Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children: A Pilot and Feasibility Study (TIC-TOC)

• ClinicalTrials.gov Identifier: NCT02840097
• Recruitment Status: Completed
• First Posted: July 21, 2016
• Results First Posted: September 5, 2021
• Last Update Posted: September 5, 2021
• Sponsor: Daniel Nishijima, MD, MAS
• Collaborator: Pediatric Emergency Care Applied Research Network
• Information provided by (Responsible Party): Daniel Nishijima, MD, MAS, University of California, Davis

Study Description

Brief Summary:

Trauma is the leading cause of death and disability in children in the United States. The long-term goal of this project is to evaluate the benefits and harms of tranexamic acid (TXA; a drug that stops bleeding) in severely injured children. This is a 40-patient pilot study to evaluate the feasibility of two subsequent large-scale studies of TXA in injured children.

Condition or disease	Intervention/treatment	Phase
Brain Injuries; Wounds and Injuries; Hemorrhage	Drug: Tranexamic Acid; Drug: Placebo	Phase 2

Detailed Description:

Tranexamic acid (TXA), a drug that stops bleeding, is the only drug treatment that improves survival in adults with serious bleeding after injuries. However, TXA has not been used routinely in children with traumatic bleeding because no studies have appropriately evaluated TXA for injured children. Such a study has the potential for significant impact in improving the lives of injured children and their families, if found to be successful. The long-term objective is to evaluate the benefits and risks of TXA in severely injured children. This will be achieved by ultimately conducting two large-scale, multicenter, randomized controlled trials of TXA use in severely injured children. One trial will evaluate TXA in children with severe injuries to the body ("torso injuries", i.e., to the abdomen and chest) and the second trial will evaluate TXA in children with moderate-to-severe traumatic brain injuries (TBIs). However, conducting a clinical trial in critically ill children is challenging due to lower disease frequency and complex parent consent/child assent procedures. The investigators will conduct a pilot study, designed similarly to the full-scale trials but with much smaller patient enrollment, to assess the feasibility of, and fill crucial information gaps for the two subsequent large-scale clinical trials. Injured children will be randomized to one of three study arms: two different TXA doses or placebo. The specific aim of the proposed pilot study is to demonstrate the ability to efficiently identify and enroll children with hemorrhagic torso injuries or TBIs into a multicenter, randomized controlled pilot study evaluating these two doses of TXA and placebo. The pilot study will enroll 40 children who meet inclusion and exclusion criteria at 4 participating sites. To demonstrate the ability to collect outcome measures, the investigators will collect the identical anticipated outcome measures for the subsequent clinical trials: total blood products transfused over the initial 48 hours of care (torso injury trial), and intracranial hemorrhage progression in first 24 hours and neurocognitive function at 6 months after randomization (TBI trial). The investigators will also collect safety outcomes, specifically venothromboembolic events (i.e., blot clots in the blood vessels) and seizures within the initial 24 hours of study drug. Additional objectives of this pilot study are to: evaluate the ability to efficiently screen, identify, consent, randomize, and initiate the study intervention within 3 hours of injury, assess protocol adherence and variability of care in enrolled patients, and identify operational efficiencies with the potential to enhance the success of the subsequent trials.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC): A Pilot and Feasibility Study
• Actual Study Start Date: March 4, 2019
• Actual Primary Completion Date: October 3, 2020
• Actual Study Completion Date: October 3, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tranexamic acid dose A; Subjects will receive a 15 mg/kg bolus of tranexamic acid over 10 minutes followed by a 2mg/kg/h over 8 hours. This represents 31mg/kg total dose of TXA.	Drug: Tranexamic Acid; Active drug is provided to participants as described based on the TXA arm they are randomized to.; Other Name: TXA
Experimental: Tranexamic acid dose B; Subjects will receive a 30 mg/kg bolus of tranexamic acid over 10 minutes followed by a 4 mg/kg/h over 8 hours. This represents 62 mg/kg total dose of TXA.	Drug: Tranexamic Acid; Active drug is provided to participants as described based on the TXA arm they are randomized to.; Other Name: TXA
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: Placebo; Normal saline is provided to participants if randomized to this treatment arm.; Other Name: 0.9% Normal Saline

Outcome Measures

Primary Outcome Measures :

1. Pediatric Quality of Life Inventory (PedsQL) [ Time Frame: 6 months ]
   Neurocognitive functioning and quality-of-life measures; range from 0 to 100 quality of life units with higher scores representing better outcomes. Measurements occur at 1 week, 1 month, 3 months, and 6 months to generate an area under the curve of quality of life units.
2. Pediatric Quality of Life Inventory (PedsQL) [ Time Frame: 1 week, 1 month, 3 months, and 6 months ]
   Neurocognitive functioning and quality-of-life measures; range from 0 to 100 with higher scores representing better outcomes

