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Prehospital Tranexamic Acid Use for Traumatic Brain Injury (TXA)

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified November 2013 by University of Washington
Sponsor:
Collaborators:
U.S. Army Medical Research and Materiel 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
ClinicalTrials.gov Identifier:
NCT01990768
First received: October 30, 2013
Last updated: November 15, 2013
Last verified: November 2013
  Purpose

SUMMARY Prehospital Tranexamic Acid (TXA) Use for Traumatic Brain Injury (TBI) 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 prehospital administration either of two dosing regimens of TXA in patients with moderate to severe TBI will not increase the proportion of patients with a favorable long-term neurologic outcome compared 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, 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 criteria: 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 IV or intraosseous (IO) access, age ≥ 15yrs (or weight ≥ 50kg if age is unknown), 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, clinical suspicion by EMS of seizure activity or known history of seizures, acute MI or stroke, CPR by EMS prior to randomization, burns > 20% 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.

Study design and infusion period: A multi-center double-blind randomized controlled clinical trial with three treatment arms:

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

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: The total sample size is 1002 (334 per group), which will allow for 80% power to detect an 8.1% absolute difference in favorable long-term neurological outcome as determined by the GOS-E 6 months after injury for each of the true TXA-placebo comparisons, 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.


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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Prehospital Tranexamic Acid Use for Traumatic Brain Injury

Resource links provided by NLM:


Further study details as provided by University of Washington:

Primary Outcome Measures:
  • Glasgow Outcome Scale Extended score (GOS-E) [ Time Frame: 6 months post-injury ] [ Designated as safety issue: No ]
    GOS-E subdivides the categories of severe and moderate disability and good recovery. Structured telephone interviews have been developed and validated for both the GOS and GOS-E and these questions will be incorporated into our follow-up survey. For each level of function, the baseline function prior to injury is assessed to ensure that the deficit can be attributed to the event.


Secondary Outcome Measures:
  • Observed volume (absolute and relative) of intracranial hemorrhage (ICH) progression [ Time Frame: On hospital arrival through 28 days or from hospital admission through the end of the hospital stay, an expected average of 14 days post injury ] [ Designated as safety issue: No ]
    All clinically indicated head CT scans obtained during the initial hospitalization or within the first 28 days will be assessed for ICH. All cerebral and carotid/vertebrobasilar CT and standard angiograms will be assessed for blunt cerebrovascular injury. Parenchymal, subdural and epidural hemorrhage volumes will be measured and quantified using volumetric software and verified by manual calculations based on the previously validated ABC/2 technique as needed.

  • Disability Rating Scale (DRS) [ Time Frame: At the end of the hospital stay, an expected average of 14 days post injury, and 6 months post injury ] [ Designated as safety issue: No ]
    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 3) psychosocial adaptability.

  • GOS-E [ Time Frame: At the end of the hospital stay, an expected average of 14 days post injury ] [ Designated as safety issue: No ]
    GOS-E subdivides the categories of severe and moderate disability and good recovery. Structured telephone interviews have been developed and validated for both the GOS and GOS-E and these questions will be incorporated into our follow-up survey. For each level of function, the baseline function prior to injury is assessed to ensure that the deficit can be attributed to the event.

  • Survival [ Time Frame: 28 days after hospital arrival ] [ Designated as safety issue: No ]
    The patient's vital status as either alive or dead at 28 days after hospital arrival.

  • Frequency of neurosurgical interventions [ Time Frame: From hospital admission through the end of the hospital stay, an expected average of 14 days post injury ] [ Designated as safety issue: No ]
    Neurosurgical interventions are surgical procedures required to treat traumatic brain injury.

  • Ventilator-free days [ Time Frame: From hospital admission through day 28 ] [ Designated as safety issue: No ]
    Ventilator-free days count any day from hospital admission through day 28 that the patient does not require mechanical ventilatory support.

  • Seizure [ Time Frame: From hospital admission through the end of the hospital stay, an expected average of 14 days post injury ] [ Designated as safety issue: Yes ]
    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.

  • Cerebral ischemic events [ Time Frame: From hospital admission through the end of the hospital stay, an expected average of 14 days post injury ] [ Designated as safety issue: Yes ]
    New focal ischemic lesions will be defined as an area of focal low attenuation in a distribution indicating an arterial ischemic cause rather than a traumatic contusion and will be rated using a validated scale for ischemic stroke.

  • Myocardial infarction [ Time Frame: From hospital admission through the end of the hospital stay, an expected average of 14 days post injury. ] [ Designated as safety issue: Yes ]
    Diagnosis of an acute myocardial infarction

  • Deep vein thrombosis (DVT) [ Time Frame: From hospital admission through the end of the hospital stay, an expected average of 14 days post injury ] [ Designated as safety issue: Yes ]
    Diagnosis of an DVT

  • Pulmonary embolus (PE) [ Time Frame: From hospital admission through the end of the hospital stay, an expected average of 14 days post injury ] [ Designated as safety issue: Yes ]
    Diagnosis of PE


Other Outcome Measures:
  • Alterations in fibrinolysis [ Time Frame: From hospital admission through 48 hours ] [ Designated as safety issue: No ]
    Alterations in fibrinolysis based on fibrinolytic pathway mediators and degree of clot lysis based on kaolin activated TEG and defined as LY30 or the per cent lysis that occurs 30 minutes after maximum amplitude (MA) is achieved.


Estimated Enrollment: 1002
Study Start Date: June 2014
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   15 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01990768

Contacts
Contact: Susanne May, PhD 206-685-1302 sjmay@uw.edu
Contact: Delores Kannas, MS, MHA 206-616-0415 deloresk@uw.edu

Locations
United States, Oregon
Oregon Health & Sciences University Not yet recruiting
Portland, Oregon, United States, 97239-3098
Contact: Martin Schreiber, MD    503-497-5300    schreibm@ohsu.edu   
Contact: Kimberly La Morticella, RN    (503) 494-4315    lamortik@ohsu.edu   
Sub-Investigator: Susan Rowell, MD         
United States, Washington
University of Washington Not yet recruiting
Seattle, Washington, United States, 98105
Contact: Susanne May, PhD    206-685-1302    sjmay@uw.edu   
Contact: Delores Kannas, MS, MHA    206-616-0415    deloresk@uw.edu   
Sub-Investigator: Eileen Bulger, MD         
Sponsors and Collaborators
University of Washington
U.S. Army Medical Research and Materiel Command
Canadian Institutes of Health Research (CIHR)
Heart and Stroke Foundation of Canada
American Heart Association
Defence Research and Development Canada
Investigators
Principal Investigator: Susanne May, PhD University of Washington
Principal Investigator: Martin Schreiber, MD FACS Oregon Health and Science University
  More Information

No publications provided

Responsible Party: Susanne May, Associate Professor, University of Washington
ClinicalTrials.gov Identifier: NCT01990768     History of Changes
Other Study ID Numbers: 46105-D, 5U01HL077863-09, TATRC Log No. 13335004-A
Study First Received: October 30, 2013
Last Updated: November 15, 2013
Health Authority: United States: Food and Drug Administration
United States: Data and Safety Monitoring Board
United States: Federal Government
United States: Institutional Review Board
Canada: Health Canada

Keywords provided by University of Washington:
tranexamic acid
traumatic brain injury
intracranial hemorrhage
prehospital
neurologic outcome
glasgow outcome scale extended
disability rating scale

Additional relevant MeSH terms:
Brain Injuries
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
Pharmacologic Actions
Hemostatics
Coagulants
Hematologic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 22, 2014