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: 10472704
• 负责人: Claudia R Morris
• 金额: $ 149.8万
• 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/10472704
• 关键词: Absence of pain sensation; Accident and Emergency department; Acute; Acute Pain; Affect; African American population; 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; Absence of pain sensation; Accident and Emergency department; Acute; Acute Pain; Affect; African American population; 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.

项目摘要/摘要 镰状细胞疾病（SCD）中的血管熟悉疼痛发作（VOE）是住院的主要原因， 急诊室（ED）访问，错过了学校，并且与死亡率提高有关。没有 当前的疗法以缓解血管封闭，干预措施仅限于水合和镇痛。一氧化氮 （NO）是由L-精氨酸的5电子氧化产生的，是有效的血管扩张剂，并对多效性作用对多效应作用 血管和循环血细胞，包括抑制血小板聚集，粘附下调 分子和缺血再灌注损伤的调节，在VOE期间对所有途径产生不利影响。我们有 发现患有VOE的小儿SCD患者的血浆L-精氨酸水平耗尽。另外，我们 现在完成了单中心随机，双盲，安慰剂对照的精氨酸治疗试验 有54名有VOE的儿童需要住院。我们观察到总阿片类药物的总使用量（mg/kg）降低了54％，并且 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明显降低 与安慰剂相比，以及减少住院时间长度约17的临床相关趋势 小时。在药代动力学研究中，我们发现静脉精氨酸诱导了剂量依赖性改善 SCD儿童的线粒体功能因疼痛而住院。我们现在建议将这些结果扩展到 L-精氨酸对VOE的关键3期试验。我们假设精氨酸是麻醉剂的安全干预措施 儿科SCD患者的保留效应会减少儿童遭受严重疼痛的时间。 本研究的目标1将确定静脉精氨酸治疗在主要终点，危机时期的疗效 SCD和VOE儿童的分辨率以及总肠胃外阿片类药物（mg/kg）和疼痛评分 安慰剂（功效）。 AIM 2将监测IV L-精氨酸（安全）的安全性。 AIM 3将表征变化 SCD和VOE儿童的精氨酸代谢组和线粒体功能，并评估其如何 受IV精氨酸疗法的影响，同时还为SCD-VOE血样的有价值的生物措施 未来的机理研究（探索性）。该建议将为产品开发提供基本数据，并 在SCD中使用精氨酸的FDA监管批准。 ED中SCD和疼痛患者的急性护理是 被忽视的研究领域。这项研究的结果最终可能导致儿童的临床实践改变 在ED和住院医院病房中都有SCD。基于ED的研究和针对目标的新疗法 SCD中需要血管封闭和疼痛的机制。