TIC-TOC: Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children: An Efficacy Study

Sponsor

Daniel Nishijima, MD, MAS (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04387305

Collaborator

Pediatric Emergency Care Applied Research Network (Other)

2,000

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Brain Injuries, Traumatic Wounds and Injury Hemorrhage Trauma Injury	Drug: Tranexamic acid injection	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

2000 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Bayesian adaptive responseBayesian adaptive response

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC): An Efficacy Study

Anticipated Study Start Date :

Apr 1, 2023

Anticipated Primary Completion Date :

Mar 31, 2028

Anticipated Study Completion Date :

Mar 31, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tranexamic acid 15 mg/kg bolus Subjects will receive a 15 mg/kg bolus of tranexamic acid over 30 minutes followed by a 2 mg/kg/h infusion over 8 hours. This represents 31 mg/kg total dose of TXA.	Drug: Tranexamic acid injection Active drug is provided to participants as described based on the TXA arm they are randomized to.
Experimental: Tranexamic acid 30 mg/kg bolus Subjects will receive a 30 mg/kg bolus of tranexamic acid over 30 minutes followed by a 4 mg/kg/h infusion over 8 hours. This represents 62 mg/kg total dose of TXA.	Drug: Tranexamic acid injection Active drug is provided to participants as described based on the TXA arm they are randomized to.
Experimental: Tranexamic acid 45 mg/kg bolus Subjects will receive a 45 mg/kg bolus of tranexamic acid over 30 minutes followed by a 6 mg/kg/h infusion over 8 hours. This represents 91 mg/kg total dose of TXA. This dosing arm will only open if a dose-effect is determined based on accumulating data.	Drug: Tranexamic acid injection Active drug is provided to participants as described based on the TXA arm they are randomized to.
Placebo Comparator: Placebo Subjects in the placebo group will receive a bolus dose of normal saline over 10 minutes followed by a normal saline infusion over 8 hours	Drug: Tranexamic acid injection Active drug is provided to participants as described based on the TXA arm they are randomized to.

Outcome Measures

Primary Outcome Measures

Pediatric Quality of Life Inventory (PedsQL) area under the curve [1 week, 1 month, 3 months, and 6 months (as measured as an area under the curve)]
Neurocognitive functioning and quality-of-life measure; 0 to 100 with higher scores representing better outcomes

Secondary Outcome Measures

Intracranial hemorrhage progression [24 hours (±6 hours)]
Intracranial hemorrhage progression on cranial computed tomography imaging
Blood transfusion [First 48 hours after randomization]
Total volume of packed red blood cells, platelets, fresh frozen plasma, and cryoprecipitate
PedsQL Physical Domain area under the curve [1 week, 1 month, 3 months, and 6 months]
Physical domain of the PedsQL measure; 0 to 100 with higher scores representing better outcomes

Other Outcome Measures

Glasgow Outcome Scale-Extended (GOS-E) Peds [1 week, 1 month, 3 months, and 6 months]
Global functioning as measured on an 8-point scale (8-death, 7-vegetative state, 6-lower severe disability, 5-upper severe disability, 4-lower moderate disability, 3-upper moderate disability, 2-lower good recovery, 1-upper good recovery)
Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue Scale [1 week, 1 month, 3 months, and 6 months]
Fatigue and cognitive function; 0 to 100 with higher scores representing better outcomes
D-dimer [Change from baseline to end of 8-hour study drug infusion]
Measure clot breakdown (ng/mL)
Plasmin-antiplasmin (PAP) complex [Change from baseline to end of 8-hour study drug infusion]
Measure fibrinolytic activity (mcg/L)
Tissue plasminogen activator (tPA) [Change from baseline to end of 8-hour study drug infusion]
Measure fibrinolytic activity (ng/mL)
Thrombosis [1 week or at hospital discharge (whichever comes first)]
Any venous or arterial thrombosis on standard diagnostic imaging post-randomization
Seizure [1 week or at hospital discharge (whichever comes first)]
Clinical or electroencephalogram-documented seizure
Behavior Rating Inventory of Executive Function (BRIEF) [6 and 12 months after injury]
Measurement of executive function after traumatic brain injury

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

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

Blunt Torso Trauma:
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

Hemothorax on chest tube placement or imaging,
Clinical suspicion of hemorrhagic blunt torso injury and Intraperitoneal fluid on abdominal ultrasonography (Focused Assessment with Sonography in Trauma),
Intra-abdominal injury on CT with either contrast extravasation or more than trace intraperitoneal fluid,
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.

Head Trauma:
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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Daniel Nishijima, MD, MAS
Pediatric Emergency Care Applied Research Network

Investigators

Principal Investigator: Daniel K Nishijima, MD, MAS, University of California, Davis
Principal Investigator: Nathan Kuppermann, MD, MPH, University of California, Davis