Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
Department of Emergency Medicine, University of California, Davis School of Medicine, Sacramento, CA, 95817, USA.
Trials. 2021 Nov 4;22(1):769. doi: 10.1186/s13063-021-05737-0.
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 E 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.
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.
在美国，创伤是儿童死亡和残疾的主要原因。氨甲环酸（TXA）可减少成人和儿童手术期间的输血需求。已有多项研究评估了 TXA 在出血性创伤的成人中的应用，但尚未有随机对照试验在创伤儿童中进行。我们提出了一项贝叶斯自适应临床试验，以研究 TXA 在脑和/或躯干出血性创伤儿童中的应用。
方法/设计：我们设计了一项双盲、贝叶斯自适应临床试验，预计将纳入 2000 名患者。我们将传统的 E 剂量反应模型扩展为包含层次结构，以便在不同的损伤人群中评估多种 TXA 剂量（孤立性头部损伤、孤立性躯干损伤或头部和躯干损伤同时存在）。将 TXA 的 3 种剂量（15mg/kg、30mg/kg 和 45mg/kg 推注剂量）与安慰剂进行比较。在每个损伤组的初始阶段，将采用安慰剂、15mg/kg 和 30mg/kg 之间的均等分配。如果根据较低剂量的观察到的关系，观察到疗效呈增加趋势，则 45mg/kg 组可能在损伤组中开放。基于反应的随机化允许每个损伤组在 TXA 的分配比例上有所不同，以便为每个损伤组确定最佳剂量。包括频繁的中期停止期，以评估疗效和无效性。通过广泛的模拟评估统计设计，以确定几种合理情况下的操作特征。该试验在每个损伤组中都具有足够的效能。
这项评估儿童出血性创伤中 TXA 的试验设计允许在单个研究框架内分析和比较三个独立的损伤人群。可以在每个损伤组内得出关于 TXA 最佳剂量的个体结论。如果有的话，确定儿童不同损伤类型的 TXA 最佳剂量可能会降低死亡率和残疾率。
