41 / 263 (15.59%)
         occurrences all number
    62
    54
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    190 / 266 (71.43%)
    183 / 263 (69.58%)
         occurrences all number
    325
    321
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    70 / 266 (26.32%)
    61 / 263 (23.19%)
         occurrences all number
    78
    67
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    18 / 266 (6.77%)
    17 / 263 (6.46%)
         occurrences all number
    18
    17
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    22 / 266 (8.27%)
    13 / 263 (4.94%)
         occurrences all number
    22
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2014
    New formulation of IMP
    13 May 2015
    Specification trial medication, new risk assessment
    21 Apr 2016
    Changes in protocol (resulted in version 22.03.2016) following updated IB (version 04-2016)
    09 Jan 2017
    Increase number of patients
    16 Nov 2017
    change of time for perfusion of the heart

    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
    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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