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

描述(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地区。抗疟疾药物可以迅速清除恶性疟原虫，但死亡率仍然很高(12%-25%)。幸存者并不是毫发无损的--~30%的人会经历包括癫痫、行为障碍和严重的神经缺陷在内的神经后遗症。急性癫痫常发生在CM中，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，而辅助呼吸是不可用的。更优化的癫痫控制可能会改善儿童CM幸存者的神经学结果，特别是如果所使用的药物负担得起，并且可以在资源有限的情况下安全和轻松地给药。我们建议对马拉维布兰太尔伊利沙伯中心医院收治的CM和癫痫发作患儿应用左乙拉西坦(LVT)进行剂量递增、安全性和可行性研究。将使用通过鼻胃管(NGT)而不是静脉(IV)配方给予的肠道LVT，因为LVT具有极好的肠道生物利用度，而且IV形成在大多数疟疾流行地区是负担不起的。LVT将根据疗效和毒性终点进行升级，其疗效定义为75%的儿童在服用LVT后24小时内无癫痫发作。一般来说，在接受标准AED治疗的CM和癫痫患儿中，只有约20%的患儿在入院后24小时内没有癫痫发作。安全评估将包括监测与NGT放置和药物输送有关的问题、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，但以其他方式耐受肠内LVT，则将评估用于其他癫痫相关情况的~3倍标准剂量的LVT剂量。由于危重儿童通常不使用肠内制剂，而且疟疾已被证明会影响一些其他药物的药物吸收和消除，因此将获得CM中LVT吸收和消除的药代动力学(PK)数据。由于目前尚无使用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，我们将在一项开放标签的非随机评估中获得初步疗效数据。这项拟议工作的安全性、可行性、PK、最佳剂量和初步疗效数据将提供所需的信息，以决定是否继续在儿童CM患者中进行LVT的随机临床试验，该试验将包括急性癫痫控制以及作为关键终点的长期神经结果。由于肠内LVT对于短期使用相对负担得起，并且可以在资源有限的情况下可行地提供 在这种情况下，这种疗法有可能扩大到在疟疾流行的非洲国家广泛使用。

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.