2/2: Sickle Cell Disease Treatment with Arginine Therapy (STArT) trial

2/2：精氨酸疗法治疗镰状细胞病 (START) 试验

基本信息

批准号：
10265464
负责人：
Theron C Casper
金额：
$ 56.51万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/10265464
关键词：
Absence of pain sensation Accident and Emergency department Acute Acute Pain Affect African American Amino Acids Area Arginine Biological Biological Availability Biometry Blood Blood Cells Blood Vessels Cell Adhesion Molecules Cell Density Cells Child Child Care Childhood Clinical Communication Complex Controlled Clinical Trials Data Data Collection Data Coordinating Center Data Set Death Rate Disease Dose Double-Blind Method Down-Regulation Drug Kinetics Electrons Emergency department visit Erythrocytes Event Goals Hemolysis Hemolytic Anemia Hospitalization Hospitals Hour Human Resources Hydration status Individual Inflammatory Inherited Inpatients Intervention Lead Leadership Length of Stay Logistics Maintenance Manuals Mitochondria Monitor Narcotics Nitric Oxide Pain Pathway interactions Patient Care Patients Perfusion Phase Physiology Placebos Plasma Platelet Aggregation Inhibition Preparation Production Protocols documentation Randomized Reperfusion Injury Reporting Research Research Personnel Resolution Safety Schools Sickle Cell Sickle Cell Anemia Specimen Supplementation Syndrome Technical Expertise Testing Therapy trial Time Training Transgenic Mice Universities Utah Vasodilator Agents acute care aged arginase arginine treatment base clinical practice clinical trial analysis clinically relevant data management design double-blind placebo controlled trial efficacious intervention efficacy testing emergency settings experience improved lung injury metabolome mitochondrial dysfunction mortality mouse model neglect new therapeutic target novel therapeutics operation opioid use oxidation pain score pediatric emergency phase III trial pleiotropism primary endpoint product development randomized placebo-controlled clinical trial safety testing standard of care trend vaso-occlusive pain ward

项目摘要

Project Summary/Abstract Vaso-occlusive painful episodes (VOE) in sickle cell disease (SCD) are the leading cause of hospitalizations, emergency room (ED) visits, and missed school, and 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 and exerts pleiotropic effects on vascular and circulating blood cells, including the inhibition of platelet aggregation, down-regulation of adhesion molecules, and 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 randomized, 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 and 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 (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 and 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 and 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) 就诊和缺课都与死亡率增加有关。目前尚无缓解血管闭塞的疗法，干预措施仅限于水合作用和一氧化氮镇痛。 (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。发现因 VOE 入院的儿科 SCD 患者血浆 L-精氨酸水平较低。现已完成一项精氨酸治疗的单中心随机、双盲、安慰剂对照试验我们观察到 54 名患有 VOE 的儿童的阿片类药物使用总量（毫克/公斤）减少了 54%，并且每 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临床相关趋势在药代动力学研究中，我们发现静脉注射精氨酸会导致剂量依赖性的改善。我们现在建议将这些结果扩展到因疼痛而住院的 SCD 儿童的线粒体功能。 L-精氨酸治疗 VOE 的关键 3 期试验我们发现精氨酸是一种节省麻醉剂的安全干预措施。对患有 VOE 的儿童 SCD 患者的影响将减少儿童经历严重疼痛的时间。本研究将确定静脉注射精氨酸治疗对主要终点（危机解决时间）的疗效，如下：以及与安慰剂相比，患有 SCD 和 VOE 的儿童的父母阿片类药物总使用量 (mg/kg) 和疼痛评分（功效）。目标 2 将监测静脉注射 L-精氨酸的安全性（安全性）。 SCD 和 VOE 儿童的精氨酸代谢组和线粒体功能，并评估其受到的影响静脉注射精氨酸疗法（探索性）该提案将为产品开发和 FDA 提供重要数据。监管机构批准在 SCD 中使用精氨酸对 SCD 患者和急诊科疼痛患者的紧急护理被忽视了。这项研究的结果可能最终会改变 SCD 儿童的临床实践。在急诊室和住院病房进行基于急诊室的研究和针对机制的新疗法。 SCD 需要血管闭塞和疼痛。