Prehospital Tranexamic Acid Use for Traumatic Brain Injury

Traumatic Brain Injury Clinical Trial

— TXA  

Official title:

Prehospital Tranexamic Acid Use for Traumatic Brain Injury

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01990768
• Other study ID #: 47114
• Secondary ID: 5U01HL077863-09T
• Status: Completed
• Phase: Phase 2
• Start date: May 2015
• Est. completion date: November 7, 2017

Study information

• Verified date: December 2018
• Source: University of Washington
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 967
• Est. completion date: November 7, 2017
• Est. primary completion date: November 7, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

Inclusion Criteria:

1. Blunt or penetrating traumatic mechanism consistent with traumatic brain injury

2. Prehospital Glasgow Coma Score (GCS) score = 12 at any time prior to randomization and administration of sedative and/or paralytic agents

3. Prehospital systolic blood pressure (SBP) = 90 mmHg prior to randomization

4. Prehospital intravenous (IV) or intraosseous (IO) access

5. Estimated Age = 15 (or estimated weight > 50 kg if age is unknown)

6. Emergency Medicine System (EMS) transport to a participating trauma center

Exclusion Criteria:

1. Prehospital GCS=3 with no reactive pupil

2. Estimated time from injury to hospital arrival > 2 hours

3. Unknown time of injury - no known reference times to support estimation

4. Clinical suspicion by EMS of seizure activity or known history of seizures, acute myocardial infarction (MI) or stroke

5. Cardio-pulmonary resuscitation (CPR) by EMS prior to randomization

6. Burns > 20% total body surface area (TBSA)

7. Suspected or known prisoners

8. Suspected or known pregnancy

9. Prehospital TXA given prior to randomization

10. Subjects who have activated the "opt-out" process when required by the local regulatory board

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Traumatic Brain Injury
• Wounds and Injuries

Intervention

Drug:
• 1 gram Tranexamic Acid (TXA)
TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin.
• 2 grams TXA
TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin.
• 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.

Locations

Country	Name	City	State
Canada	Toronto RescuNet	Toronto	Ontario
Canada	British Columbia Regional Coordinating Center	Vancouver	British Columbia
United States	Alabama Resuscitation Center	Birmingham	Alabama
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	Dallas Center for Resuscitation Research	Dallas	Texas
United States	Memorial Hermann Hospital - Texas Medical Center	Houston	Texas
United States	Milwaukee Resuscitation Research Center	Milwaukee	Wisconsin
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Oregon Health & Sciences University	Portland	Oregon
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	St Paul Regions Hospital	Saint Paul	Minnesota
United States	Harborview Medical Center	Seattle	Washington

Sponsors (7)

Lead Sponsor	Collaborator
University of Washington	American Heart Association, Canadian Institutes of Health Research (CIHR), Defence Research and Development Canada, Heart and Stroke Foundation of Canada, National Heart, Lung, and Blood Institute (NHLBI), U.S. Army Medical Research and Materiel Command

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Fibrinolysis at Hospital Admission	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).	First blood draw (average of 1.6 hours post-injury)
Primary	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	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)