Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury

ID: NCT02535949
Status: Active, not recruiting
Phase: Phase 2
Start Date: February 01, 2016
First Submitted: December 05, 2014
Last Updated: February 19, 2018
Results: N/A
Sponsors & Collaborators: Washington University School of Medicine, United States Department of Defense
Location: United States
Conditions: Hemorrhage, Shock, Wounds and Injuries
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Study Description

Brief Summary

The purpose of this study is to evaluate the effects of TXA on the immune system, its pharmacokinetics, as well as safety and efficacy in severely injured trauma patients.

Detailed Description

Trauma is the leading cause of death in persons younger than 40 years. Hemorrhage is the etiology in 30% of these deaths, and remains the leading cause of potentially preventable mortality (66-80%) on the battlefield. Death secondary to hemorrhagic shock occurs from both surgical bleeding and coagulopathy. Due to the knowledge of increased fibrinolysis promoting a hypocoagulable state in severe trauma, trials have been performed to determine if antifibrinolytics such as tranexamic acid (TXA) could reduce morbidity and mortality by reducing death from hemorrhage. TXA is an antifibrinolytic that inhibits both plasminogen activation and plasmin activity, thus preventing clot break-down rather than promoting new clot formation. Despite the extensive use of TXA in many surgical populations and an increasing use in severe trauma patients, TXA does not have an FDA approved indication for patients with traumatic injuries. The effect of TXA on immune function has not been thoroughly examined, especially in patients with severe traumatic injury. The study of the effects of TXA use on endothelial activation and injury is also important due to the inter-relationship between coagulation and endothelial function. Endothelial injury secondary to local hypoperfusion causes acute traumatic coagulopathy with fibrinolysis. Therefore a thorough and comprehensive evaluation of the effects of TXA on immune, coagulation, and endothelial parameters is important to allow for a better understanding of the mechanisms of action of this agent.

This is a randomized placebo controlled trial to obtain mechanism of action data, pharmacokinetic information, and efficacy and safety data for the use of TXA in severely injured trauma patients. Participants will be randomized into 1 of 3 treatment arms (1:1:1): TXA 2 gram IV bolus, TXA 4 gram IV bolus, or placebo. The study period is from time of enrollment to hospital discharge or transfer. The study intervention will occur only once upon enrollment in the trial. Participants will receive study drug within two hours from their initial injury. Blood samples will be drawn at multiple time points for immune parameters, Pharmacodynamics, and repository samples.

Immune parameter samples will be drawn at at approximately 0, 6, 24 and 72 hours after study drug/placebo administration.

Pharmacokinetic and pharmacodynamic samples will be drawn according to two schedules. Even number sampling times, blood will be drawn at the approximate time points: 0, 20 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and 12 hr. A patient sampled on odd number sampling times will have samples drawn at the approximate time points: 0, 10 min, 40 min, 1.5 hr, 3 hr, 6 hr, 10 hr and 24 hr.

Repository samples will be drawn at approximate time points: 0, 1, 6, 24, and 72 hours.
Condition or disease Intervention/treatment Phase

Hemorrhage

Shock

Wounds and Injuries

Drug: Tranexamic Acid
Other Names
Cyklokapron
Other: Placebo
Other Names
Phase 2

Tracking Information

First Submitted DateDecember 05, 2014
Last Update Posted DateFebruary 19, 2018
Start DateFebruary 01, 2016
Anticipated Completion DateDecember 01, 2018
Primary Completion DateDecember 01, 2018
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Differences in the proportion of activated monocytes among the 3 treatment arms (TXA dose 1, TXA dose, 2, and placebo) from time 0 to time 72 hours [Time Frame: Samples Drawn through 72 hours after study initiation]

    We will, in a RCT, analyze samples from 150 patients (50 in each study group), at multiple time points.

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • Differences in cytokine profiles between the three study groups [Time Frame: Hospital Discharge (average 10 days)]

    To evaluate the effects of TXA on immune function parameters we will, in a RCT, analyze samples from 150 patients (50 in each study group), at multiple time points. Parameters are: a. Cytokines measured from time 0 to 72 hours.

  • Differences in leukocyte function parameters between the three study groups [Time Frame: Hospital Discharge (average 10 days)]

    To evaluate the effects of TXA on immune function parameters we will, in a RCT, analyze samples from 150 patients (50 in each study group), at multiple time points. Parameters are: a. Flow cytometric analyses on leukocytes measured from time 0 to 72 hours.

  • Differences in amount of study drug present in the bloodstream at various timepoints [Time Frame: 24 hours]

    Pharmacokinetic data will be analyzed with NONMEM, using both the first-order and conditional non-Laplacian (with centering) estimation techniques. We will consider two- and three-compartment models, parameterized in terms of both compartment volumes and clearances (distribution and elimination). We will compare a basic model (in which pharmacokinetic parameters were independent of weight) to a model in which the pharmacokinetic parameters will be assumed to be proportional to weight. The optimal model will be selected on the basis of the objective function logarithm of the likelihood of the results) using standard criteria (NONMEM guide).

  • Determine the incidence of thromboembolic events (DVT, MI, PE, Stroke) in all three study groups. [Time Frame: Hospital Discharge (average 10 days)]

  • Determine the incidence of seizures at 24 hours in all three study groups. [Time Frame: Hospital Discharge (average 10 days)]

  • Determine the incidence of all adverse events in all three study groups [Time Frame: Hospital Discharge (average 10 days)]

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleTranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury
Official TitleTranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (TAMPITI TRIAL)
Brief Summary

The purpose of this study is to evaluate the effects of TXA on the immune system, its pharmacokinetics, as well as safety and efficacy in severely injured trauma patients.

