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    Clinical Trial Results:
    A multi-centre randomised, double-blind, placebo-controlled trial of pre-hospital treatment with tranexamic acid for severely injured patients at risk of acute traumatic coagulopathy.

    Summary
    EudraCT number
    		 2019-004118-33
    Trial protocol
    		 DE  
    Global end of trial date
    14 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2023
    First version publication date
    07 Oct 2023
    Other versions
    Summary report(s)
    		 ClinicalStudy Report

    Trial information

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    Trial identification
    Sponsor protocol code
    PATCH_Trauma
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02187120
    WHO universal trial number (UTN)
    		 U1111-1169-6738
    Sponsors
    Sponsor organisation name
    University Witten/Herdecke
    Sponsor organisation address
    Alfred-Herrhausen-Str. 50, Witten, Germany, D-58448
    Public contact
    IFOM, Institut für Forschung in der Operativen Medizin, 0049 02219895726, patch@uni-wh.de
    Scientific contact
    IFOM, Institut für Forschung in der Operativen Medizin, 0049 02219895726, patch@uni-wh.de
    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 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Dec 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effect of early administration of TXA, compared to placebo, on mortality and favourable outcomes (moderate disability or good recovery) at six months in severely injured adults at risk of ATC who are treated in advanced trauma systems. To determine the effect of early administration of TXA, compared to placebo, on coagulation and fibrinolysis, and on clinical outcomes that are mediated through other putative inflammatory, immune, and neurological effects of plasmin. To determine whether early administration of TXA, compared to placebo, is associated with excessive vascular occlusive events, especially among potentially higher risk patients (eg >50 years old).
    Protection of trial subjects
    Upon arrival at the scene of injury, EMS clinicians will follow usual resuscitation protocols to address immediate life-threatening conditions of the airway, breathing or circulation. Review and consider any protocol modifications or ancillary studies proposed by the study investigators after the main trial begins to ensure that these do not negatively impact on the main trial. Protocol modifications will be considered in the context of their potential impact on scientific integrity and subject safety;
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2020
    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
    Germany: 8
    Country: Number of subjects enrolled
    Australia: 1299
    Worldwide total number of subjects
    1307
    EEA total number of subjects
    8
    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)
    1307
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adult patients (age ≥18 years); • Injured through any mechanism; • COAST score ≥3; • First dose of study drug can be administered within three hours of injury; and • Patients to be transported to a participating trauma centre

    Pre-assignment
    Screening details
    		 Upon arrival at the scene of injury, EMS clinicians trained in study procedures decided whether the patient is eligible for inclusion in the trial. Patients assessed as meeting the inclusion criteria at any time during the prehospital period, with no exclusion criteria, were randomised.

    Period 1
    Period 1 title
    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
    All trial personnel and participants will be blinded to treatment allocation. An independent pharmaceutical packaging company will be responsible for labelling ampoules containing TXA or sodium chloride (placebo) and preparing trial packs. The independent pharmaceutical packaging will contain the study code to determine which patients received TXA or placebo and this will not be available to trial investigators until completion of the trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 As soon as possible after injury, EMS clinicians administered a 10 ml ampoule containing 0.9 % w/v Sodium Chloride via iv injection (ampoules containing Sodium Chloride appear identical to ampoules containing TXA). After the patient arrived at hospital, clinicians administered a second 10 ml ampoule containing 0.9 % w/v Sodium Chloride added to up to 1 litre 0.9 % w/v Sodium Chloride infused iv over 8 h.
    Arm type
    		 Placebo

    Investigational medicinal product name
    sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% sodium chloride; Mode of administration: slow intravenous injection and infused intravenously; pre-hospital administration of tranexamic acid followed by an infusion over 8 hours

    Arm title
    		 Experimental intervention - TXA
    Arm description
    		 As soon as possible after injury, emergency medical services (EMS) clinicians administered 1 g Tranexamic Acid (TXA; 10 ml ampoule containing 100 mg/ml TXA in water for injection) via iv injection. After the patient arrived at hospital, clinicians administered 1 g TXA (10 ml ampoule containing 100 mg/ml TXA in water for injection) added to up to 1 litre 0.9 % w/v Sodium Chloride infused iv over 8 h.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TXA
    Investigational medicinal product code
    Other name
    Cyclokapron
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1g TXA (in 10 ml water) and 1g TXA (in 1000 ml 0.9 % NaCl); Mode of administration: slow intravenous injection and infused intravenously; after injury, emergency medical services (EMS) clinicians administered 1 g Tranexamic Acid; After the patient arrived at hospital, clinicians administered 1 g TXA

    Number of subjects in period 1
    		Placebo Experimental intervention - TXA
    Started
    646
    661
    Completed
    559
    572
    Not completed
    87
    89
         Consent withdrawn by subject
    26
    31
         Lost to follow-up
    61
    58

    Baseline characteristics

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

    Reporting group values
    		 Overall Period Total
    Number of subjects
    		 1307 1307
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1307 1307
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.15 ( 19.3 ) -
    Gender categorical
    Units: Subjects
        Male
    		 918 918
        female
    		 382 382
        Not recorded
    		 7 7
    Subject analysis sets

    Subject analysis set title
    Primary outcomes - extended GOS-E
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population consist of all randomised patients. Dichotomised Glasgow Outcome Scale Extended (GOSE) at 6 months: A favourable outcome is defined as GOSE scores 5-8 (moderate disability or good recovery) as opposed to GOSE scores 1-4 (died=1, severe disability 2-4). The binary primary outcome of favourable GOSE (scores 5-8) was compared between treatment groups using a risk ratio together with a 95% confidence interval and p-value, estimated by a logbinomial regression model. If model convergence was not achieved, then Poisson regression with robust standard errors was applied.

    Subject analysis set title
    Primary outcomes - extended GOS-E
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population will consist of all randomised patients with the exception of those who did not receive both doses of study drug or received open label TXA or did not meet the inclusion/exclusion criteria: age <18 years, had a COAST score <3, received their study drug >3 hours after injury, were pregnant, were residents at an aged care facility or did not attend a participating study centre.

    Subject analysis set title
    Secondary outcomes -24h
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Mortality at: • 24 hours; • 28 days; • 6 months.

    Subject analysis set title
    Secondary outcomes -28 days
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Mortality at: • 24 hours; • 28 days; • 6 months.

    Subject analysis set title
    Secondary outcomes -6month
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Mortality at: • 24 hours; • 28 days; • 6 months.

    Subject analysis sets values
    		 Primary outcomes - extended GOS-E Primary outcomes - extended GOS-E Secondary outcomes -24h Secondary outcomes -28 days Secondary outcomes -6month
    Number of subjects
    1300
    847
    1300
    1300
    1300
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    1307
    847
    1307
    1307
    1307
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    44.15 ( 19.3 )
    44.75 ( 18.85 )
    44.15 ( 19.3 )
    44.15 ( 19.3 )
    44.15 ( 19.3 )
    Gender categorical
    Units: Subjects
        Male
    918
    602
    918
    918
    918
        female
    382
    245
    382
    382
    382
        Not recorded

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 As soon as possible after injury, EMS clinicians administered a 10 ml ampoule containing 0.9 % w/v Sodium Chloride via iv injection (ampoules containing Sodium Chloride appear identical to ampoules containing TXA). After the patient arrived at hospital, clinicians administered a second 10 ml ampoule containing 0.9 % w/v Sodium Chloride added to up to 1 litre 0.9 % w/v Sodium Chloride infused iv over 8 h.

    Reporting group title
    Experimental intervention - TXA
    Reporting group description
    		 As soon as possible after injury, emergency medical services (EMS) clinicians administered 1 g Tranexamic Acid (TXA; 10 ml ampoule containing 100 mg/ml TXA in water for injection) via iv injection. After the patient arrived at hospital, clinicians administered 1 g TXA (10 ml ampoule containing 100 mg/ml TXA in water for injection) added to up to 1 litre 0.9 % w/v Sodium Chloride infused iv over 8 h.

    Subject analysis set title
    Primary outcomes - extended GOS-E
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population consist of all randomised patients. Dichotomised Glasgow Outcome Scale Extended (GOSE) at 6 months: A favourable outcome is defined as GOSE scores 5-8 (moderate disability or good recovery) as opposed to GOSE scores 1-4 (died=1, severe disability 2-4). The binary primary outcome of favourable GOSE (scores 5-8) was compared between treatment groups using a risk ratio together with a 95% confidence interval and p-value, estimated by a logbinomial regression model. If model convergence was not achieved, then Poisson regression with robust standard errors was applied.

    Subject analysis set title
    Primary outcomes - extended GOS-E
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population will consist of all randomised patients with the exception of those who did not receive both doses of study drug or received open label TXA or did not meet the inclusion/exclusion criteria: age <18 years, had a COAST score <3, received their study drug >3 hours after injury, were pregnant, were residents at an aged care facility or did not attend a participating study centre.

    Subject analysis set title
    Secondary outcomes -24h
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Mortality at: • 24 hours; • 28 days; • 6 months.

    Subject analysis set title
    Secondary outcomes -28 days
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Mortality at: • 24 hours; • 28 days; • 6 months.

