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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.

项目总结/文摘