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

早产儿容易出现许多影响终生的医学并发症。其中最多的 严重的是严重的脑室出血(SIVH)，随后进展为出血后出血 脑积水(PHH)。目前，PHH的唯一治疗方法是手术，最常见的分流术是 在整个生命周期内容易发生故障。患有SIVH和PHH的儿童也是智力障碍的高危人群 残疾、行为问题、神经感觉障碍、脑瘫和癫痫。新出现的证据 提示调节脑脊液动力学的细胞和分子事件，包括脑脊液 分泌、推进和重吸收在妊娠晚期和出生后头几个月发育。 这些高度亚专业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，因此在较长一段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和重新调整用途的药物有反应，提高了 SIVH后使用药物治疗的可能性，以防止进展为PHH和分流术的需要。 临床前数据显示，当持续剂量给药时，褪黑素(MLT)和促红细胞生成素(EPO) 方案，可以防止从出生后早期SIVH进展到随后的PHH的特征，包括 巨头症和脑室肥大。需要联合治疗，因为这两种药物都不能单独预防PHH。在……里面 人类早产儿、MLT和EPO已安全地作为单一疗法用于类似剂量的临床试验 养生法。我们提出了一项针对极早产儿的I期、单一机构、随机、双盲试验 SIVH确定MLT和EPO的安全组合剂量。在IRB、IND和初级新生儿医生的批准下， 和知情同意，最多60名患有SIVH的极早产儿将被登记，通过 33w6/7d，随后至37w6/7d。新生儿将被随机分为MLT+EPO和安慰剂之间的3：1，所有 接受标准的护理。由于早产合并症的波动，需要同时控制 和死亡率。掩饰是减少归因偏差的关键。主端点是一个复合严重事件 不良事件(SAE)/剂量限制毒性(DLT)，包括死亡、潜在的MLT相关DLT：严重的肝功能 与患有SIVH和已知EPO相关SAE的年龄匹配的同龄人相比的异常：血栓形成， 红细胞增多症和高血压。到目前为止，还没有MLT相关的SAE出现在临床试验中。我们假设 MLT+EPO SAE/DLT比率不会高于安慰剂率。次要结果将是 早产的合并症。收集的探索性数据将指导未来疗效临床试验的设计 包括从临床图像获取系列神经成像指标、系列新生儿神经发育 检查，血清和尿液MLT和EPO水平，以及液体生物标志物。这一点的成功实施 初步的安全性试验将提供必要的数据来指导下一阶段的临床试验，以测试MLT+EPO是否持续 治疗可以减少手术干预的需要，并避免分流性脑积水的终身负担。

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.