SAGE Therapeutics, Cambridge, Massachusetts, U.S.A.
Epilepsia. 2013 Sep;54 Suppl 6:81-3. doi: 10.1111/epi.12286.
Refractory status epilepticus (SE) has a mortality rate of up to 35%. Current treatment protocols for the treatment of SE begin with benzodiazepines and then proceed to conventional anticonvulsants. If seizures continue, SE is considered refractory (RSE) and treatment with anesthetic agents in undertaken. Twenty-four h to 48 h after initiation of anesthesia with midazolam, pentobarbital or thiopental, or propofol, an attempt is made to wean the anesthetic. If this fails and seizures recur, SE is considered highly refractory (HRSE) and repeated attempts are undertaken. No randomized trial data are available to guide the choice of anesthetic agent in either RSE or HRSE status. Medication resistance in established SE is thought to result, in part, from internalization of synaptic γ-aminobutyric acid (GABA) receptors, making them unavailable for modulation. Neurosteroids act on both synaptic and extrasynaptic GABAA receptors, which are not internalized, and are therefore hypothesized to have a role in the treatment of RSE. SGE-102 is a neurosteroid metabolite of progesterone with demonstrated anticonvulsant properties in animal seizure models. A randomized double-blind placebo-controlled adjunctive trial of SGE will include subjects randomized at the time that initial treatment with anesthesia is initiated. Subjects will receive midazolam and either SGE-102 or placebo. Midazolam will be tapered and discontinued between hours 24 and 48. SGE-102 or placebo will be continued through hour 120. The primary end point will be the difference in proportion of subjects from each arm who remain seizure free through hour 120. Secondary end points will include the proportion of subjects who are seizure free at hour 168, 2 days after discontinuation of the experimental agent. The study will be powered to have a 90% chance of detecting a clinically meaningful reduction in seizure recurrence at 120 h. Comprehensive safety and pharmacokinetic data will also be obtained during the course of the trial.
难治性癫痫持续状态（SE）的死亡率高达 35%。目前 SE 的治疗方案从苯二氮䓬类药物开始，然后使用传统抗惊厥药物。如果癫痫持续发作，则认为 SE 为难治性（RSE），并使用麻醉剂治疗。在咪达唑仑、戊巴比妥或硫喷妥钠或丙泊酚麻醉开始后 24-48 小时，尝试停止麻醉。如果失败且癫痫再次发作，则认为 SE 为高度难治性（HRSE），并进行反复尝试。目前尚无随机临床试验数据可指导 RSE 或 HRSE 状态下麻醉剂的选择。已确立的 SE 药物耐药性部分归因于突触 γ-氨基丁酸（GABA）受体内化，使其无法进行调节。神经甾体作用于突触和 extrasynaptic GABAA 受体，这些受体不会内化，因此被假设在治疗 RSE 方面具有作用。SGE-102 是孕酮的神经甾体代谢物，在动物癫痫模型中具有抗惊厥作用。一项 SGE 的随机双盲安慰剂对照辅助试验将包括在初始麻醉治疗开始时随机分组的受试者。受试者将接受咪达唑仑和 SGE-102 或安慰剂。咪达唑仑将在 24-48 小时之间逐渐减少并停止。SGE-102 或安慰剂将持续至 120 小时。主要终点将是每个臂中从麻醉开始到 120 小时无癫痫发作的受试者比例的差异。次要终点将包括在实验药物停用后 2 天的 168 小时内无癫痫发作的受试者比例。该研究将有 90%的几率检测到在 120 小时内癫痫复发率的临床意义降低。在试验过程中还将获得全面的安全性和药代动力学数据。
