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    Clinical Trial Results:
    Efficacy and safety of 6 % hydroxyethyl starch 130/0.4 (Voluven) vs. 5% HSA in volume replacement therapy during elective open-heart surgery in paediatric patients

    Summary
    EudraCT number
    		 2008-006749-18
    Trial protocol
    		 AT   BE  
    Global end of trial date
    05 Aug 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HE06-001-C P4
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00860405
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fresenius Kabi Deutschland GmbH
    Sponsor organisation address
    Else-Kröner-Str. 1, Bad Homburg, Germany, 61352
    Public contact
    Division Medical & Clinical Affairs Generics & Standard Solutions, Volume Therapy, Fresenius Kabi Deutschland GmbH, scientific-contact@fresenius-kabi.com
    Scientific contact
    Division Medical & Clinical Affairs Generics & Standard Solutions, Volume Therapy, Fresenius Kabi Deutschland GmbH, scientific-contact@fresenius-kabi.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Dec 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Aug 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Aug 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study compared the clinical efficacy and safety of Voluven and Human Albumin during elective open-heart surgery in paediatric patients.
    Protection of trial subjects
    At the screening visit the parent(s) of patients who were considered potential candidates for the study were asked to provide a written informed consent (signed parental written informed consent) and patient assent was obtained (where achievable [patients ≥ 6 years]). The investigator considered 4 patients ≥ 6 years unable to sign the informed assent. The parent(s) and patient (if applicable) were informed in writing about their right to withdraw from the study at any time without specification of reasons. Written patient information was given to each parent and patient (if applicable) before enrolment. Patients could only participate if their eligibility had been proven. As this study dealt with a specific patient population, i.e. children at the age of 2-12 years, study specific modifications of the common terminology criteria for adverse events (CTCAE) v3.0 for vital signs and laboratory values were used. The criteria for the adverse event (AE) intensity assessment were adjusted as well. The study could also be terminated prematurely for medical or ethical reasons following consultation with the investigators. Patients who were withdrawn due to one or more (serious) AEs were to be treated and followed-up according to established medical practice to evaluate the course of the AE, and to ensure reversibility or stabilisation of the event.
    Background therapy
    		 -
    Evidence for comparator
    		 In the past, human albumin has beeen widely accepted as the therapeutic "gold standard" in paediatric volume replacement therapy because of the physiological hypoproteinemia in newborns and infants. Therefore, HSA was used as comparator.
    Actual start date of recruitment
    31 Mar 2009
    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: 21
    Country: Number of subjects enrolled
    Belgium: 40
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    59
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited in paediatric care units of 2 hospitals in Austria and Belgium from March 2009 (First Patient In) until July 2010 and were followed up until August 2010 (Last Patient Out).

    Pre-assignment
    Screening details
    		 In total 99 patients were screened in paediatric care units of the participating 2 study sites in Austria (39 patients) and Belgium (60 patients). Male or female paediatric patients, 2 to 12 years of age, suffering from congenital heart-disease and undergoing elective open-heart surgery requiring extracorporeal circulation (ECC) were eligible.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    An independent perfusionist was the only unblinded person at the study site responsible for preparing the heart-lung machine and those bottles of the study medication needed by the investigator for volume replacement.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Voluven 6% Arm
    Arm description
    		 6% Hydroxyethylstarch (HES) 130/0.4, i.v.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HES 130/0.4 (6%) in isotonic sodium chloride (0.9%) solution
    Investigational medicinal product code
    Other name
    Trade name: Voluven
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The investigational drug Voluven (6%) was given as part of the priming of the extracorporeal circulation (ECC) and for plasma volume replacement before and/or after start of ECC up to the maximum dosage of 50 mL/kg body weight/day; once the maximum dose was reached, 5% human serum albumin (HSA 50 g/L) for which there was no daily dose limitation was used as rescue colloid in both groups, if required. During the priming of the ECC the dosage depended on the patient's body weight and the total volume of the ECC.

    Arm title
    		 HSA 5% Arm
    Arm description
    		 Human Serum Albumin (HSA) 50g/L, i.v.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Human serum albumin (HSA 50g/L)
    Investigational medicinal product code
    Other name
    Trade name: Human Albumin Baxter
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The comparator human serum albumin (HSA) was given as part of the priming of the extracorporeal circulation (ECC) and for plasma volume replacement before and/or after start of ECC up to the maximum dosage of 50 mL/kg body weight/day; once the maximum dose was reached, 5% human serum albumin (HSA 50 g/L) for which there was no daily dose limitation was used as rescue colloid in both groups, if required. During the priming of the ECC the dosage depended on the patient's body weight and the total volume of the ECC.

