High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) DCC

高剂量促红细胞生成素治疗窒息和脑病 (HEAL) DCC

基本信息

批准号：
9174290
负责人：
PATRICK J HEAGERTY
金额：
$ 29.11万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9174290
关键词：
2 year old Adherence Affect Animal Model Animals Apoptotic Asphyxia Behavioral Biological Markers Birth Blood Brain Brain Hypoxia-Ischemia Brain Injuries Cause of Death Cerebral Palsy Cessation of life Classification Clinic Clinical Clinical Research Clinical Trials Clinical Trials Data Monitoring Committees Cognitive Cognitive deficits Committee Members Communication Data Data Analyses Data Collection Data Coordinating Center Data Quality Databases Death Rate Development Doctor of Philosophy Documentation Dose Drug Kinetics Economic Burden Encephalopathies Epilepsy Erythropoietin Goals Guidelines Human Impaired cognition Individual Infant Inflammatory Internet Language Lead Leadership Link Magnetic Resonance Imaging Manuals Manuscripts Monitor Motor National Institute of Neurological Disorders and Stroke Natural regeneration Neonatal Neonatal Brain Injury Nerve Regeneration Nervous System Physiology Neurodevelopmental Impairment Neurologic Neurologic Deficit Neurological outcome Newborn Infant Oligodendroglia Online Systems Outcome Oxygen Participant Pharmaceutical Preparations Placebo Control Placebos Preparation Principal Investigator Protocols documentation Publications Quality Control Questionnaires Randomized Reporting Research Design Research Personnel Risk Safety Severities Site Survivors System Testing Time Toxic effect Training Universities Washington Work base circulating biomarkers clinical research site cytokine disability double-blind placebo controlled trial experience improved improved functioning life time cost motor deficit motor impairment natural hypothermia neonatal hypoxic-ischemic brain injury neonate neurogenesis nonhuman primate operation performance site phase I trial phase II trial phase III trial primary outcome protocol development quality assurance randomized trial statistics tool trial comparing web site

项目摘要

Neonatal hypoxic-ischemic encephalopathy (HIE) refers to brain injury resulting from reduced blood and oxygen flow to a baby's brain near the time of birth. HIE affects up to 12,000 newborns each year in the U.S. Half of affected infants have a bad outcome including death, cerebral palsy and cognitive impairment despite receiving hypothermia, the only available treatment. Cerebral palsy is the most common long term neurodevelopmental impairment in survivors of HIE. Each year in the U.S., new cases of HIE resulting in cerebral palsy impose an estimated economic burden of $1.7 billion in lifetime costs. Erythropoietin (Epo) is a cytokine with remarkable neuroprotective and neuroregenerative effects demonstrated in animal models of neonatal brain injury. Epo reduces apoptotic, inflammatory and oxidative brain injury following hypoxia- ischemia, and enhances neurogenesis and oligodendrocyte survival, promoting brain regeneration and improved function. In non-human primates, Epo reduces the rate of cerebral palsy and improves neurologic function in animals undergoing hypothermia for HIE. Small human trials suggest that infants with HIE treated with Epo have better neurologic outcomes. In our phase I trial of Epo + hypothermia, we found that Epo 1000 U/Kg/dose best reproduced the pharmacokinetics of neuroprotective dosing in animal models. Long term outcomes were better than expected based on entry criteria and MRI findings. Our phase II trial compared 50 cooled infants randomized to receive Epo or placebo. Infants treated with hypothermia + Epo had less brain injury on early MRI, and better 6-month developmental outcome based on a standardized parental questionnaire. Epo is commercially available, relatively inexpensive, and safe in neonates. We hypothesize that Epo given to cooled infants with moderate/severe HIE will reduce the combined primary outcome of death or neurodevelopmental impairment from 49 to 33%. To test this hypothesis, we propose a randomized, double- blind, placebo-controlled trial of Epo therapy in 500 infants with HIE undergoing hypothermia. Our specific aims are 1) To determine if 5 doses of Epo 1000 U/kg IV reduces the rate of death, motor or cognitive deficits at 2 years; 2) To assess safety of Epo by evaluating clinical toxicity; and 3) To determine whether Epo decreases the severity of neonatal brain injury as evidenced by early MRI and circulating biomarkers of brain injury. Motor outcome will be determined by a standardized neurologic exam and by the Gross Motor Function Classification System. Cognitive outcome will be determined by Bayley III exam. In secondary analyses, we will examine the effect of Epo on cerebral palsy, severity of motor impairment, Bayley III cognitive and language scores, epilepsy and behavioral abnormalities. We anticipate that Epo will confer improved 2-year neurodevelopmental outcome, will be safe, and will decrease brain injury severity as determined by early biomarkers. The DCC will lead protocol development, data collection, quality assurance, participant management systems, interim and final data analysis, and manuscript preparation. The DCC application is linked with the CCC application.

新生儿缺氧 - 缺血性脑病（HIE）是指降低血液和氧气在出生时就流向婴儿的大脑。在美国，HIE每年影响多达12,000名新生儿一半受影响的婴儿的结果不好，包括死亡，脑瘫和认知障碍接受体温过低，这是唯一可用的治疗方法。脑瘫是最常见的长期 Hie幸存者的神经发育障碍。每年在美国，新的HIE案件导致脑瘫估计终生费用估计经济负担为17亿美元。促红细胞生成素（EPO）是在动物模型中证明了具有显着神经保护性和神经加快作用的细胞因子新生儿脑损伤。 EPO减少缺氧后凋亡，炎症和氧化性脑损伤缺血，并增强神经发生和少突胶质细胞的生存，促进脑再生和提高功能。在非人类灵长类动物中，EPO降低了脑瘫的速度并改善了神经系统在接受HIE体温过低的动物中的功能。小型人类试验表明，接受过Hie治疗的婴儿与EPO具有更好的神经系统结局。在我们的EPO +体温过低的I期试验中，我们发现EPO 1000 u/kg/剂量最好再现动物模型中神经保护剂的药代动力学。长期根据进入标准和MRI发现，结果比预期的要好。我们的II期试验比较了50个冷却婴儿随机接受EPO或安慰剂。接受体温过低 + EPO治疗的婴儿的大脑较少基于标准化的父母问卷。 EPO是商业上可用的，相对便宜，并且在新生儿中安全。我们假设给予中等/重度的冷却婴儿的EPO将减少死亡的总和总结果或神经发育障碍从49％到33％。为了检验这一假设，我们提出了一个随机的，双重的在500名患有体温过低的婴儿的EPO治疗的盲，安慰剂对照试验。我们的具体目标是1）确定5剂EPO 1000 U/kg IV是否会降低2剂的死亡率，运动或认知缺陷。年; 2）通过评估临床毒性来评估EPO的安全； 3）确定EPO是否减少新生儿脑损伤的严重程度通过早期MRI和脑损伤的生物标志物所证明。发动机结果将由标准化的神经检查和总体运动功能分类确定系统。认知结果将由Bayley III考试确定。在二次分析中，我们将检查 EPO对脑瘫的影响，运动障碍的严重程度，Bayley III认知和语言评分，癫痫和行为异常。我们预计EPO将授予改进的2年神经发育结果将是安全的，并且会减轻早期生物标志物确定的脑损伤严重程度。 DCC会领先协议开发，数据收集，质量保证，参与者管理系统，临时和最终数据分析和手稿准备。 DCC应用程序与CCC应用程序链接。