Secondary Outcome Measures :

1. Glasgow Outcome Scale-Extended (GOS-E) Peds [ Time Frame: 1 week, 1 month, 3 months, and 6 months ]
   Global functioning; range is 1 to 8 with higher scores representing better outcomes; 1=death, 2=vegetative state, 3=lower severe disability, 4=upper severe disability, 5=lower moderate disability, 6=upper moderate disability, 7=lower good recovery, 8=upper good recovery
2. Digit Span Recall Test [ Time Frame: 1 week, 1 month, 3 months, and 6 months ]
   Test of working memory; higher scores represent a better outcome, range from 0 to infinity
3. Blood Transfusion [ Time Frame: First 48 hours after randomization ]
   Total volume of packed red blood cells, platelets, fresh frozen plasma, and cryoprecipitate
4. Intracranial Hemorrhage Progression [ Time Frame: 24 hours (±6 hours) ]
   Intracranial hemorrhage progression on cranial computed tomography (CT) imaging; hemorrhage will be measured using the ABC/2 volume estimation and relative to the total brain volume (calculated by the XYZ/2 volume estimation); more intracranial hemorrhage progression represents a worse outcome. Change is calculated as the difference between the baseline and repeat cranial CT imaging. The repeat CT is conducted 24 hours (±6 hours) after the baseline CT.
5. Number of Participants With Any Non-cerebral Venous or Arterial Thrombosis [ Time Frame: Day 7 of hospitalization or hospital discharge (whichever comes first) ]
   Any non-cerebral venous or arterial thrombosis on standard diagnostic imaging post-randomization
6. Number of Participants With Seizures [ Time Frame: 24 hours after receiving drug ]
   Clinical or electroencephalogram-documented
7. Biomarker Testing [ Time Frame: Baseline and completion of 8 hour infusion ]
   Changes in coagulation biomarkers due to study intervention

Eligibility Criteria

• Ages Eligible for Study: up to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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, pelvis or thigh 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 (at least one of the following):

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

      • age-adjusted hypotension, or
      • persistent 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 tachycardia, or
      • Age-adjusted hypotension.

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:

1. Unable to administer study drug within 3 hours of traumatic event
2. Known pregnancy
3. Known prisoners
4. Known wards of the state
5. Cardiac arrest prior to randomization
6. GCS score of 3 with bilateral unresponsive pupils
7. Isolated subarachnoid hemorrhage, epidural hematoma, or diffuse axonal injury
8. Known bleeding/clotting disorders
9. Known seizure disorders
10. Known history of severe renal impairment
11. Unknown time of injury
12. Previous enrollment into the TIC-TOC trial
13. Prior TXA for current injury
14. Non-English and non-Spanish speaking
15. Known venous or arterial thrombosis

Contacts and Locations

Locations

United States, California

University of California, Davis

Sacramento, California, United States, 95817

United States, Ohio

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, Utah

Primary Children's Hospital

Salt Lake City, Utah, United States, 84113

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

  Study Documents (Full-Text)

Documents provided by Daniel Nishijima, MD, MAS, University of California, Davis:

Study Protocol and Statistical Analysis Plan  [PDF] October 24, 2018

More Information

Additional Information:

TIC-TOC trial website 

Publications of Results:

Nishijima DK, VanBuren J, Hewes HA, Myers SR, Stanley RM, Adelson PD, Barnhard SE, Bobinski M, Ghetti S, Holmes JF, Roberts I, Schalick WO 3rd, Tran NK, Tzimenatos LS, Michael Dean J, Kuppermann N; TIC-TOC Collaborators of the Pediatric Emergency Care Applied Research Network. Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC): study protocol for a pilot randomized controlled trial. Trials. 2018 Oct 30;19(1):593. doi: 10.1186/s13063-018-2974-z.

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.

• Responsible Party: Daniel Nishijima, MD, MAS, Associate Professor, Emergency Medicine, University of California, Davis
• ClinicalTrials.gov Identifier: NCT02840097
• Other Study ID Numbers: 1023599
• First Posted: July 21, 2016
• Results First Posted: September 5, 2021
• Last Update Posted: September 5, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Daniel Nishijima, MD, MAS, University of California, Davis:

Brain injuries; Wounds and injuries; Hemorrhage; Tranexamic acid; Child

Additional relevant MeSH terms:

Brain Injuries; Hemorrhage; Wounds and Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Pathologic Processes; Tranexamic Acid; Antifibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Hemostatics; Coagulants