Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305
Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305
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DOI：
10.1111/j.1528-1167.2012.03638.x
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发表时间：
2013-01-01
期刊：
影响因子：
5.6
通讯作者：
Laurenza, Antonio
中科院分区：
文献类型：
--
作者：
French, Jacqueline A.;Krauss, Gregory L.;Laurenza, Antonio
目的：评估perampanel 8 mg和12 mg每日一次与13种获批抗癫痫药物（AED）联合给药治疗不受控制的部分性癫痫发作患者的疗效和安全性。研究方法：研究305是一项多中心、双盲、安慰剂对照试验，受试者年龄≥ 12岁，既往接受过至少2种AED治疗但癫痫持续发作，目前正在接受13种AED治疗。随机分配至每日一次口服perampanel 8或12 mg或安慰剂组。患者进入19周双盲治疗期，包括6周滴定期，每周2 mg剂量增量，随后为13周维持期。主要疗效终点为应答率（治疗期间每28天癫痫发作频率相对于基线降低≥ 50%的患者比例）和每28天癫痫发作频率相对于perampanel治疗前基线的百分比变化。次要终点是复杂部分性发作加继发性全身性发作频率的百分比变化。在整个研究期间监测不良事件（AE）。主要结果：386例患者被随机分组并接受研究药物治疗。其中，321名患者完成了研究。安慰剂组、perampanel 8 mg组和perampanel 12 mg组的50%应答率（意向治疗分析）分别为14.7%、33.3%和33.9%，perampanel 8 mg组（p = 0.002）和12 mg组（p < 0.001）均较安慰剂组显著改善。安慰剂组、8 mg组和12 mg组每28天癫痫发作频率较基线的中位百分比变化（意向治疗分析）分别为-9.7%、-30.5%和-17.6%，与安慰剂组相比，8 mg组（p < 0.001）和12 mg组（p = 0.011）均显著降低。对于复杂部分性癫痫发作加上继发全身性部分性癫痫发作，频率的中位百分比变化为-32.7%（8 mg）、-21.9（12 mg）和-8.1%（安慰剂），8 mg（p < 0.001）和12 mg（p = 0.005）均显著降低。最常见的（任何治疗组≥ 10%的患者发生）治疗后出现的AE为头晕、嗜睡、疲乏和头痛，除头痛外，所有AE均存在明显的剂量效应。重要性：这项III期试验证明，每日一次perampanel 8 mg和12 mg连续治疗可有效改善12岁及以上难治性部分性癫痫发作患者的癫痫控制。这些研究结果还表明，在本研究中，8 mg和12 mg每日一次给药是安全的，耐受性可接受。Perampanel在该人群中表现出有利的风险/获益比。
Purpose: To assess the efficacy and safety of once-daily doses of perampanel 8 and 12 mg when added to 13 concomitantly administered, approved antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. Methods: Study 305 was a multicenter, double-blind, placebo-controlled trial in patients aged 12 years and older with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving 13 AEDs. Equal randomization to once-daily oral perampanel 8 or 12 mg, or placebo was performed. Patients entered a 19-week double-blind treatment phase comprising a 6-week titration period, with weekly 2-mg dose increments, followed by a 13-week maintenance period. Primary efficacy end points were the responder rate (proportion of patients who had a =50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre-perampanel baseline. A secondary end point was percent change in the frequency of complex partial plus secondarily generalized seizures. Adverse events (AEs) were monitored throughout the study. Key Findings: Three hundred eighty-six patients were randomized and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent-to-treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001). The median percent change from baseline in seizure frequency per 28 days (intent-to-treat analysis) was -9.7%, -30.5%, and -17.6% for placebo, 8 mg, and 12 mg, respectively, with significant reductions compared with placebo for both 8 mg (p < 0.001) and 12 mg (p = 0.011). For complex partial seizures plus partial seizures that secondarily generalized, the median percent change in frequency was -32.7% (8 mg), -21.9 (12 mg), and -8.1% (placebo), with significant reductions for both 8 mg (p < 0.001) and 12 mg (p = 0.005). The most frequent (occurring in =10% of patients in any treatment group) treatment-emergent AEs were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache. Significance: This phase III trial demonstrated that adjunctive treatment with once-daily perampanel at 8 mg and 12 mg was effective in improving seizure control in patients 12 years and older with refractory partial-onset seizures. These study results also demonstrated that once-daily doses of 8 mg and 12 mg were safe and acceptably tolerated in this study. Perampanel demonstrated a favorable risk/benefit ratio in this population.