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    Clinical Trial Results:
    A Single-Centre, Single Blind, Randomized, Active-Controlled Phase III Non-Inferiority Study to Investigate the Safety and Efficacy of the Cardioplegic Solution Cardioplexol when used during a Cardiac Surgical Intervention under the Assistance of a Heart-Lung Machine

    Summary
    EudraCT number
    		 2011-004198-10
    Trial protocol
    		 AT  
    Global end of trial date
    03 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Oct 2016
    First version publication date
    13 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SCT-Cpx-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swiss Cardio Technologies AG
    Sponsor organisation address
    Kehrsitenstrasse 2, Stansstad, Switzerland, 6362
    Public contact
    Hendrik Tevaearai, Swiss Cardio Technologies AG, 41 763804835, hendrik.tevaearai@swisscardiotech.com
    Scientific contact
    Hendrik Tevaearai, Swiss Cardio Technologies AG, 41 763804835, hendrik.tevaearai@swisscardiotech.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
    03 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To explore the effects of CardioplexolTM on the protection of cardiac cells during the “ischemic” period in order to allow a rapid and complete reversibility of the cardiac arrest when used during a cardiac surgical intervention under the assistance of a heart-lung machine.
    Protection of trial subjects
    The study was conducted in compliance with the ethical principals derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practise (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 Cardioplexol TM was compared to a blood cardioplegia approach as originally described by Buckberg. Blood cardioplegia is considered as a reference worldwide, and served as a comparator in this study.
    Actual start date of recruitment
    29 May 2012
    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
    Austria: 264
    Worldwide total number of subjects
    264
    EEA total number of subjects
    264
    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)
    101
    From 65 to 84 years
    163
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment territory: Austria Recruitment period: approx. 3 years Every patient who was a candidate for an elective surgical cardiac procedure was considered to be included in the current study, providing the operation was being performed via a full sternotomy and under cardiac arrest and assistance of an extra corporeal circulation.

    Pre-assignment
    Screening details
    		 It was anticipated that 260 patients would need to be screened in order to randomize and to achieve 240 completed patients (120 per treatment group). The actual patient number screened was 280. Patients who satisfied all inclusion and no exclusion criteria were randomly assigned to one of the 2 groups “Cardioplexol™” or “Buckberg” (ratio 1:1).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    not relevant

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cardioplexol (Group 1)
    Arm description
    		 After randomisation the patients underwent cardiac surgery and received the necessary volume of Cardioplexol. The necessary volume is the volume needed for cardiac arrest, which is a prerequisite for the cardiac surgery. After the cardiac arrest was achieved the patients received further doses whose number and volume depended on the duration of the cardiac surgery as well as individual factors.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cardioplexol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for cardioplegia
    Routes of administration
    Intracardiac use
    Dosage and administration details
    Administration of one single dose (100 ml) of Cardioplexol (TM). Further Cardioplexol (TM) was applied in regular intervals depending on the duration of the cardiac surgery as well as individual factors.

    Arm title
    		 Buckberg (Group 2)
    Arm description
    		 After randomisation the patients underwent cardiac surgery and received the necessary volume of Buckberg blood cardioplegia. The necessary volume is the volume needed for cardiac arrest, which is a prerequisite for the cardiac surgery. Buckberg cardioplegia consists of a cold induction solution, a cold reinfusion solution and a warm reinfusion solution (hot shot). One patient withdrew his consent shortly before surgery and was excluded from the analysis.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Buckberg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for cardioplegia
    Routes of administration
    Intracardiac use
    Dosage and administration details
    Buckberg blood cardioplegia consists of a cold induction solution for the cold induction of the cardioplegic arrest, a cold reinfusion solution for the repeated infusions every 20 minutes and a warm reinfusion solution (hot shot) for the infusion immediately before the aorta unclamping.

