NEOLEV3: A Phase IIb Dose Escalation Study of Levetiracetam in the Treatment of Neonatal Seizures of Mild to Moderate Severity IND-109622 (September 6, 2020)

项目摘要/摘要 这项提议的目的是改善新生儿癫痫的治疗。新生儿癫痫 每300名婴儿中就有1名受到影响。幸存者有很高的永久残障率(40%-60%)，例如 脑性瘫痪、全球发育迟缓和癫痫。越来越多的证据表明 癫痫发作会导致脑损伤和神经发育障碍；更好的治疗方法可能 改善长期神经发育结果。尽管随机进行了NEOLEV2临床试验 苯巴比妥(PHB)对癫痫发作有更好的控制作用，PHB引起的急性副作用增加 与标准剂量左乙拉西坦(Lev)的疗效比较。这些副作用包括 呼吸抑制、低血压和镇静。此外，人们一直担心 关于PHB的长期神经认知副作用。这项拟议的项目将完善 通过分层治疗新生儿癫痫的标准临床范例； 使用效果显著改善的抗癫痫治疗，LEV，目标是 减轻轻至中度癫痫发作负担，保留PHB及其相关副作用用于 新生儿癫痫发作负担高。 研究目标是(1)优化使用一种更新、更安全、无毒的抗惊厥药 用于新生儿癫痫发作的药物和(2)开发技术，使准确的 癫痫发作的即时自动诊断。 将进行剂量递增和安全性研究，以确定最大耐受量 利福平的剂量。在标准剂量的LEV后继续癫痫发作的婴儿将接受 较高剂量的Lev或对照药物PHB，按3：1的分配比随机分配。剂量递增将 分3个阶段进行，最大负荷量为150 mg/kg。至少10个科目将被选为 在每个剂量水平上进行研究，安全数据将确定剂量限制毒性是否 在进一步剂量升级之前就已经证明了。主端点将是允许的最大值 剂量。次要终点将是更高剂量的LEV的额外疗效 标准剂量水平。将研究大剂量LEV在新生儿体内的药代动力学。 促进新生儿癫痫的早期发现和快速治疗对 开发更好的药物来改善结果。当前癫痫发作检测的有用性 算法的精确度较低，因而受到限制。在拟议的研究中，新的和 将对改进的PerSyst新生儿癫痫检测算法进行评估。

Project Summary/Abstract The aim of this proposal is to improve the treatment of neonatal seizures. Neonatal seizures affect 1 in 300 infants. Survivors have high rates (40-60%) of permanent disabilities such as cerebral palsy, global developmental delay and epilepsy. There is mounting evidence that seizures contribute to brain injury and neurodevelopmental disability; better treatment may improve long-term neurodevelopmental outcomes. Despite the randomized NEOLEV2 clinical trial showing greater seizure control with phenobarbital (PHB), PHB produced increased acute side effects in comparison to standard dose Levetiracetam (LEV). These side effects included respiratory suppression, hypotension, and sedation. Furthermore, there has been concern regarding long-term neurocognitive side effects of PHB. This proposed project will refine the standard clinical paradigm for neonatal seizure treatment by demonstrating a stratified approach; using an anti-seizure treatment with a significantly improved effect profile, LEV, targeted at reducing mild to moderate seizure burden, reserving PHB with its associated side effects for neonates with high seizure burden. Research Objectives are to (1) optimize the use of a newer, safer, non-toxic anticonvulsant medication for neonates with seizures and (2) develop technologies that will allow for accurate immediate automated diagnosis of seizures. A dose escalation and safety study will be performed to determine the maximum tolerated dose of LEV. Infants who continue to have seizures following standard dose LEV will receive either higher dose LEV or the control drug PHB, randomized in a 3:1 allocation ratio. Dose escalation will proceed in 3 phases to the maximal loading dose of 150mg/kg. A minimum of 10 subjects will be studied at each dosing level and safety data will determine if dose limiting toxicity has been demonstrated before further dose escalation. The primary endpoint will be the maximum tolerated dose. A secondary endpoint will be the additional efficacy of higher doses of LEV compared with standard dose LEV. The pharmacokinetics of high dose LEV in neonates will be studied. Facilitating early detection and rapid treatment of neonatal seizures is of equal importance to developing better drugs in improving outcomes. The usefulness of current seizure detection algorithms is limited by their low accuracy. Within the proposed study the accuracy of the new and improved Persyst neonatal seizure detection algorithm will be evaluated.