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    Clinical Trial Results:
    Does acetylsalicylic acid reduce the mortality of patients admitted to an Intensive Care Unit

    Summary
    EudraCT number
    2012-002235-29
    Trial protocol
    AT  
    Global end of trial date
    05 Sep 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    03 Sep 2019
    First version publication date
    02 Feb 2018
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction for statistical testing: we did not test for equivalence, but for superiority

    Trial information

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    Trial identification
    Sponsor protocol code
    1.0
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02285153
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Waehringer Guertel 18-20, Vienna, Austria, 1090
    Public contact
    Medizinische Universität Wien - Uni, Medizinische Universität Wien - Universitätsklinik für klinische Pharmakologie, 0043 01404002980, klin-pharmakologie@meduniwien.ac.at
    Scientific contact
    Medizinische Universität Wien - Uni, Medizinische Universität Wien - Universitätsklinik für klinische Pharmakologie, 0043 01404002980, klin-pharmakologie@meduniwien.ac.at
    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
    10 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Sep 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate the 28-/90-day mortality of patients treated with ASA vs. placebo;
    Protection of trial subjects
    Daily blood samples were drawn on a routine basis. Furthermore physical examinations were performed every day by trained physicians.
    Background therapy
    Participation in this trial did not affect background therapy of patients. Placebo or acetylsalicylic acid were add-on therapy to the usual treatment of the patients.
    Evidence for comparator
    This was a placebo controlled trial. We investigated whether acetylsalicylic acid reduced the mortality of critically ill patients compared to placebo. Since this was an add-on treatment the use of an active comparator was not indicated.
    Actual start date of recruitment
    15 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    9
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    15 Patients participated in this trial. The first patient was included on November 15th 2012. The last patient on March 13th 2014. All were recruited in the General Hospital of Vienna, Austria.

    Pre-assignment
    Screening details
    Patients admitted to an ICU without platelet inhibitors, with no recent or planned invasive procedures or surgeries, with no active bleeding, no coagulation disorders, no low platelet counts, no terminal illness (anticipated life expectancy < 3 months), at the discretion of the treating physician were eligible for inclusion.

    Pre-assignment period milestones
    Number of subjects started
    15
    Number of subjects completed
    15

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Patients were randomized by a trained person not otherwise involved in the conduct of the trial. Treatment was prepared and the ICU ward received the study drug on each day. Verum/Placebo were not distinguishable by its physical appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo Arm
    Arm type
    Placebo

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100ml 0.9% sodium chloride solution

    Arm title
    Verum
    Arm description
    100mg Acetylsalicylic Acid per day
    Arm type
    Experimental

    Investigational medicinal product name
    Acetylsalicylic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    1 Infusion of 100mg Acetylsalicylic Acid in 100ml 0.9% sodium chloride solution

    Number of subjects in period 1
    Placebo Verum
    Started
    8
    7
    Completed
    8
    6
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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

    Reporting group title
    Verum
    Reporting group description
    100mg Acetylsalicylic Acid per day

    Reporting group values
    Placebo Verum Total
    Number of subjects
    8 7 15
    Age categorical
    Age at Inclusion
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    4 5 9
        From 65-84 years
    4 2 6
        85 years and over
    0 0 0
    Age continuous
    Age at inclusion
    Units: years
        median (standard deviation)
    63 ± 10 61 ± 15 -
    Gender categorical
    Gender
    Units: Subjects
        Female
    2 4 6
        Male
    6 3 9
    SAPS III score
    stratification variable
    Units: Subjects
        <50
    1 1 2
        >50
    7 6 13
    Age
    stratification variable
    Units: Subjects
        >60
    4 3 7
        <60
    4 4 8
    SAPS III
    Disease score
    Units: points
        arithmetic mean (standard deviation)
    63 ± 13 64 ± 19 -

    End points

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

    Reporting group title
    Verum
    Reporting group description
    100mg Acetylsalicylic Acid per day

    Primary: day 28 mortality

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    End point title
    day 28 mortality
    End point description
    primary endpoint Due to the early termination of the trial due to recruitment problems no formal statistical analysis was performed.
    End point type
    Primary
    End point timeframe
    28 days after ICU inclusion
    End point values
    Placebo Verum
    Number of subjects analysed
    8
    7
    Units: deaths
        dead
    1
    1
        alive
    7
    6
    Statistical analysis title
    Mortality
    Statistical analysis description
    Day 28/90 Mortality
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.57 [2]
    Method
    Chi-squared
    Parameter type
    Cox proportional hazard
    Point estimate
    0.434
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.039
         upper limit
    4.792
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.225
    Notes
    [1] - Chi2
    [2] - There is no significant difference in mortality between the two groups.

    Primary: 90-day mortality

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    End point title
    90-day mortality
    End point description
    Deaths within 90 days of inclusion
    End point type
    Primary
    End point timeframe
    day 90 mortality
    End point values
    Placebo Verum
    Number of subjects analysed
    8
    7
    Units: deaths
        dead
    1
    2
        alive
    7
    6
    Statistical analysis title
    Mortality
    Statistical analysis description
    Day 90 mortality between two groups
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.57 [4]
    Method
    Chi-squared
    Confidence interval
         level
    95%
    Variability estimate
    Standard error of the mean
    Notes
    [3] - Chi2
    [4] - There is no difference between the two groups.

    Secondary: Major bleeding

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    End point title
    Major bleeding
    End point description
    Major bleedings during the Treatment phase of the trial
    End point type
    Secondary
    End point timeframe
    Duration of the Treatment phase
    End point values
    Placebo Verum
    Number of subjects analysed
    8
    7
    Units: Major bleedings
        Major bleeding
    0
    1
    Statistical analysis title
    Major bleeding
    Statistical analysis description
    major bleeding in both groups.
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.467 [6]
    Method
    Chi-squared
    Confidence interval
    Notes
    [5] - Chi2 Test
    [6] - There is no significant difference between the two groups with regards to bleeding incidences.

    Secondary: Thromboembolic events

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    End point title
    Thromboembolic events
    End point description
    End point type
    Secondary
    End point timeframe
    Duration of Treatment
    End point values
    Placebo Verum
    Number of subjects analysed
    8
    7
    Units: Thromboembolic events
        Thromboembolic events
    1
    0
    Statistical analysis title
    Thromboembolic Events
    Statistical analysis description
    Thromboembolic Events during the treatment phase
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 1 [8]
    Method
    Chi-squared
    Confidence interval
    Notes
    [7] - Chi2 Test
    [8] - There was no significant difference in the number of thromboembolic events between the two groups.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The duration of the ICU Stay
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Verum
    Reporting group description
    Patients who received 100mg Acetylsalicylic acid

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Verum Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 8 (37.50%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Asystolia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    hypoxic brain damage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colon Perforation
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute renal failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Catheter infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         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
    Verum Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 7 (57.14%)
    6 / 8 (75.00%)
    Vascular disorders
    Bleeding
    Additional description: minor bleeding according to the TIMI-bleeding criteria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    atrial fibrillation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Delirium
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Obstipation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Liver function test increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 8 (25.00%)
         occurrences all number
    1
    2
    Catheter infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Wound infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    herpes virus infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0

    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.
    The trial was terminated after 15 patients due to recruitment difficulties. Thus, any statistical analysis and interpretation of trial results should only be done with caution.
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