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

1/2 镰状细胞病用精氨酸疗法治疗（START 试验）

• 批准号: 10274834
• 负责人: Claudia R Morris
• 金额: $ 154.28万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274834
• 关键词: Absence of pain sensation; Accident and Emergency department; Acute; Acute Pain; Affect; African American; Amino Acids; Applied Research; Area; Arginine; Biological Availability; Blood; Blood Cells; Blood Transfusion; Blood Vessels; Blood specimen; Cell Adhesion Molecules; Cell Density; Cells; Child; Child Care; Childhood; Clinical; Complex; Data; Death Rate; Deterioration; Disease; Dose; Down-Regulation; Drug Delivery Systems; Drug Kinetics; Electrons; Emergency Care; Emergency department visit; Erythrocytes; Event; Future; Hemolysis; Hemolytic Anemia; Hepatic; Hospitalization; Hospitals; Hour; Hydration status; Individual; Inflammatory; Infrastructure; Inherited; Inpatients; Intervention; Intravenous; Kidney; Lead; Length of Stay; Mitochondria; Monitor; Narcotics; Nitric Oxide; Opioid; Oxygen; Pain; Pathway interactions; Patient Care; Patient Outcomes Assessments; Patients; Perfusion; Phase; Physiology; Placebos; Plasma; Platelet Aggregation Inhibition; Randomized; Reperfusion Injury; Research; Resolution; Safety; Schools; Sickle Cell; Sickle Cell Anemia; Supplementation; Syndrome; Time; Time Study; Transgenic Mice; Vasodilator Agents; Veno-Occlusive Disease; Visit; acute care; acute chest syndrome; arginase; arginine treatment; base; biobank; clinical practice; clinically relevant; dietary supplements; double-blind placebo controlled trial; efficacious intervention; experience; improved; lung injury; metabolome; mitochondrial dysfunction; morphine equivalent; mortality; mouse model; neglect; new therapeutic target; novel therapeutics; off-patent; opioid sparing; opioid use; oxidation; pain outcome; pain score; pediatric emergency; phase III trial; pleiotropism; primary endpoint; product development; randomized placebo-controlled clinical trial; secondary outcome; sickle vasoocclusion; standard of care; trend; vaso-occlusive pain; ward

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.

项目概要/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 (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% 每 8 小时接受 5 天静脉注射 L-精氨酸治疗的儿童出院时的疼痛评分显着降低 与安慰剂相比，以及住院时间缩短约 17 的临床相关趋势 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 儿童的线粒体功能。我们现在建议将这些结果扩展到 L-精氨酸治疗 VOE 的关键 3 期试验。我们假设精氨酸是麻醉剂的一种安全干预措施 对患有 VOE 的儿科 SCD 患者的保护作用将减少儿童经历剧烈疼痛的时间。 本研究的目标 1 将确定静脉注射精氨酸治疗对主要终点（危机发生时间）的疗效 比较 SCD 和 VOE 儿童的分辨率、肠外阿片类药物总使用量 (mg/kg) 和疼痛评分 安慰剂（功效）。目标 2 将监测静脉注射 L-精氨酸的安全性（安全性）。目标 3 将描述以下方面的改变： SCD 和 VOE 儿童的精氨酸代谢组和线粒体功能，并评估其情况 受到静脉注射精氨酸疗法的影响，同时还为 SCD-VOE 血液样本创建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和 FDA 监管部门批准精氨酸用于 SCD。对 SCD 和急诊科疼痛患者进行紧急护理是一项重要任务 被忽视的研究领域。这项研究的结果可能最终会导致儿童临床实践的改变 急诊室和住院病房都有 SCD。基于 ED 的研究和针对目标的新疗法 SCD 需要了解血管闭塞和疼痛的机制。