Phase 2 RCT of Arginine Therapy for Pediatric SCD Pain IND #66,943 1/18/13 Active

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、缺课和死亡率增加有关。没有 目前的治疗方法是缓解血管阻塞，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，具有多效性。 血管和循环血细胞，包括抑制血小板聚集，下调黏附 分子和对缺血-再灌注损伤的调节，在VOE过程中所有通路都受到不利影响。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%， 接受L静脉滴注5天100 mg/kg/剂量的儿童出院时疼痛评分显著降低 精氨酸治疗与安慰剂的比较，以及在减少住院时间方面的临床相关趋势 大约17个小时。我们现在建议将这些结果扩展到L-精氨酸治疗VOE的第二阶段试验 收集更多的疗效和安全性数据。我们假设精氨酸是一种安全、廉价的治疗方法。 儿童SCD合并VOE患者的药物节约效应。这项研究的目标1将确定 精氨酸治疗的主要终点，SCD和VOE&儿童的阿片类药物总使用量(mg/kg) 评估负荷剂量是否提供比标准剂量(疗效)更多的益处。目标2将 监测与负荷剂量相关的潜在毒性&重复静脉注射L-精氨酸(安全)。 目的3将描述SCD和VOE儿童精氨酸代谢组的变化，并评估 静脉注射精氨酸治疗对其的影响(探索性)。该提案将为产品提供必要的数据 开发包括规划未来的多中心第三阶段试验，这最终将有助于获得产品 对SCD的批准。急诊室SCD和疼痛患者的急诊护理是一个被忽视的研究领域。这个 这项研究的结果可能最终导致SCD儿童的临床实践在ED和 住院病房。以ED为基础的研究和新的治疗方法，针对血管闭塞和 SCD需要痛苦。

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 of 100 mg/kg/dose TID IV L- arginine therapy compared to placebo, as well as a clinically relevant trend in reduced length of hospital stay of approximately 17 hours. We now propose to extend these results to a phase II trial of L-arginine for VOE to gather more efficacy and safety data. We hypothesize that arginine is a safe & inexpensive intervention with narcotic-sparing effects in pediatric SCD patients with VOE. Aim 1 of this study will determine the efficacy of IV arginine therapy on the primary endpoint, total parenteral opioid use (mg/kg) in children with SCD & VOE & to evaluate whether a loading dose provides additional benefits over standard dose (Efficacy). Aim 2 will monitor for potential toxicities associated with a loading dose & repeat administration of IV L-arginine (Safety). Aim 3 will characterize alterations in the arginine metabolome 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 including the planning of a future multi-center Phase 3 trial, which will ultimately help gain product approval for 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.