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    Clinical Trial Results:
    STEROID TREATMENT AS ANTI-INFLAMMATORY AND NEUROPROTECTIVE AGENT FOLLOWING OUT-OF-HOSPITAL CARDIAC ARREST. A RANDOMIZED TRIAL.

    Summary
    EudraCT number
    		 2020-000855-11
    Trial protocol
    		 DK  
    Global end of trial date
    28 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Feb 2024
    First version publication date
    10 Feb 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HJE-STEROHCA-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04624776
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 The STEROHCA Trial: Acronym
    Sponsors
    Sponsor organisation name
    Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen OE, Denmark, 2100
    Public contact
    Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, 45 35450572, christian.hassager@regionh.dk
    Scientific contact
    Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, 45 35450572, 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
    28 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jul 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Patients suffering from out-of-hospital cardiac arrest (OHCA) who remain in a comatose state post-resuscitation face elevated risk of mortality due to the post-cardiac arrest syndrome (PCAS). PCAS features systemic inflammation, which is associated to poor outcomes in OHCA. Hence, attenuating inflammation could potentially be beneficial following OHCA. The primary objective of this trial was to determine the efficacy of the anti-inflammatory glucocorticoid "methylprednisolone" compared with placebo. The co-primary endpoints were serial measurements of interleukin-6 and neuron-specific-enolase as markers of systemic inflammation and brain injury at admission and 24, 48 and 72 hours after admission in patients admitted after resuscitated OHCA. The secondary endpoints included other biomarkers for inflammation and brain injury, markers of organ injury, safety, and survival. The primary results have been published: https://doi.org/10.1007/s00134-023-07247-w
    Protection of trial subjects
    All patients included in the trial were treated according to international post-resuscitation guidelines, and trial participation did not restrict additional treatment. Concurrent enrollment in other trials was permissible. Patients were screened for contraindications to the intervention before enrollment, and the trial was monitored and evaluated for safety throughout the study period. The intervention, methylprednisolone, has known immunosuppressive effects and can induce hyperglycemia, but as part of standard of care, all patients received prophylactic antibiotics to potentially reduce the incidence of infections and continuous intravenous insulin for hyperglycaemia during the initial intensive care unit stay.
    Background therapy
    		 After resuscitated out-of-hospital cardiac arrest, patients underwent standard care following International post-resuscitation guidelines. This included targeted temperature management at 36°C for comatose patients, sedation primarily utilizing propofol and fentanyl, and the administration of vasopressors and inotropes as necessary. Furthermore, all comatose patients received prophylactic antibiotic treatment with intravenous piperacillin/tazobactam or cefuroxime in the event of a β-lactam allergy. Continuous intravenous insulin was also administered to address hyperglycemia.
    Evidence for comparator
    		 No significant effect was expected by the comparator (Placebo: isotonic saline 0.9%)
    Actual start date of recruitment
    10 Oct 2020
    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: 137
    Worldwide total number of subjects
    137
    EEA total number of subjects
    137
    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)
    58
    From 65 to 84 years
    74
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment period was completed in 21 months (expected period was 18 months as defined in the protocol)

    Pre-assignment
    Screening details
    		 In the study period, 207 out of 1976 patients in the study region were eligible for inclusion, with 158 patients being randomized (80 methylprednisolone, 78 placebo). Of these, 137 patients encompassed the modified intention-to-treat (21 patients excluded; methylprednisolone 12, placebo 9), which this report is based on.

    Period 1
    Period 1 title
    Overall trial period (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
    Blinding implementation details
    After opening a medicine box, the including prehospital physician and accompanying medical assistant became unblinded. Subsequently, the prehospital staff played no further role in the patient's treatment or the study post-admission. Treatment allocation remained blinded for the patient, all hospital personnel, as well as all study investigators and staff.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Isotonic saline, NaCl 0.9%
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraosseous use, Intravenous use
    Dosage and administration details
    Placebo consisted of administration of 4 mL of isotonic saline (NaCl 0.9%)

    Arm title
    		 Methylprednisolone
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Solu-medrol
    Investigational medicinal product code
    6132
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraosseous use, Intravenous use
    Dosage and administration details
    A dosis of 250 mg methylprednisolone suspended in isotonic saline to a total volume of 4 mL prior to infusion. Administration was done over a period of minimum 5 minutes.

