Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial
Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial
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DOI：
10.1016/s1474-4422(14)70191-7
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发表时间：
2014-10-01
期刊：
影响因子：
48
通讯作者：
O'Connor, Paul W.
中科院分区：
文献类型：
--
作者：
Miller, Aaron E.;Wolinsky, Jerry S.;O'Connor, Paul W.
泰瑞氟米特是一种每日一次的口服免疫调节剂，被批准用于治疗复发-缓解型多发性硬化症。我们的目的是评估泰瑞氟米特在首次临床发作提示多发性硬化症的患者中的疗效和安全性。在这项随机、双盲、安慰剂对照、平行组研究中，我们招募了来自20个国家112个中心（主要是医院）的年龄为18-55岁的临床孤立综合征患者（定义为与脱髓鞘一致的神经系统事件，开始于随机分组后90天内，并且有两个或更多t2加权MRI病变>= 3mm直径）。参与者以双盲方式（通过交互式语音应答系统）随机分配（1:1:1），每天一次口服特立氟米特14mg，特立氟米特7mg或安慰剂，长达108周。患者、管理干预措施的工作人员和结果评估人员被掩盖到治疗分配。主要终点是复发时间（与先前临床事件间隔>= 30天的新神经异常，在没有发烧或已知感染的情况下>= 24小时），这定义了临床明确的多发性硬化症的转变。关键的次要终点是复发或MM上新的钆增强或T2病变的时间，以先发生者为准。对修改意向治疗人群的主要结局进行分析；安全性分析包括所有随机分组的患者，这些患者在接受治疗时暴露于研究药物。该试验已在ClinicalTrials.gov注册，编号NCT00622700。在2008年2月13日至2012年8月22日期间，618名患者被纳入研究，随机分配到泰瑞氟米特14 mg （n=216）、泰瑞氟米特7 mg （n=205）或安慰剂组（n=197）。每个泰瑞氟米特组中都有2名患者没有接受研究药物，因此修改后的意向治疗人群包括214名泰瑞氟米特14 mg组患者，203名泰瑞氟米特7 mg组患者和197名安慰剂组患者。与安慰剂相比，泰瑞氟米特在14 mg剂量组显著降低多发性硬化症复发风险（危险比[HR] 0.574 [95% CI 0.379-0.869]; p=0.0087）和7 mg剂量组（危险比[0.628]0.416-0.949];p=0.0271）。与安慰剂相比，特立氟米特在14 mg剂量组（HR 0.651 [95% CI 0.515-0.822]; p=0.0003）和7 mg剂量组（HR 0.686 [0.54 -0.871]; p=0.0020）降低了复发或新MRI病变的风险。在研究期间，6名随机分配到安慰剂组的患者意外地在某些时候也服用了泰瑞非米特：4人服用了7毫克，2人服用了14毫克。因此，安全人群包括216名服用特立氟米特14mg的患者，207名服用特立氟米特7mg的患者和191名服用安慰剂的患者。不良事件发生的至少有10%的患者在teriflunomide集团和至少2%的发生率高于安慰剂是增加丙氨酸转氨酶(40[19%]14毫克组的216名患者,36(17%)207年7毫克组vs 27(14%) 191年在安慰剂组),头发变薄(25(12%),12(6%)和15[8%]),腹泻(23(11%)和28(14%)和12[6%]),感觉异常(22(10%),11(5%)和10 (5%)),上呼吸道感染（20[9%]和23 [11%]vs 14[7%]）。最常见的严重不良事件是丙氨酸转氨酶升高（4例[2%]和5例[2%]vs 3例[2%]）。据我们所知，TOPIC是第一个报告早期多发性硬化症患者口腔疾病改善治疗获益的研究。这些结果延长了特立氟米特显示有益效果的多发性硬化阶段。
Background Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis.Methods In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18-55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions >= 3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by >= 30 days from a preceding clinical event, present for >= 24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MM, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov, number NCT00622700.Findings Between Feb 13,2008, and Aug 22,2012,618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0.574 [95% CI 0.379-0.869]; p=0.0087) and at the 7 mg dose (0.628 [0.416-0.949]; p=0.0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0.651 [95% CI 0.515-0.822]; p=0.0003) and at the 7 mg dose (0.686 [0.540-0.871]; p=0.0020). During the study, six patients who were randomly assigned to placebo accidently also received terifiunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]).Interpretation TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect.