Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children: A Pilot and Feasibility Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Brain Injuries, Wounds and Injuries, Hemorrhage

Intervention / Treatment
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* Drug: Tranexamic Acid
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Less than 18 years old AND Penetrating torso trauma, blunt torso trauma, or head trauma as defined below. 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 Blunt Torso Trauma (at least one of the following): 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 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 tachycardia, or Age-adjusted hypotension. 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 prisoners Known wards 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 bleeding/clotting disorders Known seizure disorders Known history of severe renal impairment Unknown time of injury Previous enrollment into the TIC-TOC trial Prior TXA for current injury Non-English and non-Spanish speaking Known venous or arterial thrombosis

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tranexamic acid dose A<br>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<br>* Active drug is provided to participants as described based on the TXA arm they are randomized to.<br>* Other names: TXA;|
| Experimental: Tranexamic acid dose B<br>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<br>* Active drug is provided to participants as described based on the TXA arm they are randomized to.<br>* Other names: TXA;|
| Placebo Comparator: Placebo<br>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<br>* Normal saline is provided to participants if randomized to this treatment arm.<br>* Other names: 0.9% Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pediatric Quality of Life Inventory (PedsQL) | 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. | 6 months | 
| Pediatric Quality of Life Inventory (PedsQL) | Neurocognitive functioning and quality-of-life measures; range from 0 to 100 with higher scores representing better outcomes | 1 week, 1 month, 3 months, and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glasgow Outcome Scale-Extended (GOS-E) Peds | 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 | 1 week, 1 month, 3 months, and 6 months | 
| Digit Span Recall Test | Test of working memory; higher scores represent a better outcome, range from 0 to infinity | 1 week, 1 month, 3 months, and 6 months | 
| Blood Transfusion | Total volume of packed red blood cells, platelets, fresh frozen plasma, and cryoprecipitate | First 48 hours after randomization | 
| Intracranial Hemorrhage Progression | 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. | 24 hours (±6 hours) | 
| Number of Participants With Any Non-cerebral Venous or Arterial Thrombosis | Any non-cerebral venous or arterial thrombosis on standard diagnostic imaging post-randomization | Day 7 of hospitalization or hospital discharge (whichever comes first) | 
| Number of Participants With Seizures | Clinical or electroencephalogram-documented | 24 hours after receiving drug | 
| Biomarker Testing | Changes in coagulation biomarkers due to study intervention | Baseline and completion of 8 hour infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain injuries, Wounds and injuries, Hemorrhage, Tranexamic acid, Child