    Number of subjects in period 1
    		Voluven 6% Arm HSA 5% Arm
    Started
    31
    30
    Day 28 follow-up performed
    31
    29
    Completed treatment
    31
    29
    Completed
    26
    26
    Not completed
    5
    4
         Randomised in error (not treated)
    -
    1
         Lost to follow-up
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Voluven 6% Arm
    Reporting group description
    		 6% Hydroxyethylstarch (HES) 130/0.4, i.v.

    Reporting group title
    HSA 5% Arm
    Reporting group description
    		 Human Serum Albumin (HSA) 50g/L, i.v.

    Reporting group values
    		 Voluven 6% Arm HSA 5% Arm Total
    Number of subjects
    		 31 30 61
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5.2 ( 2.9 ) 4 ( 2 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 16 13 29
        Male
    		 15 17 32
    Region of Enrollment
    Units: Subjects
        Belgium
    		 20 20 40
        Austria
    		 11 10 21
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 18.2 ( 8.9 ) 15.4 ( 4.4 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 106.6 ( 16.8 ) 101.3 ( 12.8 ) -

    End points

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    End points reporting groups
    Reporting group title
    Voluven 6% Arm
    Reporting group description
    		 6% Hydroxyethylstarch (HES) 130/0.4, i.v.

    Reporting group title
    HSA 5% Arm
    Reporting group description
    		 Human Serum Albumin (HSA) 50g/L, i.v.

    Primary: Total volume of colloid solution required intraoperatively

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    End point title
    		 Total volume of colloid solution required intraoperatively
    End point description
    The primary efficacy variable was the total volume of colloid solution (Voluven/HSA plus rescue colloid, if applicable) in mL/kg body weight required for intraoperative volume replacement therapy including priming of the ECC.
    End point type
    Primary
    End point timeframe
    Study drug was used intraoperatively before ECC, for priming of the heart-lung-machine, and after ECC until end of surgery according to the patient's demands.
    End point values
    		 Voluven 6% Arm HSA 5% Arm
    Number of subjects analysed
    29 [1]
    26 [2]
    Units: ml/kg
        arithmetic mean (standard deviation)
    36.6 ( 11.76 )
    36.97 ( 11.86 )
    Notes
    [1] - Per-protocol (PP) population
    [2] - Per-protocol (PP) population
    Statistical analysis title
    		 Therapeutic Equivalence
    Statistical analysis description
    The aim of the study was to prove equivalence, i.e. H0: μVoluven/μHSA ≤ 0.55 or μVoluven/μHSA ≥ 1.82 H1: 0.55 < μVoluven/μHSA < 1.82 where μVoluven was the mean infused volume of Voluven and μHSA was the mean infused volume of HSA 5%.
    Comparison groups
    HSA 5% Arm v Voluven 6% Arm
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    		 ANOVA
    Parameter type
    		 Ratio of LS-means (LS = Least square)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.16
    Notes
    [3] - Assuming a CV of 0.363 and a desired power of 90 % with a type I level of 2.5 %, N=11 patients per treatment group were needed. Nevertheless, more patients were required for the assessment of safety, therefore 2 × 30 patients were planned to be included in this study. Primary endpoint specified and analysed for PP and ITT population. Confirmatory analysis based on PP population only, no adjustment for multiplicity. Considered ratio: μVoluven/μHSA = LS-mean of Voluven/LS-mean of HSA 5%

    Secondary: Mean arterial pressure (MAP)

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    End point title
    		 Mean arterial pressure (MAP)
    End point description
    Mean arterial pressure (MAP) from beginning of anaesthesia (baseline) until arrival on intensive care unit (ICU). Description of time points: T0 Baseline: Immediately after induction of anaesthesia T1 Treatment period: Immediately before ECC T2 Treatment period: Immediately after protamine application T3 Treatment period: After skin closure T4 Treatment period: Arrival on the intensive care unit (ICU) (after complete installation)
    End point type
    Secondary
    End point timeframe
    Beginning of anaesthesia (baseline) until arrival on intensive care unit (ICU)
    End point values
    		 Voluven 6% Arm HSA 5% Arm
    Number of subjects analysed
    29
    26
    Units: mm Hg
    arithmetic mean (standard deviation)
        T0, Baseline
    64.1 ( 11.3 )
    66.5 ( 12.5 )
        T1, before ECC (Extracorporeal circulation)
    54 ( 7.4 )
    51.3 ( 8 )
        T2, after ECC
    56.6 ( 7.6 )
    58.2 ( 9.7 )
        T3, after skin closure
    61.2 ( 9.7 )
    62 ( 9.9 )
        T4, arrival on ICU
    65.3 ( 14.8 )
    65.2 ( 8.8 )
    No statistical analyses for this end point

