Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Epilepsy Unit, and Brain and Spine Institute, Pitié-Salpêtrière Hospital and Université Pierre et Marie Curie, Paris, France.
AP-HP, Necker-Enfants Malades Hospital, SAMU 75, and Université Paris Descartes, Paris, France.
Lancet Neurol. 2016 Jan;15(1):47-55. doi: 10.1016/S1474-4422(15)00296-3. Epub 2015 Nov 28.
Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE.
We did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2.5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35.
Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference -10.3%, 95% CI -24.0 to 3.4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group.
The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment.
UCB Pharma.
全身性强直阵挛性癫痫持续状态（GCSE）应尽快治疗。苯二氮䓬类药物是迄今为止唯一有效的入院前药物治疗。我们评估了在苯二氮䓬类药物氯硝西泮中添加抗癫痫药物左乙拉西坦是否会改善 GCSE 的院前治疗。
我们在法国的 13 个急救医疗服务中心和 26 个医院科室进行了一项院前、随机、双盲、三期、安慰剂对照、优效性试验，以确定氯硝西泮（1mg）中添加静脉注射左乙拉西坦（2.5g）对 GCSE 的治疗效果。在巴黎笛卡尔临床研究单位使用计算机生成的随机数列表进行随机分组。患有持续时间超过 5 分钟的癫痫发作的成年人通过院前医生随机（1:1）分配接受左乙拉西坦或安慰剂联合氯硝西泮治疗。所有医生和护理人员都对分组情况进行了盲法。如果在药物注射后癫痫持续超过 5 分钟，则给予第二剂 1mg 氯硝西泮。主要结局是在药物注射后 15 分钟内停止癫痫发作。我们分析了至少接受过一次氯硝西泮和左乙拉西坦或安慰剂注射的改良意向治疗人群，排除无有效同意的患者和多次随机分组的患者。该试验在 EudraCT 注册，编号为 2007-005782-35。
2009 年 7 月 20 日至 2012 年 12 月 15 日期间，107 名患者被随机分配接受安慰剂，96 名患者被分配接受左乙拉西坦。2012 年 12 月 15 日，中期分析显示没有治疗差异的证据时，试验停止，每组 68 名患者纳入改良意向治疗分析。接受氯硝西泮和安慰剂的 68 名患者中有 57 名（84%）和接受氯硝西泮和左乙拉西坦的 68 名患者中有 50 名（74%）在药物注射后 15 分钟停止癫痫发作（差异百分比-10.3%，95%CI-24.0 至 3.4）。在左乙拉西坦组报告了 3 例死亡、19 例（40%）严重不良事件和 90 例（46%）非严重不良事件，在安慰剂组报告了 4 例死亡、28 例（60%）严重事件和 107 例（54%）非严重事件。
在入院前，与单独使用氯硝西泮相比，左乙拉西坦联合氯硝西泮治疗在 GCSE 的控制方面没有优势。未来的院前试验可以评估单独使用氯硝西泮作为癫痫持续状态一线治疗的疗效，以及使用另一种抗癫痫药物进行第二次氯硝西泮注射作为二线治疗的疗效。
UCB Pharma。
