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）： 这项针对成人口服托吡酯 (TPM) 的首次人体 1 期研究的目的是为进一步开发 TPM 作为治疗患有 HIE（一种罕见疾病）的新生儿癫痫发作的孤儿产品提供重要信息。这项研究的结果将为 HIE 新生儿 IV TPM 的 2/3 期临床试验奠定基础。每 1,000 次分娩中大约有 0.5-0.75 名婴儿发生缺氧缺血性脑病，每年估计有 2,500 例。 HIE 引起的癫痫发作和脑损伤通常会导致终身发病，包括认知障碍。目前选择的药物苯巴比妥和苯妥英从未经过充分对照的临床试验。 在不受控制的研究中，不到 50% 的婴儿对治疗有反应，并且这两种药物都会产生严重的不良反应，包括进一步的脑损伤、急性全身毒性和显着的药物相互作用。 美国国家神经疾病和中风研究所已将改善新生儿癫痫发作的治疗确定为一项重大的未满足需求。托吡酯是一种用于成人和儿童治疗癫痫的抗癫痫药。 最近的研究表明，TPM 在控制癫痫发作方面非常有效，并且对癫痫持续状态和脑缺血模型中的新生实验动物具有神经保护作用。 TPM 对年龄较大儿童和成人癫痫发作的安全性和有效性已得到证实，加上大量实验室证据表明 HIE 模型有益，强烈表明 TPM 可用于治疗 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，美国食品和药物管理局 (FDA) 要求首先在成人中进行研究。 研究人员提议对口服 TPM 的成年患者进行新型静脉注射 TPM 制剂的药代动力学和安全性研究。 在患者早晨常规口服剂量的同时，将给予小剂量（25 毫克）稳定标记（非放射性）静脉注射 TPM。可以测量口服和静脉注射 TPM 剂量的血浆 TPM 浓度，并可以确定完整的药代动力学特征，而无需中断患者的维持方案。 研究人员表示，这项试点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 对新生儿神经保护和癫痫发作控制的有效性和安全性的对照临床试验。