Clinical trial NCT04387305: Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children: an Efficacy Study
Official title: Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC): an Efficacy Study
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Brain Injuries, Traumatic
Wounds and Injury
Hemorrhage
Trauma Injury
Keywords: Tranexamic acid
Brain Injuries
Hemorrhage
Clinical Trial
Children
Pediatric
Trauma
Lead sponsor: University of California, Davis
Sponsor class: OTHER
Collaborators: name: Pediatric Emergency Care Applied Research Network
First posted: 2020-05-13
Enrollment: 2000
Sex: ALL
Minimum age (years): 0
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Bayesian adaptive response
Primary purpose: TREATMENT

Brief summary: Trauma is the leading cause of death and disability in children in the United States. The objective of this study is to evaluate the benefits and harms of tranexamic acid (TXA; a drug that stops bleeding) in severely injured children with hemorrhagic brain and/or torso injuries. Using thromboelastography, we will measure baseline fibrinolysis to assess for treatment effects of TXA at different levels of fibrinolysis.

Detailed description: The TIC-TOC efficacy trial is a multicenter, adaptive allocation, randomized controlled trial of children younger than 18 years with hemorrhagic injuries to the torso and/or brain to evaluate the efficacy of TXA on functional outcome as measured by the PedsQL. Children will be randomized to one of three arms: 1) TXA 15 mg/kg bolus over 30 minutes, followed by a 2 mg/kg/hr infusion over 8 hours), 2) TXA 30 mg/kg bolus over 30 minutes, followed by a 4 mg/kg/hr infusion over 8 hours), and 3) normal saline placebo. A third TXA dose (45 mg/kg bolus dose over 30 minutes, followed by a 6 mg/kg/hr infusion over 8 hours) may be added later in the trial if a dose effect based on accumulating data is noted. The trial will be conducted in the Pediatric Emergency Care Applied Research Network (PECARN) across 40 sites over 4 years of enrollment for a maximum sample size of 2000 patients.

A Bayesian adaptive randomization design will be used to evaluate the efficacy of TXA in children with hemorrhagic brain and/or torso injuries. Because different types of injury have different pathophysiology and potential response to TXA, three different injury strata will be evaluated: isolated hemorrhagic brain injury, isolated hemorrhagic torso injury, and both hemorrhagic brain and torso injuries. The efficacy of TXA will be analyzed across all enrolled children as well as across each type of injury.

The Bayesian adaptive trial design also efficiently evaluates the effectiveness of TXA across different TXA doses. The trial will randomize the first 500 patients to two doses of TXA and placebo at a fixed 1:1:1 ratio. Interim analyses will be conducted when 500, 750, 1000, 1250, 1500, and 1750 patients have been enrolled. At each interim analysis, randomization probabilities will be adjusted in order to preferentially allocate patients to better performing doses, while allocation to the placebo arm will stay fixed. The adaptive randomization will be based entirely on pre-planned rules using accumulating data. A Bayesian hierarchical model will be used to estimate the treatment effect for each of the injury types to be informed by the data accumulated from all injury types. At interim analyses, if a dose effect is noted towards the higher dose of TXA (30 mg/kg bolus then a 4 mg/kg/hr infusion) being more efficacious using pre-specified criteria, then a higher dose study arm (TXA 45 mg/kg bolus then a 6 mg/kg/hr infusion) will be opened later in the trial. If the dose response curve is flat, suggesting that TXA is ineffective, then futility stopping rules can end the trial early.

Eligibility criteria: Inclusion Criteria:

1. Less than 18 years old AND
2. Penetrating torso trauma, blunt torso trauma, or head trauma as defined below:
3. Penetrating Torso Trauma:

   a. Penetrating trauma to the chest, abdomen, neck, or pelvis with at least one of the following:
   * age-adjusted hypotension, or
   * age-adjusted tachycardia despite adequate resuscitation fluids, or
   * radiographic evidence of internal hemorrhage, or
   * clinician suspicion of ongoing internal hemorrhage
4. Blunt Torso Trauma:

