Prehospital Tranexamic Acid Use for Traumatic Brain Injury (TXA)

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ClinicalTrials.gov Identifier: NCT01990768

Recruitment Status : Completed

First Posted : November 21, 2013

Results First Posted : January 14, 2019

Last Update Posted : January 14, 2019

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborators:

National Heart, Lung, and Blood Institute (NHLBI)

U.S. Army Medical Research and Development Command

Canadian Institutes of Health Research (CIHR)

Heart and Stroke Foundation of Canada

American Heart Association

Defence Research and Development Canada

Information provided by (Responsible Party):

Susanne May, University of Washington

Study Description

Brief Summary:

Primary aim: To determine the efficacy of two dosing regimens of TXA initiated in the prehospital setting in patients with moderate to severe TBI (GCS score ≤12).

Primary hypothesis: The null hypothesis is that random assignment to prehospital administration of TXA in patients with moderate to severe TBI will not change the proportion of patients with a favorable long-term neurologic outcome compared to random assignment to placebo, based on the GOS-E at 6 months.

Secondary aims: To determine differences between TXA and placebo in the following outcomes for patients with moderate to severe TBI treated in the prehospital setting with 2 dosing regimens of TXA:

Clinical outcomes: ICH progression, Marshall and Rotterdam CT classification scores, DRS at discharge and 6 months, GOS-E at discharge, 28-day survival, frequency of neurosurgical interventions, and ventilator-free, ICU-free, and hospital-free days.
Safety outcomes: Development of seizures, cerebral ischemic events, myocardial infarction, deep venous thrombosis, and pulmonary thromboembolism.
Mechanistic outcomes: Alterations in fibrinolysis based on fibrinolytic pathway mediators and degree of clot lysis based on TEG.

Inclusion: Blunt and penetrating traumatic mechanism consistent with TBI with prehospital GCS ≤ 12 prior to administration of sedative and/or paralytic agents, prehospital SBP ≥ 90 mmHg, prehospital intravenous (IV) access, age ≥ 15yrs (or weight ≥ 50kg if age is unknown), EMS transport destination based on standard local practices determined to be a participating trauma center.

Exclusion: Prehospital GCS=3 with no reactive pupil, estimated time from injury to start of study drug bolus dose >2 hours, unknown time of injury, clinical suspicion by EMS of seizure activity, acute MI or stroke or known history, to the extent possible, of seizures, thromboembolic disorders or renal dialysis, CPR by EMS prior to randomization, burns > 20% TBSA, suspected or known prisoners, suspected or known pregnancy, prehospital TXA or other pro-coagulant drug given prior to randomization, subjects who have activated the "opt-out" process when required by the local regulatory board.

A multi-center double-blind randomized controlled trial with 3 treatment arms:

Bolus/maintenance: 1 gram IV TXA bolus in the prehospital setting followed by a 1 gram IV maintenance infusion initiated on hospital arrival and infused over 8 hours.
Bolus only: 2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Placebo: Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.

Condition or disease	Intervention/treatment	Phase
Traumatic Brain Injury	Drug: 1 gram Tranexamic Acid (TXA) Drug: 2 grams TXA Drug: 0.9% Sodium Chloride injectable	Phase 2

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Detailed Description:

Overview This multi-center, Phase II trial is designed to determine if Tranexamic Acid (TXA) initiated in the prehospital setting improves long-term neurologic outcome compared to placebo in patients with moderate to severe TBI who are not in shock. This study protocol will be conducted as part of the Resuscitation Outcomes Consortium (ROC) at trauma centers in the United States and Canada. ROC is funded by the National Heart Lung and Blood Institute (NHLBI) in partnership with the US Army Medical Research and Materiel Command (USAMRMC), Canadian Institutes of Health Research, the Heart & Stroke Foundation of Canada, the American Heart Association (AHA), and the Defense Research and Development Canada. ROC is a clinical trials network focusing on research primarily in the area of prehospital cardiopulmonary arrest and severe traumatic injury. The mission of ROC is to provide infrastructure and project support for clinical trials and other outcome-oriented research in the areas of cardiopulmonary arrest and severe traumatic injury that lead to evidence-based change in clinical practice.
Specific Aims/Hypothesis Statement

2.1 Clinical Hypotheses and Aims

Specific aim 1: To compare 6-month neurologic outcome between subjects who are randomly assigned to TXA to subjects who are randomly assigned to placebo by evaluating the Glasgow Outcome Scale Extended score (GOS-E) at 6 months post-injury.

