Prehospital Tranexamic Acid Use for Traumatic Brain Injury

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. 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.

Official Title
-----------------
Prehospital Tranexamic Acid Use for Traumatic Brain Injury

Conditions
-----------------
Traumatic Brain Injury

Intervention / Treatment
-----------------
* Drug: 1 gram Tranexamic Acid (TXA)
* Drug: 2 grams TXA
* Drug: 0.9% Sodium Chloride injectable


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 15 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 gram Tranexamic Acid (TXA)<br>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)<br>* TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin.<br>* Other names: Cyklokapron;|
| Experimental: 2 grams TXA<br>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<br>* TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin.<br>* Other names: Cyklokapron;|
| Placebo Comparator: 0.9% Sodium Chloride injectable<br>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<br>* 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.<br>* Other names: Normal saline solution;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dichotomized Glasgow Outcome Scale Extended (GOS-E) at 6 Months | 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. | 6 months post-injury | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Died Within 28 Days | The counts of patients who died on or before day 28 are reported. | 28 days after hospital arrival | 
| Disability Rating Scale (DRS) at 6 Months | 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). | 6 months post-injury | 
| Number of Participants With Unfavorable Outcome on Dichotomized Glasgow Outcome Scale Extended (GOS-E) at Discharge | 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. | At the end of the hospital stay (average of 9 days post injury) | 
| Disability Rating Scale (DRS) at Discharge | 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). | At the end of the hospital stay (average of 9 days post injury) | 
| Number of Participants With Intracranial Hemorrhage (ICH) Progression | 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. | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 13 days among patients with multiple scans) | 
| Marshall Computed Tomography (CT) Score on Initial Head CT | 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. | Initial head CT (average of 1.9 hours post-injury) | 
| Rotterdam Computed Tomography (CT) Score Among Subjects With Intracranial Hemorrhage (ICH) on Initial Head CT | 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. | Initial head CT (average of 1.9 hours post-injury) | 
| Number of Participants With One or More Neurosurgical Interventions | Neurosurgical interventions include craniotomy, craniectomy, and placement of a neuromonitoring or drainage device. Counts are of subjects 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 | Hospital-free days count any day from hospital admission through day 28 that the patient is alive and out of the hospital. | From hospital admission through day 28 | 
| Intensive Care Unit (ICU)-Free Days | 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. | From hospital admission through day 28 | 
| Ventilator-free Days | 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. | From hospital admission through day 28 | 
| Number of Participants With Seizure | 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. | 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 Cerebral Ischemic Event | Diagnosis of cerebral ischemic event | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) | 
| Number of Participants With Myocardial Infarction (MI) | Diagnosis of an acute myocardial infarction | 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) | Diagnosis of 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) | Diagnosis of PE | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) | 
| Number of Participants With Any Thromboembolic Event | 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 | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
tranexamic acid, traumatic brain injury, intracranial hemorrhage, prehospital, neurologic outcome, glasgow outcome scale extended, disability rating scale