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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

Tracking Information
First Submitted Date  ICMJE December 5, 2014
First Posted Date  ICMJE August 31, 2015
Last Update Posted Date February 20, 2018
Study Start Date  ICMJE February 2016
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 26, 2015)
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  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 26, 2015)
  • 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  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury
Official Title  ICMJE Tranexamic 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Hemorrhage
  • Shock
  • Wounds and Injuries
Intervention  ICMJE
  • 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
  • Other: Placebo
    Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Study Arms  ICMJE
  • Experimental: Tranexamic Acid 2 Gram
    One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury
    Intervention: 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
    Intervention: Drug: Tranexamic Acid
  • Placebo Comparator: Placebo
    Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
    Intervention: Other: Placebo
Publications * Spinella PC, Thomas KA, Turnbull IR, Fuchs A, Bochicchio K, Schuerer D, Reese S, Coleoglou Centeno AA, Horn CB, Baty J, Shea SM, Meledeo MA, Pusateri AE, Levy JH, Cap AP, Bochicchio GV; TAMPITI Investigators. The Immunologic Effect of Early Intravenous Two and Four Gram Bolus Dosing of Tranexamic Acid Compared to Placebo in Patients With Severe Traumatic Bleeding (TAMPITI): A Randomized, Double-Blind, Placebo-Controlled, Single-Center Trial. Front Immunol. 2020 Sep 8;11:2085. doi: 10.3389/fimmu.2020.02085. eCollection 2020.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: August 26, 2015)
150
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2018
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02535949
Other Study ID Numbers  ICMJE TAMPITI TRIAL
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE United States Department of Defense
Investigators  ICMJE
Principal Investigator: Philip C Spinella, MD Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP