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: 7936708
• 负责人: JAMES C. CLOYD
• 金额: $ 3.77万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936708
• 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）： 在接受口服托吡酯（TPM）的成年人中，第1阶段研究的目的是为TPM作为孤儿产物的进一步发展提供信息，以治疗新生儿的新生儿癫痫发作，患有罕见的医学障碍。这项研究的结果将为HIE新生儿中IV TPM的2/3期临床试验奠定了基础。低氧 - 缺血性脑病大约每1000次分娩约0.5-0.75，或估计每年2500例。 HIE引起的癫痫发作和脑损伤通常会导致终身发病率，包括认知障碍。当前选择的药物，苯巴比妥和苯妥英，从未受过适当控制的临床试验。 在不受控制的研究中，只有不到50％的婴儿对治疗做出反应，两种药物都与严重的不良反应有关，包括进一步的脑损伤，急性全身毒性和严重的药物相互作用。 美国国家神经系统疾病和中风研究所已确定对新生儿癫痫发作的治疗方法是巨大的未满足需求。托吡酯是一种用于治疗癫痫病的成人和儿童的抗癫痫药。 最近的研究表明，TPM在控制癫痫发作方面非常有效，并且在新生儿实验室动物中具有神经保护作用。 TPM对年龄较大的儿童和成人癫痫发作的可靠安全性和有效性以及大量的实验室证据表明，在强烈的HIE模型中，TPM的好处表明TPM将有助于治疗HIE引起的新生儿癫痫发作并提供神经保护作用。 在研究新生儿的研究药物之前，食品药品监督管理局（FDA）要求首先在成年人中进行研究。 研究人员建议对接受口服TPM的成年患者进行新的IV TPM制剂进行药代动力学和安全性研究。 一小剂量（25毫克）稳定标记的（非放射性）IV TPM将在患者服用他或她通常的早晨口服剂量的同时服用。可以测量口服和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。 研究人员指出，这项试验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神经保护和神经保护和癫痫发作控制新生儿的疗效和安全性的对照临床试验。