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    Clinical Trial Results:
    Efficacy and safety of 72-hour infusion of Prostacyclin (1 ng/kg/min) in trauma patients with haemorrhagic shock induced endotheliopathy – a multicentre randomized, placebo-controlled, blinded, investigator-initiated trial

    Summary
    EudraCT number
    		 2019-000936-24
    Trial protocol
    		 DK   NO  
    Global end of trial date
    12 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jan 2024
    First version publication date
    24 Jan 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SHINE-TRAUMA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03903939
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, DK-2100
    Public contact
    Pär I Johansson, Section for Transfusion Medicine, Capital Region Blood Bank, Copenhagen University Hospital, +45 35452030, per.johansson@regionh.dk
    Scientific contact
    Pär I Johansson, Section for Transfusion Medicine, Capital Region Blood Bank, Copenhagen University Hospital, 35452030 35452030, per.johansson@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
    20 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective in this trial is to investigate whether continuos infusion of iloprost at a dose of 1 ng/kg/min for 72-hours is safe and significantly increase the number of ICU free days, within 28 days from admission compared to infusion of placebo in trauma patients with haemorrhagic shock and SHINE.
    Protection of trial subjects
    Patients included in this trial is admitted to the trauma center, therefore these patients will receive the best possible care and monitored closely during their hospital stay.
    Background therapy
    		 Standard of care
    Evidence for comparator
    		 These patients revieve a lot of fluid and blood product upon arrival at the trauma center. Saline 0.9 % (NaCl) is chosen as comparator to maintain blinding in the trial as iloprost is diluted in saline. Patients receiving placebo will receive an equal volume of fluid administered in the same way as the iloprost infusion.
    Actual start date of recruitment
    03 Jun 2019
    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
    Norway: 47
    Country: Number of subjects enrolled
    Denmark: 182
    Worldwide total number of subjects
    229
    EEA total number of subjects
    229
    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)
    171
    From 65 to 84 years
    50
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited upon admission to the trauma center with the need for activation of massive transfusion protocol due to traume. Only patient at 18 years of age or above were incluted.

    Pre-assignment
    Screening details
    		 Patients are subject for screening if they are admitted to the trauma center with heamorrhagic shock requiring massive blood transfusion.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    The trial is double-blinded with saline 0.9 % (NaCl) as placebo to maintain blinding. iloprost is diluted in saline and therefore both solutions are colorless fluids. Patients receiving placebo will receive an equal volume of fluid administered in the same way as the iloprost infusion. The preparation of trial medication will be done by an unblinded study staff, who will be responsible for preparing the investigational drug so that it can be administered in blinded fashion

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention arm
    Arm description
    		 Iloprost (Ilomedin®) is a marketed product which will be administered in this trial as the IMP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ilomedin
    Investigational medicinal product code
    Other name
    Prostacyclin
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    All patients will receive 72-hour continuous infusion of either active investigational drug or placebo. Patients on active treatment will receive continuous infusion of 1.0 ng/kg/min iloprost. The infusion volume of the active investigational drug and placebo will be 72 ml per 24h.

    Arm title
    		 Placebo arm
    Arm description
    		 Saline 0.9% is used as comparator. Given in equal volumen as investigational drug
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline 0.9%
    Investigational medicinal product code
    Other name
    sodium chloride
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    All patients will receive 72-hour continuous infusion of either active investigational drug or placebo. Patients on placebo will receive continuous infusion equivalent to iloprost. The infusion volume of the active investigational drug and placebo will be 72 ml per 24h.

    Number of subjects in period 1
    		Intervention arm Placebo arm
    Started
    119
    110
    Completed
    116
    105
    Not completed
    3
    5
         Consent withdrawn by subject
    1
    3
         Adverse event, non-fatal
    2
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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

    Reporting group values
    		 Overall Total
    Number of subjects
    		 229 229
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 171 171
        From 65-84 years
    		 50 50
        85 years and over
    		 8 8
    Gender categorical
    Units: Subjects
        Female
    		 47 47
        Male
    		 182 182

    End points

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    End points reporting groups
    Reporting group title
    Intervention arm
    Reporting group description
    		 Iloprost (Ilomedin®) is a marketed product which will be administered in this trial as the IMP.