    Number of subjects in period 1
    		Cardioplexol (Group 1) Buckberg (Group 2)
    Started
    132
    132
    Completed
    117
    124
    Not completed
    15
    8
         Adverse event, serious fatal
    1
    5
         not operated under study protocol
    13
    3
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cardioplexol (Group 1)
    Reporting group description
    		 After randomisation the patients underwent cardiac surgery and received the necessary volume of Cardioplexol. The necessary volume is the volume needed for cardiac arrest, which is a prerequisite for the cardiac surgery. After the cardiac arrest was achieved the patients received further doses whose number and volume depended on the duration of the cardiac surgery as well as individual factors.

    Reporting group title
    Buckberg (Group 2)
    Reporting group description
    		 After randomisation the patients underwent cardiac surgery and received the necessary volume of Buckberg blood cardioplegia. The necessary volume is the volume needed for cardiac arrest, which is a prerequisite for the cardiac surgery. Buckberg cardioplegia consists of a cold induction solution, a cold reinfusion solution and a warm reinfusion solution (hot shot). One patient withdrew his consent shortly before surgery and was excluded from the analysis.

    Reporting group values
    		 Cardioplexol (Group 1) Buckberg (Group 2) Total
    Number of subjects
    		 132 132 264
    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)
    		 48 53 101
        From 65-84 years
    		 84 79 163
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 69 (39 to 80) 68 (34 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 47 33 80
        Male
    		 85 99 184
    Logistic EURO Score
    method of calculating predicted operative mortality for patients undergoing cardiac surgery
    Units: calculated points
        median (inter-quartile range (Q1-Q3))
    		 2.4 (1.4 to 4) 2.5 (1.5 to 4.1) -

    End points

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    End points reporting groups
    Reporting group title
    Cardioplexol (Group 1)
    Reporting group description
    		 After randomisation the patients underwent cardiac surgery and received the necessary volume of Cardioplexol. The necessary volume is the volume needed for cardiac arrest, which is a prerequisite for the cardiac surgery. After the cardiac arrest was achieved the patients received further doses whose number and volume depended on the duration of the cardiac surgery as well as individual factors.

    Reporting group title
    Buckberg (Group 2)
    Reporting group description
    		 After randomisation the patients underwent cardiac surgery and received the necessary volume of Buckberg blood cardioplegia. The necessary volume is the volume needed for cardiac arrest, which is a prerequisite for the cardiac surgery. Buckberg cardioplegia consists of a cold induction solution, a cold reinfusion solution and a warm reinfusion solution (hot shot). One patient withdrew his consent shortly before surgery and was excluded from the analysis.

    Primary: Max values of Trop-T during the first 24h following myocardial perfusion ITT

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    End point title
    		 Max values of Trop-T during the first 24h following myocardial perfusion ITT
    End point description
    Based on the data from published literature, max. of troponin T values was determined as a suitable primary endpoint reflecting a clear benefit for the patient. Measurements to evaluate maximal value of troponin-T were performed at 6, 12, and 24 hours following myocardial reperfusion. Continuous endpoints are analysed by a Student’s t-test on the log-scale and in the ITT population.
    End point type
    Primary
    End point timeframe
    first 24 hours following myocardial perfusion
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: ng/ml
        geometric mean (confidence interval 95%)
    0.83 (0.73 to 0.93)
    0.78 (0.7 to 0.87)
    Statistical analysis title
    		 Cpx vs BB: max Troponin T during first 24h (ITT)
    Statistical analysis description
    The primary endpoint was compared between the treatment groups by a Student’s t-test. The analysis was performed on the log-transformed values. A two-sided 95% confidence interval for the difference on the log scale (Cardioplexol-Buckberg) was calculated and then back transformed (anti log) to give a 95% confidence interval for ratio of means. The max value was calculated from the remaining Trop T values if 1 or 2 values were missing. If no values were available, multiple imputation was used.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.49
    Method
    		 t-test, 2-sided
    Parameter type
    		 geometric mean ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.25
    Notes
    [1] - Pre-defined non-inferiority margin was 1.20 for the upper limit of the 95% confidence interval of the geometric mean ratio. For the primary endpoint both ITT and PP Analysis were considered equally important.