Primary Hypotheses: We will perform a one-sided test of the following null hypothesis: The proportion of subjects who have a favorable neurologic outcome (GOS-E > 4) at six months post injury who are randomly assigned to TXA is not different from the proportion of subjects who have a favorable neurologic outcome (GOS-E > 4) who are randomly assigned to placebo. This hypothesis will be tested versus the alternative that the proportion of subjects with a favorable neurologic outcome who are randomly assigned to TXA is higher than in subjects who are randomly assigned to placebo at the .1 level and versus the alternative that the proportion of subjects with a favorable neurologic outcome who are randomly assigned to TXA is lower than it is in the placebo group at the .025 level

Specific aim 2: To assess differences in morbidity and mortality measured from randomization through 28 days or initial hospital discharge and differences in neurologic outcomes at 6 months between subjects in the bolus/maintenance arm, bolus only arm, and placebo arm.

Secondary Hypotheses: The null hypotheses are that there will be no difference between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo in the following: both absolute and relative volume of intracranial hemorrhage (ICH) progression, proportion of subjects with ICH progression, frequency of neurosurgical interventions, GOS-E measured at discharge and 6 months, Disability Rating Scale score (DRS) measured at discharge and 6 months, 28-day survival, and ventilator-free, intensive care unit (ICU)-free, and hospital-free days.

Specific aim 3: To assess differences in adverse events measured from randomization to initial hospital discharge between subjects in the bolus/maintenance arm, bolus only arm, and placebo arm.

Tertiary Hypotheses: The null hypotheses are that there will be no difference between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo in the following: proportion of subjects experiencing seizures, cerebral ischemic events, myocardial infarction (MI), deep venous thrombosis (DVT), or pulmonary thromboembolism (PE) post randomization through 28 days or discharge, whichever occurs first.

2.2 Laboratory Hypotheses and Aims

Specific aim 1: To compare coagulation profiles over time using kaolin activated thrombelastography (TEG) results between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.

Primary hypothesis: The null hypothesis is that there will be no difference in the degree of fibrinolysis as assessed by percentage of clot lysis determined 30 minutes after the maximum amplitude is reached (LY30) between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.

Specific aim 2: To explore the underlying mechanism of TXA by comparing fibrinolytic pathway mediator activity between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.

Secondary hypothesis: The null hypothesis is that there will be no change in fibrinolytic pathway mediators between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.

Specific aim 3: To estimate the association between the degree of fibrinolysis based on kaolin activated TEG results and fibrinolytic pathway mediators on primary and secondary clinical outcomes.

Tertiary hypothesis: The null hypothesis is that no association will exist between the degree of fibrinolysis and fibrinolytic pathway mediators and primary and secondary clinical outcomes.
Study Enrollment

EMS agencies will carry blinded sealed study drug kits. Once the seal is broken in the presence of the patient, the patient is randomized. The EMS study drug kit will contain a vial of either 1 gram TXA, 2 grams TXA, or placebo. EMS will mix the study drug in a 250 mL bag of 0.9% sodium chloride and administer the bolus infusion as soon as life-saving interventions are performed. After randomization, EMS will provide the study drug kit ID# to the receiving pharmacy. The hospital pharmacist will obtain the randomization assignment from the coordinating center and prepare the appropriate drug to be administered in the hospital.
Sample Size and Statistical Analysis

The total sample size is 963 (321 per group) starting treatment, which will allow for 80% power to detect a 7.1% absolute difference in favorable long-term neurological outcome as determined by the GOS-E 6 months after injury comparing the combined TXA treatment groups to placebo, using a one-sided, level 0.1 test.

Statistical analysis of primary hypothesis: Modified intention-to-treat analysis using logistic regression to test for association and estimate the strength of the association of treatment group with a favorable 6-month outcome (defined as a GOS-E > 4), after adjustment for study site.
Human subjects protection

This study qualifies for the exception from informed consent (EFIC) required for emergency research outlined in FDA regulation 21CFR50.24. EFIC applies because of life-threatening situation, intervention must be administered before consent is feasible, no reasonable way to identify prospectively individuals at risk, patients have the prospect of benefit from the treatment, and the research could not practically be carried out without the waiver of consent.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	967 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Prehospital Tranexamic Acid Use for Traumatic Brain Injury
Study Start Date :	May 2015
Actual Primary Completion Date :	November 7, 2017
Actual Study Completion Date :	November 7, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Traumatic Brain Injury

