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    Clinical Trial Results:
    Randomized double blind placebo-controlled phase II study on the effects of EA-230 on the innate immune response following on-pump cardiac surgery

    Summary
    EudraCT number
    		 2015-005600-28
    Trial protocol
    		 NL  
    Global end of trial date
    22 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Aug 2022
    First version publication date
    07 Aug 2022
    Other versions
    Summary report(s)
    		 Randomized double blind placebo-controlled phase II study on the effects of EA-230 on the innate immune response following on-pump cardiac surgery

    Trial information

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    Trial identification
    Sponsor protocol code
    EBI-CABG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03145220
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboud University Nijmegen Medical Centre
    Sponsor organisation address
    Geert Grooteplein 10, Nijmegen, Netherlands, 6500 HB
    Public contact
    Roger van Groenendael, Radboud University Medical Center, r.vangroenendael@radoudumc.nl
    Scientific contact
    Roger van Groenendael, Radboud University Medical Center, r.vangroenendael@radoudumc.nl
    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
    17 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess safety and tolerability of EA-230 in patients undergoing cardiac surgery with cardiopulmonary bypass. To assess the anti-inflammatory effect of EA-230 in patients with systemic inflammation following cardiac surgery.
    Protection of trial subjects
    In part 1 (phase IIa) a total of 30 patients receiving active treatment will be included.In part 2 (phase IIb) 60 patients per treatment group will be included. After enrolment in the study, patients will be monitored for a follow‐up time of 90 days. After inclusion of all patients in the first study part, a report containing all the relevant safety data including (S)AE’s and SUSARs will be provided to the DSMB and to the ethics committee (CMO). After unblinded analysis of all safety data, the DSMB will report an advice whether to proceed with part 2 of the study or not. Additionally, safety data will be re‐evaluated at a second interim analysis after a total of 90 patients have been included (including patients from both part 1 and part 2) The ethics committee will be provided with a copy of the interim safety report along with the evaluation regarding safety parameters by the DSMB.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2016
    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
    Netherlands: 179
    Worldwide total number of subjects
    179
    EEA total number of subjects
    179
    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)
    65
    From 65 to 84 years
    112
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients older than 18 years scheduled for elective coronary artery bypass grafting (CABG) procedure, with or without valve surgery, with use of CPB were eligible for participation. A standardized protocol was used for the surgical procedure and anesthetic management. Patients that were immune-compromised were excluded.

    Pre-assignment
    Screening details
    		 440 patients assessed for eligibilit 120 declined participation 140 ineligible 71 immuno-acve drugs 19 immunocompromised 15 iodine-contrast allergy 35 other 180 patients included 89 randomized to receive placebo 90 randomized to receive EA-230,

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 placebo
    Arm description
    		 NaCl in water for injection, osmotic strength 800‐1000 mOsm/L; pH 4.5‐7.0. Before administration placebo will be diluted in 1000 mL NaCl 0.9% to reach an osmotic strength of <400 mOsmol/L. Start of administration at first incision until stop of ECC pump, with a maximum total infusion time of 4 hours.
    Arm type
    		 Placebo

    Investigational medicinal product name
    NaCl 0.9%
    Investigational medicinal product code
    Other name
    Normal saline
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    NaCl in water for injection, osmotic strength 800‐1000 mOsm/L; pH 4.5‐7.0. Before administration placebo will be diluted in 1000 mL NaCl 0.9% to reach an osmotic strength of <400 mOsmol/L. Start of administration at first incision until stop of ECC pump, with a maximum total infusion time of 4 hours.

    Arm title
    		 EA-230
    Arm description
    		 300 mg/mL EA‐230 in water for injection; osmotic strength 800‐1000 mOsmol/L; pH 4.0 – 8.0. Before administration IMP will be diluted in 1000 mL NaCl 0.9% to obtain an osmotic strength of <400 mOsmol/L. Start of administration at first incision until stop of ECC pump, with a maximum total infusion time of 4 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    EA-230
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    300 mg/mL EA‐230 in water for injection; osmotic strength 800‐1000 mOsmol/L; pH 4.0 – 8.0. Before administration IMP will be diluted in 1000 mL NaCl 0.9% to obtain an osmotic strength of <400 mOsmol/L. Start of administration at first incision until stop of ECC pump, with a maximum total infusion time of 4 hours.

    Number of subjects in period 1
    		placebo EA-230
    Started
    89
    90
    Completed
    89
    90

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    placebo
    Reporting group description
    		 NaCl in water for injection, osmotic strength 800‐1000 mOsm/L; pH 4.5‐7.0. Before administration placebo will be diluted in 1000 mL NaCl 0.9% to reach an osmotic strength of <400 mOsmol/L. Start of administration at first incision until stop of ECC pump, with a maximum total infusion time of 4 hours.

    Reporting group title
    EA-230
    Reporting group description
    		 300 mg/mL EA‐230 in water for injection; osmotic strength 800‐1000 mOsmol/L; pH 4.0 – 8.0. Before administration IMP will be diluted in 1000 mL NaCl 0.9% to obtain an osmotic strength of <400 mOsmol/L. Start of administration at first incision until stop of ECC pump, with a maximum total infusion time of 4 hours.

    Reporting group values
    		 placebo EA-230 Total
    Number of subjects
    		 89 90 179
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 30 35 65
        From 65-84 years
    		 58 54 112
        85 years and over
    		 1 1 2
    Gender categorical
    Units: Subjects
        Female
    		 12 10 22
        Male
    		 77 80 157

    End points

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    End points reporting groups
    Reporting group title
    placebo
    Reporting group description
    		 NaCl in water for injection, osmotic strength 800‐1000 mOsm/L; pH 4.5‐7.0. Before administration placebo will be diluted in 1000 mL NaCl 0.9% to reach an osmotic strength of <400 mOsmol/L. Start of administration at first incision until stop of ECC pump, with a maximum total infusion time of 4 hours.