    Primary: Max values of Trop-T during the first24h following myocardial perfusion PP

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    End point title
    		 Max values of Trop-T during the first24h following myocardial perfusion PP
    End point description
    Based on the data from published literature, max. of troponin T values was determined as a suitable primary endpoint reflecting a clear benefit for the patient. Measurements to evaluate maximal value of troponin-T were performed at 6, 12, and 24 hours following myocardial reperfusion. Continuous endpoints are analysed by a Student’s t-test on the log-scale and in the PP population.
    End point type
    Primary
    End point timeframe
    first 24 hours following myocardial perfusion
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    100
    126
    Units: ng/ml
        geometric mean (confidence interval 95%)
    0.77 (0.69 to 0.86)
    0.78 (0.7 to 0.87)
    Statistical analysis title
    		 Cpx vs BB: max Troponin T during first 24h (PP)
    Statistical analysis description
    The primary endpoint was compared between the treatment groups by a Student’s t-test. The analysis was performed on the log-transformed values. A two-sided 95% confidence interval for the difference on the log scale (Cardioplexol-Buckberg) was calculated and then back transformed (anti log) to give a 95% confidence interval for ratio of means. The max value was calculated from the remaining Trop T values if 1 or 2 values were missing. If no values were available, multiple imputation was used.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.87
    Method
    		 t-test, 2-sided
    Parameter type
    		 geometric mean ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.16
    Notes
    [2] - Pre-defined non-inferiority margin was 1.20 for the upper limit of the 95% confidence interval of the geometric mean ratio. For the primary endpoint both ITT and PP Analysis were considered equally important.

    Secondary: Max value of CK-MB during the first 24h following myocardial perfusion

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    End point title
    		 Max value of CK-MB during the first 24h following myocardial perfusion
    End point description
    CK-MB is related to the primary endpoint troponin-T and was therefore chosen as the key secondary endpoint. Maximal value of CK-MB was analysed using a Student’s t-test on the log-scale in the ITT population. Max. values of CK-MB Levels were measured at 3, 6, 12 and 24h following myocardial perfusion.
    End point type
    Secondary
    End point timeframe
    first 24 hours following myocardial perfusion
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: U/l
        geometric mean (confidence interval 95%)
    56.4 (50 to 63)
    53.8 (49.2 to 58.8)
    Statistical analysis title
    		 Cpx vs BB: max CK-MB during first 24h
    Statistical analysis description
    Maximal value of CK-MB was analysed using a Student’s t-test on the log-scale. A two-sided 95% confidence interval for the ratio of means (Cardioplexol/Buckberg) was reported. Missing data: The maximum value was calculated from the remaining CK-MB values if up to 3 values were missing. If no values were available, multiple imputation was used to replace the missing max value. Multiple imputations were based on selected baseline and postoperative variables. Chained equations were used.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 t-test, 2-sided
    Parameter type
    		 geometric mean ratio
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.21

    Secondary: Time between aortic cross-clamping and complete cardiac arrest

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    End point title
    		 Time between aortic cross-clamping and complete cardiac arrest
    End point description
    no details required
    End point type
    Secondary
    End point timeframe
    Time from aortic cross-clamping to complete cardiac arrest
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: second
        geometric mean (confidence interval 95%)
    14.1 (12.1 to 16.6)
    77.5 (69.3 to 86.7)
    Statistical analysis title
    		 Time to complete cardiac arrest
    Statistical analysis description
    Time between the aortic cross-clamping and the complete cardiac arrest was analysed using Student’s t-tests on the log-scale in the ITT population. If any of those values were not normally distributed after log-transformation, analysis on the normal scale (if normally distributed) or the use of non-parametric methods was planned to be included as sensitivity analyses.
    Comparison groups
    Buckberg (Group 2) v Cardioplexol (Group 1)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 geometric mean ratio
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.22

