Phase I Study in Patients Supporting IV TPM for Neonatal Seizures (9/07, IND7899)

支持 IV TPM 治疗新生儿癫痫患者的 I 期研究（9/07，IND7899）

• 批准号: 7564660
• 负责人: JAMES C. CLOYD
• 金额: $ 19.57万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-20 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564660
• 关键词: Phase; Study; Patients; Supporting; IV

DESCRIPTION (provided by applicant): The aim of this first-in-humans, Phase 1 study in adults taking oral topiramate (TPM) is to provide information essential to the further development of TPM as an orphan product for the treatment of neonatal seizures in newborns with HIE, a rare medical disorder. The results from this study will set the stage for Phase 2/3 clinical trials of IV TPM in newborns with HIE. Hypoxic-ischemic encephalopathy occurs in approximately 0.5-0.75 babies per 1,000 deliveries, or an estimated 2,500 cases per year. Seizures and brain injury arising from HIE often result in life-long morbidity including cognitive impairment. The current drugs of choice, phenobarbital and phenytoin, have never been subjected to adequately controlled clinical trials. In uncontrolled studies, fewer than 50% of babies respond to therapy and both drugs are associated with serious adverse effects including further brain injury, acute systemic toxicity, and significant drug interactions. The National Institute of Neurological Disorders and Stroke has identified improved treatment of neonatal seizures as a significant unmet need. Topiramate is an antiepileptic drug used in adults and children to treat epilepsy. Recent research has shown that TPM is highly effective in controlling seizures and is neuroprotective in newborn laboratory animals in models of status epilepticus and cerebral ischemia. The proven safety and effectiveness of TPM for seizures in older children and adults together with substantial laboratory evidence showing benefit in models of HIE strongly suggest TPM would be useful in the treatment of neonatal seizures resulting from HIE and provide neuroprotection. Prior to studies of investigational drugs in newborns, the Food and Drug Administration (FDA) requires that studies first be done in adults. The investigators propose to carry out a pharmacokinetic and safety study of a novel IV TPM formulation in adult patients taking oral TPM. A small (25 mg) dose of a stable-labeled (non-radioactive) IV TPM will be administered at the same time as the patient takes his or her usual morning oral dose. Plasma TPM concentrations from both oral and IV TPM doses can be measured and a full pharmacokinetic profile can be determine without interrupting patients' maintenance regimen. The investigators state that the results from this pilot study will inform the design of subsequent studies, including controlled clinical trials intended to determine the efficacy and safety of IV TPM for neuroprotection and seizure control in neonates.

描述（由申请人提供）： 这项在口服托吡酯（TPM）的成人中进行的首次人体I期研究的目的是为进一步开发TPM作为治疗新生儿HIE（一种罕见医学疾病）新生儿癫痫发作的孤儿药提供必要信息。本研究的结果将为IV TPM治疗新生儿HIE的2/3期临床试验奠定基础。缺氧缺血性脑病发生在每1，000次分娩中约0.5-0.75名婴儿中，或估计每年2，500例。 由HIE引起的癫痫发作和脑损伤通常导致终身发病，包括认知障碍。目前的药物选择，苯巴比妥和苯妥英，从来没有受到充分控制的临床试验。 在非对照研究中，不到50%的婴儿对治疗有反应，两种药物都与严重的不良反应有关，包括进一步的脑损伤，急性全身毒性和显著的药物相互作用。 美国国家神经疾病和中风研究所已经确定，改善新生儿癫痫发作的治疗是一个重大的未满足的需求。托吡酯是一种用于成人和儿童治疗癫痫的抗癫痫药物。 最近的研究表明，TPM在控制癫痫发作方面非常有效，并且在癫痫持续状态和脑缺血模型中的新生实验室动物中具有神经保护作用。TPM对大龄儿童和成人癫痫发作的安全性和有效性以及大量实验室证据表明在HIE模型中获益，这强烈表明TPM可用于治疗由HIE引起的新生儿癫痫发作并提供神经保护。 在对新生儿进行研究药物研究之前，美国食品药品监督管理局（FDA）要求首先在成人中进行研究。 研究人员建议在口服TPM的成人患者中开展一项新型IV TPM制剂的药代动力学和安全性研究。 在患者服用其常规早晨口服剂量的同时，将给予小剂量（25 mg）稳定标记（非放射性）IV TPM。可以测量来自口服和IV TPM剂量的血浆TPM浓度，并且可以在不中断患者的维持方案的情况下确定完整的药代动力学特征。 研究者指出，这项初步研究的结果将为后续研究的设计提供信息，包括旨在确定IV TPM用于新生儿神经保护和癫痫控制的有效性和安全性的对照临床试验。