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：
10488190
负责人：
Theron C Casper
金额：
$ 55.34万
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/10488190
关键词：
Absence of pain sensation Accident and Emergency department Acute Acute Pain Affect African American population 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 Placebo Control 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）访问和错过学校，并与死亡率提高有关。有目前没有挽救血管包的疗法，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电子氧化物产生的，是一种潜在的血管扩张剂，并对多效性作用对多效应作用血管和循环的血细胞，包括抑制血小板聚集，粘合剂的下调分子和缺血再灌注损伤的调节，在VOE期间都受到了不利影响。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，我们现在已经完成了单中心随机，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％，并且出院时出院时疼痛评分的明显降低，每8小时接受5天IV L-精氨酸治疗与安慰剂相比，医院住院时间降低的临床趋势大约 17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。我们假设精氨酸是一种安全的干预措施小儿SCD患者的影响会减少儿童遭受严重疼痛的时间。目标1 这项研究将确定IV精氨酸治疗在主要终点，即危机时间分辨率的效力与安慰剂相比（效率）。 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，并评估其如何影响 IV精氨酸疗法（探索性）。该建议将为产品开发和FDA提供基本数据在SCD中使用精氨酸的法规批准。 ED中SCD和疼痛患者的急性护理被忽略研究领域。这项研究的结果最终可能导致SCD儿童的临床实践改变在ED和住院医院病房中。基于ED的研究和新的疗法针对的机制 SCD中需要血管封闭和疼痛。