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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Hemorrhage; Brain Injuries, Traumatic; Trauma Injury; Wounds and Injury
• Intervention / Treatment: Drug: Tranexamic acid injection

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 Type: Interventional
• Enrollment (Estimated): 2000
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Daniel K Nishijima, MD, MAS; Phone Number: 916.734.3884; Email: dnishijima@ucdavis.edu
• Study Contact Backup: Name: Nathan Kuppermann, MD, MPH; Phone Number: 916.734.1535; Email: nkuppermann@ucdavis.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glasgow Outcome Scale-Extended (GOS-E) Peds	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)	1 week, 1 month, 3 months, and 6 months
Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue Scale	Fatigue and cognitive function; 0 to 100 with higher scores representing better outcomes	1 week, 1 month, 3 months, and 6 months
D-dimer	Measure clot breakdown (ng/mL)	Change from baseline to end of 8-hour study drug infusion
Plasmin-antiplasmin (PAP) complex	Measure fibrinolytic activity (mcg/L)	Change from baseline to end of 8-hour study drug infusion
Tissue plasminogen activator (tPA)	Measure fibrinolytic activity (ng/mL)	Change from baseline to end of 8-hour study drug infusion
Thrombosis	Any venous or arterial thrombosis on standard diagnostic imaging post-randomization	1 week or at hospital discharge (whichever comes first)
Seizure	Clinical or electroencephalogram-documented seizure	1 week or at hospital discharge (whichever comes first)
Behavior Rating Inventory of Executive Function (BRIEF)	Measurement of executive function after traumatic brain injury	6 and 12 months after injury

Collaborators and Investigators

• Sponsor: Daniel Nishijima, MD, MAS
• Collaborators: 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

Publications and helpful links

General Publications

• 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.
• 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. Erratum In: J Trauma Acute Care Surg. 2022 May 1;92(5):949.
• 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.

Helpful Links

• TIC-TOC trial website

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): March 31, 2030
• Study Completion (Estimated): March 31, 2030

Study Registration Dates

• First Submitted: May 5, 2020
• First Submitted That Met QC Criteria: May 12, 2020
• First Posted (Actual): May 13, 2020

Study Record Updates

• Last Update Posted (Actual): November 15, 2023
• Last Update Submitted That Met QC Criteria: November 13, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Children; Pediatric; Clinical Trial; Trauma; Hemorrhage; Tranexamic acid; Brain Injuries
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Hemorrhage; Brain Injuries, Traumatic; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid
• Other Study ID Numbers: 128206

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: A public use database will be produced and will be completely de-identified in accordance with the definitions provided in the Health Insurance Portability and Accountability Act (HIPAA).
• IPD Sharing Time Frame: 12 months after publication of primary manuscript.
• IPD Sharing Access Criteria: Approval through NIH and PECARN
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No