    Secondary: cumulative dose of catecholamines during aortic cross-clamping

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    End point title
    		 cumulative dose of catecholamines during aortic cross-clamping
    End point description
    no further details required.
    End point type
    Secondary
    End point timeframe
    time during aortic cross-clamping
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: inotropic score
        geometric mean (confidence interval 95%)
    759 (614 to 940)
    775 (619 to 969)
    Statistical analysis title
    		 Cpx vs BB: catecholamines during cross-clamp. time
    Statistical analysis description
    Analyses was performed using Student’s t-tests on the log-scale in the ITT population. If any of those values were not normally distributed after log-transformation, analysis on the normal scale (if normally distributed) or the use of non-parametric methods was planned to be included as sensitivity analyses.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 t-test, 2-sided
    Parameter type
    		 geometric mean ratio
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.33

    Secondary: cumulative dose of catecholamines during the first 24 hours

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    End point title
    		 cumulative dose of catecholamines during the first 24 hours
    End point description
    This is an additional secondary endpoint demonstrating the overall benefit for the patients.
    End point type
    Secondary
    End point timeframe
    within first 24 hours after reperfusion
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: inotropic score
        geometric mean (confidence interval 95%)
    5384 (4257 to 6808)
    7569 (6129 to 9349)
    Statistical analysis title
    		 Cpx vs BB: catecholamines during first 24h
    Statistical analysis description
    Analyses was performed using Student’s t-tests on the log-scale in the ITT population. If any of those values were not normally distributed after log-transformation, analysis on the normal scale (if normally distributed) or the use of non-parametric methods was planned to be included as sensitivity analyses.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.035
    Method
    		 t-test, 2-sided
    Parameter type
    		 geometric mean ratio
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.98

    Secondary: Maximal ST-elevation during the first 24 hours

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    End point title
    		 Maximal ST-elevation during the first 24 hours
    End point description
    This is an additional secondary endpoint demonstrating the overall benefit for the patients.
    End point type
    Secondary
    End point timeframe
    the first 24 hours following coronary reperfusion or until ICU discharge (if discharge occurs before 24 hours)
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: mm
        arithmetic mean (confidence interval 95%)
    1.7 (1.44 to 2)
    1.79 (1.53 to 2.09)
    Statistical analysis title
    		 Cpx vs BB: Max ST-elevation during first 24h
    Statistical analysis description
    Analyses was performed using Student’s t-tests on the log-scale in the ITT population. If any of those values were not normally distributed after log-transformation, analysis on the normal scale (if normally distributed) or the use of non-parametric methods was planned to be included as sensitivity analyses.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 0.36

    Secondary: Defibrillation rate after aorta unclamping and coronary reperfusion

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    End point title
    		 Defibrillation rate after aorta unclamping and coronary reperfusion
    End point description
    no further details required.
    End point type
    Secondary
    End point timeframe
    after aorta unclamping and coronary reperfusion
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: number of patients
    20
    67
    Statistical analysis title
    		 Cpx vs BB: Defibrillation rate
    Statistical analysis description
    This binary secondary outcome was expressed as risk ratio within corresponding 95% confidence interval (based on a normal approximation for log risk ratio) and compared using chi square tests. Analysis is performed on ITT Population.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.47

    Secondary: Installation of an IABP

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    End point title
    		 Installation of an IABP
    End point description
    This is an additional secondary endpoint demonstrating the overall benefit for the patients.
    End point type
    Secondary
    End point timeframe
    during the first 24 hours following coronary reperfusion or until ICU discharge (if discharge occurs before 24 hours)
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: number of patients
    3
    5
    Statistical analysis title
    		 Cpx vs BB: Installation of IABP in the first 24
    Statistical analysis description
    This binary secondary outcome was expressed as risk ratio within corresponding 95% confidence interval (based on a normal approximation for log risk ratio) and compared using chi square tests. Analysis is performed on ITT poluation.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 3.08

    Secondary: Mortality

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    End point title
    		 Mortality
    End point description
    This is an additional secondary endpoint demonstrating the overall benefit for the patients.
    End point type
    Secondary
    End point timeframe
    during the first 24 hours following coronary reperfusion or until ICU discharge (if discharge occurs before 24 hours)
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    119
    129
    Units: number of patients
    1
    2
    Statistical analysis title
    		 Cpx vs BB: Mortality
    Statistical analysis description
    This binary secondary outcome was expressed as risk ratio within corresponding 95% confidence interval (based on a normal approximation for log risk ratio) and compared using chi square tests. Mulitple imputation was not done due to the low number of events, complete case analysis.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 5.9

