Clinical trial NCT02535949: Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury
Official title: Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (TAMPITI TRIAL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hemorrhage
Shock
Wounds and Injuries
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2015-08-31
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in HLA-DR Expression on Monocytes 72 Hours After Drug or Placebo Administration in Patient Groups (0g TXA (Placebo); 2g TXA; 4g TXA)."
timeFrame: Samples Drawn through 72 hours after study initiation
Secondary outcomes:
measure: Differences in Cytokine Profiles Between the Three Study Groups
timeFrame: Samples Drawn through 72 hours after study initiation
measure: Differences in Leukocyte Function Parameters Between the Three Study Groups
timeFrame: Samples Drawn through 72 hours after study initiation
measure: Total Transfusion Volume CL
timeFrame: 24 hours
measure: Determine the Incidence of Thromboembolic Events (DVT, MI, PE, Stroke) in All Three Study Groups.
timeFrame: Hospital Discharge (average 10 days)
measure: Determine the Incidence of Seizures at 24 Hours in All Three Study Groups.
timeFrame: 24 hours following TXA
measure: Determine the Incidence of All Adverse Events in All Three Study Groups
timeFrame: Hospital Discharge (average 10 days)
measure: Platelet Count CL
timeFrame: 24 hours
measure: Near Infrared Spectroscopy CL
timeFrame: 24 hours
measure: Creatinine Count CL
timeFrame: 24 hours
measure: V2- Peripheral Volume (L/70kg)
timeFrame: 24 hours
measure: Q- Intercompartmental Clearance (L/70kg)
timeFrame: 24 hours
measure: V1- Central Volume (L/70kg)
timeFrame: 24 hours
measure: CL- Clearance of TXA (mL/(Min*70kg))
timeFrame: 24 hours
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Barnes Jewish Hospital
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Philip C Spinella, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.