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    Clinical Trial Results:
    Randomized double blind placebo-controlled clinical safety, tolerability and pharmacokinetic/-dynamic study on the effects of escalating single intravenous doses of EA-230 on the innate immune response during experimental human endotoxemia

    Summary
    EudraCT number
    		 2014-002481-78
    Trial protocol
    		 NL  
    Global end of trial date
    26 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 May 2021
    First version publication date
    05 May 2021
    Other versions
    Summary report(s)
    		 A randomized double‐blind, placebo‐controlled clinical phase IIa trial on safety, immunomodulatory effects and pharmacokinetics of EA‐230 during experimental human endotoxaemia

    Trial information

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    Trial identification
    Sponsor protocol code
    EBI-EA230-LPS-2014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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
    Lucas van Eijk, Radboud UMC, Research Intensive care, lucas.vanEijk@radboudumc.nl
    Scientific contact
    Lucas van Eijk, Radboud UMC, Research Intensive care, lucas.vanEijk@radboudumc.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
    15 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1: To assess the safety, tolerability and pharmacokinetic-dynamic response, of single escalating doses of EA-230 in healthy subjects. Part 2: To assess the dose-and plasma concentration-response relation of single escalating doses EA-230 on inflammation and LPS-induced changes in markers for renal function, and to assess safety, tolerability and PK of EA-230 under the condition of experimental endotoxemia.
    Protection of trial subjects
    All subjects provided informed consent. Safety and tolerability assessments were performed continuously from the start of study drug treatment until 8 hours afterwards and at 4 consecutive study visits during the 14‐day follow‐up period. Safety parameters included vital signs (blood pressure and heart rate), 12‐lead ECG and routine laboratory haematology and biochemistry. AEs were recorded throughout the complete study period. All AEs were judged by the investigator with regard to severity (mild, moderate or severe) according to Common Terminology Criteria for Adverse Events guidelines 4.0,36 and their relation to the study drug (definitely related, probably related, possibly related, unlikely to be related or unrelated). LPS‐induced flu‐like symptoms were scored separately, as explained below, and for practical considerations excluded from safety analyses. SAEs included death, life‐threatening, persistent and/or significant disability and/or incapacity and hospitalization and/or prolongation of inpatient hospitalization. Safety parameters were reported to and reviewed by an independent Data Safety Monitoring Board (DSMB) after completion of each dosing group.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2014
    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
    Netherlands: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    36
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 36 healthy adult males enrolled

    Pre-assignment
    Screening details
    		 Health status of the participants was determined by medical history, physical examination, electrocardiogram (ECG) and routine laboratory blood tests.

    Period 1
    Period 1 title
    Full study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EA-230, 15 mg/kg/h
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    EA-230
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg/h

    Arm title
    		 EA-230, 45 mg/kg/h
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    EA-230
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    45 mg/kg/h

    Arm title
    		 EA-230, 90 mg/kg/h
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    EA-230
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/kg/h

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Osmolar equivalent of 29 mg/mL sodium chloride solution

    Number of subjects in period 1
    		EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h Placebo
    Started
    8
    8
    8
    12
    Completed
    8
    8
    8
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EA-230, 15 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    EA-230, 45 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    EA-230, 90 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h Placebo Total
    Number of subjects
    		 8 8 8 12 36
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 8 8 8 12 36
    Gender categorical
    Units: Subjects
        Male
    		 8 8 8 12 36

    End points

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    End points reporting groups
    Reporting group title
    EA-230, 15 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    EA-230, 45 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    EA-230, 90 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Safety and tolerability of EA-230

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    End point title
    		 Safety and tolerability of EA-230 [1]
    End point description
    End point type
    Primary
    End point timeframe
    During complete study period
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed as this concerns safety data.
    End point values
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h Placebo
    Number of subjects analysed
    8
    8
    8
    12
    Units: (Severe) adverse events
        Severe adverse events
    2
    2
    3
    7
        Adverse events
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Effects of EA‐230 on circulating levels of inflammatory mediators and adhesion molecules during endotoxaemia

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    End point title
    		 Effects of EA‐230 on circulating levels of inflammatory mediators and adhesion molecules during endotoxaemia
    End point description
    End point type
    Secondary
    End point timeframe
    Ethylenediaminetetraacetic acid (EDTA)‐anticoagulated blood samples for measurement of inflammatory parameters were obtained at time points t = 0, 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hours
    End point values
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h Placebo
    Number of subjects analysed
    8
    8
    8
    12
    Units: Area under the curve
    median (inter-quartile range (Q1-Q3))
        IL-6
    2433 (872 to 4700)
    1671 (869 to 2960)
    797 (372 to 1730)
    1768 (914 to 2435)
        TNFa
    145 (76 to 202)
    116 (64 to 163)
    100 (72 to 150)
    121 (86 to 160)
        IL-10
    346 (277 to 421)
    451 (173 to 623)
    529 (183 to 1089)
    454 (301 to 653)
        IL-8
    957 (773 to 1107)
    1123 (699 to 1454)
    1034 (713 to 1137)
    544 (474 to 893)
        MCP-1
    7902 (7558 to 11029)
    12238 (6480 to 12632)
    8234 (5867 to 10847)
    5328 (4743 to 10038)
    Statistical analysis title
    		 Differences over time
    Comparison groups
    EA-230, 90 mg/kg/h v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Repeated measures 2‐way ANOVA (interacti
    Confidence interval

    Secondary: Effects of EA‐230 on leucocyte counts and differentiation during endotoxaemia

