A DOSE-ESCALATION, SAFETY AND FEASIBILITY STUDY OF ENTERAL LEVETIRACETAM FOR SEIZ

描述（由申请人提供）：脑型疟疾（CM）每年影响约300万儿童，主要在撒哈拉以南非洲。抗疟药物可以迅速清除恶性疟原虫，但死亡率仍然很高（12-25%）。幸存者并非毫发无伤-约30%的患者会出现神经系统后遗症，包括癫痫、行为障碍和严重的神经系统缺陷。急性癫痫发作常发生在CM，并与较高的神经系统发病率和死亡率。疟疾流行地区的癫痫发作管理具有挑战性，因为现有的抗癫痫药物（AED）会引起呼吸抑制，辅助通气不可用。更佳的癫痫控制可能会改善儿童CM幸存者的神经功能结局，特别是如果所使用的药物是负担得起的，并且可以在资源有限的情况下安全轻松地提供。我们建议在马拉维布兰太尔伊丽莎白女王中心医院收治的CM和癫痫发作儿童中进行左乙拉西坦（LVT）肠内给药的剂量递增、安全性和可行性研究。将使用经鼻胃管（NGT）而不是静脉（IV）制剂给予的肠内LVT，因为LVT具有优异的肠内生物利用度，并且IV制剂在大多数疟疾流行地区无法负担。LVT将根据疗效和毒性终点进行递增，疗效定义为LVT给药后24小时内75%的儿童无癫痫发作。一般来说，只有约20%接受标准AED治疗的CM和癫痫发作儿童在入院后的前24小时内保持无癫痫发作。安全性评估将包括监测与NGT放置和药物输送相关的问题、LVT后24小时和7天的实验室参数以及总体病死率。如果未达到疗效终点，但肠内LVT在其他方面耐受，则将评估约3倍于用于其他糖尿病相关疾病的标准剂量的LVT剂量。将获得CM中LVT吸收和消除的药代动力学（Pk）数据，因为肠内制剂通常不用于重症儿童，并且疟疾已被证明会影响一些其他药物的药物吸收和消除。由于没有关于使用LVT控制儿童CM癫痫发作的疗效数据，使用确定为最佳的LVT剂量，我们将在开放标签、非随机评估中获得初步疗效数据。这项拟定工作的安全性、可行性、Pk、最佳剂量和初步疗效数据将提供确定是否在儿童CM患者中继续进行LVT随机临床试验所需的信息，该临床试验将包括急性癫痫控制以及长期神经学结局作为关键终点。由于肠内LVT对于短期使用相对经济实惠，并且可以在资源有限的情况下进行可行的输送， 在某些情况下，这种疗法可能会扩大规模，在疟疾流行的非洲国家广泛使用。 公共卫生相关性：小儿脑型疟疾（CM）每年影响超过300万儿童，约20%的儿童死亡，三分之一的幸存者留下长期的神经和精神后遗症。癫痫发作通常发生在CM中，并与死亡和神经精神残疾的风险增加相关。在这项基于马拉维的左乙拉西坦肠内给药治疗儿童CM的剂量递增、安全性和可行性研究中，我们将为未来旨在改善癫痫发作控制并最终降低儿童CM神经系统发病率的疗效研究奠定基础。

DESCRIPTION (provided by applicant): Cerebral malaria (CM) affects ~3 million children each year, primarily in sub-Saharan Africa. Antimalarial medications can rapidly clear P. falciparum parasites, but mortality rates remain high (12-25%). Survivors do not escape unscathed--~30% experience neurologic sequelae including epilepsy, behavioral disorders and gross neurologic deficits. Acute seizures occur commonly in CM and are associated with higher neurologic morbidity and mortality. Seizure management in malaria endemic regions is challenging because the available antiepileptic drugs (AED) induce respiratory suppression and assisted ventilation is unavailable. More optimal seizure control may improve neurologic outcomes in pediatric CM survivors, especially if the medication used is affordable and can be delivered safely and easily in resource limited settings. We propose to conduct a dose- escalation, safety and feasibility study of enteral levetiracetam (LVT) for seizure control in children with CM and seizures admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Enteral LVT given via nasogastric tube (NGT) rather than an intravenous (IV) formulation will be used since LVT has excellent enteral bioavailability and IV formations are not affordable in most malaria-endemic regions. LVT will be escalated based upon efficacy and toxicity endpoints with efficacy defined as seizure freedom in 75% of children during the 24 hours post LVT administration. Generally, only ~20% of children admitted with CM and seizures who receive standard AED treatment remain seizure free during the first 24 hours after admission. Safety assessments will include monitoring for problems related to NGT placement and medication delivery, laboratory parameters at 24 hours and 7 days post LVT, and overall case fatality rates. If efficacy endpoints are not met but enteral LVT is otherwise tolerated, LVT doses of ~3 times the standard dose used for other seizure-related conditions will be assessed. Pharmacokinetic (Pk) data on the absorption and elimination of LVT in CM will be obtained since enteral formulations are not typically used in critically ill children and malaria has been shown to impact drug absorption and elimination for some other medications. Since there is no efficacy data on the use of LVT for seizure control in pediatric CM, using the LVT dose determined to be optimal, we will obtain preliminary efficacy data in an open label, non-randomized assessment. The safety, feasibility, Pk, optimal dosing and preliminary efficacy data from this proposed work will provide the information needed to determine whether to proceed with a randomized clinical trial of LVT in pediatric CM patients which would include acute seizure control as well as long term neurologic outcomes as critical endpoints. Since enteral LVT is relatively affordable for short-term use and could be feasibly delivered in resource limited settings, this therapy could potentially be scaled up for broad use throughout malaria endemic African countries. PUBLIC HEALTH RELEVANCE: Pediatric cerebral malaria (CM) affects more than 3 million children each year killing ~20% and leaving one third of survivors with long term neurologic and psychiatric sequelae. Seizures occur commonly with CM and are associated with an increased risk of death and neuropsychiatric disabilities. In this Malawi-based dose- escalation, safety and feasibility study of enteral levetiracetam in pediatric CM, we will lay the groundwork for future efficacy studies aimed at improving seizure control and ultimately decreasing the neurologic morbidity of pediatric CM.