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    Clinical Trial Results:
    Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response after Out-of-Hospital Cardiac Arrest

    Summary
    EudraCT number
    		 2018-002686-19
    Trial protocol
    		 DK  
    Global end of trial date
    31 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Sep 2021
    First version publication date
    15 Sep 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2018-HJEPharma-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03863015
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 The IMICA Trial: Acronym
    Sponsors
    Sponsor organisation name
    Prof. Hassager, Dept. Cardiology, Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Department of Cardiology, Copenhagen University Hospital Rigshospitalet, christian.hassager@regionh.dk
    Scientific contact
    Department of Cardiology, Copenhagen University Hospital Rigshospitalet, christian.hassager@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
    03 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Out-of-hospital cardiac arrest (OHCA) patients remaining comatose after resuscitation are at high risk of morbidity and mortality due to the post cardiac arrest syndrome (PCAS). Systemic inflammation is a major component of PCAS, and interleukin-6 (IL-6) levels are associated with severity of PCAS. Therefore, tocilizumab, which is an IL-6 receptor antagonist, could potentially dampen inflammation after OHCA. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after OHCA of presumed cardiac cause and thereby potentially mitigate organ injury. The primary endpoint of the study was difference in CRP response between the tocilizumab and placebo group during initial 72 hours. Secondary endpoints included markers of inflammation, organ injury, neurologic outcome, safety and survival. For a comprehensive presentation and discussion of trial results please see: https://doi.org/10.1161/CIRCULATIONAHA.120.053318
    Protection of trial subjects
    Participation in the trial did not limit the access to any additional treatments and patients were treated according to standard of care as well (described below). Co-participation in other trials was allowed as well. Patients with know contraindications to treatment with the study drug (tocilizumab) were excluded during screening. Exclusion criteria included previous allergic reactions to tocilizumab, significant liver impairment, and significant infection as there is a potential immunosuppressive effect of tocilizumab. Further, all patients participating in the trial were treated with prophylactic antibiotics to possibly limit the occurrence of infections during the initial ICU stay.
    Background therapy
    		 In addition to the trial associated treatment, all patients received "standard of care" including sedation, ventilation and targeted temperature management for at least 24 hours, as well as vasopressors/inotropy as needed. Further all patients received prophylactic antibiotics.
    Evidence for comparator
    		 Isotonic saline was chosen as placebo treatment, and no significant effect of this was expected.
    Actual start date of recruitment
    04 Mar 2019
    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: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    41
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was completed in 9 months (ahead of schedule)

    Pre-assignment
    Screening details
    		 Brief inclusion criteria: Adult comatose patients resuscitated from OHCA of presumed cardiac cause. We screened 117 patients and randomized 85 patients - tocilizumab: 42, placebo: 43; 5 patients were excluded prior to analysis (tocilizumab: 3; placebo: 2). Data in this report refer to the resulting modified intention-to-treat population of 80.

    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, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tocilizumab
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients allocated to the tocilizumab group received a 1-h infusion of 8 mg tocilizumab per kilogram body weight (maximum dose 800 mg, i.e. 40 mL of concentrate); the study drug was suspended in normal saline to a total volume of 100 mL.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Isotonic saline, NaCl
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients allocated to the placebo arm received a 1-h infusion of 100 mL of normal saline.

    Number of subjects in period 1
    		Tocilizumab Placebo
    Started
    39
    41
    Completed
    39
    41

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tocilizumab
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Tocilizumab Placebo Total
    Number of subjects
    		 39 41 80
    Age categorical
    Units: Subjects
    Age continuous
    Age at time of OHCA
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 65 (53 to 73) 60 (57 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7 14
        Male
    		 32 34 66

    End points

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    End points reporting groups
    Reporting group title
    Tocilizumab
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: C-reactive protein

