Background

Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABA_A receptors, binding at a non-benzodiazepine site.

Objective

We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques.

Methods

We systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or double-blinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome.

Results

Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67–2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93–7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85–2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08–4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02–1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia.

Conclusions

Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

中文翻译：

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成人局灶性癫痫发作的辅助 Cenobamate：系统评价和荟萃分析。

背景

Cenobamate 是一种新型四唑衍生的氨基甲酸酯化合物，具有双重作用机制。这种药物可以增强电压门控钠通道的失活状态，优先抑制钠通道电流的持续成分，并作为 GABA _A受体的正变构调节剂，在非苯二氮卓位点结合。

客观的

我们使用荟萃分析技术评估了辅助性西诺贝特治疗成年癫痫患者局灶性癫痫发作的有效性和安全性。

方法

我们系统地检索了（2020 年 5 月，第 4 周）MEDLINE（由 PubMed 访问）、Cochrane 对照试验中央注册中心 (CENTRAL) 和美国国立卫生研究院临床试验注册中心 (http://www.clinicaltrials.gov) . 没有日期限制或语言限制。确定了在患有不受控制的局灶性癫痫发作的成年患者中使用 cenobamate 的随机、安慰剂对照、单盲或双盲附加试验。主要结果包括与基线相比，维持治疗期间癫痫发作频率≥ 50 和 100% 降低的患者比例以及停药和不良事件 (AE) 的发生率。对每个结果估计了具有 95% 置信区间 (CI) 的风险比 (RR)。

结果

纳入了两项试验，总共招募了 659 名患者（442 名用于添加 cenobamate 组和 217 名用于添加安慰剂组）。在随机分配至西诺巴酯组的患者中，50.1% 的患者和 23.5% 的安慰剂组患者在维持阶段的癫痫发作频率降低至少 50%（RR 2.18，95% CI 1.67–2.85；p  < 0.001）。与安慰剂相比，cenobamate 组达到无癫痫发作的汇总估计 RR 为 3.71（95% CI 1.93–7.14；p  < 0.001）。分别有 16.7% 和 11.1% 的受试者退出随机治疗（RR 1.34，95% CI 0.85–2.09；p = 0.205）。在活动组和对照组中，12.2% 和 4.1% 的患者因 AE 停止治疗（RR 2.27，95% CI 1.08–4.79；p  = 0.031）。在使用西诺贝特和安慰剂治疗期间，76.9% 和 66.8% 的患者报告了 AE（RR 1.14，95% CI 1.02–1.26；p  = 0.021）。cenobamate 相关的 AE 包括嗜睡、头晕、疲劳、平衡障碍和复视。

结论

与安慰剂相比，在患有不受控制的局灶性癫痫发作的成年患者中辅助使用西诺贝特与癫痫发作频率的更大降低和更高的 AE 发生率相关。