Detailed Description

Trauma is the leading cause of death in persons younger than 40 years. Hemorrhage is the etiology in 30% of these deaths, and remains the leading cause of potentially preventable mortality (66-80%) on the battlefield. Death secondary to hemorrhagic shock occurs from both surgical bleeding and coagulopathy. Due to the knowledge of increased fibrinolysis promoting a hypocoagulable state in severe trauma, trials have been performed to determine if antifibrinolytics such as tranexamic acid (TXA) could reduce morbidity and mortality by reducing death from hemorrhage. TXA is an antifibrinolytic that inhibits both plasminogen activation and plasmin activity, thus preventing clot break-down rather than promoting new clot formation. Despite the extensive use of TXA in many surgical populations and an increasing use in severe trauma patients, TXA does not have an FDA approved indication for patients with traumatic injuries. The effect of TXA on immune function has not been thoroughly examined, especially in patients with severe traumatic injury. The study of the effects of TXA use on endothelial activation and injury is also important due to the inter-relationship between coagulation and endothelial function. Endothelial injury secondary to local hypoperfusion causes acute traumatic coagulopathy with fibrinolysis. Therefore a thorough and comprehensive evaluation of the effects of TXA on immune, coagulation, and endothelial parameters is important to allow for a better understanding of the mechanisms of action of this agent.

This is a randomized placebo controlled trial to obtain mechanism of action data, pharmacokinetic information, and efficacy and safety data for the use of TXA in severely injured trauma patients. Participants will be randomized into 1 of 3 treatment arms (1:1:1): TXA 2 gram IV bolus, TXA 4 gram IV bolus, or placebo. The study period is from time of enrollment to hospital discharge or transfer. The study intervention will occur only once upon enrollment in the trial. Participants will receive study drug within two hours from their initial injury. Blood samples will be drawn at multiple time points for immune parameters, Pharmacodynamics, and repository samples.

Immune parameter samples will be drawn at at approximately 0, 6, 24 and 72 hours after study drug/placebo administration.

Pharmacokinetic and pharmacodynamic samples will be drawn according to two schedules. Even number sampling times, blood will be drawn at the approximate time points: 0, 20 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and 12 hr. A patient sampled on odd number sampling times will have samples drawn at the approximate time points: 0, 10 min, 40 min, 1.5 hr, 3 hr, 6 hr, 10 hr and 24 hr.

Repository samples will be drawn at approximate time points: 0, 1, 6, 24, and 72 hours.

Study TypeInterventional
Study PhasePhase 2
Estimated Enrollment
150
Allocation
Randomized
Interventional Model
Single Group Assignment
Masking
Triple
Primary Purpose
Treatment
Conditions
Hemorrhage
Shock
Wounds and Injuries
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: Tranexamic Acid

Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.

Other Names
Cyklokapron
Other: Placebo

Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury

Other Names
Study Groups/Cohorts
Tranexamic Acid 2 Gram
One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury

Tranexamic Acid 4 Gram
One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury

Placebo
Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury

Study Arms
Placebo Comparator Placebo
Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Other : Placebo
Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury

Experimental Tranexamic Acid 2 Gram
One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury
Drug : Tranexamic Acid
Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.

Experimental Tranexamic Acid 4 Gram
One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury
Drug : Tranexamic Acid
Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.

Arm Intervention/Treatment
Placebo Comparator Placebo
Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Other : Placebo
Experimental Tranexamic Acid 2 Gram
One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury
Drug : Tranexamic Acid
Experimental Tranexamic Acid 4 Gram
One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury
Drug : Tranexamic Acid

Recruitment Information

Recruitment Status:Active, not recruiting
Enrollment150
Completion DateDecember 01, 2018
Eligibility Criteria: Inclusion Criteria:
1. Patients with traumatic injury that are ordered to receive at least 1 blood product and/or
2. Patients admitted to the Emergency Department with a traumatic injury and require immediate transfer to the operating room to control the bleeding
3. Able to receive the study drug within 2 hours from estimated time of injury **Please note that in circumstances where the patient initially met inclusion/exclusion criteria (i.e. received blood products in the ED before a full evaluation of their injuries is complete) but is later found to only have a soft tissue involved injury or does not have a traumatic bleeding source), the Investigator may determine that the patient should not be randomized into the trial and the patient should be considered a screen failure

Exclusion Criteria:
1. Patients known to be < 18 years of age
2. Suspected Acute MI or stroke(thromboembolic and/or hemorrhagic) on admission
3. Known inherited coagulation disorders
4. Known history of thromboembolic events (DVT, PE, MI, Stroke)
• Please note that past medical history of hemorrhagic stroke is permitted, but not current admission with hemorrhagic stroke
5. Known history of seizures and/or seizure after injury/on admission related to this hospitalization
6. Suspected or known pregnancy
7. Known to be lactating
8. Suspected or known prisoners
9. Futile care
10. Known current state of immunosuppression (i.e. on high dose steroids, chemotherapeutics, etc.)
11. Unknown estimated time of injury 12). Patients wearing an "Opt Out" TAMPITI Study bracelet 13). Known presence of subarachnoid hemorrhage.
14.) Isolated injuries to hands and/or feet (distal) 15.) Administration of antifibrinolytics pre-hospital and/or during this ED admission prior to enrollment
GenderAll
Age18 Years to N/A
Accepts Healthy VolunteersNo
Contacts
Not Available
Listed Location Countries
United States

Administrative Information

NCT Number:NCT02535949
Other Study ID Numbers
TAMPITI TRIAL
Has Data Monitoring CommitteeYes
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
Washington University School of Medicine
Collaborators
United States Department of Defense
Investigators
Principal Investigator
Philip C Spinella, MD
Washington University School of Medicine