Centre de Ressources et de Compétences Sclerose En Plaques, Neurologie Pasteur 2, CHU de Nice, Université Cote d'Azur, UMR2CA-URRIS, Nice, France.
Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkiye.
JAMA Neurol. 2023 Oct 1;80(10):1080-1088. doi: 10.1001/jamaneurol.2023.2815.
Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system.
To determine the time to onset of symptoms consistent with MS.
DESIGN, SETTING, AND PARTICIPANTS: From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144.
Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred.
Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs.
Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant.
Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum.
ClinicalTrials.gov Identifier: NCT03122652.
放射孤立综合征 (RIS) 代表多发性硬化症 (MS) 最早可检测到的临床前阶段，其间中枢神经系统偶然出现磁共振成像 (MRI) 白质异常。
确定符合 MS 的症状开始出现的时间。
设计、地点和参与者：这项多中心、双盲、3 期、随机临床试验于 2017 年 9 月至 2022 年 10 月进行，研究了特立氟胺在 RIS 个体中延迟 MS 的疗效，随访 3 年。该研究地点包括法国、瑞士和土耳其的转诊中心。年龄大于 18 岁且符合 2009 年 RIS 标准的参与者被随机分配（1:1）接受每日口服特立氟胺 14mg 或安慰剂，直至第 96 周，或可选地延长至第 144 周。
在基线和每年进行临床、MRI 和患者报告的结局 (PRO) 评估，直至第 96 周，如果没有出现症状，则在分配组中进行可选的第 3 年评估。
主要分析在意向治疗人群中进行，相应地评估安全性。次要终点包括 MRI 结局和 PRO。
在 124 名评估合格的参与者中，有 35 名因拒绝参与、不符合纳入标准或随访丢失而被排除。89 名参与者（平均 [标准差] 年龄，37.8 [12.1] 岁；63 名女性 [70.8%]）被纳入（安慰剂组，45 [50.6%]；特立氟胺组，44 [49.4%]）。18 名参与者（安慰剂组，9 [50.0%]；特立氟胺组，9 [50.0%]）退出了研究，导致因不良事件（3 [16.7%]）、同意退出（4 [22.2%]）、失访（5 [27.8%]）、自愿退出（4 [22.2%]）、妊娠（1 [5.6%]）和研究终止（1 [5.6%]）的退出率为 20%。与安慰剂相比，特立氟胺组的首次临床事件时间明显延长，在未调整分析（风险比 [HR]，0.37；95%CI，0.16-0.84；P=0.02）和调整分析（HR，0.28；95%CI，0.11-0.71；P=0.007）中均如此。次要影像学终点结果包括新或新增大的 T2 病变的累积数量比较（比率比 [RR]，0.57；95%CI，0.27-1.20；P=0.14）、新的钆增强病变（RR，0.33；95%CI，0.09-1.17；P=0.09）和新病变参与者的比例（比值比，0.72；95%CI，0.25-2.06；P=0.54）无显著差异。
与安慰剂相比，特立氟胺治疗使首次临床脱髓鞘事件的未调整风险降低 63%，调整风险降低 72%。这些数据表明，在 MS 疾病谱中早期治疗可能有益。
ClinicalTrials.gov 标识符：NCT03122652。