    Secondary: Fluid input

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    End point title
    		 Fluid input
    End point description
    Quantity of total fluids administered from beginning of anaesthesia until 2nd postop morning
    End point type
    Secondary
    End point timeframe
    2 days
    End point values
    		 Voluven 6% Arm HSA 5% Arm
    Number of subjects analysed
    29
    26
    Units: ml/kg
        arithmetic mean (standard deviation)
    246.76 ( 119.29 )
    248.2 ( 105.76 )
    No statistical analyses for this end point

    Secondary: Fluid output

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    End point title
    		 Fluid output
    End point description
    Quantity of total fluids excreted or lost from beginning of anaesthesia until 2nd postop morning
    End point type
    Secondary
    End point timeframe
    2 days
    End point values
    		 Voluven 6% Arm HSA 5% Arm
    Number of subjects analysed
    29
    26
    Units: ml/kg
        arithmetic mean (standard deviation)
    195.48 ( 95.67 )
    181.13 ( 68.29 )
    No statistical analyses for this end point

    Secondary: Fluid balance

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    End point title
    		 Fluid balance
    End point description
    Fluid balance was calculated as total fluid input minus total fluid output
    End point type
    Secondary
    End point timeframe
    2 days
    End point values
    		 Voluven 6% Arm HSA 5% Arm
    Number of subjects analysed
    29
    26
    Units: ml/kg
        arithmetic mean (standard deviation)
    51.28 ( 47.46 )
    67.07 ( 62.57 )
    No statistical analyses for this end point

    Other pre-specified: Calculated perioperative Red Blood Cell (RBC) loss

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    End point title
    		 Calculated perioperative Red Blood Cell (RBC) loss
    End point description
    Calculated perioperative RBC loss = Predicted blood volume [1] × (hematocrit [baseline] – hematocrit [2nd postop morning]) + transfused RBC volume [2]; [1] Predicted blood volume (mL) = 80 × body weight (kg) [2] Transfused RBC volume = 0.7 × infused packed RBC
    End point type
    Other pre-specified
    End point timeframe
    2 days
    End point values
    		 Voluven 6% Arm HSA 5% Arm
    Number of subjects analysed
    31 [4]
    29 [5]
    Units: ml/kg
        arithmetic mean (standard deviation)
    14.45 ( 14.38 )
    15.35 ( 15.48 )
    Notes
    [4] - Safety population
    [5] - Safety population
    No statistical analyses for this end point

    Other pre-specified: Length of stay on the intensive care unit (ICU)

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    End point title
    		 Length of stay on the intensive care unit (ICU)
    End point description
    Length of stay (number of days) on the intensive care unit (ICU).
    End point type
    Other pre-specified
    End point timeframe
    From admission to ICU until discharge from ICU
    End point values
    		 Voluven 6% Arm HSA 5% Arm
    Number of subjects analysed
    31
    29
    Units: Days
        median (inter-quartile range (Q1-Q3))
    3.08 (1.96 to 5.79)
    3.06 (2.29 to 6.92)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event recording was performed throughout the study (from signing the informed consent until the follow-up visit at 28 days after discharge from operating room).
    Adverse event reporting additional description
    Regular assessment by Pharmacovigilance and Safety Assessor. Only treatment emergent adverse events were reported and summarized in tables.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Voluven Arm
    Reporting group description
    		 6% Hydroxyethylstarch 130/0.4, i.v.

    Reporting group title
    HSA 5% Arm (Comparison group)
    Reporting group description
    		 Human Serum Albumin (HSA) 50g/L, i.v.

