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    Clinical Trial Results:
    Pilot Trial: The effects of intravenous heme arginate on HO-1 expression and oxidative stress in the human heart

    Summary
    EudraCT number
    		 2013-000887-27
    Trial protocol
    		 AT  
    Global end of trial date
    13 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2020
    First version publication date
    04 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2.0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02314780
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Währinger Gürtel 18-20, Vienna, Austria, 1090
    Public contact
    Prof. Dr. Martin Andreas, Medical University of Vienna, +43 14040069660, martin.andreas@meduniwien.ac.at
    Scientific contact
    Prof. Dr. Martin Andreas, Medical University of Vienna, +43 14040069660, martin.andreas@meduniwien.ac.at
    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
    29 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the effects of heme arginate administration in two different doses on myocardial HO-1 induction.
    Protection of trial subjects
    The trial was conducted according to the principles of Good Clinical Practice and the Declaration of Helsinki and in agreement with the Austrian laws and regulation. The Ethics Committee of the Medical University of Vienna approved the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    8
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients who were scheduled for elective surgical aortic valve replacement were assessed for eligibility after hospitalization. A sample size of 24 subjects was calculated. The ethical board approved up to 36 subjects with an interim analysis of the first 24 subjects. The trial was stopped after the interim analysis because of significant results.

    Pre-assignment
    Screening details
    		 A total of 31 patients signed the informed consent to participate in the trial. Of them, 27 subjects were randomized.

    Pre-assignment period milestones
    Number of subjects started
    		 31
    Number of subjects completed
    		 27

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 organizational reasons: 3
    Reason: Number of subjects
    		 other reason: 1
    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, Carer
    Blinding implementation details
    A non-transparent infusion kit was used for the administration of the investigational medicinal products in order to maintain the blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Normosang (high dose)
    Arm description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of heme arginate at a dose of 3 mg/kg diluted to 110 ml with 0,9% sodium chloride.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Normosang
    Investigational medicinal product code
    1-27260
    Other name
    heme arginate
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0,9% sodium chloride was administered at a single intravenous infusion using an infusion pump. To avoid any local irritation from drug infusion, 250ml 0,9% sodium chloride solution was administered thereafter.

    Arm title
    		 Normosang (low dose)
    Arm description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of heme arginate at a dose of 1 mg/kg diluted to 110 ml with 0,9% sodium chloride.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Normosang
    Investigational medicinal product code
    1-27260
    Other name
    heme arginate
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0,9% sodium chloride was administered at a single intravenous infusion using an infusion pump. To avoid any local irritation from drug infusion, 250ml 0,9% sodium chloride solution was administered thereafter.

    Arm title
    		 Placebo
    Arm description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0,9% sodium chloride solution.
    Arm type
    		 Placebo

    Investigational medicinal product name
    0,9% Sodium chloride solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    24 hours prior to the planned surgical aortic valve replacement, an equivalent volume of sodium chloride solution was administered at a single intravenous infusion using an infusion pump.

    Number of subjects in period 1 [1]
    		Normosang (high dose) Normosang (low dose) Placebo
    Started
    9
    10
    8
    Completed
    9
    7
    8
    Not completed
    0
    3
    0
         no operation 24 hours after drug administration
    -
    3
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 31 subjects were enrolled in the trial. Of them, 4 patients (3 patients for organizational reasons and 1 patient for other reasons) were excluded from the trial prior to randomization and drug administration.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Normosang (high dose)
    Reporting group description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of heme arginate at a dose of 3 mg/kg diluted to 110 ml with 0,9% sodium chloride.

    Reporting group title
    Normosang (low dose)
    Reporting group description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of heme arginate at a dose of 1 mg/kg diluted to 110 ml with 0,9% sodium chloride.

    Reporting group title
    Placebo
    Reporting group description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0,9% sodium chloride solution.

    Reporting group values
    		 Normosang (high dose) Normosang (low dose) Placebo Total
    Number of subjects
    		 9 10 8 27
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 2 1 3 6
        From 65-84 years
    		 7 9 5 21
    Gender categorical
    Units: Subjects
        Male
    		 3 5 3 11
        Female
    		 6 5 5 16

    End points

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    End points reporting groups
    Reporting group title
    Normosang (high dose)
    Reporting group description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of heme arginate at a dose of 3 mg/kg diluted to 110 ml with 0,9% sodium chloride.

    Reporting group title
    Normosang (low dose)
    Reporting group description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of heme arginate at a dose of 1 mg/kg diluted to 110 ml with 0,9% sodium chloride.

    Reporting group title
    Placebo
    Reporting group description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0,9% sodium chloride solution.