   1. Clinician suspicion of hemorrhagic blunt torso injury and at least one of the following:

      * age-adjusted hypotension, or
      * age-adjusted tachycardia despite adequate resuscitation fluids
   2. Hemothorax on chest tube placement or imaging,
   3. Clinical suspicion of hemorrhagic blunt torso injury and Intraperitoneal fluid on abdominal ultrasonography (Focused Assessment with Sonography in Trauma),
   4. Intra-abdominal injury on CT with either contrast extravasation or more than trace intraperitoneal fluid,
   5. Pelvic fracture with contrast extravasation or hematoma on abdominal/pelvic CT scan with at least one of the following:

      * Age-adjusted hypotension, or
      * Age-adjusted tachycardia.
5. Head Trauma:

   1. Initial Glasgow Coma Scale (GCS) score 3 to 13 with associated intracranial hemorrhage on cranial CT scan (enroll after cranial CT scan)

Exclusion Criteria:

* Unable to administer study drug within 3 hours of traumatic event
* Known pregnancy
* Known ward of the state
* Cardiac arrest prior to randomization
* GCS score of 3 with bilateral unresponsive pupils
* Isolated subarachnoid hemorrhage, epidural hematoma, or diffuse axonal injury
* Known venous or arterial thrombosis
* Known bleeding/clotting disorders
* Known seizure disorders
* Known history of severe renal impairment
* Known allergy to TXA
* Unknown time of injury (includes suspected non-accidental trauma)
* Previous enrollment into the TIC-TOC trial
* Prior TXA for current injury
* Prior opt-out
* Non-English and non-Spanish speaking

Primary outcomes:
measure: Pediatric Quality of Life Inventory (PedsQL) area under the curve
timeFrame: 1 week, 1 month, 3 months, and 6 months (as measured as an area under the curve)
Secondary outcomes:
measure: Intracranial hemorrhage progression
timeFrame: 24 hours (±6 hours)
measure: Blood transfusion
timeFrame: First 48 hours after randomization
measure: PedsQL Physical Domain area under the curve
timeFrame: 1 week, 1 month, 3 months, and 6 months
Other outcomes:
measure: Glasgow Outcome Scale-Extended (GOS-E) Peds
timeFrame: 1 week, 1 month, 3 months, and 6 months
measure: Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue Scale
timeFrame: 1 week, 1 month, 3 months, and 6 months
measure: D-dimer
timeFrame: Change from baseline to end of 8-hour study drug infusion
measure: Plasmin-antiplasmin (PAP) complex
timeFrame: Change from baseline to end of 8-hour study drug infusion
measure: Tissue plasminogen activator (tPA)
timeFrame: Change from baseline to end of 8-hour study drug infusion
measure: Thrombosis
timeFrame: 1 week or at hospital discharge (whichever comes first)
measure: Seizure
timeFrame: 1 week or at hospital discharge (whichever comes first)
measure: Behavior Rating Inventory of Executive Function (BRIEF)
timeFrame: 6 and 12 months after injury
Locations:
Study officials:
affiliation: University of California, Davis
name: Daniel K Nishijima, MD, MAS
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Nathan Kuppermann, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nishijima DK, Gosdin M, Naz H, Tancredi DJ, Hewes HA, Myers SR, Stanley RM, Adelson PD, Burd RS, Finkelstein Y, VanBuren J, Casper TC, Kuppermann N; TIC-TOC Collaborators of the Pediatric Emergency Care Applied Research Network (PECARN). Assessment of primary outcome measures for a clinical trial of pediatric hemorrhagic injuries. Am J Emerg Med. 2021 May;43:210-216. doi: 10.1016/j.ajem.2020.03.001. Epub 2020 Mar 9.
citation: Trappey AF 3rd, Thompson KM, Kuppermann N, Stephenson JT, Nuno MA, Hewes HA, Meyers SR, Stanley RM, Galante JM, Nishijima DK; Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC) Collaborators of the Pediatric Emergency Care Applied Research Network (PECARN). Development of transfusion guidelines for injured children using a Modified Delphi Consensus Process. J Trauma Acute Care Surg. 2019 Oct;87(4):935-943. doi: 10.1097/TA.0000000000002432.
citation: Powers PE, Shore KK, Perez S, Ritley D, Kuppermann N, Holmes JF, Tzimenatos LS, Shawargga H, Nishijima DK. Public Deliberation as a Novel Method for an Exception From Informed Consent Community Consultation. Acad Emerg Med. 2019 Oct;26(10):1158-1168. doi: 10.1111/acem.13827. Epub 2019 Jul 24.