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

极早产儿容易出现许多具有终身影响的医学并发症。其中最 严重的是严重的脑室内出血（sIVH），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， 在整个生命周期中容易出现故障。患有sIVH和PHH的儿童也处于智力障碍的高风险中。 残疾、行为问题、感觉神经损伤、脑瘫和癫痫。新出现的证据 提示调节脑脊液（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出生后的最初几个月期间发展。 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，因此在较长时间内容易受到伤害。最重要的是， 这些过程对神经恢复性干预有反应，重新使用药物， 在sIVH后使用药物治疗的可能性，以防止进展为PHH和需要分流。 临床前数据显示，褪黑激素（MLT）和促红细胞生成素（EPO），当以持续剂量给药时， 方案，可以防止从出生后早期sIVH进展到随后的PHH的标志，包括 大头畸形和脑室扩大。需要联合治疗，因为单独使用药物均不能预防PHH。在 人类早产儿、MLT和EPO在临床试验中以相似剂量安全地用作单一疗法 养生法我们提出了一项I期、单机构、随机、双盲试验，用于极早产儿， sIVH以确定MLT和EPO的安全组合剂量。经IRB、IND和初级兽医师批准， 并获得知情同意，最多将入组60例患有sIVH的极早产新生儿，通过 33 w 6/7 d后继续至37 w 6/7 d。新生儿将在MLT+EPO和安慰剂之间以3：1随机分配，所有 接受标准护理。由于早产合并症的波动，需要同时进行控制 and mortality.掩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）/剂量限制性毒性（DLT），包括死亡、潜在MLT相关DLT：重度肝功能 与年龄匹配的sIVH患者相比的异常，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，临床试验中未出现MLT相关SAE。我们假设 MLT+EPO SAE/DLT发生率不会高于安慰剂发生率。次要结局将是 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系列神经成像度量、系列新生儿神经发育 检查、血清和尿MLT和EPO水平以及液体生物标志物。成功实施这一 初步的安全性试验将提供必要的数据，以指导下一阶段的临床试验，以测试是否持续MLT+EPO 治疗可以减少手术干预的需要，并避免分流脑积水的终身负担。

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.