    Subject analysis set title
    Secondary outcomes -6month
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Mortality at: • 24 hours; • 28 days; • 6 months.

    Primary: GOS-E

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    End point title
    		 GOS-E
    End point description
    End point type
    Primary
    End point timeframe
    6 month
    End point values
    		 Placebo Experimental intervention - TXA Primary outcomes - extended GOS-E Primary outcomes - extended GOS-E
    Number of subjects analysed
    559
    572
    1131
    727
    Units: Subject
    646
    661
    1300
    1300
    Statistical analysis title
    		 Primary outcome analysis – favourable 6-month GOSE
    Comparison groups
    Placebo v Experimental intervention - TXA
    Number of subjects included in analysis
    1131
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.95
    Method
    		 log-binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.12
    Variability estimate
    Standard deviation

    Secondary: Death within 24hr

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    End point title
    		 Death within 24hr
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours after injury
    End point values
    		 Placebo Experimental intervention - TXA Secondary outcomes -24h
    Number of subjects analysed
    559
    572
    1297
    Units: Subject
    643
    657
    1300
    Statistical analysis title
    		 secondary endpoint analyses - 24hr
    Comparison groups
    Placebo v Experimental intervention - TXA
    Number of subjects included in analysis
    1131
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 log-binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.94
    Variability estimate
    Standard deviation

    Secondary: Death within 28 days

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    End point title
    		 Death within 28 days
    End point description
    End point type
    Secondary
    End point timeframe
    28 days after injury
    End point values
    		 Placebo Experimental intervention - TXA Secondary outcomes -28 days
    Number of subjects analysed
    559
    572
    1290
    Units: Subject
    643
    657
    1300
    Statistical analysis title
    		 secondary endpoint analyses - 28 days
    Comparison groups
    Placebo v Experimental intervention - TXA
    Number of subjects included in analysis
    1131
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 log-binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 0.99

    Secondary: Death within 6 month

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    End point title
    		 Death within 6 month
    End point description
    End point type
    Secondary
    End point timeframe
    death by 6 month after injury
    End point values
    		 Placebo Experimental intervention - TXA Secondary outcomes -6month
    Number of subjects analysed
    559
    572
    1277
    Units: Subject
    643
    657
    1300
    Statistical analysis title
    		 secondary endpoint analyses - 6 month
    Comparison groups
    Placebo v Experimental intervention - TXA
    Number of subjects included in analysis
    1131
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 log-binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.03

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    overal period: 6 month July 2014 - March 2021
    Adverse event reporting additional description
    Any untoward medical occurrence in study participant which does not necessarily have to have a causal relationship with the study drug, but which was of concern to the organisation/site principal investigator’s clinical judgement. Ae´s in this study included (but were not limited to) vascular occlusive events, seizures, cardiac arrest, anaphylax
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CPMP/ICH/377/95
    Dictionary version
    July 2000
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 As soon as possible after injury, EMS clinicians administered a 10 ml ampoule containing 0.9 % w/v Sodium Chloride via iv injection (ampoules containing Sodium Chloride appear identical to ampoules containing TXA). After the patient arrived at hospital, clinicians administered a second 10 ml ampoule containing 0.9 % w/v Sodium Chloride added to up to 1 litre 0.9 % w/v Sodium Chloride infused iv over 8 h.

    Reporting group title
    Experimental intervention - TXA
    Reporting group description
    		 As soon as possible after injury, emergency medical services (EMS) clinicians administered 1 g Tranexamic Acid (TXA; 10 ml ampoule containing 100 mg/ml TXA in water for injection) via iv injection. After the patient arrived at hospital, clinicians administered 1 g TXA (10 ml ampoule containing 100 mg/ml TXA in water for injection) added to up to 1 litre 0.9 % w/v Sodium Chloride infused iv over 8 h.

    Serious adverse events
    		 Placebo Experimental intervention - TXA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 643 (0.62%)
    3 / 657 (0.46%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Complication of procedure
         subjects affected / exposed
    1 / 643 (0.16%)
    0 / 657 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    2 / 643 (0.31%)
    2 / 657 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Heparin-induced thrombocytopenia (HITS)
         subjects affected / exposed
    1 / 643 (0.16%)
    0 / 657 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 643 (0.00%)
    1 / 657 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Experimental intervention - TXA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 643 (1.24%)
    16 / 657 (2.44%)
    Injury, poisoning and procedural complications
    Others
         subjects affected / exposed
    8 / 643 (1.24%)
    16 / 657 (2.44%)
         occurrences all number
    19
    25

    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/3731424
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