Pilot: Levetiracetam to Prevent Post-Traumatic Epilepsy

试点：左乙拉西坦预防创伤后癫痫

• 批准号: 7110881
• 负责人: PAVEL KLEIN
• 金额: $ 5.83万
• 依托单位: MEDSTAR HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110881
• 关键词: anticonvulsants; blood tests; brain disorder chemotherapy; brain injury; chronic disease /disorder; clinical research; clinical trials; drug administration rate /duration; drug administration routes; drug adverse effect; drug screening /evaluation; epilepsy; human subject; human therapy evaluation; longitudinal human study; medical complication; patient oriented research; pharmacokinetics; questionnaires; therapy compliance

DESCRIPTION (provided by applicant): Head injury is the cause of approximately 5% of all epilepsy. Individuals with severe head trauma carry a 15-50% risk of developing post-traumatic epilepsy. Past attempts at preventing epilepsy by treatment with older Anti-Epileptic Drugs (AEDs) have been unsuccessful. Levetiracetam is a new generation AED with a favorable side-effect, and pharmacokinetic profile that has potent anti-epileptogenic effects in animal models of epilepsy. It may thus be useful in preventing the development of epilepsy following Traumatic Brain Injury (TBI). However, there has been no experience in administering levetiracetam rapidly to individuals with acute TBI, including comatose patients. In this pilot study, therefore, we propose to initiate the evaluation of levetiracetam in prevention of post-traumatic epilepsy by determining the safety, tolerability, pharmacokinetics, and feasibility of acute and chronic administration of levetiracetam to individuals with head injury with a high risk for developing post-traumatic epilepsy. This will be single-dose, open-label study. 60 male and female individuals aged 6 years (40 adults, 20 children) will be enrolled. All will have head injury, with a high risk for developing post-traumatic epilepsy (injury with intracranial hemorrhage or penetrating wound injury). Individuals will receive levetiracetam 55 mg/kg/day by mouth, or via orogastric tube if unable to swallow. Treatment will start within 8 hours of head injury, and will continue for six months. In addition, individuals will receive phenytoin for one week following head injury as standard clinical care. Serum pharmacokinetic profile of levetiracetam will be checked on treatment days three and twenty eight in 20 adult and 12 pediatric subjects, divided into equal groups of those who can, and those who cannot swallow during the acute phase after head injury. The primary outcome measures will be the frequency and severity of side effects of levetiracetam, and the pharmacokinetics of orogastric administration of levetiracetam to individuals with acute head injury. Secondary outcome measures will include the rate of enrollment into, and the rate of drop-out from the study. Frequency of unprovoked seizures at 2-7 days after head injury ("early seizure"), and time to occurrence of unprovoked seizures at >7 days after head injury ("late seizure"), will be monitored but will not represent outcome criteria. The results of the present study will be used to design a large study to assess efficacy of levetiracetam in the prevention of epilepsy in individuals with head injury with a high risk for developing post-traumatic epilepsy. A positive finding of such a study would be the first successful attempt at prevention of epilepsy, a lifelong debilitating illness.

描述（由申请人提供）：大约 5% 的癫痫症是由头部受伤引起的。 患有严重头部外伤的人患外伤后癫痫的风险为 15-50%。 过去通过使用较旧的抗癫痫药物 (AED) 治疗来预防癫痫的尝试均未成功。 左乙拉西坦是新一代 AED，具有良好的副作用和药代动力学特征，在癫痫动物模型中具有有效的抗癫痫作用。 因此，它可能有助于预防创伤性脑损伤（TBI）后癫痫的发展。 然而，尚无对急性 TBI 患者（包括昏迷患者）快速施用左乙拉西坦的经验。 因此，在这项初步研究中，我们建议通过确定左乙拉西坦的安全性、耐受性、药代动力学以及对头部受伤高风险个体急性和长期给药的可行性，开始评估左乙拉西坦预防创伤后癫痫的作用。发展为创伤后癫痫。 这将是单剂量、开放标签研究。 将招募 60 名 6 岁男性和女性（40 名成人，20 名儿童）。 所有人都会有头部受伤，发生外伤后癫痫（颅内出血或穿透伤）的风险很高。 个体将通过口腔接受左乙拉西坦 55 mg/kg/天，如果无法吞咽，则通过口胃管接受。 治疗将在头部受伤后 8 小时内开始，并持续六个月。 此外，作为标准临床护理，个人在头部受伤后将接受苯妥英治疗一周。 将在治疗第 3 天和第 28 天对 20 名成人和 12 名儿童受试者检查左乙拉西坦的血清药代动力学特征，将其分为相等的组，将能够吞咽的受试者和在头部受伤后急性期不能吞咽的受试者分成相等的组。 主要结果指标是左乙拉西坦副作用的频率和严重程度，以及急性颅脑损伤患者经口胃给药左乙拉西坦的药代动力学。 次要结果指标将包括研究的入学率和退出率。 将监测头部受伤后 2-7 天无端癫痫发作的频率（“早期癫痫发作”），以及头部受伤后 > 7 天无端癫痫发作的时间（“晚期癫痫发作”），但不代表结果标准。 本研究的结果将用于设计一项大型研究，以评估左乙拉西坦预防头部损伤且具有发生创伤后癫痫高风险的个体癫痫的功效。 这项研究的积极发现将是预防癫痫这种终生衰弱疾病的首次成功尝试。