    Secondary: Duration of intubation

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    End point title
    		 Duration of intubation
    End point description
    no further details required.
    End point type
    Secondary
    End point timeframe
    from timepoint of intubation to timepoint of extubation
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: hours
        median (confidence interval 95%)
    13 (12 to 14)
    13.5 (12.5 to 14.5)
    Statistical analysis title
    		 Cpx vs BB: Duration of intubation
    Statistical analysis description
    This secondary endpoint was analysed using parametric accelerated failure time (AFT) models with a generalized gamma survival time distribution. Results were reported as time ratio with 95% confidence interval and p-value.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 AFT models
    Parameter type
    		 time ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.02

    Secondary: Patients requiring catecholamines

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    End point title
    		 Patients requiring catecholamines
    End point description
    no further details required.
    End point type
    Secondary
    End point timeframe
    during aortic cross-clamping
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    118
    129
    Units: number of patients
    118
    128
    Statistical analysis title
    		 Cpx vs BB: Patients requiring catecholamines
    Statistical analysis description
    This binary secondary outcome was expressed as risk ratio within corresponding 95% confidence interval (based on a normal approximation for log risk ratio) and compared using chi square tests. Multiple imputation was not done due to the high number of events, complete case analysis.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.02

    Secondary: Duration of ICU stay

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    End point title
    		 Duration of ICU stay
    End point description
    End point type
    Secondary
    End point timeframe
    from timepoint of ICU admission to timepoint of ICU discharge
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: hours
        median (confidence interval 95%)
    37.8 (22.1 to 46.1)
    44 (26.3 to 45.5)
    Statistical analysis title
    		 Cpx vs BB: Duration of ICU stay
    Statistical analysis description
    This secondary endpoint was analysed using parametric accelerated failure time (AFT) models. Patients who did not reach the endpoint because of death were censored at the time of death. Results were reported as time ratio with 95% confidence interval and p-value.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 AFT models
    Parameter type
    		 time ratio
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 0.95

    Secondary: Duration of hospitalization

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    End point title
    		 Duration of hospitalization
    End point description
    no further description required.
    End point type
    Secondary
    End point timeframe
    from date of hospital admission to date of hospital discharge
    End point values
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Number of subjects analysed
    132
    132
    Units: days
        median (confidence interval 95%)
    10 (10 to 11)
    11 (10 to 11)
    Statistical analysis title
    		 Cpx vs BB: Duration of hospitalization
    Statistical analysis description
    This secondary endpoint was analysed using parametric accelerated failure time (AFT) models with a generalized gamma survival time distribution. Patients that did not reach the endpoint because of death were censored at the time of death. Patients still hospitalized at 30 days were censored at 30 days. Results were reported as time ratio with 95% confidence interval and p-value.
    Comparison groups
    Cardioplexol (Group 1) v Buckberg (Group 2)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97
    Method
    		 AFT models
    Parameter type
    		 time ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.05

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE collection started after signature of the informed consent form, irrespective of whether or not they may be related to the study intervention. Investigators followed-up adverse events until resolution or the end of the study (= follow up visit)
    Adverse event reporting additional description
    At each assessment, all AEs either observed by the Investigator or one of his clinical collaborators or reported by the patient spontaneously or in response to a direct question were evaluated by the Investigator. Nature of each event, date and time (where appropriate) of onset, outcome, severity and relationship to administration were established.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Cardioplexol (Group 1)
    Reporting group description
    		 After randomisation the patients underwent cardiac surgery and received the necessary volume of Cardioplexol. The necessary volume is the volume needed for cardiac arrest, which is a prerequisite for the cardiac surgery. After the cardiac arrest was achieved the patients received further doses whose number and volume depended on the duration of the cardiac surgery as well as individual factors.

    Reporting group title
    Buckberg (Group 2)
    Reporting group description
    		 After randomisation the patients underwent cardiac surgery and received the necessary volume of Buckberg blood cardioplegia. The necessary volume is the volume needed for cardiac arrest, which is a prerequisite for the cardiac surgery. Buckberg cardioplegia consists of a cold induction solution, a cold reinfusion solution and a warm reinfusion solution (hot shot).

