Prehospital Tranexamic Acid Use for Traumatic Brain Injury

NCT ID: NCT01990768

Last Updated: 2019-01-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 967 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-05-31
• Study Completion Date: 2017-11-07

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

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.

Conditions

Traumatic Brain Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: EXPERIMENTAL

1 gram Tranexamic Acid (TXA)

Intervention Type: DRUG

TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin.

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

Group Type: EXPERIMENTAL

2 grams TXA

Intervention Type: DRUG

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

Group Type: PLACEBO_COMPARATOR

0.9% Sodium Chloride injectable

Intervention Type: DRUG

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.

Interventions

1 gram Tranexamic Acid (TXA)

TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin.

Intervention Type: DRUG

2 grams TXA

TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Cyklokapron; Cyklokapron; Normal saline solution

Eligibility 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

• Minimum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

U.S. Army Medical Research and Development Command

FED

Sponsor Role: collaborator

Canadian Institutes of Health Research (CIHR)

OTHER_GOV

Sponsor Role: collaborator

Heart and Stroke Foundation of Canada

OTHER

Sponsor Role: collaborator

American Heart Association

OTHER

Sponsor Role: collaborator

Defence Research and Development Canada

INDUSTRY

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: lead

Responsible Party

Susanne May

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Susanne May, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Martin Schreiber, MD FACS

Role: PRINCIPAL_INVESTIGATOR

Oregon Health and Science University

Locations

Alabama Resuscitation Center

Birmingham, Alabama, United States

Hennepin County Medical Center

Minneapolis, Minnesota, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

St Paul Regions Hospital

Saint Paul, Minnesota, United States

University of Cincinnati Medical Center

Cincinnati, Ohio, United States

Oregon Health & Sciences University

Portland, Oregon, United States

Dallas Center for Resuscitation Research

Dallas, Texas, United States

Memorial Hermann Hospital - Texas Medical Center

Houston, Texas, United States

Harborview Medical Center

Seattle, Washington, United States

Milwaukee Resuscitation Research Center

Milwaukee, Wisconsin, United States

British Columbia Regional Coordinating Center

Vancouver, British Columbia, Canada

Toronto RescuNet

Toronto, Ontario, Canada

Countries

United States; Canada

References

Rowell S, Meier EN, Hoyos Gomez T, Fleming M, Jui J, Morrison L, Bulger E, Sopko G, Weisfeldt M, Christenson J, Klotz P, McMullan J, Callum J, Sheehan K, Tibbs B, Aufderheide T, Cotton B, Gandhi R, Idris A, Frascone RJ, Ferrara M, Richmond N, Kannas D, Schlamp R, Robinson B, Dries D, Tallon J, Hendrickson A, Gamber M, Garrett J, Simonson R, McKinley WI, Schreiber M. The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: A subgroup analysis from the prehospital TXA for TBI trial. J Trauma Acute Care Surg. 2024 Oct 1;97(4):572-580. doi: 10.1097/TA.0000000000004354. Epub 2024 Apr 30.

Reference Type: DERIVED

PMID: 38685481 (View on PubMed)

Hoefer LE, Benjamin AJ, Polcari AM, Schreiber MA, Zakrison TL, Rowell SE. TXA does not affect levels of TBI-related biomarkers in blunt TBI with ICH: A secondary analysis of the prehospital TXA for TBI trial. J Trauma Acute Care Surg. 2024 Jan 1;96(1):94-100. doi: 10.1097/TA.0000000000004130. Epub 2023 Oct 9.

Reference Type: DERIVED

PMID: 37807179 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35358154 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32897344 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol in force at beginning of enrollment

View Document

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol after Amendment 2

View Document

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol after Amendment 2.1

View Document

Other Identifiers

5U01HL077863-09

Identifier Type: NIH

Identifier Source: secondary_id

View Link

TATRC Log No. 13335004-A

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

47114

Identifier Type: -

Identifier Source: org_study_id