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

肠内左乙拉西坦控制小儿脑型疟疾癫痫发作的剂量递增、安全性和可行性研究

• 批准号: 8739553
• 负责人: GRETCHEN L. BIRBECK
• 金额: $ 54.7万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8739553
• 关键词: Acute; Admission activity; Affect; Africa South of the Sahara; African; Antiepileptic Agents; Antimalarials; Behavior Disorders; Biological Availability; Case Fatality Rates; Cerebral Malaria; Cessation of life; Child; Childhood; Chronic; Clinical Trials; Coma; Conscious; Country; Critically ill children; Data; Diazepam; Dose; Drug Formulations; Drug Kinetics; Electroencephalography; Enrollment; Enteral; Environmental air flow; Epilepsy; Feasibility Studies; Freedom; Future; Guidelines; Health; High Prevalence; Hospitals; Hour; Intravenous; Laboratories; Language; Left; Levetiracetam; Malaria; Malawi; Mechanical Ventilators; Monitor; Morbidity - disease rate; Motor; Neurologic; Neurologic Deficit; Neurological outcome; Oral; Outcome Measure; Parasites; Patients; Pediatric Research; Pharmaceutical Preparations; Phase III Clinical Trials; Phenobarbital; Phenytoin; Plasmodium falciparum; Population; Problem behavior; Randomized Clinical Trials; Resolution; Resources; Risk; Safety; Seizures; Sensory; Subclinical Seizures; Survivors; Therapeutic; Time; Toxic effect; Tube; Vomiting; Work; World Health Organization; absorption; base; clinically significant; cost; disability; experience; improved; killings; meetings; mortality; neuropsychiatry; open label; patient population; primary outcome; respiratory; safety study; scale up; secondary outcome; ward

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.

描述（由申请人提供）：脑型疟疾 (CM) 每年影响约 300 万儿童，主要分布在撒哈拉以南非洲地区。抗疟药物可以快速清除恶性疟原虫，但死亡率仍然很高（12-25%）。幸存者也未能毫发无伤——约 30% 的人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，并且无法提供辅助通气。更优化的癫痫发作控制可能会改善儿科 CM 幸存者的神经系统结果，特别是如果所使用的药物价格实惠，并且可以在资源有限的环境中安全、轻松地提供。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患有 CM 和癫痫发作的儿童进行肠内左乙拉西坦 (LVT) 控制癫痫发作的剂量递增、安全性和可行性研究。将使用通过鼻胃管 (NGT) 给予的肠内 LVT，而不是静脉注射 (IV) 制剂，因为 LVT 具有出色的肠内生物利用度，而静脉注射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升级，疗效定义为在 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% 因 CM 和癫痫发作而入院接受标准 AED 治疗的儿童在入院后 24 小时内保持无癫痫发作。安全评估将包括监测与 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，但可以耐受肠内 LVT，则将评估用于其他癫痫相关病症的标准剂量的约 3 倍的 LVT 剂量。由于肠内制剂通常不用于危重儿童，并且疟疾已被证明会影响某些其他药物的吸收和消除，因此将获得有关 CM 中 LVT 吸收和消除的药代动力学 (Pk) 数据。由于没有使用 LVT 控制儿科 CM 癫痫发作的疗效数据，因此使用确定为最佳的 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，以确定是否在儿科 CM 患者中进行 LVT 随机临床试验，其中包括急性癫痫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 对于短期使用来说相对便宜，并且可以在资源有限的情况下可行地提供 在某些情况下，这种疗法有可能扩大规模，在疟疾流行的非洲国家广泛使用。