    Number of subjects in period 1
    		Placebo Methylprednisolone
    Started
    69
    68
    Completed
    69
    68

    Baseline characteristics

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

    Reporting group title
    Methylprednisolone
    Reporting group description
    		 -

    Reporting group values
    		 Placebo Methylprednisolone Total
    Number of subjects
    		 69 68 137
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age at time of OHCA
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 66 (56 to 75) 67 (57 to 74) -
    Gender categorical
    Units: Subjects
        Female
    		 13 12 25
        Male
    		 56 56 112

    End points

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

    Reporting group title
    Methylprednisolone
    Reporting group description
    		 -

    Primary: Interleukin 6, IL-6

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    End point title
    		 Interleukin 6, IL-6
    End point description
    End point type
    Primary
    End point timeframe
    Measured at admission, 24, 48, and 72 hours
    End point values
    		 Placebo Methylprednisolone
    Number of subjects analysed
    69
    68
    Units: pg/mL
    geometric mean (confidence interval 95%)
        Admission
    15.0 (10.4 to 21.7)
    15.0 (10.4 to 21.6)
        24 hours
    29.8 (18.9 to 46.8)
    2.1 (1.3 to 3.2)
        48 hours
    10.1 (6.7 to 15.1)
    5.7 (3.8 to 8.4)
        72 hours
    3.4 (2.2 to 5.4)
    4.3 (2.7 to 6.6)
    Statistical analysis title
    		 Interleukin 6, mixed model analysis
    Statistical analysis description
    Interleukin 6 levels from admission to 72 hours after admission
    Comparison groups
    Placebo v Methylprednisolone
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 ≤ 0.0001 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - Linear mixed model without baseline adjustment
    [2] - P value for the treatment-by-time interaction listed above. Time specific comparisons of methylprednisolone vs placebo at admission: p=0.9, 24 hours: p<0.0001, 48 hours: p=0.05, and 72 hours: p=0.5.

    Primary: Neuron-specific enolase, NSE

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    End point title
    		 Neuron-specific enolase, NSE
    End point description
    End point type
    Primary
    End point timeframe
    Measured at admission, 24, 48, and 72 hours
    End point values
    		 Placebo Methylprednisolone
    Number of subjects analysed
    69
    68
    Units: ug/L
    geometric mean (confidence interval 95%)
        Admission
    17.2 (14.8 to 20.0)
    19.6 (16.9 to 22.7)
        24 hours
    17.2 (14.3 to 20.7)
    19.1 (15.9 to 22.9)
        48 hours
    14.8 (11.2 to 19.4)
    18.8 (14.4 to 24.6)
        72 hours
    14.7 (11.1 to 19.5)
    15.7 (11.9 to 20.9)
    Statistical analysis title
    		 Neuron-specific enolase, mixed model analysis
    Statistical analysis description
    Neuron-specific enolase levels from admission to 72 hours after admission
    Comparison groups
    Methylprednisolone v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.22 [4]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - Linear mixed model without baseline adjustment
    [4] - P value for the treatment-by-time interaction listed above. Time specific comparisons of methylprednisolone vs placebo at admission: p=0.24, 24 hours: p=0.42, 48 hours: p=0.21, and 72 hours: p=0.75.

    Secondary: Survival after 180 days

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    End point title
    		 Survival after 180 days
    End point description
    End point type
    Secondary
    End point timeframe
    Survival 180 days after cardiac arrest
    End point values
    		 Placebo Methylprednisolone
    Number of subjects analysed
    69
    68
    Units: No.
    number (not applicable)
        Alive at 180 days
    44
    51
    Statistical analysis title
    		 Survival after 180 days
    Comparison groups
    Placebo v Methylprednisolone
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.17
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.2

    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 of ≥3 indicating a poor neurologic outcome, including death
    End point type
    Secondary
    End point timeframe
    CPC evaluated 180 days after cardiac arrest
    End point values
    		 Placebo Methylprednisolone
    Number of subjects analysed
    69
    68
    Units: Score
    number (not applicable)
        180 days after cardiac arrest
    26
    19
    Statistical analysis title
    		 CPC score 180 days after OHCA
    Statistical analysis description
    Comparing poor neurologic outcome (score ≥3) in the two treatment arms
    Comparison groups
    Placebo v Methylprednisolone
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.28
    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 of ≥4 indicating a poor neurologic outcome, including death
    End point type
    Secondary
    End point timeframe
    mRS evaluated 180 days after cardiac arrest
    End point values
    		 Placebo Methylprednisolone
    Number of subjects analysed
    69
    68
    Units: Score
    number (not applicable)
        180 days after cardiac arrest
    17
    26
    Statistical analysis title
    		 mRS score 180 days after OHCA
    Statistical analysis description
    Comparing poor neurologic outcome (score ≥4) in the two treatment arms
    Comparison groups
    Placebo v Methylprednisolone
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.14
    Method
    		 Fisher exact
    Confidence interval

