Safety of Combinatorial Therapy with Erythropoietin and Melatonin for Preterm Infants with Intraventricular Hemorrhage

促红细胞生成素和褪黑素联合治疗早产儿脑室内出血的安全性

基本信息

批准号：
10634495
负责人：
SHENANDOAH ROBINSON
金额：
$ 68.71万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-03 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634495
关键词：
Affect Age Biological Markers Brain Brain Injuries Calpain Caring Cell physiology Central Nervous System Cerebral Palsy Cerebrospinal Fluid Cessation of life Child Clinical Clinical Trials Clinical Trials Design Combined Modality Therapy Complex Data Development Diagnosis Dose Dose Limiting Double-blind trial Enrollment Enzymes Epilepsy Erythropoietin Event Face Family Fluids and Secretions Future Head Health Care Costs Hemorrhage Hospitalization Hydrocephalus Hypertension Image Impairment Incidence Individual Indwelling Catheter Infection Inflammation Informed Consent Injury Institution Institutional Review Boards Intellectual functioning disability Intervention Life Liquid substance Liver Longevity Macrocephaly Medical Melatonin Metabolic Modeling Molecular Monitor Morbidity - disease rate Natural History Neonatal Neonatal Intensive Care Units Neurons Operative Surgical Procedures Outcome Oxidative Stress Pathogenesis Perinatal Pharmaceutical Preparations Phase Phase II Clinical Trials Placebos Polycythemia Population Premature Birth Premature Infant Problem behavior Procedures Process Randomized Rattus Regimen Regulation Reporting Research Design Risk Role Safety Serious Adverse Event Serum Shunt Device Signal Transduction Societies Stress Structure of choroid plexus Testing Third Pregnancy Trimester Thrombosis Thrombus Time Toxic effect Urine Ventricular absorption brain magnetic resonance imaging brain repair cilium motility clinical imaging clinically relevant combinatorial comorbidity design drug repurposing efficacy clinical trial efficacy testing endoplasm extreme prematurity fetal follow-up glymphatic system high risk insight intraamniotic infection intraventricular hemorrhage iron supplementation liver function medical complication mitochondrial dysfunction mortality neonatal sepsis neonate neuroimaging neuroimaging marker neuroinflammation neurorestoration neurosensory older patient patient population peer phase II trial postnatal pre-clinical preterm newborn prevent primary endpoint recruit research study screening secondary outcome societal costs standard of care systemic inflammatory response trend ultrasound

项目摘要

Very preterm infants are prone to numerous medical complications with lifelong impact. Amongst the most serious are severe intraventricular hemorrhage (sIVH) and the subsequent progression to posthemorrhagic hydrocephalus (PHH). Currently, the only treatment for PHH is surgery, most commonly with shunts that are prone to malfunction across the lifespan. Children with sIVH and PHH are also at high risk for intellectual disability, behavioral problems, neurosensory impairment, cerebral palsy and epilepsy. Emerging evidence suggests that the cellular and molecular events regulating cerebrospinal fluid (CSF) dynamics, including CSF secretion, propulsion and reabsorption, develop during the third trimester and the first few months postnatally. Maturation of these highly subspecialized and metabolically active cellular processes spatially and temporally overlaps with preterm birth and IVH, and are thus vulnerable to injury over an extended period. Most importantly, these processes are responsive to neurorestorative interventions with re-purposed medications, raising the possibility of using medical treatment after sIVH to prevent progression to PHH and the need for shunts. Preclinical data show that melatonin (MLT) and erythropoietin (EPO), when administered in a sustained dosing regimen, can prevent the hallmarks of progression from early postnatal sIVH to subsequent PHH, including macrocephaly and ventriculomegaly. Combination therapy is required as neither agent alone prevents PHH. In human preterm infants, MLT and EPO have been safely used as monotherapy in clinical trials with similar dosing regimens. We propose a Phase I, single institution, randomized, double-blind trial for very preterm infants with sIVH to define a safe combination dose of MLT and EPO. With IRB, IND and primary neonatologist approval, and informed consent, a maximum of 60 very preterm neonates with sIVH will be enrolled, treated through 33w6/7d, and followed to 37w6/7d. Neonates will be randomized 3:1 between MLT+EPO and placebo, with all receiving standard of care. Concurrent controls are needed due to fluctuations in preterm birth co-morbidities and mortality. Masking is essential to reduce attribution bias. The primary endpoint is a composite serious adverse event (SAE)/dose limiting toxicity (DLT) including death, potential MLT-realted DLT: severe liver function abnormalities compared to age-matched peers with sIVH, and known EPO-related SAE: thrombosis, polycythemia, and hypertension. No MLT-related SAE have emerged in clinical trials thus far. We hypothesize that the MLT+EPO SAE/DLT rate will not be higher than the placebo rate. Secondary outcomes will be rate of co-morbidities of preterm birth. Exploratory data, collected to guide design of future clinical trials for efficacy, will include serial neuro-imaging metrics acquired from clinical images, serial neonatal neurodevelopmental examinations, serum and urine MLT and EPO levels, and liquid biomarkers. Successful implementation of this initial safety trial will provide essential data to guide the next stage of clinical trials to test if sustained MLT+EPO treatment can reduce the need for surgical intervention, and avoid the lifelong burden of shunted hydrocephalus.