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    End point title
    		 Effects of EA‐230 on leucocyte counts and differentiation during endotoxaemia
    End point description
    End point type
    Secondary
    End point timeframe
    EDTA anticoagulated blood samples were obtained at time points t = −1, 0, 1, 2, 4, 8, 24 and 48 hours
    End point values
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h Placebo
    Number of subjects analysed
    8
    8
    8
    12
    Units: Area under the curve
    median (inter-quartile range (Q1-Q3))
        Leucocytes
    10.1 (8.5 to 12.0)
    12.5 (10.7 to 14.6)
    11.8 (10.6 to 15.7)
    10.3 (7.8 to 12.2)
        Neutrophils
    12.9 (10.5 to 16.3)
    15.2 (13.2 to 17.4)
    16.2 (12.4 to 18.0)
    13.3 (9.8 to 15.2)
        Lymphocytes
    3.9 (2.6 to 4.8)
    3.7 (2.6 to 5.5)
    3.0 (2.5 to 4.7)
    4.2 (3.3 to 5.3)
        Monocytes
    1.1 (0.7 to 1.5)
    1.3 (1.1 to 1.8)
    1.0 (0.9 to 1.2)
    1.0 (0.9 to 1.5)
    Statistical analysis title
    		 Differences over time
    Comparison groups
    EA-230, 15 mg/kg/h v EA-230, 45 mg/kg/h v EA-230, 90 mg/kg/h v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Repeated measures 2‐way ANOVA (interacti
    Confidence interval

    Secondary: Effects of EA‐230 on vital signs and symptoms during endotoxaemia (body temperature)

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    End point title
    		 Effects of EA‐230 on vital signs and symptoms during endotoxaemia (body temperature)
    End point description
    End point type
    Secondary
    End point timeframe
    Every 30 minutes, temperature was measured from t=0 to t=8 (hours) after endotoxin administration
    End point values
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h Placebo
    Number of subjects analysed
    8
    8
    8
    12
    Units: Area under the curve
        median (inter-quartile range (Q1-Q3))
    529 (527 to 530)
    529 (524 to 534)
    529 (525 to 534)
    530 (526 to 534)
    Statistical analysis title
    		 Differences over time
    Comparison groups
    EA-230, 15 mg/kg/h v EA-230, 45 mg/kg/h v EA-230, 90 mg/kg/h v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Repeated measures 2‐way ANOVA (interacti
    Confidence interval

    Secondary: Effects of EA‐230 on vital signs and symptoms during endotoxaemia (symptom score)

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    End point title
    		 Effects of EA‐230 on vital signs and symptoms during endotoxaemia (symptom score)
    End point description
    End point type
    Secondary
    End point timeframe
    LPS‐induced flu‐like symptoms were scored per symptom every 30 minutes from t=0 to t=8 (hours) after endotoxin administration
    End point values
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h Placebo
    Number of subjects analysed
    8
    8
    8
    12
    Units: Area under the curve
    median (inter-quartile range (Q1-Q3))
        total symptom score
    11.0 (3.5 to 23.5)
    15.5 (8.3 to 22.1)
    6.0 (4.0 to 12.0)
    19.5 (9.0 to 27.4)
    Statistical analysis title
    		 Differences over time
    Comparison groups
    EA-230, 15 mg/kg/h v EA-230, 45 mg/kg/h v EA-230, 90 mg/kg/h v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Repeated measures 2‐way ANOVA (interacti
    Confidence interval

    Secondary: Pharmacokinetics of EA‐230 during endotoxaemia (AUC, 0-last)

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    End point title
    		 Pharmacokinetics of EA‐230 during endotoxaemia (AUC, 0-last) [2]
    End point description
    End point type
    Secondary
    End point timeframe
    t = 0 to the time of the last measured concentration
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No drug was adminstered in the baseline period yet, so no need for statistical comparison.
    End point values
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h
    Number of subjects analysed
    8
    8
    8
    Units: h.ug/L
        geometric mean (confidence interval 95%)
    2672 (2097 to 3403)
    7647 (5431 to 10766)
    19658 (15428 to 25046)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of EA‐230 during endotoxaemia (AUC, 0-inf)

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    End point title
    		 Pharmacokinetics of EA‐230 during endotoxaemia (AUC, 0-inf) [3]
    End point description
    End point type
    Secondary
    End point timeframe
    t = 0 to infinity extrapolated
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No drug was adminstered in the baseline period yet, so no need for statistical comparison.
    End point values
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h
    Number of subjects analysed
    3
    5
    8
    Units: h.ug/L
        geometric mean (confidence interval 95%)
    3349 (1244 to 9014)
    6519 (4243 to 10015)
    19658 (15429 to 25046)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of EA‐230 during endotoxaemia (Cmax)

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    End point title
    		 Pharmacokinetics of EA‐230 during endotoxaemia (Cmax) [4]
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout complete study period
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No drug was adminstered in the baseline period yet, so no need for statistical comparison.
    End point values
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h
    Number of subjects analysed
    8
    8
    8
    Units: ug/L
        geometric mean (confidence interval 95%)
    1983 (1725 to 2279)
    6030 (4190 to 8676)
    15657 (13100 to 18714)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the complete study period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE guidelines
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    EA-230, 15 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    EA-230, 45 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    EA-230, 90 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EA-230, 15 mg/kg/h EA-230, 45 mg/kg/h EA-230, 90 mg/kg/h Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 8 (25.00%)
    3 / 8 (37.50%)
    7 / 12 (58.33%)
    Nervous system disorders
    Head discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    General disorders and administration site conditions
    Infusion site reaction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    4 / 12 (33.33%)
         occurrences all number
    1
    0
    1
    4
    Feeling hot
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    upper abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Soft faeces
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    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.
    Human endotoxaemia model (model vs. clinical situation), only adult males, non-complete PK parameter dataset of subjects subjected to lower dosage EA230 group, no definite conclusions of optimal timing of EA230 administration

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30919998
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