    Secondary: C-reactive protein, CRP

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    End point title
    		 C-reactive protein, CRP
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at admission, 24, 48, and 72 hours
    End point values
    		 Placebo Methylprednisolone
    Number of subjects analysed
    69
    68
    Units: mg/L
    geometric mean (confidence interval 95%)
        Admission
    3.15 (2.18 to 4.13)
    2.13 (1.49 to 2.78)
        24 hours
    72.40 (55.91 to 88.89)
    24.90 (19.31 to 30.49)
        48 hours
    122.82 (90.08 to 155.56)
    35.58 (26.28 to 44.89)
        72 hours
    96.46 (69.61 to 123.30)
    45.35 (32.88 to 57.81)
    Statistical analysis title
    		 CRP, mixed model analysis
    Statistical analysis description
    CRP levels from admission to 72 hours after admission
    Comparison groups
    Placebo v Methylprednisolone
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [5] - Linear mixed model without baseline adjustment
    [6] - P value for the treatment-by-time interaction listed above. Time specific comparisons of methylprednisolone vs placebo at admission: p=0.08, 24 hours: p <0.0001, 48 hours: p<0.0001, and 72 hours: p<0.001.

    Secondary: Neurofilament light chain, NfL

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    End point title
    		 Neurofilament light chain, NfL
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at admission, 24, 48, and 72 hours
    End point values
    		 Placebo Methylprednisolone
    Number of subjects analysed
    69
    68
    Units: pg/mL
    geometric mean (confidence interval 95%)
        Admission
    68.3 (54.3 to 82.2)
    68.0 (53.9 to 82.2)
        24 hours
    184.1 (98.0 to 270.2)
    190.4 (103.2 to 277.5)
        48 hours
    230.5 (110.3 to 350.7)
    248.8 (121.9 to 375.8)
        72 hours
    243.2 (120.0 to 366.3)
    263.2 (132.8 to 393.6)
    Statistical analysis title
    		 NfL, mixed model analysis
    Statistical analysis description
    NfL levels from admission to 72 hours after admission
    Comparison groups
    Placebo v Methylprednisolone
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.96 [8]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [7] - Linear mixed model without baseline adjustment
    [8] - P value for the treatment-by-time interaction listed above. Time specific comparisons of methylprednisolone vs placebo at admission: p=0.9, 24 hours: p=0.9, 48 hours: p=0.8, and 72 hours: p=0.8.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of randomization till 180 days after cardiac arrest
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Study protocol
    Dictionary version
    3.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Methylprednisolone
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Methylprednisolone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 69 (53.62%)
    35 / 68 (51.47%)
         number of deaths (all causes)
    25
    17
         number of deaths resulting from adverse events
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    10 / 69 (14.49%)
    7 / 68 (10.29%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Nervous system disorders
    Seizure
         subjects affected / exposed
    13 / 69 (18.84%)
    12 / 68 (17.65%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    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
    4 / 69 (5.80%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Dialysis
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    4 / 69 (5.80%)
    5 / 68 (7.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolic disorder
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Placebo Methylprednisolone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 69 (47.83%)
    49 / 68 (72.06%)
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    7 / 69 (10.14%)
    7 / 68 (10.29%)
         occurrences all number
    8
    9
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Bleeding
         subjects affected / exposed
    3 / 69 (4.35%)
    2 / 68 (2.94%)
         occurrences all number
    3
    2
    Electrolyte imbalance
         subjects affected / exposed
    15 / 69 (21.74%)
    25 / 68 (36.76%)
         occurrences all number
    17
    30
    Infections and infestations
    Infection
         subjects affected / exposed
    4 / 69 (5.80%)
    2 / 68 (2.94%)
         occurrences all number
    5
    3
    Metabolism and nutrition disorders
    Metabolic disorder
         subjects affected / exposed
    8 / 69 (11.59%)
    27 / 68 (39.71%)
         occurrences all number
    8
    30

    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/36414975
    http://www.ncbi.nlm.nih.gov/pubmed/37943300
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