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

描述(由申请人提供)： 这项首次在成人中进行的口服托吡酯(TPM)第一阶段研究的目的是为TPM作为孤儿产品进一步发展提供必要的信息，用于治疗新生儿缺氧缺血性脑病(一种罕见的医学疾病)的新生儿癫痫。这项研究的结果将为新生儿缺氧缺血性脑病静脉注射TPM的2/3期临床试验奠定基础。每1000次分娩中约有0.5-0.75名婴儿发生缺氧缺血性脑病，估计每年有2500例。缺氧缺血性脑病引起的癫痫发作和脑损伤通常会导致终生疾病，包括认知障碍。目前的首选药物苯巴比妥和苯妥英钠从未经过充分的临床试验。在非对照研究中，只有不到50%的婴儿对治疗有反应，这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。国家神经疾病和中风研究所已经确定，改善新生儿癫痫的治疗是一个重要的未得到满足的需求。托吡酯是一种成人和儿童用于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，并对新生的实验动物癫痫持续状态和脑缺血模型具有神经保护作用。TPM对年龄较大的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显示对HIE模型的益处，有力地表明TPM在治疗HIE引起的新生儿癫痫方面将是有用的，并提供神经保护。在对新生儿进行研究药物之前，食品和药物管理局(FDA)要求首先在成年人身上进行研究。研究人员建议在口服TPM的成人患者中进行一项新的IV TPM制剂的药代动力学和安全性研究。小剂量(25毫克)的稳定标记(非放射性)静脉注射TPM将在患者服用他或她通常的早晨口服剂量的同时给予。可以测量口服和静脉注射TPM剂量的血浆TPM浓度，并且可以在不中断患者维持方案的情况下确定完整的药代动力学曲线。研究人员表示，这项先导性研究的结果将为后续研究的设计提供参考，包括旨在确定静脉注射TPM对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。

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.