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    Clinical Trial Results:
    Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDR-RCA): Safety and efficacy of low-dose Iloprost administration and blood pressure target in addition to standard therapy, as compared to standard therapy alone, in post-cardiac-arrest-syndrome patients – a randomized, controlled, double-blinded investigator-initiated trial.

    Summary
    EudraCT number
    		 2014-002998-11
    Trial protocol
    		 DK  
    Global end of trial date
    27 Feb 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ENDO-RCA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02685618
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet, Capital Region Bloodbank 2034, Section for Transfusion Medicine
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, DK-2100
    Public contact
    Sponsor (Pär I. Johansson), Rigshospitalet, Capital Region Bloodbank 2034, Section for Transfusion Medicine, 0045 35452030, per.johansson@regionh.dk
    Scientific contact
    Sponsor (Pär I. Johansson), Rigshospitalet, Capital Region Bloodbank 2034, Section for Transfusion Medicine, 0045 35452030, per.johansson@regionh.dk
    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
    21 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Assessment of the safety and efficacy of low-dose Iloprost administration on endothelial damage and blood pressure in post-cardiac-arrest-syndrome patients. To evaluate a possible interaction between exogenously administered catecholamines and iloprost efficacy on the endothelium.
    Protection of trial subjects
    All patients receive standard of care treatment including standardized temperature management and guideline supported achievement of mean arterial artery pressure using noradrenalin and dopamin during the intensive unit care stay. Patients with ROSC (return of spontaneous circulation) above 240 minuts before screening, un-witnessed arrest with systoles as the initial rhythm, suspected or known acute intracranial hemorrhage or stroke were excluded from the trial. Patients are in a critical acute condition resulting in mental impairment or sedation, therefore scientific guardians will co-sign the informed consent form. Next-of-kin and the patients' general practitioner will co-sign.
    Background therapy
    		 Standard of care.
    Evidence for comparator
    		 saline is used as placebo in this trial.
    Actual start date of recruitment
    25 Feb 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    26
    From 65 to 84 years
    19
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period 01.03.2016 to 31.08.2016. All patients were recruited at: Department Cardiology 2143, Copenhagen University Hospital, Denmark. Inclusion criteria were patients 18 years or older with (out-of-hospital-cardiac-arrest (OHCA)

    Pre-assignment
    Screening details
    		 A total of 77 patients were pre-screened of these 66 patients were assessed for eligibility. Of these 50 patients were randomised but only 46 patients were included in the trial of these 40 completed the 96-hour endpoint. Patients were recruited in 1:2 ration (active:placebo).

    Pre-assignment period milestones
    Number of subjects started
    		 50 [1]
    Number of subjects completed
    		 46

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 other nationality: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Died prior to intervention: 1
    Reason: Number of subjects
    		 Protocol deviation: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 4 patients were not included in the trial.
    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
    		 Investigator, Monitor, Data analyst, Subject, Carer, Assessor
    Blinding implementation details
    To circumvent selection bias, researchers and healthcare personnel was blinded to the treatment assignment. furthermore, to avoid investigator, healthcare staff and patient performance and detection bias, patients was randomized by computer to receive either iloprost or placebo similar in colour, consistency and volumen. Unblinded study nurse performed preparation of the study drug.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Iloprost
    Arm description
    		 Patients receiving iloprost.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iloprost
    Investigational medicinal product code
    Other name
    Ilomedin
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of 1 ng/kg/min for 48 hours. Iloprost was diluated in 0.9% saline to a final volumen of 100 ml. Infusion rate was 4 ml / hours.

    Investigational medicinal product name
    Isotonic saline
    Investigational medicinal product code
    Other name
    natriumchloride 0.9%
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Iloprost is diluted into saline to a final volumen of 100 ml

    Arm title
    		 Placebo
    Arm description
    		 Saline infusion 0.9%
    Arm type
    		 Placebo

    Investigational medicinal product name
    isotonic saline
    Investigational medicinal product code
    Other name
    natriumchloride 0.9%
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Infusion: 0.9% saline to a final volumen of 100 ml with an infusion rate of 4 ml/hours for 48 hours.

    Number of subjects in period 1
    		Iloprost Placebo
    Started
    13
    33
    Completed
    11
    33
    Not completed
    2
    0
         Adverse event, serious fatal
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Iloprost
    Reporting group description
    		 Patients receiving iloprost.

    Reporting group title
    Placebo
    Reporting group description
    		 Saline infusion 0.9%

    Reporting group values
    		 Iloprost Placebo Total
    Number of subjects
    		 13 33 46
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 15 24
        From 65-84 years
    		 4 17 21
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 57 (50 to 67) 63 (55 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 4 2 6
        Male
    		 9 31 40

    End points

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    End points reporting groups
    Reporting group title
    Iloprost
    Reporting group description
    		 Patients receiving iloprost.

    Reporting group title
    Placebo
    Reporting group description
    		 Saline infusion 0.9%

    Primary: Change in endothelial biomarkers

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    End point title
    		 Change in endothelial biomarkers
    End point description
    Change in biomarkers of endothelial damage at 48 hours post baseline. The 2 arms were compared using baseline corrected Proc Mixed repeated measurement models.
    End point type
    Primary
    End point timeframe
    At 48 hours post baseline
    End point values
    		 Iloprost Placebo
    Number of subjects analysed
    11
    33
    Units: ng/ml
    median (inter-quartile range (Q1-Q3))
        Thrombomodulin
    6.91 (5.75 to 9.76)
    8.57 (7.77 to 11.20)
        E-Selectin
    99.44 (82.43 to 123.73)
    123.62 (95.04 to 146.51)
        VEcad
    2005.60 (1709.70 to 2458.40)
    1896.90 (1773.60 to 2372.50)
        VEGF
    24.45 (15.10 to 33.85)
    28.39 (14.22 to 50.49)
        Syndecan
    27.21 (17.03 to 46.70)
    42.02 (29.78 to 64.47)
    Attachments
    		 Untitled (Filename: Endothel biomarkører - ENDO-RCA.pdf)
    Statistical analysis title
    		 Thrombomodulin
    Statistical analysis description
    Change in the biomarker thrombomodulin from baseline to 48 hours.
    Comparison groups
    Iloprost v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.16 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - Exploratory
    [2] - Group*Time at the 48-hour endpoints
    Statistical analysis title
    		 Syndecain
    Statistical analysis description
    Change in the biomarker syndecain from baseline to 48 hours.
    Comparison groups
    Iloprost v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.12 [4]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - Exploratory
    [4] - Group*Time at the 48-hour endpoints
    Statistical analysis title
    		 VEcad
    Statistical analysis description
    Change in the biomarker VE-Cadherine from baseline to 48 hours.
    Comparison groups
    Iloprost v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.81 [6]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [5] - Exploratory
    [6] - Group*Time at the 48-hour endpoints
    Statistical analysis title
    		 E-Selectin
    Statistical analysis description
    Change in the biomarker E-selectin from baseline to 48 hours.
    Comparison groups
    Iloprost v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.1 [8]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [7] - Exploratory
    [8] - Group*Time at the 48-hour endpoints
    Statistical analysis title
    		 VEGF
    Statistical analysis description
    Change in the biomarker VEGF from baseline to 48 hours.
    Comparison groups
    Iloprost v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.6 [10]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [9] - Exploratory
    [10] - Group*Time at the 48-hour endpoints

    Primary: Chnage in plasma levels of Adrenaline/Noradrenaline

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    End point title
    		 Chnage in plasma levels of Adrenaline/Noradrenaline
    End point description
    Change in plasma levels over time from baseline to 48 hours. The 2 arms were compaired using baseline corected proc Mixed models
    End point type
    Primary
    End point timeframe
    At 48 hours post baseline
    End point values
    		 Iloprost Placebo
    Number of subjects analysed
    11
    33
    Units: pg/L
    median (inter-quartile range (Q1-Q3))
        Adrenaline
    27.06 (15.71 to 239.31)
    55.20 (33.73 to 165.93)
        Noradrenaline
    1159.00 (398.59 to 2706.68)
    1608.65 (491.16 to 5137.72)
    Statistical analysis title
    		 Change in adrenaline level at 48 h
    Statistical analysis description
    Change in plasma levels over time from baseline to 48 hours
    Comparison groups
    Iloprost v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.88 [11]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [11] - Group*Time at the 48-hour endpoints
    Statistical analysis title
    		 Change in noradrenaline level at 48 h
    Statistical analysis description
    Change in plasma levels over time from baseline to 48 hours
    Comparison groups
    Iloprost v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.89 [12]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [12] - Group*Time at the 48-hour endpoints

    Primary: Change in endothelial biomarker (sTM) at 96 hours

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    End point title
    		 Change in endothelial biomarker (sTM) at 96 hours
    End point description
    Changes in endothelial damage and activation from baseline. The 2 arms were compared using baseline corrected proc Mixed models
    End point type
    Primary
    End point timeframe
    At 96 hours post baseline
    End point values
    		 Iloprost Placebo
    Number of subjects analysed
    10
    30
    Units: ng/ml
    median (inter-quartile range (Q1-Q3))
        Thrombomodulin
    7.11 (6.78 to 9.94)
    7.56 (5.53 to 8.86)
    Statistical analysis title
    		 Endpoint sTM at 96 hours
    Comparison groups
    Placebo v Iloprost
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.021 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.0909
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7426
         upper limit
    		 1.4392
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6966
    Notes
    [13] - Group*Time at the 96-hour endpoints

    Other pre-specified: Mortality

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    End point title
    		 Mortality
    End point description
    Number of death within 30, 90 and 180 days post baseline
    End point type
    Other pre-specified
    End point timeframe
    30, 90 and 180 days post intervention
    End point values
    		 Iloprost Placebo
    Number of subjects analysed
    13
    33
    Units: number
        Death within 30 days
    6
    8
        Death within 90 days
    6
    8
        Death within 180 days
    8
    8
    Statistical analysis title
    		 90-day mortality
    Comparison groups
    Iloprost v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.14
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 180-day mortality
    Comparison groups
    Iloprost v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.02
    Method
    		 Fisher exact
    Parameter type
    		 Log hazard ratio
    Point estimate
    2.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 7.4
    Statistical analysis title
    		 30-day mortality
    Comparison groups
    Iloprost v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.14
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported until day 30 post intervention start
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 The 13 patients in this intervention group

    Reporting group title
    Placebo
    Reporting group description
    		 All patients receiving placebo

    Serious adverse events
    		 Intervention Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 13 (15.38%)
    3 / 33 (9.09%)
         number of deaths (all causes)
    8
    8
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    traumatic bleeding
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Intervention Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 13 (61.54%)
    19 / 33 (57.58%)
    Vascular disorders
    Thrombocytopenia
         subjects affected / exposed
    3 / 13 (23.08%)
    9 / 33 (27.27%)
         occurrences all number
    3
    9
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    4 / 13 (30.77%)
    9 / 33 (27.27%)
         occurrences all number
    4
    9
    Seizure
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 33 (3.03%)
         occurrences all number
    1
    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.
    Electronic randomization allocation patients in a 2:1 manner instead of 1:1. The randomization allocation 1:2 resulted in a small sample size in the iloprost group with increased risk of type I and type II errors. Also limitation due to pilot trial

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31710844
    http://www.ncbi.nlm.nih.gov/pubmed/31945586
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