A Dose-Escalation, Safety and Feasibility Study of Enteral Levetiracetam for Seizure Control in Pediatric Cerebral Malaria

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%）。幸存者并非毫发无损——约30%的幸存者会经历神经系统后遗症，包括癫痫、行为障碍和严重神经功能缺陷。急性癫痫发作常见于CM，并与较高的神经系统发病率和死亡率相关。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）会导致呼吸抑制和辅助通气。更优的癫痫发作控制可能改善小儿CM幸存者的神经系统预后，特别是如果所使用的药物是负担得起的，并且在资源有限的情况下可以安全方便地交付。我们建议对马拉维布兰太尔伊丽莎白女王中心医院收治的CM和癫痫发作儿童进行左乙拉西坦（LVT）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，而在大多数疟疾流行地区，静脉制剂负担不起。LVT将根据疗效和毒性终点升级，疗效定义为75%的儿童在LVT给药后24小时内癫痫发作自由。一般来说，在接受标准AED治疗的患有CM和癫痫发作的儿童中，只有~20%在入院后24小时内没有癫痫发作。安全性评估将包括监测与NGT放置和给药有关的问题、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耐受，则评估LVT剂量为用于其他癫痫相关疾病的标准剂量的3倍。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危重儿童，而且疟疾已被证明会影响某些其他药物的吸收和消除。由于没有关于LVT用于小儿CM癫痫发作控制的疗效数据，因此我们将使用确定为最佳的LVT剂量，通过开放标签、非随机评估获得初步疗效数据。这项工作的安全性、可行性、Pk、最佳剂量和初步疗效数据将为确定是否继续进行LVT儿童CM患者的随机临床试验提供所需的信息，该试验将包括急性发作控制以及长期神经系统结局作为关键终点。由于肠内LVT短期使用相对负担得起，并且在资源有限的情况下是可行的

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.