The design of a Bayesian adaptive clinical trial of tranexamic acid in severely injured children

Abstract

Background Trauma is the leading cause of death and disability in children in the USA. Tranexamic acid (TXA) reduces the blood transfusion requirements in adults and children during surgery. Several studies have evaluated TXA in adults with hemorrhagic trauma, but no randomized controlled trials have occurred in children with trauma. We propose a Bayesian adaptive clinical trial to investigate TXA in children with brain and/or torso hemorrhagic trauma. Methods/design We designed a double-blind, Bayesian adaptive clinical trial that will enroll up to 2000 patients. We extend the traditional Emax dose-response model to incorporate a hierarchical structure so multiple doses of TXA can be evaluated in different injury populations (isolated head injury, isolated torso injury, or both head and torso injury). Up to 3 doses of TXA (15 mg/kg, 30 mg/kg, and 45 mg/kg bolus doses) will be compared to placebo. Equal allocation between placebo, 15 mg/kg, and 30 mg/kg will be used for an initial period within each injury group. Depending on the dose-response curve, the 45 mg/kg arm may open in an injury group if there is a trend towards increasing efficacy based on the observed relationship using the data from the lower doses. Response-adaptive randomization allows each injury group to differ in allocation proportions of TXA so an optimal dose can be identified for each injury group. Frequent interim stopping periods are included to evaluate efficacy and futility. The statistical design is evaluated through extensive simulations to determine the operating characteristics in several plausible scenarios. This trial achieves adequate power in each injury group. Discussion This trial design evaluating TXA in pediatric hemorrhagic trauma allows for three separate injury populations to be analyzed and compared within a single study framework. Individual conclusions regarding optimal dosing of TXA can be made within each injury group. Identifying the optimal dose of TXA, if any, for various injury types in childhood may reduce death and disability.

Prehospital Tranexamic Acid in Major Pediatric Trauma Within a Physician-Led Emergency Medical Services System: A Multicenter Retrospective Study

“…This is especially true for younger children as they received less frequently TXA compared with older children even if they fulfilled criteria for appropriate TXA use. The Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC) trial (NCT04387305), a double-blind, multicenter clinical trial, could soon provide new evidences regarding the TXA efficacy in children with brain and/or torso hemorrhagic injury (31).…”

The Design of Nested Adaptive Clinical Trials of Multiple Organ Dysfunction Syndrome Children in a Single Study

“…Technical aspects of our TRIPS RAR design, such as fixed placebo arm allocation and delaying RAR implementation until 180 of the target 500 patients have been enrolled, were selected to minimize inference issues with use of frequentist approaches under this design. We firmly believe that the RAR design used is appropriate for the TRIPS trial due to potential benefits in the resulting trial's ability to "efficiently" identify treatment differences (or lack thereof) between the study arms, as illustrated in the examples above and reported by others (15,22,23). When comparing individual arms to control, there is a risk of concluding a spurious finding due to random noise.…”

Tranexamic acid in pediatric hemorrhagic trauma

“…36 They plan to use a double-blind, Bayesian adaptive approach, which includes a dose-response model to help identify the ideal dosing in children. 37 With VHA and other coagulation testing, they will also evaluate the efficacy of TXA across the fibrinolytic spectrum. Hopefully, this study will provide clear evidence for the appropriate timing, dose, and patient selection for administering TXA in pediatric trauma.…”

“…To address these questions, the TIC-TOC (traumatic injury clinical trial evaluating tranexamic acid in children) collaborators have proposed an RCT evaluating the efficacy of TXA in 2,000 severely injured children with hemorrhagic brain and/or torso injuries 36 . They plan to use a double-blind, Bayesian adaptive approach, which includes a dose-response model to help identify the ideal dosing in children 37 . With VHA and other coagulation testing, they will also evaluate the efficacy of TXA across the fibrinolytic spectrum.…”