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Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (TAMPITI)

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ClinicalTrials.gov Identifier: NCT02535949
Recruitment Status : Unknown
Verified February 2018 by Washington University School of Medicine.
Recruitment status was:  Active, not recruiting
First Posted : August 31, 2015
Last Update Posted : February 20, 2018
Sponsor:
Collaborator:
United States Department of Defense
Information provided by (Responsible Party):
Washington University School of Medicine

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.

Condition or disease Intervention/treatment Phase
Hemorrhage Shock Wounds and Injuries Drug: Tranexamic Acid Other: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (TAMPITI TRIAL)
Study Start Date : February 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Other Name: Cyklokapron

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.
Other Name: Cyklokapron

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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.


  2. 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.


  3. 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).

  4. Determine the incidence of thromboembolic events (DVT, MI, PE, Stroke) in all three study groups. [ Time Frame: Hospital Discharge (average 10 days) ]
  5. Determine the incidence of seizures at 24 hours in all three study groups. [ Time Frame: Hospital Discharge (average 10 days) ]
  6. Determine the incidence of all adverse events in all three study groups [ Time Frame: Hospital Discharge (average 10 days) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02535949


Locations
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United States, Missouri
Barnes Jewish Hospital
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
United States Department of Defense
Investigators
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Principal Investigator: Philip C Spinella, MD Washington University School of Medicine
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02535949    
Other Study ID Numbers: TAMPITI TRIAL
First Posted: August 31, 2015    Key Record Dates
Last Update Posted: February 20, 2018
Last Verified: February 2018
Additional relevant MeSH terms:
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Hemorrhage
Wounds and Injuries
Pathologic Processes
Tranexamic Acid
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants