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: 8501701
• 负责人: Janet Susan Soul
• 金额: $ 57.62万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501701
• 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; public health relevance; 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，并且与其他年龄段相比，新生儿癫痫发作更常见（每 1000 名活产儿中有 2-3.5 例）。在新生儿中，75% 的癫痫发作是由缺氧缺血性脑病 (HIE) 等急性神经系统疾病引起的。动物和人类数据均表明，癫痫发作会加剧新生儿缺氧缺血性脑损伤；因此，改进癫痫治疗可能会减少与 HIE 引起的新生儿癫痫发作相关的频繁且致残的长期后遗症。尽管新生儿癫痫发作的发生率很高且后果严重，但治疗主要以经验管理为指导，因为仅对新生儿进行了一项抗癫痫药物 (AED) 的随机试验。该试验和其他研究表明，传统 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，快速诊断和治疗难治性癫痫发作快速发作的 HIE 危重新生儿的癫痫发作还面临着重大挑战。为了解决这些问题，拟议的试验将： 1) 测试早期入组和快速、持续和长期脑电图监测的新颖试验设计的可行性，以便在更有效地控制癫痫发作时，可以在新生儿癫痫发作过程的早期测试 AED。最需要的。 2) 在 I 期试验中评估布美他尼 (BTN) 在因 HIE 引起的难治性癫痫发作的新生儿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儿大脑中高度表达的特定氯离子转运蛋白，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，BTN 与苯巴比妥 (PB) 联合使用时对癫痫发作特别有效，苯巴比妥 (PB) 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，几十年来一直作为利尿剂安全用于新生儿，因此是一种理想的新生儿测试新型 AED。 该研究设计将是一项随机、双盲、对照、剂量递增研究，将 BTN 作为附加疗法，用于治疗由初始负荷剂量 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患有 HIE 的新生儿、快速应用完整蒙太奇脑电图以及持续审查脑电图数据以检测初始负荷剂量 PB 后发生的难治性癫痫发作的可行性。当脑电图证实在服用负荷剂量 PB 后至少 30 分钟发生癫痫发作时，新生儿将被随机分配接受 BTN 或安慰剂与第二剂 PB 联合治疗。将分析 BTN 给药后获得的临床、实验室和连续脑电图监测数据，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。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功效。