极早产儿很容易出现许多影响终生的医疗并发症。其中最严重的是严重脑室内出血（sIVH）以及随后进展为出血后脑积水（PHH）。目前，PHH 的唯一治疗方法是手术，最常见的是分流术。在整个使用寿命期间容易出现故障。患有 sIVH 和 PHH 的儿童也面临智力低下的高风险残疾、行为问题、神经感觉障碍、脑瘫和癫痫。新出现的证据表明调节脑脊液 (CSF) 动力学的细胞和分子事件，包括 CSF 分泌、推进和重吸收在妊娠晚期和产后最初几个月内发育。这些高度亚特化和代谢活跃的细胞过程在空间和时间上的成熟与早产和 IVH 重叠，因此很容易在较长时间内受到伤害。最重要的是，这些过程对使用重新调整用途的药物进行的神经恢复干预有反应，从而提高了 sIVH 后使用药物治疗以防止进展为 PHH 和需要分流的可能性。临床前数据表明，持续给药时，褪黑激素 (MLT) 和促红细胞生成素 (EPO) 方案，可以预防从产后早期 sIVH 进展为随后的 PHH 的标志，包括巨头畸形和脑室扩大。需要联合治疗，因为单独使用这两种药物都不能预防 PHH。在对于人类早产儿，MLT 和 EPO 已在临床试验中以相似剂量安全地用作单一疗法治疗方案。我们建议对患有以下疾病的极早产儿进行一项 I 期、单一机构、随机、双盲试验： sIVH 定义 MLT 和 EPO 的安全组合剂量。经 IRB、IND 和初级新生儿科医生批准，并知情同意后，最多将招募 60 名患有 sIVH 的极早产新生儿，并通过 33w6/7d，然后是 37w6/7d。新生儿将按照 3:1 的比例随机分配至 MLT+EPO 和安慰剂组，所有患者接受标准护理。由于早产并发症的波动，需要同步控制和死亡率。屏蔽对于减少归因偏差至关重要。主要终点是复合严重不良事件 (SAE)/剂量限制毒性 (DLT)，包括死亡、潜在的 MLT 相关 DLT：严重肝功能与患有 sIVH 的年龄匹配同龄人相比存在异常，以及已知的 EPO 相关 SAE：血栓形成、红细胞增多症和高血压。迄今为止，临床试验中尚未出现与 MLT 相关的 SAE。我们假设 MLT+EPO SAE/DLT 率不会高于安慰剂率。次要结果将是早产的并发症。为指导未来疗效临床试验的设计而收集的探索性数据将包括从临床图像获得的连续神经影像指标、连续新生儿神经发育指标检查、血清和尿液 MLT 和 EPO 水平以及液体生物标志物。此次成功实施初步安全性试验将为指导下一阶段的临床试验提供必要的数据，以测试 MLT+EPO 是否持续有效治疗可以减少手术干预的需要，并避免分流脑积水的终生负担。