    Serious adverse events
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 119 (46.22%)
    59 / 129 (45.74%)
         number of deaths (all causes)
    1
    5
         number of deaths resulting from adverse events
    1
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 119 (0.00%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    0 / 119 (0.00%)
    3 / 129 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Aortic valve repair
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemostasis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device implantation
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternotomy
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracotomy
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 119 (0.84%)
    4 / 129 (3.10%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    1 / 1
    1 / 4
    Drug ineffective
         subjects affected / exposed
    2 / 119 (1.68%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiorgan failure
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 119 (0.84%)
    3 / 129 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 119 (1.68%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reactive psychosis
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood pressure decreased
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram Q waves
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    10 / 119 (8.40%)
    5 / 129 (3.88%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative thoracic procedure complication
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpericardiotomy syndrome
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular bypass dysfunction
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 119 (0.00%)
    5 / 129 (3.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 119 (0.00%)
    4 / 129 (3.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atriventricular block complete
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 119 (0.00%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    heart failure
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 119 (2.52%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Visual field defect
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    35 / 119 (29.41%)
    37 / 129 (28.68%)
         occurrences causally related to treatment / all
    0 / 35
    0 / 38
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Actinomycotic pulmonary infection
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 119 (0.84%)
    4 / 129 (3.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Cardioplexol (Group 1) Buckberg (Group 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    99 / 119 (83.19%)
    102 / 129 (79.07%)
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    2 / 119 (1.68%)
    2 / 129 (1.55%)
         occurrences all number
    2
    2
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    19 / 119 (15.97%)
    19 / 129 (14.73%)
         occurrences all number
    19
    20
    Atrial fibrillation
         subjects affected / exposed
    14 / 119 (11.76%)
    17 / 129 (13.18%)
         occurrences all number
    14
    18
    Bradycardia
         subjects affected / exposed
    3 / 119 (2.52%)
    4 / 129 (3.10%)
         occurrences all number
    4
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 119 (8.40%)
    8 / 129 (6.20%)
         occurrences all number
    10
    8
    Thrombocytopenia
         subjects affected / exposed
    2 / 119 (1.68%)
    4 / 129 (3.10%)
         occurrences all number
    2
    4
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    4 / 119 (3.36%)
    2 / 129 (1.55%)
         occurrences all number
    4
    2
    Pain
         subjects affected / exposed
    2 / 119 (1.68%)
    2 / 129 (1.55%)
         occurrences all number
    2
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 119 (1.68%)
    4 / 129 (3.10%)
         occurrences all number
    2
    4
    Nausea
         subjects affected / exposed
    3 / 119 (2.52%)
    2 / 129 (1.55%)
         occurrences all number
    3
    2
    Vomiting
         subjects affected / exposed
    1 / 119 (0.84%)
    4 / 129 (3.10%)
         occurrences all number
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 119 (2.52%)
    6 / 129 (4.65%)
         occurrences all number
    3
    6
    Lung infiltration
         subjects affected / exposed
    2 / 119 (1.68%)
    2 / 129 (1.55%)
         occurrences all number
    2
    2
    Pleural effusion
         subjects affected / exposed
    6 / 119 (5.04%)
    11 / 129 (8.53%)
         occurrences all number
    6
    14
    Pneumothorax
         subjects affected / exposed
    4 / 119 (3.36%)
    3 / 129 (2.33%)
         occurrences all number
    4
    3
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    3 / 119 (2.52%)
    1 / 129 (0.78%)
         occurrences all number
    3
    1
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    2 / 119 (1.68%)
    3 / 129 (2.33%)
         occurrences all number
    2
    3
    Reactive psychosis
         subjects affected / exposed
    2 / 119 (1.68%)
    6 / 129 (4.65%)
         occurrences all number
    2
    6
    Infections and infestations
    Infection
         subjects affected / exposed
    3 / 119 (2.52%)
    1 / 129 (0.78%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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