2/2: Sickle Cell Disease Treatment with Arginine Therapy (STArT) trial

项目摘要/摘要 镰状细胞病(SCD)中的血管闭塞性疼痛发作(VOE)是住院的主要原因， 急诊室就诊和缺课，与死亡率增加有关。确实有 目前还没有缓解血管闭塞的治疗方法，干预措施仅限于水合和止痛。一氧化氮 (NO)是由L精氨酸的5电子氧化产生的，是一种有效的血管扩张剂，并对血管产生多效性作用。 血管和循环血细胞，包括抑制血小板聚集，下调黏附 分子，以及对缺血再灌注损伤的调控，在VOE过程中所有的通路都受到不利的影响。我们有 研究发现，收治VOE的儿童SCD患者存在血浆L-精氨酸水平下降。此外，我们 现已完成一项单中心、随机、双盲、安慰剂对照的精氨酸治疗试验 54名VOE儿童需要住院治疗。我们观察到阿片类药物的总使用量(mg/kg)减少了54%， fi可显著降低每8小时静脉注射L精氨酸5天的儿童出院时疼痛评分 与安慰剂相比，以及临床相关的趋势是住院时间减少了大约 17个小时。在药代动力学研究中，我们发现静脉注射精氨酸可引起剂量依赖性的改善。 因疼痛住院的SCD患儿的线粒体功能。我们现在建议将这些结果扩展到一个 L-精氨酸治疗VOE的关键3期试验。我们假设精氨酸是一种安全的药物节制干预方法。 对患有VOE的儿童SCD患者的影响将减少儿童经历剧烈疼痛的时间。目标1 这项研究将确定静脉注射精氨酸治疗对主要终点、危机解决时间的EFfi的影响，如 与安慰剂相比，SCD和VOE儿童的肠外阿片类药物总使用量(mg/kg)和疼痛评分 (EFfiCacy)。目标2将监测静脉注射L-精氨酸(安全性)的安全性。目标3将描述 SCD和VOE患儿精氨酸代谢体和线粒体功能及其影响 静脉注射精氨酸治疗(探索性)。该提案将为产品开发和FDA提供必要的数据 监管部门批准在SCD中使用精氨酸。急诊室SCD和疼痛患者的急诊护理被忽视 研究领域。这项研究的结果可能最终导致SCD儿童的临床实践发生变化。 在急诊室和住院病房都有。以ED为基础的研究和新的治疗方法 SCD需要血管闭塞和疼痛。

Project Summary/Abstract Vaso-occlusive painful episodes (VOE) in sickle cell disease (SCD) are the leading cause of hospitalizations, emergency room (ED) visits, and missed school, and are associated with an increased mortality rate. There are no current therapies to relieve vaso-occlusion, with interventions limited to hydration and analgesia. Nitric oxide (NO), produced by the 5-electron oxidation of L-arginine, is a potent vasodilator and exerts pleiotropic effects on vascular and circulating blood cells, including the inhibition of platelet aggregation, down-regulation of adhesion molecules, and modulation of ischemia-reperfusion injury, all pathways adversely affected during VOE. We have found that pediatric SCD patients admitted with VOE have depleted plasma L-arginine levels. Additionally, we have now completed a single-center randomized, double-blinded, placebo-controlled trial of arginine therapy in 54 children with VOE requiring hospitalization. We observed a reduction in total opioid use (mg/kg) by 54% and significantly lower pain scores at discharge in children who received 5 days IV L-arginine therapy every 8 hours compared to placebo, as well as a clinically relevant trend in reduced length of hospital stay of approximately 17 hours. In pharmacokinetic studies, we found that IV arginine induced a dose-dependent improvement in mitochondrial function in children with SCD hospitalized for pain. We now propose to extend these results to a pivotal phase 3 trial of L-arginine for VOE. We hypothesize that arginine is a safe intervention with narcotic-sparing effects in pediatric SCD patients with VOE that will decrease the time children experience severe pain. Aim 1 of this study will determine the efficacy of IV arginine therapy on the primary endpoint, time-to-crisis resolution, as well as total parenteral opioid use (mg/kg) and pain scores in children with SCD and VOE compared to placebo (Efficacy). Aim 2 will monitor for safety of IV L-arginine (Safety). Aim 3 will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD and VOE, and evaluate how it is impacted by IV arginine therapy (Exploratory). This proposal will provide essential data for product development and FDA regulatory approval for use of arginine in SCD. Acute care of patients with SCD and pain in the ED is a neglected area of research. The results of this study may ultimately lead to change in clinical practice for children with SCD in both the ED and inpatient hospital wards. ED-based studies and novel therapies that target mechanisms of vaso-occlusion and pain are needed in SCD.