Pilot Trial of Bumetanide for Neonatal Seizures

描述(申请人提供)：癫痫发作是新生儿急性神经系统疾病最常见的临床表现，新生儿癫痫发作(每1000名活产儿中有2-3.5例)比任何其他年龄段都更常见。在新生儿中，75%的癫痫发作是由急性神经疾病引起的，如缺氧缺血性脑病(HIE)。动物和人类的数据都表明，癫痫发作会加剧新生儿缺氧缺血性脑损伤；因此，改进癫痫发作的治疗方法可能会减少与HIE引起的新生儿癫痫发作相关的频繁和致残的长期后遗症。尽管新生儿癫痫的发生率高且后果严重，但治疗在很大程度上是由经验性治疗指导的，因为只有一项针对新生儿抗癫痫药物(AED)的随机试验。该试验和其他研究表明，传统的抗癫痫药物在控制难治性新生儿癫痫方面相对无效。除了缺乏以前的试验外，对于患有HIE的危重新生儿来说，快速诊断和治疗癫痫是一个重要的挑战，因为他们有快速发作的难治性癫痫。为了解决这些问题，拟议的试验将：1)测试早期登记和快速、连续和长期的脑电监测的新试验设计的可行性，以便在最需要更有效的癫痫控制时，在新生儿癫痫发作过程中及早检测AEDs。2)在I期试验中评价布美他尼(BTN)在新生儿HIE难治性癫痫发作中的药代动力学和安全性。基础科学研究表明，BTN通过阻断一种特定的氯离子转运蛋白，有效地减少了新生动物的癫痫发作活动，这种转运蛋白在啮齿动物和人类的新生大脑中高度表达。进一步的实验数据表明，BTN与苯巴比妥(PB)联合使用时，对癫痫特别有效，苯巴比妥(PB)是治疗人类新生儿癫痫的第一种标准药物。此外，BTN是一种商业上可获得的药物，作为利尿剂在新生儿中安全使用了数十年，因此是一种理想的新生儿AED试验新药。这项研究设计将是一项随机、双盲、可控的剂量递增研究，将BTN作为辅助治疗方法，用于治疗不受PB初始负荷剂量控制的HIE引起的难治性癫痫。这项试验将测试早期登记患有HIE的新生儿、快速应用完整的蒙太奇EEG以及持续审查EEG数据以在初始负荷剂量PB后立即发现难治性癫痫发作的可行性。当脑电证实的癫痫发作发生在负荷量PB后至少30分钟时，新生儿将被随机接受BTN或安慰剂与第二剂量PB的联合治疗。服用BTN后获得的临床、实验室和连续脑电监测数据将被分析，以通过比较治疗组和标准治疗组的数据来确定BTN的药代动力学和安全性。这项研究解决了试验设计中的重要挑战，并为改善新生儿癫痫治疗的试验奠定了基础。这项先导性研究的数据将用于指导计划中的第三阶段多中心试验的设计，以测试BTN控制难治性新生儿癫痫的有效性。

DESCRIPTION (provided by applicant): Abstract Seizures are the most frequent overt manifestation of acute neurologic disorders in newborns, and seizures occur more commonly in newborns (2-3.5 per 1000 live births) than at any other age. In newborns, 75% of seizures are caused by an acute neurologic disorder such as hypoxic-ischemic encephalopathy (HIE). Both animal and human data show that seizures exacerbate neonatal hypoxic-ischemic brain injury; thus improved treatment of seizures may reduce the frequent and disabling long-term sequelae associated with neonatal seizures caused by HIE. Despite the high incidence and serious consequences of neonatal seizures, treatment is largely guided by empiric management, as only one randomized trial has been conducted of any antiepileptic drugs (AEDs) in newborns. That trial and other studies show that conventional AEDs are relatively ineffective in controlling refractory neonatal seizures. In addition to the lack of previous trials, there are important challenges to diagnosing and treating seizures quickly in critically ill newborns with HIE who have rapid onset of refractory seizures. To address these problems, the proposed trial will: 1) Test the feasibility of a novel trial design of early enrollment and rapid, continuous and prolonged EEG monitoring so that AEDs can be tested early in the course of neonatal seizures when more effective seizure control is most needed. 2) Evaluate the pharmacokinetics and safety of bumetanide (BTN) in newborns with refractory seizures caused by HIE in a Phase I Trial. Basic science research has shown BTN to be effective in reducing seizure activity in neonatal animals by blocking a specific chloride transporter which is highly expressed in the newborn brain of rodents and humans. Further experimental data show BTN to be particularly effective against seizures when used in combination with phenobarbital (PB), the standard first drug given to treat seizures in human newborns. In addition, BTN is a commercially available drug used safely in newborns as a diuretic for decades, and thus is an ideal novel AED to test in newborns. The study design will be a randomized, double-blind, controlled, dose escalation study of BTN as add-on therapy to treat refractory seizures caused by HIE not controlled by an initial loading dose of PB. The trial will test the feasibility of early enrollment of newborns with HIE, rapid application of a full montage EEG, and continuous review of EEG data to detect refractory seizures as soon as they occur following an initial loading dose of PB. When an EEG-proven seizure occurs at least 30 minutes following a loading dose of PB, the newborn will be randomized to receive either BTN or placebo in conjunction with a second dose of PB. Clinical, laboratory and continuous EEG monitoring data obtained after BTN administration will be analyzed to determine the pharmacokinetics and safety of BTN by comparing data from treatment and standard therapy groups. This study address important challenges in trial design and sets the stage for trials to improve treatment of neonatal seizures. Data from this pilot study will be used to guide design of a planned Phase III multicenter trial to test the efficacy of BTN to control refractory neonatal seizures.