Majumdar S, McKinley K W, Chamberlain J, Thomas B, Margulies S, Nickel R S, Darbari D S, Campbell A, Berul C, Summar M, Kalsi G
Departments of Hematology at Children's National Hospital, United States.
Departments of Emergency Medicine at Children's National Hospital, United States.
Contemp Clin Trials Commun. 2023 Jan 16;32:101077. doi: 10.1016/j.conctc.2023.101077. eCollection 2023 Apr.
Vaso-occlusive pain crisis (VOC) is the most frequent cause for Emergency Department (ED) visits and hospital admissions for patients with sickle cell disease (SCD). Nitric oxide plays a critical role in the pathogenesis of vaso-occlusion. The amino acid, citrulline, is the main endothelial nitric oxide booster that offers the potential to ameliorate vaso-occlusion and decrease the risk of hospitalization.
In this two-part study, the goal of the first part is to determine the pharmacokinetic profile of intravenous (IV) l-citrulline and optimal dose for the second part of the study, which is to determine the efficacy and tolerability of the intervention in patients with SCD.
A phase I/IIA open-label dose-finding study with subsequent double-blind, placebo-controlled, randomized Study of l-citrulline in children and adolescents with SCD presenting to the ED in VOC.
Part 1: Subjects experiencing VOC are enrolled in an open-label, ascending dose of IV l-citrulline to identify the optimum dose with endpoints of pharmacokinetic parameters, pain scores, reduction of opioid use, quality of life, proportion admitted to the hospital for treatment of pain, readmission rates, and assessment of adverse events. Part 2 of the trial is a double-blind, placebo-controlled adaptive "pick-the-winner" design to evaluate the efficacy and tolerability of IV l-citrulline in patients with SCD while receiving standard of care therapy for VOC.
This ED based sickle cell adaptive trial will determine the optimal dose for IV citrulline and whether the intervention improves outcome as a potential novel therapy for VOC in SCD.
血管闭塞性疼痛危机（VOC）是镰状细胞病（SCD）患者前往急诊科（ED）就诊和住院的最常见原因。一氧化氮在血管闭塞的发病机制中起关键作用。氨基酸瓜氨酸是主要的内皮一氧化氮增强剂，具有改善血管闭塞和降低住院风险的潜力。
在这项分为两部分的研究中，第一部分的目标是确定静脉注射L-瓜氨酸的药代动力学特征以及研究第二部分的最佳剂量，第二部分旨在确定该干预措施对SCD患者的疗效和耐受性。
一项I/IIA期开放标签剂量探索性研究，随后是双盲、安慰剂对照、随机的L-瓜氨酸对因VOC前往ED就诊的SCD儿童和青少年的研究。
第1部分：经历VOC的受试者参加一项开放标签、静脉注射L-瓜氨酸剂量递增的研究，以确定最佳剂量，终点为药代动力学参数、疼痛评分、阿片类药物使用减少情况、生活质量、因疼痛住院治疗的比例、再入院率以及不良事件评估。试验的第2部分是双盲、安慰剂对照的适应性“选出优胜者”设计，以评估静脉注射L-瓜氨酸在SCD患者接受VOC标准治疗时的疗效和耐受性。
这项基于急诊科的镰状细胞适应性试验将确定静脉注射瓜氨酸的最佳剂量，以及该干预措施作为SCD中VOC的潜在新疗法是否能改善结局。
