Preterm Epo Neuroprotection Trial (PENUT Trial) CCC

早产儿 Epo 神经保护试验（PENUT 试验）CCC

• 批准号: 8918787
• 负责人: Sandra E Juul
• 金额: $ 23.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918787
• 关键词: 9 year old; Accounting; Acute; Acute Brain Injuries; Age; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Biochemical; Biological Markers; Blinded; Blindness; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Caring; Cerebellum; Cerebral Palsy; Cessation of life; Chronic Brain Injury; Classification; Clinical; Cognitive; Control Groups; Data; Data Analyses; Data Collection; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Documentation; Dose; Encephalitis; Enrollment; Erythropoiesis; Erythropoietin; Evaluation; Experimental Models; FDA approved; Family; Funding; Gestational Age; Goals; Health; Healthcare Systems; Hospital Charges; Hospitals; Hour; Hydrocephalus; Impaired cognition; Impairment; Individual; Infant; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intervention; Leadership; Lesion; Link; Magnetic Resonance Imaging; Measurement; Measures; Monitor; Morbidity - disease rate; Motor; Neonatal; Neurodevelopmental Disability; Neurodevelopmental Impairment; Neurologic; Neurological outcome; Neuroprotective Agents; Newborn Infant; Oligodendroglia; Outcome; Outcome Measure; Perinatal Care; Phase I/II Trial; Placebo Control; Placebos; Pregnancy; Premature Infant; Publishing; Quality Control; Randomized; Randomized Controlled Trials; Recombinant Erythropoietin; Reporting; Risk; Safety; Severities; Site; Structure; Survivors; System; Testing; Time; Toddler; Visual impairment; Work; angiogenesis; arm; base; cohort; cost; cytokine; deafness; disability; experience; gray matter; high risk; high risk infant; improved; intraventricular hemorrhage; mortality; motor impairment; neonate; neurodevelopment; neurogenesis; neuroprotection; novel; novel strategies; phase 3 study; pre-clinical; premature; primary outcome; prospective; recombinant human erythropoietin; secondary outcome; statistics; white matter; white matter injury

DESCRIPTION (provided by applicant): In the U.S., approximately 30,600 infants per year are born before 28 weeks of gestation (40 weeks is term). These infants, termed Extremely Low Gestational Age Neonates (ELGANs), experience high morbidity and mortality: 20% of ELGANs admitted to an NICU die before discharge, 20% of survivors have severe and 20% moderate neurodevelopmental impairment (NDI). Perinatal care costs for these infants exceed $18 billion every year and account for approximately half of total hospital charges for newborn care. New approaches are needed to improve these outcomes. Recombinant erythropoietin (Epo) is a promising novel neuroprotective agent. It is widely available, affordable, and has been used safely in neonates to stimulate erythropoiesis. There are extensive preclinical data to support its use as a neuroprotective intervention: Epo decreases acute brain injury following hypoxia ischemia by decreasing inflammation, oxidative and excitotoxic injury which results in decreased apoptosis; Epo also promotes normal brain maturation by increasing neurogenesis, angiogenesis, and by protecting oligodendrocytes. We hypothesize that neonatal Epo treatment of ELGANs will decrease the combined outcome of death or severe NDI from 40% to 30% (primary outcome), or moderate NDI from 60% to 40% (secondary outcome) measured at 24-26 months post menstrual age (PMA). Our specific aims are to compare 376 Epo-treated with 376 control infants to determine: 1) whether Epo decreases the combined outcome of death or NDI at 24-26 months PMA (NDI is defined as the presence of: CP or Bayley III Scales of Infant and Toddler Development cognitive or motor scale < 70); 2) the short-, intermediate- and long-term safety of neonatal high dose Epo administration to ELGANs; 3) whether neonatal Epo treatment decreases serial measures of circulating inflammatory mediators, and biomarkers of brain injury; 4) whether Epo treatment improves brain structure (volume of gray matter, white matter and cerebellum, brain gyrification, and tract-based spatial statistics) at 36 weeks PMA as measured by MRI. In an exploratory aim, we will determine which MRI quantitative measures best predict neurodevelopment at 24-26 months PMA. We anticipate that Epo treatment of ELGANs will confer improved neurodevelopmental outcome at 24-26 months PMA compared to placebo, and will provide a much-needed therapy for this group of vulnerable infants. Furthermore, we anticipate that Epo treatment will be safe, will decrease biomarkers of brain injury and inflammation, and will be associated with less preterm brain injury as determined by MRI at 36 weeks PMA. The CCC will work closely with the linked DCC to accomplish the proposed goals. The CCC will provide the clinical leadership and support for all sites, and the DCC will provide the systems and oversight for data collection, management, quality control, operational support and data analyses for the monitoring and final reporting of the study.

描述（由申请人提供）：在美国，每年大约有 30,600 名婴儿在妊娠 28 周（足月 40 周）之前出生。这些婴儿被称为极低胎龄新生儿 (ELGAN)，发病率和死亡率很高：入住 NICU 的 ELGAN 中有 20% 在出院前死亡，20% 的幸存者患有严重的神经发育障碍 (NDI)，20% 的幸存者患有中度神经发育障碍 (NDI)。这些婴儿的围产期护理费用每年超过 180 亿美元，约占医院新生儿护理总费用的一半。需要新的方法来改善这些结果。重组促红细胞生成素（Epo）是一种有前途的新型神经保护剂。它广泛可用、价格实惠，并且已安全地用于新生儿刺激红细胞生成。有大量的临床前数据支持其 用作神经保护干预措施：Epo 通过减少炎症、氧化和兴奋性毒性损伤（导致细胞凋亡减少）来减轻缺氧缺血后的急性脑损伤； Epo 还通过增加神经发生、血管生成和保护少突胶质细胞来促进正常的大脑成熟。我们假设 ELGAN 的新生儿 Epo 治疗会将月经后 24-26 个月测量的死亡或严重 NDI 的综合结果从 40% 降低到 30%（主要结果），或将中度 NDI 从 60% 降低到 40%（次要结果）。年龄（PMA）。我们的具体目标是比较 376 名接受 Epo 治疗的婴儿与 376 名对照婴儿，以确定：1) Epo 是否会降低 24-26 个月 PMA 时死亡或 NDI 的综合结果（NDI 定义为存在：CP 或 Bayley III 量表）婴幼儿发展认知或运动量表 < 70)； 2) ELGAN 新生儿高剂量 Epo 给药的短期、中期和长期安全性； 3）新生儿Epo治疗是否会降低循环炎症介质和脑损伤生物标志物的一系列指标； 4) 通过 MRI 测量，Epo 治疗是否可以改善 PMA 36 周时的大脑结构（灰质、白质和小脑的体积、脑回旋和基于束的空间统计）。在探索性目标中，我们将确定哪些 MRI 定量测量最能预测 24-26 个月 PMA 时的神经发育。我们预计，与安慰剂相比，ELGAN 的 Epo 治疗将在 24-26 个月 PMA 时改善神经发育结果，并将为这组脆弱婴儿提供急需的治疗。此外，我们预计 Epo 治疗将是安全的，将减少脑损伤和炎症的生物标志物，并且与 36 周 PMA 时 MRI 确定的早产脑损伤有关。 CCC 将与相关的 DCC 密切合作，以实现拟议的目标。 CCC 将为所有中心提供临床领导和支持，DCC 将为研究的监测和最终报告的数据收集、管理、质量控制、操作支持和数据分析提供系统和监督。