1/2 Sickel Cell Disease Treatment with Arginine Therapy (STArT Trial)

项目总结/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（艾德）就诊、缺课以及与死亡率增加相关。没有 目前缓解血管闭塞的治疗方法，干预措施仅限于水合作用和镇痛。一氧化氮 (NO)由L-精氨酸的5-电子氧化产生，是一种有效的血管扩张剂， 血管和循环血细胞，包括抑制血小板聚集，下调粘附 分子，以及缺血-再灌注损伤的调节，所有途径在VOE期间受到不利影响。我们有 发现患有VOE的儿童SCD患者的血浆L-精氨酸水平已耗尽。另外我们 现在已经完成了一个单中心随机，双盲，安慰剂对照试验精氨酸治疗， 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%， 每8小时接受5天IV L-精氨酸治疗的儿童出院时疼痛评分显著降低 与安慰剂相比，以及住院时间缩短约17 小时在药代动力学研究中，我们发现静脉注射精氨酸可诱导剂量依赖性的改善， 因疼痛住院的SCD儿童的线粒体功能。我们现在建议将这些结果推广到 L-精氨酸治疗VOE的关键III期试验。我们假设精氨酸是一种安全的麻醉药物- 在患有VOE的儿童SCD患者中的保留效应，将减少儿童经历剧烈疼痛的时间。 本研究的目的1将确定静脉注射精氨酸治疗对主要终点--至危象时间--的疗效 SCD和VOE儿童的缓解以及总的胃肠外阿片类药物使用（mg/kg）和疼痛评分， 安慰剂（疗效）。目标2将监测IV L-精氨酸的安全性（安全性）。目标3将描述 SCD和VOE儿童精氨酸代谢组学和线粒体功能，并评估其如何 受静脉精氨酸治疗的影响，同时也为SCD-VOE血液样本创造了一个有价值的生物储存库， 未来机制研究（探索性）。该提案将为产品开发提供必要的数据， FDA批准精氨酸用于SCD。在艾德中对SCD和疼痛患者的急性护理是一种 被忽视的研究领域。这项研究的结果可能最终导致儿童临床实践的改变 在艾德和住院病房都有SCD。基于ED的研究和新疗法， SCD中需要血管闭塞和疼痛的机制。

Project Summary/Abstract Vaso-occlusive painful episodes (VOE) in sickle cell disease (SCD) are the leading cause of hospitalizations, emergency room (ED) visits, missed school, & 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 & exerts pleiotropic effects on vascular & circulating blood cells, including the inhibition of platelet aggregation, down-regulation of adhesion molecules, & 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 randomize, 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 & 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, while also creating a valuable biorepository of SCD-VOE blood samples for future mechanism studies (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 & 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 & inpatient hospital wards. ED-based studies and novel therapies that target mechanisms of vaso-occlusion and pain are needed in SCD.