Pilot: Levetiracetam to Prevent Post-Traumatic Epilepsy

试点：左乙拉西坦预防创伤后癫痫

• 批准号: 7076242
• 负责人: PAVEL KLEIN
• 金额: $ 52.68万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076242
• 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）：头部受伤是所有癫痫的大约5％的原因。 严重的头部创伤患者患创伤后癫痫的风险为15-50％。 过去通过用较旧的抗癫痫药（AED）治疗预防癫痫的尝试未成功。 Levetiracetam是一种新一代AED，具有有利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，这对于防止创伤性脑损伤（TBI）后癫痫的发展可能很有用。 但是，没有经验来迅速对急性TBI（包括昏迷患者）的患者施用左美甲酰胺。 因此，在这项试验研究中，我们建议通过确定对左上尿的安全性，耐受性，药代动力学以及左乙拉替坦对急性和慢性给药的可行性的安全性，耐受性，药代动力学以及对具有高风险具有高风险的人的急性和长期给药的可行性，从而启动对左上尿中预防创伤后癫痫的评估。发展创伤后癫痫。 这将是单剂量的开放标签研究。 将招募60名6岁（40名成人，20名儿童）的男性和女性。 所有人都将遭受头部损伤，患有创伤后癫痫病的风险很高（颅内出血或穿透伤口损伤）。 如果无法吞咽的话，个人将通过口腔或通过Oogastric Tube收到55 mg/kg/day的左甲曲霉。 治疗将在头部受伤后的8小时内开始，并将持续六个月。 此外，作为标准临床护理，头部受伤后的一个星期将在一个星期内接受苯妥英。 在治疗的第三天和二十八个成人和12名儿科受试者中，将检查左甲乙酰氨酸的血清药代动力学特征，分为相等的人群，以及在头部受伤后急性期无法吞咽的人。 主要结果指标将是左甲乙酰氨酸副作用的频率和严重程度，以及左乙拉西坦对急性头部损伤患者的胃胃施用药代动力学。 次要结果指标将包括入学率和研究的辍学率。 头部受伤后2-7天无端癫痫发作的频率（“提早癫痫发作”），并在头部受伤后> 7天（“晚癫痫发作”）发生无端癫痫发作的时间，但不会代表结果标准。 本研究的结果将用于设计一项大型研究，以评估左甲拉西坦在预防头部损伤患者中癫痫病的功效，患有高风险发生创伤后癫痫。 对这样的研究的积极发现将是第一次成功预防癫痫病，这是一种终生使人衰弱的疾病。

项目成果

Results of phase II levetiracetam trial following acute head injury in children at risk for posttraumatic epilepsy.

• DOI: 10.1111/epi.12326
• 发表时间: 2013-09
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Pearl PL;McCarter R;McGavin CL;Yu Y;Sandoval F;Trzcinski S;Atabaki SM;Tsuchida T;van den Anker J;He J;Klein P
• 通讯作者: Klein P