University Claude Bernard Lyon 1, Lyon, France.
University of Toronto, Toronto, ON, Canada.
Lancet Neurol. 2014 Mar;13(3):247-56. doi: 10.1016/S1474-4422(13)70308-9. Epub 2014 Jan 23.
Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing-remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis.
This international, randomised, double-blind, placebo-controlled, phase 3 study enrolled adults aged 18-55 years with relapsing multiple sclerosis, one or more relapse in the previous 12 months or two or more in the previous 24 months but no relapse in the previous 30 days, and an Expanded Disability Status Scale (EDSS) score of 5.5 points or less. Patients were recruited from 189 sites in 26 countries and randomly assigned (1:1:1) to once-daily placebo, teriflunomide 7 mg, or teriflunomide 14 mg via an interactive voice recognition system. Treatment duration was variable, ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate (number of relapses per patient-year) and the key secondary endpoint was time to sustained accumulation of disability (an EDSS score increase of at least 1 EDSS point sustained for a minimum of 12 weeks), both analysed in the modified intention-to-treat population (all patients who received at least one dose of assigned study medication). This study is registered with ClinicalTrials.gov, number NCT00751881.
Between Sept 17, 2008, and Feb 17, 2011, 1169 patients were randomly assigned to a treatment group, of whom 388, 407, and 370 patients received at least one dose of placebo, teriflunomide 7 mg, or teriflunomide 14 mg, respectively. By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0.50 [95% CI 0.43-0.58]) than in those assigned to teriflunomide 14 mg (0.32 [0.27-0.38]; p=0.0001) or teriflunomide 7 mg (0.39 [0.33-0.46]; p=0.0183). Compared with placebo, teriflunomide 14 mg reduced the risk of sustained accumulation of disability (hazard ratio [HR] 0.68 [95% CI 0.47-1.00]; log-rank p=0.0442); however, teriflunomide 7 mg had no effect on sustained accumulation of disability (HR 0.95 [0.68-1.35]; log-rank p=0.7620). The most common adverse events were alanine aminotransferase increases (32 [8%] of 385 patients in the placebo group vs 46 [11%] of 409 patients in the teriflunomide 7 mg group vs 52 [14%] of 371 patients in the teriflunomide 14 mg group), hair thinning (17 [4%] vs 42 [10%] vs 50 [13%]), and headache (42 [11%] vs 60 [15%] vs 46 [12%]). Incidence of serious adverse events was similar in all treatment groups (47 [12%] vs 52 [13%] vs 44 [12%]). Four deaths occurred, none of which was considered to be related to study drug (respiratory infection in the placebo group, traffic accident in the teriflunomide 7 mg group, and suicide and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy in the teriflunomide 14 mg group).
Teriflunomide 14 mg was associated with a lower relapse rate and less disability accumulation compared with placebo, with a similar safety and tolerability profile to that reported in previous studies. These results confirm the dose effect reported in previous trials and support the use of teriflunomide 14 mg in patients with relapsing multiple sclerosis.
Genzyme, a Sanofi company.
特立氟胺是一种口服疾病修正治疗药物，批准用于治疗复发型或复发缓解型多发性硬化症。我们旨在为特立氟胺在复发型多发性硬化症患者中的安全性和疗效提供进一步的证据。
这项国际性、随机、双盲、安慰剂对照、3 期研究纳入了年龄在 18-55 岁之间的复发型多发性硬化症患者，这些患者在过去 12 个月中有一次或多次复发，在过去 24 个月中有两次或更多次复发，但在过去 30 天内没有复发，扩展残疾状况量表（EDSS）评分为 5.5 分或以下。患者来自 26 个国家的 189 个地点，通过交互式语音识别系统以 1:1:1 的比例随机分配至每日一次安慰剂、特立氟胺 7mg 或特立氟胺 14mg。治疗持续时间各不相同，最后一次患者入组后 48 周结束。主要终点是年复发率（每名患者的复发次数/患者年），关键次要终点是持续性残疾累积（EDSS 评分至少增加 1 分且持续至少 12 周），均在改良意向治疗人群（所有至少接受一次研究药物剂量的患者）中进行分析。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT00751881。
在 2008 年 9 月 17 日至 2011 年 2 月 17 日期间，共有 1169 名患者被随机分配至治疗组，其中 388、407 和 370 名患者分别接受了至少一剂安慰剂、特立氟胺 7mg 和特立氟胺 14mg。研究结束时，与安慰剂组（0.50[95%CI 0.43-0.58]）相比，特立氟胺 14mg 组（0.32[0.27-0.38]；p=0.0001）和特立氟胺 7mg 组（0.39[0.33-0.46]；p=0.0183）的年复发率更高。与安慰剂相比，特立氟胺 14mg 降低了持续性残疾累积的风险（风险比[HR]0.68[95%CI 0.47-1.00]；对数秩检验 p=0.0442）；然而，特立氟胺 7mg 对持续性残疾累积没有影响（HR 0.95[0.68-1.35]；对数秩检验 p=0.7620）。最常见的不良事件是丙氨酸氨基转移酶升高（安慰剂组 385 名患者中有 32 名[8%]，特立氟胺 7mg 组 409 名患者中有 46 名[11%]，特立氟胺 14mg 组 371 名患者中有 52 名[14%]），头发稀疏（安慰剂组 17 名[4%]，特立氟胺 7mg 组 42 名[10%]，特立氟胺 14mg 组 50 名[13%]）和头痛（安慰剂组 42 名[11%]，特立氟胺 7mg 组 60 名[15%]，特立氟胺 14mg 组 46 名[12%]）。所有治疗组的严重不良事件发生率相似（47[12%]比 52[13%]比 44[12%]）。有 4 例死亡发生，均与研究药物无关（安慰剂组为呼吸道感染，特立氟胺 7mg 组为交通事故，特立氟胺 14mg 组为自杀和革兰氏阴性感染并发弥漫性血管内凝血引起的败血症）。
与安慰剂相比，特立氟胺 14mg 与较低的复发率和较少的残疾累积相关，与先前研究报告的安全性和耐受性相似。这些结果证实了先前试验中报告的剂量效应，并支持在复发型多发性硬化症患者中使用特立氟胺 14mg。
Genzyme，一家 Sanofi 公司。