    Reporting group title
    EA-230
    Reporting group description
    		 300 mg/mL EA‐230 in water for injection; osmotic strength 800‐1000 mOsmol/L; pH 4.0 – 8.0. Before administration IMP will be diluted in 1000 mL NaCl 0.9% to obtain an osmotic strength of <400 mOsmol/L. Start of administration at first incision until stop of ECC pump, with a maximum total infusion time of 4 hours.

    Primary: Adverse events

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    End point title
    		 Adverse events
    End point description
    End point type
    Primary
    End point timeframe
    until 90-days post-surgery
    End point values
    		 placebo EA-230
    Number of subjects analysed
    89
    90 [1]
    Units: AEs
        Treatment-emergent AEs
    218
    217
        Treatment-emergent SAEs
    19
    13
        SUSARs
    1
    0
        Major clinical AEs related to cardiac surgery
    15
    11
    Notes
    [1] - 1 patients was excluded because of a last-minute decision to perform surgery without CPB
    Statistical analysis title
    		 Not applicable
    Statistical analysis description
    Not applicable as this concerns safety data.
    Comparison groups
    placebo v EA-230
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 1
    Method
    		 NA
    Confidence interval
    Notes
    [2] - Not applicable as this concerns safety data.

    Primary: Plasma Il-6 levels

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    End point title
    		 Plasma Il-6 levels
    End point description
    End point type
    Primary
    End point timeframe
    From pre-surgery until the first postoperative day
    End point values
    		 placebo EA-230
    Number of subjects analysed
    89
    90 [3]
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    213 (154 to 287)
    189 (141 to 293)
    Notes
    [3] - 1 patients was excluded because of a last-minute decision to perform surgery without CPB
    Statistical analysis title
    		 Comparison
    Comparison groups
    placebo v EA-230
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.99
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Until day 90 post-surgery (so also post-treatment)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    placebo
    Reporting group description
    		 NaCl in water for injection, osmotic strength 800‐1000 mOsm/L; pH 4.5‐7.0. Before administration placebo will be diluted in 1000 mL NaCl 0.9% to reach an osmotic strength of <400 mOsmol/L. Start of administration at first incision until stop of ECC pump, with a maximum total infusion time of 4 hours.

    Reporting group title
    EA-230
    Reporting group description
    		 300 mg/mL EA‐230 in water for injection; osmotic strength 800‐1000 mOsmol/L; pH 4.0 – 8.0. Before administration IMP will be diluted in 1000 mL NaCl 0.9% to obtain an osmotic strength of <400 mOsmol/L. Start of administration at first incision until stop of ECC pump, with a maximum total infusion time of 4 hours.

    Serious adverse events
    		 placebo EA-230
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 89 (19.10%)
    12 / 90 (13.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    N/A
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    N/A
         subjects affected / exposed
    6 / 89 (6.74%)
    4 / 90 (4.44%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    N/A
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    N/A
         subjects affected / exposed
    2 / 89 (2.25%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    N/A
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    N/A
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    N/A
         subjects affected / exposed
    2 / 89 (2.25%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 placebo EA-230
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    81 / 89 (91.01%)
    78 / 90 (86.67%)
    Vascular disorders
    N/A
         subjects affected / exposed
    29 / 89 (32.58%)
    26 / 90 (28.89%)
         occurrences all number
    29
    26
    Cardiac disorders
    N/A
         subjects affected / exposed
    45 / 89 (50.56%)
    44 / 90 (48.89%)
         occurrences all number
    45
    44
    Nervous system disorders
    N/A
         subjects affected / exposed
    14 / 89 (15.73%)
    11 / 90 (12.22%)
         occurrences all number
    14
    11
    Blood and lymphatic system disorders
    N/A
         subjects affected / exposed
    8 / 89 (8.99%)
    5 / 90 (5.56%)
         occurrences all number
    8
    5
    General disorders and administration site conditions
    N/A
         subjects affected / exposed
    22 / 89 (24.72%)
    17 / 90 (18.89%)
         occurrences all number
    22
    17
    Gastrointestinal disorders
    N/A
         subjects affected / exposed
    23 / 89 (25.84%)
    21 / 90 (23.33%)
         occurrences all number
    23
    21
    Respiratory, thoracic and mediastinal disorders
    N/A
         subjects affected / exposed
    14 / 89 (15.73%)
    13 / 90 (14.44%)
         occurrences all number
    14
    13
    Psychiatric disorders
    N/A
         subjects affected / exposed
    13 / 89 (14.61%)
    9 / 90 (10.00%)
         occurrences all number
    13
    9
    Renal and urinary disorders
    N/A
         subjects affected / exposed
    11 / 89 (12.36%)
    4 / 90 (4.44%)
         occurrences all number
    11
    4
    Infections and infestations
    N/A
         subjects affected / exposed
    17 / 89 (19.10%)
    13 / 90 (14.44%)
         occurrences all number
    17
    13
    Product issues
    N/A
         subjects affected / exposed
    9 / 89 (10.11%)
    9 / 90 (10.00%)
         occurrences all number
    9
    9
    Metabolism and nutrition disorders
    N/A
         subjects affected / exposed
    14 / 89 (15.73%)
    10 / 90 (11.11%)
         occurrences all number
    14
    10

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33591006
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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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