Drug Information available for: Tranexamic acid Sodium chloride

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1 gram Tranexamic Acid (TXA) Loading dose of 1 gram TXA given prior to hospital arrival followed by a 1 gram TXA infusion over 8 hours after hospital arrival	Drug: 1 gram Tranexamic Acid (TXA) TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin. Other Name: Cyklokapron
Experimental: 2 grams TXA Loading dose of 2 gram TXA given prior to hospital arrival followed by a placebo of 0.9% Sodium Chloride solution infusion over 8 hours after hospital arrival	Drug: 2 grams TXA TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin. Other Name: Cyklokapron
Placebo Comparator: 0.9% Sodium Chloride injectable Loading dose of 0.9% Sodium Chloride solution given prior to hospital arrival followed by a placebo of 0.9% Sodium Chloride solution infusion over 8 hours after hospital arrival	Drug: 0.9% Sodium Chloride injectable Loading dose of 0.9% Sodium Chloride solution given prior to hospital arrival followed by a placebo of 0.9% Sodium Chloride solution infusion over 8 hours after hospital arrival. No active drug is added to the solution. Other Name: Normal saline solution

Outcome Measures

Primary Outcome Measures :

Dichotomized Glasgow Outcome Scale Extended (GOS-E) at 6 Months [ Time Frame: 6 months post-injury ]
GOS-E subdivides the categories of severe and moderate disability and good recovery using a scale of 1 to 8 where 1 = death, 2 = vegetative state, 3 = lower severe disability, 4 = upper severe disability, 5 = lower moderate disability, 6 = upper moderate disability, 7 = lower good recovery, and 8 = upper good recovery. Structured telephone interviews have been developed and validated for the GOS-E and these questions were incorporated into the follow-up survey. GOS-E was dichotomized into unfavorable (1 to 4) and favorable (5 to 8) outcomes.

Secondary Outcome Measures :

Number of Participants Who Died Within 28 Days [ Time Frame: 28 days after hospital arrival ]
The counts of patients who died on or before day 28 are reported.
Disability Rating Scale (DRS) at 6 Months [ Time Frame: 6 months post-injury ]
The DRS is designed to classify patients based on their degree of function after brain injury. The DRS consists of 8 items that fall into 4 categories: (a) arousability, awareness and responsivity, (b) cognitive ability for self-care activities, (c) dependence on others, and (d) psychosocial adaptability. The score ranges from 0 (no disability) to 30 (death).
Number of Participants With Unfavorable Outcome on Dichotomized Glasgow Outcome Scale Extended (GOS-E) at Discharge [ Time Frame: At the end of the hospital stay (average of 9 days post injury) ]
GOS-E subdivides the categories of severe and moderate disability and good recovery using a scale of 1 to 8 where 1 = death, 2 = vegetative state, 3 = lower severe disability, 4 = upper severe disability, 5 = lower moderate disability, 6 = upper moderate disability, 7 = lower good recovery, and 8 = upper good recovery. Structured telephone interviews have been developed and validated for the GOS-E and these questions were incorporated into the follow-up survey. GOS-E was dichotomized into unfavorable (1 to 4) and favorable (5 to 8) outcomes. The number of subjects with unfavorable outcome is reported.
Disability Rating Scale (DRS) at Discharge [ Time Frame: At the end of the hospital stay (average of 9 days post injury) ]
The DRS is designed to classify patients based on their degree of function after brain injury. The DRS consists of 8 items that fall into 4 categories: (a) arousability, awareness and responsivity, (b) cognitive ability for self-care activities, (c) dependence on others, and (d) psychosocial adaptability. The score ranges from 0 (no disability) to 30 (death).
Number of Participants With Intracranial Hemorrhage (ICH) Progression [ Time Frame: From hospital admission through 28 days or the end of the hospital stay if sooner (average of 13 days among patients with multiple scans) ]
All clinically indicated head computed tomography (CT) scans obtained during the initial hospitalization or within the first 28 days were assessed for ICH. Parenchymal (IPH), subdural (SDH) and epidural (EDH) hemorrhage volumes were measured and quantified using volumetric software and verified by manual calculations based on the previously validated ABC/2 technique. The sum of the IPH, SDH, and EDH volumes were compared across scans. A relative increase of 33% (and at least a 1 ml increase) on any subsequent scan compared to the initial scan was defined as a progression.
Marshall Computed Tomography (CT) Score on Initial Head CT [ Time Frame: Initial head CT (average of 1.9 hours post-injury) ]
The Marshall classification categorizes patients into one of six categories (I to VI) of increasing severity on the basis of findings on non-contrast CT scan of the brain. Higher categories have worse prognosis and survival.
Rotterdam Computed Tomography (CT) Score Among Subjects With Intracranial Hemorrhage (ICH) on Initial Head CT [ Time Frame: Initial head CT (average of 1.9 hours post-injury) ]
The Rotterdam classification includes four independently scored elements: degree of basal cistern compression, degree of midline shift, presence of epidural hematomas, and presence of intraventricular or subarachnoid blood. The elements are combined to form an overall score from 1 to 6 with higher scores having worse prognosis and survival.
Number of Participants With One or More Neurosurgical Interventions [ Time Frame: From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) ]
Neurosurgical interventions include craniotomy, craniectomy, and placement of a neuromonitoring or drainage device. Counts are of subjects with one or more neurosurgical interventions.
Hospital-free Days [ Time Frame: From hospital admission through day 28 ]
Hospital-free days count any day from hospital admission through day 28 that the patient is alive and out of the hospital.
Intensive Care Unit (ICU)-Free Days [ Time Frame: From hospital admission through day 28 ]
ICU-free days count any day from hospital admission through day 28 that the patient is alive and not in the ICU. Subjects who die prior to discharge (even if after 28 days) are assigned a value of 0.
Ventilator-free Days [ Time Frame: From hospital admission through day 28 ]
Ventilator-free days count any day from hospital admission through day 28 that the patient is alive and does not require mechanical ventilatory support. Subjects who die prior to discharge (even if after 28 days) are assigned a value of 0.
Number of Participants With Seizure [ Time Frame: From start of study drug infusion through 28 days or the end of the hospital stay if sooner (average of 9 days) ]
Seizures may cause involuntary changes in body movement or function, sensation, awareness, or behavior. Seizures are often associated with a sudden and involuntary contraction of a group of muscles and loss of consciousness. Seizures or episodes of seizure-like activity were reported by medics in the field following the start of study drug infusion through hand-off to the trauma center and by trauma center staff through discharge. Reported events were included if providers gave anti-seizure medication and/or the event was confirmed by EEG.
Number of Participants With Cerebral Ischemic Event [ Time Frame: From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) ]
Diagnosis of cerebral ischemic event
Number of Participants With Myocardial Infarction (MI) [ Time Frame: From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) ]
Diagnosis of an acute myocardial infarction
Number of Participants With Deep Vein Thrombosis (DVT) [ Time Frame: From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) ]
Diagnosis of DVT
Number of Participants With Pulmonary Embolus (PE) [ Time Frame: From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) ]
Diagnosis of PE
Number of Participants With Any Thromboembolic Event [ Time Frame: From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) ]
Diagnosis of one or more of the following: cerebral ischemic event, myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE), or any other thromboembolic event

Other Outcome Measures:

Fibrinolysis at Hospital Admission [ Time Frame: First blood draw (average of 1.6 hours post-injury) ]
Alterations in fibrinolysis based on fibrinolytic pathway mediators and degree of clot lysis based on kaolin-activated thromboelastography (TEG) and defined as LY30 or the per cent lysis that occurs 30 minutes after maximum amplitude (MA) is achieved. LY30 is categorized as <0.8% (fibrinolysis shutdown), 0.8-3% (normal), and >3% (hyperfibrinolysis).

Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:	15 Years and older (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Blunt or penetrating traumatic mechanism consistent with traumatic brain injury
Prehospital Glasgow Coma Score (GCS) score ≤ 12 at any time prior to randomization and administration of sedative and/or paralytic agents
Prehospital systolic blood pressure (SBP) ≥ 90 mmHg prior to randomization
Prehospital intravenous (IV) or intraosseous (IO) access
Estimated Age ≥ 15 (or estimated weight > 50 kg if age is unknown)
Emergency Medicine System (EMS) transport to a participating trauma center

Exclusion Criteria:

Prehospital GCS=3 with no reactive pupil
Estimated time from injury to hospital arrival > 2 hours
Unknown time of injury - no known reference times to support estimation
Clinical suspicion by EMS of seizure activity or known history of seizures, acute myocardial infarction (MI) or stroke
Cardio-pulmonary resuscitation (CPR) by EMS prior to randomization
Burns > 20% total body surface area (TBSA)
Suspected or known prisoners
Suspected or known pregnancy
Prehospital TXA given prior to randomization
Subjects who have activated the "opt-out" process when required by the local regulatory board

