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（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%， 接受5天100 mg/kg/剂TID IV L-的儿童出院时疼痛评分显著降低 与安慰剂相比，精氨酸治疗，以及临床相关的趋势， 大约17小时。我们现在建议将这些结果扩展到L-精氨酸治疗VOE的II期试验， 收集更多有效性和安全性数据。我们假设精氨酸是一种安全廉价的干预措施， 对伴有VOE的儿童SCD患者的麻醉保护作用。本研究的目的1将确定 静脉注射精氨酸治疗对SCD & VOE儿童的主要终点，全胃肠外阿片类药物使用（mg/kg）， 评价负荷剂量是否提供超过标准剂量的额外获益（疗效）。目标2将 监测与负荷剂量和重复IV L-精氨酸给药相关的潜在毒性（安全性）。 目的3将描述SCD和VOE儿童精氨酸代谢组的改变，并评估 静脉精氨酸治疗如何影响（探索性）。该提案将为产品提供必要的数据 包括未来多中心3期试验的规划，这将最终有助于获得产品 批准SCD。在艾德，对SCD和疼痛患者的急性护理是一个被忽视的研究领域。的 这项研究的结果可能最终导致在艾德和 住院病房。基于ED的研究和针对血管闭塞机制的新疗法， SCD需要疼痛。

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.