Pilot Trial of Bumetanide for Neonatal Seizures

癫痫发作是新生儿急性神经系统疾病最常见的显性表现，与其他年龄相比，癫痫发作在新生儿中更为常见（每1000例活产2-3.5例）。在新生儿中，75%的癫痫发作是由急性神经系统疾病引起的，如缺氧缺血性脑病（HIE）。动物和人类数据均显示癫痫发作加重新生儿缺氧缺血性脑损伤；因此，改善癫痫发作的治疗可以减少新生儿癫痫发作引起的频繁和致残的长期后遗症。尽管新生儿癫痫发作的发病率高且后果严重，但治疗主要以经验管理为指导，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aed在控制难治性新生儿癫痫发作方面相对无效。除了缺乏先前的试验外，对于快速发作难治性癫痫发作的HIE危重新生儿，快速诊断和治疗癫痫发作也存在重要挑战。为了解决这些问题，本试验将：1)测试早期入组和快速、连续和长时间脑电图监测的新试验设计的可行性，以便在新生儿癫痫发作过程的早期测试aed，此时最需要更有效的癫痫控制。2)在I期临床试验中评估布美他尼（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通过阻断在啮齿动物和人类新生大脑中高度表达的特定氯化物转运体，有效地减少了新生动物的癫痫活动。进一步的实验数据表明，BTN与苯巴比妥（苯巴比妥是治疗新生儿癫痫发作的第一种标准药物）联合使用时，对癫痫发作特别有效。此外，BTN是一种可安全用于新生儿的市售药物，作为利尿剂已使用数十年，因此是一种理想的用于新生儿试验的新型AED。研究设计将是一项随机、双盲、对照、剂量递增的研究，BTN作为附加疗法治疗不受初始负荷剂量PB控制的HIE引起的难治性癫痫发作。该试验将测试早期招募新生儿HIE的可行性，快速应用全蒙太奇脑电图，以及持续检查脑电图数据，以便在初始负荷剂量PB后立即发现难固性癫痫发作。当脑电图证实癫痫发作发生在PB负荷剂量后至少30分钟，新生儿将随机接受BTN或安慰剂与第二剂量的PB。对BTN给药后获得的临床、实验室和连续脑电图监测数据进行分析，通过比较治疗组和标准治疗组的数据，确定BTN的药代动力学和安全性。本研究解决了试验设计中的重要挑战，并为改善新生儿癫痫发作治疗的试验奠定了基础。该试点研究的数据将用于指导计划中的III期多中心试验的设计，以测试BTN控制难治性新生儿癫痫发作的有效性。

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. PUBLIC HEALTH RELEVANCE: Narrative Newborn babies have the highest incidence of seizures, but medications currently used to treat them are relatively ineffective, and their seizures are often associated with serious long-term consequences such as cognitive impairments, cerebral palsy and epilepsy. Recent basic science research shows that the commercially available drug bumetanide is effective in suppressing seizures in newborns through an age- specific mechanism of action. The proposed pilot trial will determine the feasibility of a novel trial design to test new drugs to treat seizures in newborns, and will determine the pharmacokinetics and safety of bumetanide in newborns.