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    End point title
    		 C-reactive protein
    End point description
    End point type
    Primary
    End point timeframe
    Measured at admission, 24, 48, and 72 hours
    End point values
    		 Tocilizumab Placebo
    Number of subjects analysed
    39
    41
    Units: mg/L
    median (inter-quartile range (Q1-Q3))
        Admission
    2 (1 to 10)
    2 (1 to 3)
        24 hours
    23 (10 to 45)
    123.5 (90 to 169.5)
        48 hours
    13 (5 to 32)
    202 (151 to 270)
        72 hours
    7 (3 to 18)
    146.5 (112 to 205)
    Statistical analysis title
    		 CRP, mixed model analysis
    Statistical analysis description
    CRP from admission till 72 hours.
    Comparison groups
    Tocilizumab v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - Linear mixed model, baseline adjusted.
    [2] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 24 hours: p < 0.001 At 48 hours: p < 0.001 At 72 hours: p < 0.001

    Secondary: Leukocytes

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    End point title
    		 Leukocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at admission, 24, 48 and 72 hours
    End point values
    		 Tocilizumab Placebo
    Number of subjects analysed
    39
    41
    Units: 10^9/L
    median (inter-quartile range (Q1-Q3))
        Admission
    14.5 (10.5 to 17.9)
    18.2 (14.1 to 21)
        24 hours
    7.5 (4.8 to 13.5)
    12.8 (10.35 to 16.15)
        48 hours
    7.3 (5.8 to 12.8)
    12 (10.15 to 14.85)
        72 hours
    7.7 (5.7 to 10.6)
    11.45 (9.6 to 12.6)
    Statistical analysis title
    		 Leukocytes, mixed model analysis
    Statistical analysis description
    Leukocytes from admission till 72 hours
    Comparison groups
    Tocilizumab v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0005 [4]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - Linear mixed model, baseline adjusted.
    [4] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 24 hours: p < 0.001 At 48 hours: p = 0.004 At 72 hours: p = 0.129

    Secondary: Troponin T (TnT)

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    End point title
    		 Troponin T (TnT)
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at admission, 6, 12, 24, 36, 48 and 72 hours.
    End point values
    		 Tocilizumab Placebo
    Number of subjects analysed
    39
    41
    Units: ug/L
    median (inter-quartile range (Q1-Q3))
        Admission
    190.5 (102 to 606)
    217 (108 to 634)
        6 hours
    908 (206 to 2680)
    1330 (764 to 3080)
        12 hours
    665 (206 to 2550)
    1150 (484 to 3420)
        24 hours
    435 (169 to 2830)
    881.5 (310.5 to 3345)
        36 hours
    370.5 (109.5 to 1970)
    666 (304 to 2900)
        48 hours
    289.5 (113 to 1660)
    548 (225 to 2530)
        72 hours
    256 (92.5 to 1935)
    536 (175 to 1860)
    Statistical analysis title
    		 TnT, mixed model analysis
    Statistical analysis description
    TnT from admission till 72 hours.
    Comparison groups
    Tocilizumab v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.0932 [6]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [5] - Linear mixed model, baseline adjusted.
    [6] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 6 hours: p = 0.002 At 12 hours: p = 0.008 At 24 hours: p = 0.065 At 36 hours: NS At 48 hours: NS At 72 hours: NS

    Secondary: Creatine kinase myocardial band (CKMB)

