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

新生儿缺氧缺血性脑病(HIE)是指由于血供减少和缺氧引起的脑损伤。 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结局，包括死亡、脑瘫和认知障碍，尽管 接受低温治疗，这是唯一可用的治疗方法。脑性瘫痪是最常见的长期 缺氧缺血性脑病幸存者的神经发育障碍。在美国，每年新的缺氧缺血性脑病病例导致 脑瘫造成的经济负担估计为终生成本17亿美元。促红细胞生成素(EPO)是一种 具有显著神经保护和神经再生作用的细胞因子在动物模型中的显示 新生儿脑损伤。促红细胞生成素减少缺氧后的细胞凋亡、炎症和氧化损伤- 脑缺血，促进神经发生和少突胶质细胞存活，促进脑再生和 改进了功能。在非人类灵长类动物中，EPO可降低脑瘫的发生率并改善神经学 低体温治疗缺氧缺血性脑病动物的功能。小型人体试验表明，患有HIE的婴儿可以治疗 促红细胞生成素有更好的神经学结果。在我们的EPO+低温的I期试验中，我们发现EPO 1000 U/kg/剂量最好地再现了神经保护性剂量在动物模型中的药代动力学。长期 根据入选标准和MRI结果，结果好于预期。我们的第二阶段试验比较了50 降温婴儿随机接受促红细胞生成素或安慰剂。接受低温+促红细胞生成素治疗的婴儿大脑较少 早期MRI上的损伤，以及基于标准化父母的更好的6个月发育结果 问卷调查。促红细胞生成素在商业上可以买到，相对便宜，对新生儿来说是安全的。我们假设 对中、重度HIE的冷冻儿给予促红细胞生成素治疗可降低合并死亡的主要结局 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 促红细胞生成素治疗500例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剂EPO 1000U/kg静脉注射是否能降低死亡率、运动或认知障碍 2)通过评估临床毒性来评估EPO的安全性；3)确定EPO是否减少 早期MRI和脑损伤的循环生物标志物显示新生儿脑损伤的严重程度。马达 结果将由标准化的神经学检查和粗大运动功能分类来决定 系统。认知结果将由贝利III考试决定。在二次分析中，我们将研究 促红细胞生成素对脑性瘫痪、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两年的神经发育 结果，将是安全的，并将降低早期生物标记物确定的脑损伤严重程度。联合国儿童基金会将 启动和监控站点，协调患者登记和后续工作，收集临床和安全数据，以及 维护内部评级委员会和法规的合规性。此CCC申请与DCC申请相链接。

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 CCC will initiate and monitor sites, coordinate patient enrollment and follow-up, collect clinical and safety data, and maintain IRB and regulatory compliance. This CCC application is linked with the DCC application.