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    Clinical Trial Results:
    Steroids in Cardiac Surgery (SIRS) trial

    Summary
    EudraCT number
    		 2011-001495-18
    Trial protocol
    		 BE  
    Global end of trial date
    01 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jun 2022
    First version publication date
    02 Jun 2022
    Other versions
    Summary report(s)
    		 SIRS Lancet Publication

    Trial information

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    Trial identification
    Sponsor protocol code
    2010-04-23
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00427388
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 EudraCT Austria: 2011-001099-21, EudraCT Ireland: 2011-000591-34-IE, EudraCT Belgium: 2011-001495-18-BE, EudraCT Italy: 2010-023093-39
    Sponsors
    Sponsor organisation name
    Population Health Research Institute
    Sponsor organisation address
    237 Barton Street East, Hamilton, ON, Canada, L8L 2X2
    Public contact
    SIRS Project Office, Population Health Research Institute, 905 522-1155 x40635, Sirs@phri.ca
    Scientific contact
    Dr. Richard Whitlock, Population Health Research Institute, 905 521-2100 x40306, Richard.Whitlock@phri.ca
    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
    26 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Cardiopulmonary bypass (CPB) initiates a systemic inflammatory response syndrome that is associated with postoperative morbidity and mortality. Steroids suppress inflammatory responses and might improve outcomes in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass. The objective of this study is to assess the effects of steroids in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass. More specifically, this will be assessed by administering 500 mg of methylprednisolone divided into two intravenous doses of 250 mg each, one during anesthetic induction and the other on CPB initiation, or matching placebo.
    Protection of trial subjects
    An independent data and safety monitoring board reviewed the interim analyses when 50% and 75% of the 30-day follow-up data were available. SAS version 9.1 was used for all analyses.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jun 2007
    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
    Argentina: 18
    Country: Number of subjects enrolled
    Australia: 453
    Country: Number of subjects enrolled
    Belgium: 88
    Country: Number of subjects enrolled
    Brazil: 101
    Country: Number of subjects enrolled
    Canada: 2614
    Country: Number of subjects enrolled
    Chile: 14
    Country: Number of subjects enrolled
    China: 912
    Country: Number of subjects enrolled
    Colombia: 462
    Country: Number of subjects enrolled
    Czechia: 155
    Country: Number of subjects enrolled
    Greece: 150
    Country: Number of subjects enrolled
    India: 803
    Country: Number of subjects enrolled
    Iran, Islamic Republic of: 301
    Country: Number of subjects enrolled
    Ireland: 14
    Country: Number of subjects enrolled
    Hong Kong: 73
    Country: Number of subjects enrolled
    Italy: 420
    Country: Number of subjects enrolled
    Spain: 119
    Country: Number of subjects enrolled
    United States: 710
    Country: Number of subjects enrolled
    Austria: 100
    Worldwide total number of subjects
    7507
    EEA total number of subjects
    1046
    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)
    2514
    From 65 to 84 years
    3771
    85 years and over
    1222

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited between June 21, 2007, and Dec 19, 2013. Complete 30-day data was available for all 7507 patients randomly assigned to methylprednisolone (n=3755) and to placebo (n=3752).

    Pre-assignment
    Screening details
    		 7507 enrolled and randomly assigned patients; 3755 patients allocated to receive methylprednisolone (146 did not receive allocated intervention) and 3752 patients allocated to placebo (154 did not receive allocated intervention)

    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
    Blinding implementation details
    Patients were assigned by block randomization with random block sizes of 2, 4, or 6, stratified by centre. Methylprednisolone was obtained from the centre’s local pharmacy, and the study drug was prepared and masked by the local pharmacy following procedures described in a provided study manual. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active Methylprednisolone
    Arm description
    		 Intravenous methylprednisolone, divided. 250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass

    Arm title
    		 Active Placebo
    Arm description
    		 Intravenous placbeo, divided. 250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass

    Number of subjects in period 1
    		Active Methylprednisolone Active Placebo
    Started
    3755
    3752
    Completed
    3755
    3752

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active Methylprednisolone
    Reporting group description
    		 Intravenous methylprednisolone, divided. 250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass.

    Reporting group title
    Active Placebo
    Reporting group description
    		 Intravenous placbeo, divided. 250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass.

