From the Mid-Atlantic Epilepsy and Sleep Center (P.K.), Bethesda, MD; Austin Epilepsy Care Center (S.A.), Austin, TX; Bethel Epilepsy Centre (C.B.), Mara Hospital, Bielefeld, Germany; SK Life Science, Inc. (F.D.), Paramus, NJ; Johns Hopkins University School of Medicine (G.L.K.), Baltimore, MD; MedVal Scientific Information Services (S.M.), Princeton, NJ; Unidad de Epilepsia (J.C.S.-A.), Hospital Vithas la Salud, Granada, Spain; Kork Epilepsy Center (B.J.S.), Kehl-Kork, Germany; Department of Neurology and Neurophysiology (B.J.S.), University of Freiburg, Germany; and Refractory Epilepsy Unit (V.V.), Hospital Universitari i Politècnic La Fe, Valencia, Spain.
Neurology. 2022 Sep 5;99(10):e989-e998. doi: 10.1212/WNL.0000000000200792.
To evaluate long-term efficacy (percent seizure frequency reduction and responder rates), safety, and tolerability of adjunctive cenobamate (CNB) in an open-label extension (OLE) of the randomized, double-blind, placebo-controlled study.
Patients (aged 18-70 years) with uncontrolled focal seizures despite treatment with 1-3 antiseizure medications who completed the 18-week double-blind study (n = 360) could enter the OLE, where they underwent a 2-week blinded conversion to CNB (target dose, 300 mg/d; min/max, 50/400 mg/d).
Three hundred fifty-five patients were included in the OLE safety population (265 originally randomized to CNB, 90 originally randomized to placebo), and 354 were included in the OLE modified intent-to-treat population. As of July 2019, 58.9% of patients (209/355) were continuing CNB treatment and 141 had discontinued, including 16.6% (59/355) because of lack of efficacy, 8.7% (31/355) because of withdrawal by patient, and 7.6% (27/355) because of adverse events. The median (range) duration of OLE exposure was 53.9 (1.1-68.7) months. Retention rates at 12, 24, 36, and 48 months were 83%, 71%, 65%, and 62%, respectively. Median percent seizure frequency reduction over baseline increased with each 6-month OLE interval, up to 76.1% at months 43-48. Among observed patients, 16.4% (36/220) achieved 100% and 39.1% (86/220) achieved ≥90% seizure reduction during >36-48 months. Among the initial OLE modified intent-to-treat population, 10.2% of patients (36/354) achieved 100% and 24.3% (86/354) achieved ≥90% seizure reduction during >36-48 months. Similar to the double-blind study, adverse events (AEs) included dizziness, somnolence, fatigue, and headache. Serious AEs occurred in 20.3% of patients (72/355).
Long-term efficacy, including 100% and ≥90% seizure reduction, was sustained during 48 months of CNB treatment, with 71% retention at 24 months. No new safety issues were identified. These results confirm the findings of the double-blind study and support the potential long-term clinical benefit of CNB.
This study provides Class IV evidence that oral CNB 50-400 mg/d is effective as an adjunctive treatment for the long-term management of patients with uncontrolled focal seizures previously treated with 1-3 ASMs.
ClinicalTrials.gov NCT01866111 (clinicaltrials.gov/ct2/show/results/NCT01866111).
评估在一项随机、双盲、安慰剂对照研究的开放性扩展（OLE）中，加用依诺生（CNB）的长期疗效（癫痫发作频率减少的百分比和应答率）、安全性和耐受性。
完成了 18 周双盲研究的患者（年龄 18-70 岁，尽管使用了 1-3 种抗癫痫药物治疗，但仍存在不受控制的局灶性癫痫发作）可以进入 OLE，他们在 2 周的双盲转换期间接受 CNB 治疗（目标剂量 300mg/d；最小/最大剂量 50/400mg/d）。
355 例患者被纳入 OLE 安全性人群（265 例最初随机分配到 CNB，90 例最初随机分配到安慰剂），354 例被纳入 OLE 修改后的意向治疗人群。截至 2019 年 7 月，58.9%（209/355）的患者（58.9%）继续接受 CNB 治疗，141 例已停药，包括 16.6%（59/355）因疗效不佳，8.7%（31/355）因患者停药，7.6%（27/355）因不良反应。OLE 暴露的中位（范围）持续时间为 53.9（1.1-68.7）个月。12、24、36 和 48 个月的保留率分别为 83%、71%、65%和 62%。与基线相比，中位癫痫发作频率减少百分比随 OLE 间隔的每 6 个月增加，在 43-48 个月时达到 76.1%。在观察到的患者中，16.4%（36/220）在>36-48 个月期间达到了 100%和 39.1%（86/220）达到了≥90%的癫痫发作减少。在初始 OLE 修改后的意向治疗人群中，10.2%（36/354）在>36-48 个月期间达到了 100%和 24.3%（86/354）达到了≥90%的癫痫发作减少。与双盲研究相似，不良反应（AE）包括头晕、嗜睡、疲劳和头痛。20.3%（72/355）的患者发生严重 AE。
在 48 个月的 CNB 治疗期间，疗效持续，包括 100%和≥90%的癫痫发作减少，24 个月时保留率为 71%。未发现新的安全性问题。这些结果证实了双盲研究的发现，并支持 CNB 的潜在长期临床获益。
本研究提供了 IV 级证据，表明口服 CNB 50-400mg/d 作为以前使用 1-3 种 AMS 治疗的不受控制的局灶性癫痫发作患者的长期管理的附加治疗是有效的。
ClinicalTrials.gov NCT01866111（clinicaltrials.gov/ct2/show/results/NCT01866111）。