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    End point title
    		 Creatine kinase myocardial band (CKMB)
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at admission, 6, 12, 24, 36, 48 and 72 hours.
    End point values
    		 Tocilizumab Placebo
    Number of subjects analysed
    39
    41
    Units: ug/L
    median (inter-quartile range (Q1-Q3))
        Admission
    7.7 (4 to 31.8)
    9.8 (7.1 to 31.9)
        6 hours
    27.7 (10.2 to 171)
    62.75 (30.6 to 185)
        12 hours
    30.6 (10.8 to 170)
    61.7 (21.6 to 186)
        24 hours
    23.4 (8.9 to 116)
    44 (18.5 to 131.5)
        36 hours
    18.35 (6.95 to 54.85)
    25.45 (10.7 to 64.4)
        48 hours
    8.85 (4.75 to 25.95)
    13.5 (7.6 to 35.4)
        72 hours
    5.95 (2.75 to 16.25)
    7.8 (3.7 to 11.2)
    Statistical analysis title
    		 CKMB, mixed model analysis
    Statistical analysis description
    CKMB from admission till 72 hours
    Comparison groups
    Tocilizumab v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.0035 [8]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [7] - Linear mixed model, baseline adjusted.
    [8] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 6 hours: p < 0.001 At: 12 hours: p = 0.001 At 24 hours: p = 0.050 At 36 hours: NS At 48 hours: NS At 72 hour: NS

    Secondary: N-terminal pro B-type natriuretic peptide (NT-proBNP)

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    End point title
    		 N-terminal pro B-type natriuretic peptide (NT-proBNP)
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at admission and 48 hours.
    End point values
    		 Tocilizumab Placebo
    Number of subjects analysed
    39
    41
    Units: pmol/L
    median (inter-quartile range (Q1-Q3))
        Admission
    97.6 (27.7 to 427)
    44.9 (14.3 to 162)
        48 hours
    122.5 (52.85 to 374.5)
    179 (88.2 to 491)
    Statistical analysis title
    		 NT-proBNP, mixed model analysis
    Statistical analysis description
    NT-proBNP from admission till 48 hours.
    Comparison groups
    Tocilizumab v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.0002 [10]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [9] - Linear mixed model, baseline adjusted.
    [10] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 48 hours: p < 0.001

    Secondary: Neuron-specific enolase (NSE)

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    End point title
    		 Neuron-specific enolase (NSE)
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 48 and 72 hours.
    End point values
    		 Tocilizumab Placebo
    Number of subjects analysed
    39
    41
    Units: ug/L
    median (inter-quartile range (Q1-Q3))
        48 hours
    24 (17.6 to 56.8)
    20.85 (14.5 to 37)
        72 hours
    20 (17.1 to 30)
    17 (12.8 to 22.4)
    Statistical analysis title
    		 NSE, mixed model
    Comparison groups
    Tocilizumab v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.27 [12]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [11] - Linear mixed model.
    [12] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 48 hours: p = 0.22 At 72 hours: p = 0.39

    Secondary: Cerebral Performance Category (CPC) after 180 days

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    End point title
    		 Cerebral Performance Category (CPC) after 180 days
    End point description
    A score ≥3 indicate a poor neurologic outcome (incl. death)
    End point type
    Secondary
    End point timeframe
    180 days after Out-of-hospital cardiac arrest
    End point values
    		 Tocilizumab Placebo
    Number of subjects analysed
    39
    41
    Units: Score
        ≥3
    15
    15
    Statistical analysis title
    		 CPC after 180 days
    Statistical analysis description
    Comparing the frequency of a poor neurologic outcome in the two groups
    Comparison groups
    Tocilizumab v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Modified Rankin Scale (mRS) after 180 days

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    End point title
    		 Modified Rankin Scale (mRS) after 180 days
    End point description
    A score ≥4 indicate a poor neurologic outcome (incl. death)
    End point type
    Secondary
    End point timeframe
    180 days after Out-of-hospital cardiac arrest
    End point values
    		 Tocilizumab Placebo
    Number of subjects analysed
    39
    41
    Units: Score
        ≥4
    16
    14
    Statistical analysis title
    		 mRS after 180 days
    Statistical analysis description
    Comparing the frequency of a poor neurologic outcome in the two groups
    Comparison groups
    Tocilizumab v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.65
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Mortality after 180 days