    Serious adverse events
    		 Voluven Arm HSA 5% Arm (Comparison group)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 31 (35.48%)
    7 / 29 (24.14%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         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
    Cardiac procedure complication
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endotracheal intubation complication
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         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
    Coagulopathy
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         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
    Device breakage
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Internal hernia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (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
    Apnoea
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chylothorax
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         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
    0 / 31 (0.00%)
    3 / 29 (10.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural pneumonia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection fungal
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Voluven Arm HSA 5% Arm (Comparison group)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 31 (96.77%)
    29 / 29 (100.00%)
    Vascular disorders
    Arterial thrombosis limb
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Haemodynamic instability
         subjects affected / exposed
    4 / 31 (12.90%)
    4 / 29 (13.79%)
         occurrences all number
    4
    4
    Hypotension
         subjects affected / exposed
    10 / 31 (32.26%)
    4 / 29 (13.79%)
         occurrences all number
    13
    4
    General disorders and administration site conditions
    Device occlusion
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    0
    3
    Exposure to contaminated device
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Impaired healing
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Infusion site extravasation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Infusion site urticaria
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 29 (3.45%)
         occurrences all number
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Aspiration
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Atelectasis
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Bradypnoea
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Bronchospasm
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Haemoptysis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Hypercapnia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Hyperventilation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Hypoxia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Increased bronchial secretion
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Lung disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Pleural effusion
         subjects affected / exposed
    7 / 31 (22.58%)
    0 / 29 (0.00%)
         occurrences all number
    7
    0
    Pneumothorax
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    2
    2
    Pulmonary congestion
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Pulmonary oedema
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Respiratory acidosis
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Respiratory depression
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Stridor
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    6 / 31 (19.35%)
    3 / 29 (10.34%)
         occurrences all number
    6
    3
    Anxiety
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 31 (19.35%)
    4 / 29 (13.79%)
         occurrences all number
    6
    4
    Blood urea increased
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Blood lactic acid increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Enterovirus test positive
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Venous oxygen saturation decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Cardiac procedure complication
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Dilutional coagulopathy
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Endotracheal intubation complication
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Fall
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Procedural vomiting
         subjects affected / exposed
    7 / 31 (22.58%)
    6 / 29 (20.69%)
         occurrences all number
    8
    8
    Traumatic haematoma
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Wound
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Bradycardia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Cardiac aneurysm
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Nodal rhythm
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Pericardial effusion
         subjects affected / exposed
    5 / 31 (16.13%)
    3 / 29 (10.34%)
         occurrences all number
    6
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Myoclonus
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Phrenic nerve paralysis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    2
    2
    Coagulopathy
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Leukocytosis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Ascites
         subjects affected / exposed
    4 / 31 (12.90%)
    1 / 29 (3.45%)
         occurrences all number
    4
    1
    Constipation
         subjects affected / exposed
    7 / 31 (22.58%)
    4 / 29 (13.79%)
         occurrences all number
    7
    4
    Dyspepsia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    13 / 31 (41.94%)
    9 / 29 (31.03%)
         occurrences all number
    13
    10
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Pruritus allergic
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Purpura
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Anuria
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    2
    2
    Haematuria
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Oliguria
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Renal impairment
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Urinary retention
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    2
    2
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Aspergillosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Enterobiasis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Device related infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    H1n1 Influenza
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Laryngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    4 / 29 (13.79%)
         occurrences all number
    1
    4
    Lobar pneumonia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Lung infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Post procedural pneumonia
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Pneumonia
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Postoperative wound infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Sepsis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Skin candida
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    17 / 31 (54.84%)
    13 / 29 (44.83%)
         occurrences all number
    22
    14
    Hyperlactacidaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Hypernatraemia
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Hypocalcaemia
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 29 (3.45%)
         occurrences all number
    2
    1
    Hypoglycaemia
         subjects affected / exposed
    4 / 31 (12.90%)
    2 / 29 (6.90%)
         occurrences all number
    4
    2
    Hypokalaemia
         subjects affected / exposed
    4 / 31 (12.90%)
    6 / 29 (20.69%)
         occurrences all number
    4
    6
    Hyponatraemia
         subjects affected / exposed
    3 / 31 (9.68%)
    3 / 29 (10.34%)
         occurrences all number
    3
    3
    Hypophosphataemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Hypoproteinaemia
         subjects affected / exposed
    10 / 31 (32.26%)
    0 / 29 (0.00%)
         occurrences all number
    10
    0
    Hypovolaemia
         subjects affected / exposed
    2 / 31 (6.45%)
    4 / 29 (13.79%)
         occurrences all number
    2
    4
    Metabolic acidosis
         subjects affected / exposed
    8 / 31 (25.81%)
    8 / 29 (27.59%)
         occurrences all number
    8
    9
    Metabolic alkalosis
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jan 2009
    In the first protocol amendment the study drug label for Belgium was revised as required by the Belgian Competent Authority.
    28 May 2009
    In the second protocol amendment the recipient of serious adverse event (SAE) reports/emergency contact during out-of office hours at the sponsor was updated. It was clarified that intraoperative study drug administration could already be started before ECC, but remained limited to the intraoperative period. The maximum daily dosage for the study drug was not changed. Therefore this change in the treatment schedule was not considered relevant regarding evaluations of efficacy and safety in this study. Furthermore stratum ( ≤ 12 kg, > 12 kg ) was included in ANOVA and ANCOVA models, the unit of pump flow corrected in the footer of the study schedule and section 12.3.3, the use of a cell saver device was allowed as this device was introduced as routine procedure in paediatric cardiac surgery, the total volumes of ECC were clarified and in Appendix 5b the symbol < for ranges of SaO2 and SpO2 was corrected and changed to >.

    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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    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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