Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome
Christine Lebrun-Frénay, Aksel Siva, Maria Pia Sormani, Cassandre Landes-Chateau, Lydiane Mondot, Francesca Bovis, Patrick Vermersch, Caroline Papeix, Eric Thouvenot, Pierre Labauge, Françoise Durand-Dubief, Husnu Efendi, Emmanuelle Le Page, Murat Terzi, Nathalie Derache, Bertrand Bourre, Robert Hoepner, Rana Karabudak, Jérôme De Seze, Jonathan Ciron, Pierre Clavelou, Sandrine Wiertlewski, Omer Faruk Turan, Nur Yucear, Mikael Cohen, Christina Azevedo, Orhun H. Kantarci, Darin T. Okuda, Daniel Pelletier, Pierre Branger, Mouloud Abrous, Hélène Zéphir, Julie Petit, Sandra Vukusic, Céline Gelet, Clarisse Carra-Dallière, Xavier Ayrignac, Mélanie Russello, David Laplaud, Alina Gaultier, Fabienne Le Frère, Céline Callier, Cynthia Caillon, Eglantine Gueydan, Céline Louapre, Damien Galanaud, Aurelian Ungureanu, Sylvie Coudoin, Benjamin Hebant, Emmanuel Gerard, Christine Vimont, Damien Biotti, Fabrice Bonneville, Noellie Freitas, Taskin Duman, Erhan Kilic, Melih Tutuncu, Ugur Uygunoglu, Sena Destan, Sedat Sen, Christoph Friedli, Franca Wagner, Lea Weber, Annaig Tchoubar, Emilie Dumont, Asli Eryilmaz, Tanguy Roman, Christopher Pelletreau, Aurélie Grateau, Yanica Mathieu, Sarhan Yaiche, Felix Rintelen, Isabel Firmino, Aymeric De Chastenier, Amel Gheribenblidia, Burcu Zeydan,- Neurology (clinical)
Importance
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.
Objective
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.
Interventions
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.
Main outcomes
Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs.
Results
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.
Conclusion and Relevance
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.
Trial Registration
ClinicalTrials.gov Identifier: