Prehospital Tranexamic Acid Use for Traumatic Brain Injury
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- University of Washington
- Enrollment
- 967
- Locations
- 12
- Primary Endpoint
- Dichotomized Glasgow Outcome Scale Extended (GOS-E) at 6 Months
Study Overview
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.
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 15 Years to — (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
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
Intervention: 1 gram Tranexamic Acid (TXA) (Drug)
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
Intervention: 2 grams TXA (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
Intervention: 0.9% Sodium Chloride injectable (Drug)
Outcomes
Primary Outcomes
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 Outcomes
- Disability Rating Scale (DRS) at 6 Months(6 months post-injury)
- Number of Participants With Intracranial Hemorrhage (ICH) Progression(From hospital admission through 28 days or the end of the hospital stay if sooner (average of 13 days among patients with multiple scans))
- Number of Participants With Any Thromboembolic Event(From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days))
- Number of Participants Who Died Within 28 Days(28 days after hospital arrival)
- Number of Participants With Unfavorable Outcome on Dichotomized Glasgow Outcome Scale Extended (GOS-E) at Discharge(At the end of the hospital stay (average of 9 days post injury))
- Disability Rating Scale (DRS) at Discharge(At the end of the hospital stay (average of 9 days post injury))
- Marshall Computed Tomography (CT) Score on Initial Head CT(Initial head CT (average of 1.9 hours post-injury))
- Number of Participants With Cerebral Ischemic Event(From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days))
- Rotterdam Computed Tomography (CT) Score Among Subjects With Intracranial Hemorrhage (ICH) on Initial Head CT(Initial head CT (average of 1.9 hours post-injury))
- Number of Participants With One or More Neurosurgical Interventions(From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days))
- Hospital-free Days(From hospital admission through day 28)
- Intensive Care Unit (ICU)-Free Days(From hospital admission through day 28)
- Ventilator-free Days(From hospital admission through day 28)
- Number of Participants With Seizure(From start of study drug infusion through 28 days or the end of the hospital stay if sooner (average of 9 days))
- Number of Participants With Myocardial Infarction (MI)(From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days))
- Number of Participants With Deep Vein Thrombosis (DVT)(From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days))
- Number of Participants With Pulmonary Embolus (PE)(From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days))
Investigators
Susanne May
Associate Professor
University of Washington