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01990768

Locations

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United States, Alabama
Alabama Resuscitation Center
Birmingham, Alabama, United States, 35249
United States, Minnesota
Hennepin County Medical Center
Minneapolis, Minnesota, United States, 55415
Mayo Clinic Rochester
Rochester, Minnesota, United States, 55905
St Paul Regions Hospital
Saint Paul, Minnesota, United States, 55101
United States, Ohio
University of Cincinnati Medical Center
Cincinnati, Ohio, United States, 45267
United States, Oregon
Oregon Health & Sciences University
Portland, Oregon, United States, 97239-3098
United States, Texas
Dallas Center for Resuscitation Research
Dallas, Texas, United States, 75390
Memorial Hermann Hospital - Texas Medical Center
Houston, Texas, United States, 77030
United States, Washington
Harborview Medical Center
Seattle, Washington, United States, 98104
United States, Wisconsin
Milwaukee Resuscitation Research Center
Milwaukee, Wisconsin, United States, 53226
Canada, British Columbia
British Columbia Regional Coordinating Center
Vancouver, British Columbia, Canada, V5Z 1 M9
Canada, Ontario
Toronto RescuNet
Toronto, Ontario, Canada, M5B 1W8

Sponsors and Collaborators

University of Washington

National Heart, Lung, and Blood Institute (NHLBI)

U.S. Army Medical Research and Development Command

Canadian Institutes of Health Research (CIHR)

Heart and Stroke Foundation of Canada

American Heart Association

Defence Research and Development Canada

Investigators

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Principal Investigator:	Susanne May, PhD	University of Washington
Principal Investigator:	Martin Schreiber, MD FACS	Oregon Health and Science University

Study Documents (Full-Text)

Documents provided by Susanne May, University of Washington:

Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol in force at beginning of enrollment [PDF] April 3, 2015

Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol after Amendment 2 [PDF] July 29, 2015

Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol after Amendment 2.1 [PDF] August 2, 2016

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Harmer JW, Dewey EN, Meier EN, Rowell SE, Schreiber MA. Tranexamic acid is not inferior to placebo with respect to adverse events in suspected traumatic brain injury patients not in shock with a normal head computed tomography scan: A retrospective study of a randomized trial. J Trauma Acute Care Surg. 2022 Jul 1;93(1):98-105. doi: 10.1097/TA.0000000000003635. Epub 2022 Mar 28.

Rowell SE, Meier EN, McKnight B, Kannas D, May S, Sheehan K, Bulger EM, Idris AH, Christenson J, Morrison LJ, Frascone RJ, Bosarge PL, Colella MR, Johannigman J, Cotton BA, Callum J, McMullan J, Dries DJ, Tibbs B, Richmond NJ, Weisfeldt ML, Tallon JM, Garrett JS, Zielinski MD, Aufderheide TP, Gandhi RR, Schlamp R, Robinson BRH, Jui J, Klein L, Rizoli S, Gamber M, Fleming M, Hwang J, Vincent LE, Williams C, Hendrickson A, Simonson R, Klotz P, Sopko G, Witham W, Ferrara M, Schreiber MA. Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury. JAMA. 2020 Sep 8;324(10):961-974. doi: 10.1001/jama.2020.8958. Erratum In: JAMA. 2020 Oct 27;324(16):1683.

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Responsible Party:	Susanne May, Associate Professor, University of Washington
ClinicalTrials.gov Identifier:	NCT01990768
Other Study ID Numbers:	47114 5U01HL077863-09 ( U.S. NIH Grant/Contract ) TATRC Log No. 13335004-A ( Other Grant/Funding Number: US Army Medical Research Acquisition Activity (USAMRAA) )
First Posted:	November 21, 2013 Key Record Dates
Results First Posted:	January 14, 2019
Last Update Posted:	January 14, 2019
Last Verified:	December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	Public use data set will be shared with NHLBI. It will include individual patient data that are de-identified. It will be available 3 years after study completion. This is currently expected for the end of 2020. The data should then be available at <https://biolincc.nhlbi.nih.gov/studies/>.

Keywords provided by Susanne May, University of Washington:


tranexamic acid traumatic brain injury intracranial hemorrhage prehospital	neurologic outcome glasgow outcome scale extended disability rating scale

Additional relevant MeSH terms:

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Brain Injuries Brain Injuries, Traumatic Wounds and Injuries Brain Diseases Central Nervous System Diseases Nervous System Diseases Craniocerebral Trauma	Trauma, Nervous System Tranexamic Acid Antifibrinolytic Agents Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action Hemostatics Coagulants

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