Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC): study protocol for a pilot randomized controlled trial

This pilot study is a double-blind, randomized, controlled trial of children younger than 18 years with hemorrhagic injuries to the torso and brain. We will enroll a maximum of 40 children during the study. Children will be randomized into one of three arms: (1) TXA dose A (15 mg/kg bolus dose over 20 min, followed by 2 mg/kg/hr infusion over 8 h), (2) TXA dose B (30 mg/kg bolus dose over 20 min, followed by 4 mg/kg/hr infusion over 8 h), and (3) normal saline placebo. This pilot study will be conducted in preparation for a confirmatory clinical trial of TXA administration for children with hemorrhagic torso and/or brain injuries (Fig. 1). SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines were followed and a checklist completed (Additional file 1) [25].

The pilot study will be conducted at 4 clinical sites. All sites are American College of Surgery (ACS) verified Level I pediatric trauma centers.

Enrolled patients will be randomized to one of three study arms: TXA dose A, TXA dose B, or placebo. A systematic review demonstrated substantial variability in TXA dosing for pediatric surgical patients, ranging from initial loading doses of 2 to 100 mg/kg intravenously (IV), and a continuous infusion ranging from 3 to 10 mg/kg/h [17]. Doses selected for this study and rationale are as follows:

The study drug will be discontinued if any of the following occur: suspected anaphylactic reaction, severe renal impairment (creatinine clearance less than 29 mL/min/1.73m²) is identified on subsequent laboratory measurements, withdrawal of consent by the patient’s legal guardian or legally authorized representative, or discovery of new information which makes the patient ineligible to continue participation in the study.

Both study patients and study team members are blinded to the interventional arm. Blinding is provided by the use of identical study drugs, packaging, volume, and rates of infusion. Unblinding will not be allowed as there is no reversal agent for TXA. Clinicians will be asked to assume the patient has received TXA and treat accordingly.

Due to the narrow window of efficacy of TXA based on the CRASH-2 trial, randomization must only minimally delay treatment. To complete the randomization quickly, the study intervention will be pre-assigned using a central randomization process. Prior to enrollment at each site, a study drug box containing a vial of masked study drug with a numeric identification code corresponding to the treatment assignment will be designated.

Because we will be evaluating TXA for different injury patterns (hemorrhagic torso injury, hemorrhagic brain injury, and combined hemorrhagic torso and brain injuries), randomization will be stratified by injury pattern. Eligible patients will be randomized into one of the three arms in a 1:1:1 ratio (TXA dose A, TXA dose B, or placebo). We will perform permuted-block randomization across injury pattern (i.e., torso or brain or both torso and brain). To ensure a sufficient number of injury types, we will limit the enrollment of patients meeting the inclusion criteria for isolated brain injury to 20 patients (as it is anticipated these will be the most common eligible patients evaluated at the participating sites). A patient is considered enrolled when randomization occurs.

We will collect the following outcome data: the Pediatric Quality of Life Inventory (PedsQL) score, the Pediatric Glasgow Outcome Scale - Extended (GOS-E Peds) score, digit span recall (a test of working memory), total blood products (ml/kg) transfused over the initial 48 h of care (children with torso injuries), intracranial hemorrhage progression in first 24 h (children with brain injuries), coagulation biomarkers, and adverse events.

We will assess neurocognitive functioning and other quality-of-life measures using the PedsQL and the GOS-E Peds 1 week, 1 month, 3 months, and 6 months after ED presentation for all enrolled children (Fig. 3). We will assess working memory using the digit span recall test 1 week, 1 month, 3 months, and 6 months after ED presentation for all enrolled children 3 years and older. Blood product transfusion will be calculated as the total ml/kg blood products received from randomization to 48 h after randomization. Blood products in the calculation will include red blood cell components, platelet components, plasma components, and cryoprecipitate. Prior to study initiation, collaborating trauma surgeons, transfusion medicine physicians, pediatric critical care physicians, pediatric anesthesiologists, and pediatric emergency medicine physicians will establish general guidelines for indications and thresholds for blood product transfusion. We will perform non-contrast cranial computed tomography (CT) scans 24 (± 6) hours after randomization to assess intracranial hemorrhage progression (for those who have not received a second CT scan during the specified time frame in the course of clinical care). We will exclude those who received a neurosurgical intervention from assessment of the 24 h CT scan. Additional brain-imaging studies may be performed at the discretion of the treating physician as a part of routine care. A study neuroradiologist, blinded to clinical data, will review cranial CT scans and calculate intracranial hemorrhage progression using the ABC/2 volume estimation [29]. Intracranial hemorrhage will be assessed relative to the total brain volume (calculated by the XYZ/2 volume estimation) [30, 31]. We will also measure coagulation biomarker tests before and after study drug infusion. These tests include: kaolin activated TEG (measuring fibrinolysis as the percentage of clot lysis at 30 min post-maximum clot strength), d-dimer, tissue plasminogen activator (tPA), plasmin-antiplasmin (PAP) complex, and plasmin generation. Parameters are performed at a central laboratory to eliminate inter-assay variability and to standardize testing. Safety outcomes will be assessed on the 7th day after randomization or at hospital discharge (whichever comes first) via review of the electronic medical record and include:

All study patients will be followed for 180 days after randomization or death, whichever comes first, regardless of whether or not the patient has completed the study intervention.

The study Data Coordinating Center (at the University of Utah) will create the electronic data capture system and worksheets. Data will be entered via the internet into the electronic data capture system. Worksheets and study documents will be maintained in locked file cabinets in locked offices at each site.

A trained site monitor will conduct site-monitoring visits during the study period to ensure regulatory compliance and patient safety, and to monitor the quality of data collected at each enrolling site. The site monitor will provide each site with a written report, and sites will be required to follow-up on any deficiencies.

The study will have a Data Safety Monitoring Board (DSMB) approved by the funding agency to advise the sponsors and principal investigators regarding the continuing safety of study patients and the continuing scientific merit of the study. The DSMB will have a charter, approve the protocol prior to implementation, and will review interim analyses as applicable. The DSMB is responsible for monitoring accrual of study patients, ensuring adherence to the study protocol, assessing data quality, reviewing the performance of individual clinical sites, and monitoring serious adverse events and other patient safety issues. The DSMB will include a biostatistician, an ethicist, a pediatric trauma surgeon, a pediatric neurosurgeon, a patient advocate, and an emergency medicine physician.

As this study is a pilot trial to assess the feasibility of study procedures, the study is not powered for a particular endpoint. We estimate that there will be 1.25 eligible patients per site per month. This eligibility rate would justify the feasibility of conducting a subsequent confirmatory clinical trial evaluating the safety and efficacy of TXA in severely injured children. We will also evaluate the feasibility of enrolling patients with parent or legal guardian written informed consent only. If these consent procedures are not feasible (particularly given the 3 h from time of injury enrollment window and the frequent absence of parents/guardians at the time of ED presentation and study eligibility), we will apply to use EFIC procedures if parents or legal guardians are not available to provide written informed consent. We set a priori thresholds for recruitment futility to convert to the use of EFIC for patient enrollment. We will collect detailed information on missed eligible patients to evaluate the feasibility of consent processes to determine if and when to initiate EFIC procedures. Ultimately our a priori thresholds to convert to EFIC procedures were met. Our trial protocol was revised to include EFIC procedures if parents or guardians are not available or able to provide written informed consent.

This manuscript is based on protocol version 2.03 (August 22, 2018). The trial opened for enrollment in July 2018 and we anticipate the trial will be completed by December 2019.