    Reporting group title
    Placebo arm
    Reporting group description
    		 Saline 0.9% is used as comparator. Given in equal volumen as investigational drug

    Primary: ICU free days

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    End point title
    		 ICU free days
    End point description
    Mean number of days alive and not admitted to an intensive care unit
    End point type
    Primary
    End point timeframe
    Baseline to day 28
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    119
    110
    Units: day
        number (not applicable)
    15.65
    13.99
    Statistical analysis title
    		 Primary endpoint - ITT
    Statistical analysis description
    Mean days
    Comparison groups
    Intervention arm v Placebo arm
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2844
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6338
         upper limit
    		 1.378

    Primary: ICU free days - PP

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    End point title
    		 ICU free days - PP
    End point description
    Number of days alive and not admitted to an intensive care unit - measured for the Per Protocol analysis
    End point type
    Primary
    End point timeframe
    Baseline to day 28
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    116
    105
    Units: day
        number (not applicable)
    15.83
    13.98
    Statistical analysis title
    		 Primary endpoint - Per protocol
    Comparison groups
    Intervention arm v Placebo arm
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2269
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.861
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.886
         upper limit
    		 1.165

    Secondary: Mortality day 28

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    End point title
    		 Mortality day 28
    End point description
    Percentage dead from baseline to day 28
    End point type
    Secondary
    End point timeframe
    Baseline to day 28
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    119
    110
    Units: percent
        number (not applicable)
    18.8
    19.63
    Statistical analysis title
    		 Secondary endpoint (ITT) - Mortality day28
    Comparison groups
    Intervention arm v Placebo arm
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5751
         upper limit
    		 1.755
    Variability estimate
    Standard deviation

    Secondary: Mortality day 90

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    End point title
    		 Mortality day 90
    End point description
    Percentage dead from baseline to day 90
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    119
    110
    Units: percent
        number (not applicable)
    19.83
    20.19
    Statistical analysis title
    		 Secondary endpoint (ITT) - Mortality day90
    Comparison groups
    Intervention arm v Placebo arm
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9863
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5582
         upper limit
    		 1.704
    Variability estimate
    Standard deviation

    Secondary: Lenght of stay

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    End point title
    		 Lenght of stay
    End point description
    Mean number of days admitted to the hospital until day 90
    End point type
    Secondary
    End point timeframe
    Baseline to day 90
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    119
    110
    Units: day
        number (not applicable)
    19.96
    27.32
    Statistical analysis title
    		 Secondary endpoint (ITT) - Length of stay
    Comparison groups
    Placebo arm v Intervention arm
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.01285
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    7.838
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.66
         upper limit
    		 14.02

    Secondary: Vasopressor free days

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    End point title
    		 Vasopressor free days
    End point description
    Number of days alive and without use of vasopressor until day 28
    End point type
    Secondary
    End point timeframe
    Baseline to day 28
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    119
    110
    Units: day
        number (not applicable)
    19.86
    18.07
    Statistical analysis title
    		 Secondary endpoint (ITT) - Vasopressor free days
    Comparison groups
    Intervention arm v Placebo arm
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2118
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.442
         upper limit
    		 0.9426

    Secondary: Ventilator free days

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    End point title
    		 Ventilator free days
    End point description
    Number of days alive and without use of mechanical ventilation until day 28
    End point type
    Secondary
    End point timeframe
    Baseline to day 28
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    119
    110
    Units: day
        number (not applicable)
    18.03
    16.4
    Statistical analysis title
    		 Secondary endpoint (ITT) - Ventilator free days
    Comparison groups
    Intervention arm v Placebo arm
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3064
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.576
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.625
         upper limit
    		 1.474

    Secondary: RRT free days

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    End point title
    		 RRT free days
    End point description
    Number of days alive and without use of renal replacement therapy (RRT) until day 28
    End point type
    Secondary
    End point timeframe
    baseline to day 28
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    119
    110
    Units: day
        number (not applicable)
    23.11
    22.99
    Statistical analysis title
    		 Secondary endpoint (ITT) - RRT free days
    Comparison groups
    Intervention arm v Placebo arm
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9841
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.02558
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.49
         upper limit
    		 2.541

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Baseline to day 4
    Adverse event reporting additional description
    Only SAEs and SARs were recorded due to the severity of the condition treated
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    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: There are no non-serious adverse events recorded for these results. Only certain SAE is reported in this trial due to the severity ilness of the incluted patients.
    Serious adverse events
    		 Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracerebral haematoma evacuation
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    4 / 9 (44.44%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 9 (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/37962189
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