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

精氨酸治疗小儿 SCD 疼痛 IND 的 2 期随机对照试验

• 批准号: 9123549
• 负责人: Claudia R Morris
• 金额: $ 40万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-10 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123549
• 关键词: Phase; RCT; Arginine; Therapy; Pediatric

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.

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 (ED) 就诊、缺课等都与死亡率增加有关。没有 目前缓解血管闭塞的疗法仅限于水合和镇痛。一氧化氮 (NO)，由 L-精氨酸的 5 电子氧化产生，是一种有效的血管舒张剂，对 血管和循环血细胞，包括抑制血小板聚集、下调粘附 分子和缺血再灌注损伤的调节，所有通路在 VOE 期间都受到不利影响。我们有 发现因 VOE 入院的儿科 SCD 患者血浆 L-精氨酸水平较低。此外，我们 现已完成一项精氨酸治疗的单中心随机、双盲、安慰剂对照试验 54 名患有 VOE 的儿童需要住院治疗。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- 治疗的儿童出院时疼痛评分显着降低 精氨酸治疗与安慰剂相比，以及住院时间缩短的临床相关趋势 约17小时。我们现在建议将这些结果扩展到 VOE 的 L-精氨酸 II 期试验 收集更多功效和安全性数据。我们假设精氨酸是一种安全且廉价的干预措施 患有 VOE 的儿科 SCD 患者的麻醉效果。本研究的目标 1 将确定以下方法的功效： 静脉注射精氨酸治疗主要终点，患有 SCD 和 VOE 的儿童的肠外阿片类药物总使用量 (mg/kg) 评估负荷剂量是否比标准剂量提供额外的益处（功效）。目标2将 监测与负荷剂量和重复静脉注射 L-精氨酸相关的潜在毒性（安全性）。 目标 3 将表征 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有何影响（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三期试验，这最终将有助于获得产品 批准SCD。对 SCD 和急诊科疼痛患者的紧急护理是一个被忽视的研究领域。这 这项研究的结果可能最终会导致急诊室和急诊室 SCD 儿童的临床实践发生变化。 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。