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    End point title
    		 Mortality after 180 days
    End point description
    End point type
    Secondary
    End point timeframe
    180 days after Out-of-hospital cardiac arrest
    End point values
    		 Tocilizumab Placebo
    Number of subjects analysed
    39
    41
    Units: No.
        Deaths after 180 days
    14
    14
    Statistical analysis title
    		 Mortality after 180 days
    Comparison groups
    Placebo v Tocilizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization till 6 months after
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Study protocol
    Dictionary version
    1.91
    Reporting groups
    Reporting group title
    Tocilizumab
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Tocilizumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 39 (51.28%)
    21 / 41 (51.22%)
         number of deaths (all causes)
    14
    14
         number of deaths resulting from adverse events
    14
    14
    Cardiac disorders
    Arrhythmia
    Additional description: An AE of arrhythmia that fulfilled the criteria for being classifies as a SAE.
         subjects affected / exposed
    3 / 39 (7.69%)
    4 / 41 (9.76%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    General disorders and administration site conditions
    Bleeding
    Additional description: An AE of bleeding that fulfilled the criteria for being a SAE.
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Other
    Additional description: An AE of "other" that fulfilled the criteria for being a SAE. This category also includes deaths as a result of withdrawal of life sustaining therapy due to irreversible brain injury after the cardiac arrest.
         subjects affected / exposed
    17 / 39 (43.59%)
    17 / 41 (41.46%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 17
         deaths causally related to treatment / all
    0 / 14
    0 / 10
    Infections and infestations
    Infection
    Additional description: An AE of infection that fulfilled the criteria for being a SAE. By definition all infections in the trial was classified as "possibly" related to the intervention.
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Tocilizumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 39 (89.74%)
    40 / 41 (97.56%)
    Cardiac disorders
    Arrhythmia
    Additional description: Defined as the occurrence of VF, VT, AF, need for pacing, or circulatory collapse
         subjects affected / exposed
    7 / 39 (17.95%)
    16 / 41 (39.02%)
         occurrences all number
    8
    19
    Nervous system disorders
    Seizures
    Additional description: Defined as the occurrence of seizures, including tonic-clonic, myoclonic, status epilepticus
         subjects affected / exposed
    9 / 39 (23.08%)
    8 / 41 (19.51%)
         occurrences all number
    9
    8
    General disorders and administration site conditions
    Bleeding
    Additional description: Defined as the occurrence of bleeding, either diagnosed in-hospital or requiring in-hospital treatment.
         subjects affected / exposed
    11 / 39 (28.21%)
    6 / 41 (14.63%)
         occurrences all number
    13
    6
    Other
    Additional description: Other adverse events potentially related to the intervention.
         subjects affected / exposed
    8 / 39 (20.51%)
    7 / 41 (17.07%)
         occurrences all number
    10
    7
    Renal and urinary disorders
    Dialysis
    Additional description: Temporary use of dialysis/renal replacement therapy during ICU stay
         subjects affected / exposed
    10 / 39 (25.64%)
    2 / 41 (4.88%)
         occurrences all number
    10
    2
    Infections and infestations
    Infection
    Additional description: Defined as the occurrence infections either diagnosed in-hospital or requiring in-hospital treatment. By definition all infections occurring in the trial were classified as being at least "possibly" related to the intervention.
         subjects affected / exposed
    4 / 39 (10.26%)
    9 / 41 (21.95%)
         occurrences all number
    5
    11
    Metabolism and nutrition disorders
    Electrolyte imbalance
    Additional description: Defined as a serum K <3 or >5
         subjects affected / exposed
    23 / 39 (58.97%)
    20 / 41 (48.78%)
         occurrences all number
    29
    22
    Metabolic disorder
    Additional description: Defined as the occurrence of a serum glucose <3mM, or >10mM for >4 hours
         subjects affected / exposed
    18 / 39 (46.15%)
    27 / 41 (65.85%)
         occurrences all number
    20
    28

    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/33081828
    http://www.ncbi.nlm.nih.gov/pubmed/33745292
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