Pilot Trial of Bumetanide for Neonatal Seizures

布美他尼治疗新生儿癫痫的试点试验

• 批准号: 8693029
• 负责人: Janet Susan Soul
• 金额: $ 56.72万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-02 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693029
• 关键词: Acute; Address; Age; Antiepileptic Agents; Basic Science; Birth; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Bumetanide; Cerebral Palsy; Chloride Ion; Chlorides; Clinical; Clinical Trials; Clinical Trials Design; Data; Diagnosis; Diuretics; Dose; Double-Blind Method; Drug Kinetics; Drug usage; Early identification; Electroencephalography; Enrollment; Epilepsy; Feasibility Studies; Functional disorder; Goals; Human; Impaired cognition; Incidence; Laboratories; Live Birth; Monitor; Multicenter Trials; Neonatal; Neurologic; Neurological outcome; Newborn Animals; Newborn Infant; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenobarbital; Pilot Projects; Placebos; Population; Randomized; Refractory; Research; Research Design; Rodent; Safety; Seizures; Serious Adverse Event; Staging; Testing; Therapeutic; Work; abstracting; animal data; critically ill newborn; design; disability; efficacy testing; efficacy trial; human data; improved; natural hypothermia; neonatal hypoxic-ischemic brain injury; nervous system disorder; novel; pilot trial; randomized trial; standard care

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.

描述（由申请人提供）：摘要癫痫发作是新生儿急性神经系统疾病最常见的明显表现，新生儿癫痫发作（每1000例活产2-3.5例）比任何其他年龄的新生儿更常见。在新生儿中，75%的癫痫发作是由急性神经系统疾病如缺氧缺血性脑病（HIE）引起的。动物和人类数据均显示，癫痫发作会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能会减少与HIE引起的新生儿癫痫发作相关的频繁和致残性长期后遗症。尽管新生儿癫痫发作的发病率高，后果严重，但治疗主要是通过经验管理来指导的，因为只有一项随机试验在新生儿中进行了任何抗癫痫药物（AED）。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。除了缺乏以前的试验，有重要的挑战，以诊断和治疗癫痫发作迅速危重新生儿缺氧缺血性脑病谁有快速发作的难治性癫痫发作。为了解决这些问题，拟议的试验将：1）测试一种新的试验设计的可行性，即早期入组和快速，连续和长期的EEG监测，以便在最需要更有效的癫痫控制的新生儿癫痫发作过程中早期测试AED。2)在I期试验中评价布美他尼（BTN）治疗新生儿HIE所致难治性癫痫发作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儿大脑中高度表达的特定氯化物转运蛋白，可有效减少新生动物的癫痫发作活动。进一步的实验数据表明，当与苯巴比妥（PB）联合使用时，BTN对癫痫发作特别有效，苯巴比妥是治疗人类新生儿癫痫发作的第一种标准药物。此外，BTN是一种市售药物，几十年来一直安全地用于新生儿利尿，因此是一种理想的新型AED，可用于新生儿测试。 研究设计将是一项随机、双盲、对照、剂量递增的研究，将BTN作为添加治疗，用于治疗初始负荷剂量PB无法控制的HIE引起的难治性癫痫发作。该试验将测试早期入组HIE新生儿、快速应用完整导联EEG和持续审查EEG数据的可行性，以便在PB初始负荷剂量后发生难治性癫痫发作时立即检测到这些癫痫发作。当EEG证实的癫痫发作在PB负荷剂量后至少30分钟发生时，新生儿将随机接受BTN或安慰剂联合第二剂PB。将分析BTN给药后获得的临床、实验室和连续EEG监测数据，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。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发作治疗的试验奠定了基础。这项初步研究的数据将用于指导计划的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疗效。

项目成果

Effect of neonatal seizure burden and etiology on the long-term outcome: data from a randomized, controlled trial.

新生儿癫痫发作负担和病因对长期结果的影响：来自随机对照试验的数据。

• DOI: 10.1002/cns3.8
• 发表时间: 2023
• 期刊: Annals of the Child Neurology Society
• 作者: Trowbridge,SaraK;Condie,LoisO;Landers,JessicaR;Bergin,AnnM;Grant,PatriciaE;Krishnamoorthy,Kalpathy;Rofeberg,Valerie;Wypij,David;Staley,KevinJ;Soul,JanetS;BostonBumetanideTrialGroup
• 通讯作者: BostonBumetanideTrialGroup