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

新生儿缺氧缺血性脑病（HIE）是指由于血液和组织的减少而导致的脑损伤。 氧气在婴儿出生时流入大脑。在美国，HIE每年影响多达12，000名新生儿。 一半受影响的婴儿有不良后果，包括死亡，脑瘫和认知障碍， 接受低温治疗，这是唯一可行的治疗方法脑瘫是最常见的一种 新生儿缺氧缺血性脑病幸存者的神经发育障碍。每年在美国，新生儿缺氧缺血性脑病病例， 脑性麻痹造成的经济负担估计为17亿美元的终生费用。促红细胞生成素（Epo）是一种 细胞因子具有显著的神经保护和神经再生作用，在动物模型中证实， 新生儿脑损伤EPO减少缺氧后的凋亡、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存活，促进脑再生， 改进功能。在非人类灵长类动物中，Epo降低了脑瘫的发病率， 在缺氧缺血性脑病的低温动物中的功能。小型人体试验表明， 有更好的神经功能结果。在我们的Epo +低温的I期试验中，我们发现Epo 1000 U/Kg/剂量最好地再现了动物模型中神经保护性给药的药代动力学。长期 结果好于基于入选标准和MRI结果的预期。我们的二期试验比较了50例 冷却婴儿随机接受Epo或安慰剂。接受低温+ Epo治疗的婴儿的大脑 早期MRI显示的损伤，以及基于标准化父母的6个月发育结果 问卷促红细胞生成素是可商购的，相对便宜，对新生儿安全。我们假设 给予中度/重度HIE的冷却婴儿Epo将减少死亡的综合主要结局 或神经发育障碍从49%降到33%。为了验证这一假设，我们提出了一个随机的，双- Epo治疗500例接受低温治疗的新生儿缺氧缺血性脑病的盲法、安慰剂对照试验我们的具体目标 1）确定5个剂量的Epo 1000 U/kg IV是否降低了在2 2）通过评价临床毒性来评估Epo的安全性;和3）确定Epo是否降低 新生儿脑损伤的严重程度，如早期MRI和脑损伤的循环生物标志物所证明的。电机 结果将通过标准化神经学检查和粗大运动功能分类来确定 系统认知结果将由Bayley III检查确定。在二次分析中，我们将检查 Epo对脑瘫、运动障碍严重程度、Bayley III认知和语言评分的影响， 癫痫和行为异常。我们预计促红细胞生成素将改善2年的神经发育 结果，将是安全的，并将降低脑损伤的严重程度，如早期生物标志物所确定的。DCC将 领导规程制定、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。

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.