    Reporting group values
    		 Active Methylprednisolone Active Placebo Total
    Number of subjects
    		 3755 3752 7507
    Age categorical
    Units: Subjects
        <65
    		 1250 1264 2514
        65-80
    		 1897 1874 3771
        >80
    		 608 614 1222
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.6 ( 13.6 ) 67.3 ( 13.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1498 1472 2970
        Male
    		 2257 2280 4537
    EuroSCORE
    Units: Subjects
        4-5
    		 518 504 1022
        6-8
    		 2454 2495 4949
        >8
    		 400 398 798
        Missing data
    		 383 355 738
    Receipt of at least one dose of study drug or placebo
    Units: Subjects
        Received at least 1 dose of study drug or placebo
    		 3364 3353 6717
        Did not receive at least 1 dose of study drug or p
    		 146 154 300
        Missing data
    		 245 245 490
    Operative Characteristics (Procedure)
    Units: Subjects
        Isolated cardiac valve
    		 1209 1228 2437
        Isolated coronary artery bypass
    		 825 762 1587
        Other
    		 1721 1762 3483
    Non-study Postoperative Steroids
    Units: Subjects
        Received non-study postoperative steroids
    		 75 85 160
        Did not receive non-study postoperative steroids
    		 3680 3667 7347
    Bypass time (min)
    Units: Minuntes
        median (inter-quartile range (Q1-Q3))
    		 108 (82 to 144) 110 (84 to 142) -

    End points

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    End points reporting groups
    Reporting group title
    Active Methylprednisolone
    Reporting group description
    		 Intravenous methylprednisolone, divided. 250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass.

    Reporting group title
    Active Placebo
    Reporting group description
    		 Intravenous placbeo, divided. 250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass.

    Primary: Primary End Point

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    End point title
    		 Primary End Point
    End point description
    End point type
    Primary
    End point timeframe
    >
    End point values
    		 Active Methylprednisolone Active Placebo
    Number of subjects analysed
    3755
    3752
    Units: Subjects
        Death
    154
    177
        Death, MI, Stroke, Renal/Resp. failure
    909
    885
        Myocardial injury
    486
    399
        Stroke
    71
    79
        New renal failure
    139
    160
        Respiratory failure
    343
    375
    Statistical analysis title
    		 Co-primary outcome #1
    Statistical analysis description
    Effect of Methylprednisolone vs Placebo on Death
    Comparison groups
    Active Methylprednisolone v Active Placebo
    Number of subjects included in analysis
    7507
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.041
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.07
    Statistical analysis title
    		 Co-primary outcome #2
    Statistical analysis description
    Effect of Methylprednisolone vs Placebo on the composite of death, myocardial injury, stroke, new renal failure, or respiratory failure
    Comparison groups
    Active Methylprednisolone v Active Placebo
    Number of subjects included in analysis
    7507
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [1]
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.11
    Notes
    [1] - First primary outcome of death @ 0.041 level of significance & second primary outcome @ 0.01. It maintained the overall type I error rate for both comparisons at 5%, under the assumption that the overlap between the two outcomes was at least 15%.

    Secondary: Secondary End Point

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    End point title
    		 Secondary End Point
    End point description
    End point type
    Secondary
    End point timeframe
    >
    End point values
    		 Active Methylprednisolone Active Placebo
    Number of subjects analysed
    3755
    3752
    Units: subjects
        Death or myocardial injury
    605
    530
        New atrial fibrillation
    821
    846
        Transfusions
    1832
    1865
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Patients were followed up for 30 days for all outcomes and for 6 months for vital status.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Active Methylprednisolone
    Reporting group description
    		 Intravenous methylprednisolone, divided. 250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass.

    Reporting group title
    Active Placebo
    Reporting group description
    		 Intravenous placbeo, divided. 250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Data not collected.
    Serious adverse events
    		 Active Methylprednisolone Active Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    137 / 3755 (3.65%)
    135 / 3752 (3.60%)
         number of deaths (all causes)
    154
    177
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    23 / 3755 (0.61%)
    14 / 3752 (0.37%)
         occurrences causally related to treatment / all
    0 / 24
    1 / 14
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiac disorders
    Cardiac tamponade
         subjects affected / exposed
    28 / 3755 (0.75%)
    37 / 3752 (0.99%)
         occurrences causally related to treatment / all
    0 / 30
    0 / 37
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    15 / 3755 (0.40%)
    10 / 3752 (0.27%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 10
         deaths causally related to treatment / all
    0 / 5
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    48 / 3755 (1.28%)
    59 / 3752 (1.57%)
         occurrences causally related to treatment / all
    0 / 49
    0 / 59
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    23 / 3755 (0.61%)
    15 / 3752 (0.40%)
         occurrences causally related to treatment / all
    0 / 23
    2 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Active Methylprednisolone Active Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 3755 (0.00%)
    0 / 3752 (0.00%)

    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/26501386
    http://www.ncbi.nlm.nih.gov/pubmed/24766975
    http://www.ncbi.nlm.nih.gov/pubmed/30833491
    http://www.ncbi.nlm.nih.gov/pubmed/26460660
    http://www.ncbi.nlm.nih.gov/pubmed/27775998
    http://www.ncbi.nlm.nih.gov/pubmed/28683994
    http://www.ncbi.nlm.nih.gov/pubmed/24598306
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