    Primary: Myocardial HO-1 mRNA levels (atrial tissue)

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    End point title
    		 Myocardial HO-1 mRNA levels (atrial tissue)
    End point description
    The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling.
    End point type
    Primary
    End point timeframe
    intraoperative
    End point values
    		 Normosang (high dose) Normosang (low dose) Placebo
    Number of subjects analysed
    9
    7
    8
    Units: arbitrary unit
        arithmetic mean (standard deviation)
    392.7 ( 195.7 )
    229.8 ( 173.1 )
    10.8 ( 8.8 )
    Statistical analysis title
    		 HO-1 mRNA concentrations (appendage)
    Comparison groups
    Normosang (low dose) v Placebo v Normosang (high dose)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 ANOVA
    Confidence interval

    Primary: Myocardial HO-1 mRNA levels (ventricular tissue before aortic cross-clamping)

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    End point title
    		 Myocardial HO-1 mRNA levels (ventricular tissue before aortic cross-clamping)
    End point description
    A small biopsy was taken from the right ventricular free wall directly before aortic cross-clamping. The tissue samples were snap-frozen in the operating theater after sampling.
    End point type
    Primary
    End point timeframe
    intraoperative
    End point values
    		 Normosang (high dose) Normosang (low dose) Placebo
    Number of subjects analysed
    9
    7
    8
    Units: arbitrary units
        arithmetic mean (standard deviation)
    203.6 ( 148.7 )
    88.6 ( 49.1 )
    7.9 ( 5.0 )
    Statistical analysis title
    		 HO-1 mRNA level (ventricle pre)
    Comparison groups
    Normosang (high dose) v Normosang (low dose) v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002
    Method
    		 ANOVA
    Confidence interval

    Primary: Myocardial HO-1 mRNA levels (ventricular tissue after aortic cross-clamping)

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    End point title
    		 Myocardial HO-1 mRNA levels (ventricular tissue after aortic cross-clamping)
    End point description
    A small biopsy was taken from the right ventricular free wall after aortic clamp release before weaning from cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling.
    End point type
    Primary
    End point timeframe
    intraoperative
    End point values
    		 Normosang (high dose) Normosang (low dose) Placebo
    Number of subjects analysed
    9
    7
    8
    Units: arbitrary units
        arithmetic mean (standard deviation)
    219.4 ( 162.8 )
    108.1 ( 73.2 )
    8.3 ( 5.4 )
    Statistical analysis title
    		 HO-1 mRNA (ventricle post)
    Comparison groups
    Normosang (high dose) v Normosang (low dose) v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002
    Method
    		 ANOVA
    Confidence interval

    Primary: Myocardial HO-1 protein concentrations (atrial tissue)

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    End point title
    		 Myocardial HO-1 protein concentrations (atrial tissue)
    End point description
    The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling.
    End point type
    Primary
    End point timeframe
    intraoperative
    End point values
    		 Normosang (high dose) Normosang (low dose) Placebo
    Number of subjects analysed
    9
    7
    8
    Units: pixels under the curve
        arithmetic mean (standard deviation)
    29022 ( 8583 )
    28585 ( 10692 )
    8401 ( 3889 )
    Statistical analysis title
    		 HO-1 protein concentration (appendage)
    Comparison groups
    Normosang (high dose) v Normosang (low dose) v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Primary: Myocardial HO-1 protein concentrations (ventricular tissue before aortic cross-clamping)

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    End point title
    		 Myocardial HO-1 protein concentrations (ventricular tissue before aortic cross-clamping)
    End point description
    A small biopsy was taken from the right ventricular free wall directly before aortic cross-clamping. The tissue samples were snap-frozen in the operating theater after sampling.
    End point type
    Primary
    End point timeframe
    intraoperative
    End point values
    		 Normosang (high dose) Normosang (low dose) Placebo
    Number of subjects analysed
    9
    7
    8
    Units: pixels unter the curve
        arithmetic mean (standard deviation)
    13752 ( 8069 )
    10534 ( 4686 )
    6842 ( 4343 )
    Statistical analysis title
    		 HO-1 protein concentrations (ventricle pre)
    Comparison groups
    Normosang (high dose) v Normosang (low dose) v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.138
    Method
    		 ANOVA
    Confidence interval

    Primary: Myocardial HO-1 protein concentrations (ventricular tissue after aortic cross-clamping)

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    End point title
    		 Myocardial HO-1 protein concentrations (ventricular tissue after aortic cross-clamping)
    End point description
    A small biopsy was taken from the right ventricular free wall after aortic clamp release before weaning from cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling.
    End point type
    Primary
    End point timeframe
    intraoperative
    End point values
    		 Normosang (high dose) Normosang (low dose) Placebo
    Number of subjects analysed
    9
    7
    8
    Units: pixels under the curve
        arithmetic mean (standard deviation)
    17062 ( 18164 )
    11277 ( 3918 )
    12037 ( 10962 )
    Statistical analysis title
    		 HO-1 protein concentrations (ventricle post)
    Comparison groups
    Normosang (high dose) v Normosang (low dose) v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.696
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events occuring within 96 hours after the administration of Normosang/sodium chloride solution were reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Normosang (high dose)
    Reporting group description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of heme arginate at a dose of 3 mg/kg diluted to 110 ml with 0,9% sodium chloride.

    Reporting group title
    Normosang (low dose)
    Reporting group description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of heme arginate at a dose of 1 mg/kg diluted to 110 ml with 0,9% sodium chloride.

    Reporting group title
    Placebo
    Reporting group description
    		 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of 100 ml 0,9% sodium chloride solution.

    Serious adverse events
    		 Normosang (high dose) Normosang (low dose) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery compression
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Normosang (high dose) Normosang (low dose) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    5 / 10 (50.00%)
    4 / 8 (50.00%)
    Investigations
    Blood culture positive
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Procedural pneumothorax
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 10 (30.00%)
    3 / 8 (37.50%)
         occurrences all number
    1
    3
    3
    Blood and lymphatic system disorders
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Acute stress disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0

    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.
    Biopsy samples were small and protein concentration could not be measured in every sample. The sample size is small for a 3-arm randomized controlled trial.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30354231
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