Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome
Authors: Lebrun-Frénay Christine , Siva Aksel , Sormani Maria Pia , Landes-Chateau Cassandre , Mondot Lydiane , Bovis Francesca , Vermersch Patrick , Papeix Caroline , Thouvenot Eric , Labauge Pierre , Durand-Dubief Françoise , Efendi Husnu , Le Page Emmanuelle , Terzi Murat , Derache Nathalie , Bourre Bertrand , Hoepner Robert , Karabudak Rana , De Seze Jérôme , Ciron Jonathan , Clavelou Pierre , Wiertlewski Sandrine , Turan Omer Faruk , Yucear Nur , Cohen Mikael , Azevedo Christina , Kantarci Orhun H. , Okuda Darin T. , Pelletier Daniel ,   TERIS Study Group, Branger Pierre , Abrous Mouloud , Zéphir Hélène , Petit Julie , Vukusic Sandra , Gelet Céline , Carra-Dallière Clarisse , Ayrignac Xavier , Russello Mélanie , Laplaud David , Gaultier Alina , Le Frère Fabienne , Callier Céline , Caillon Cynthia , Gueydan Eglantine , Louapre Céline , Galanaud Damien , Ungureanu Aurelian , Coudoin Sylvie , Hebant Benjamin , Gerard Emmanuel , Vimont Christine , Biotti Damien , Bonneville Fabrice , Freitas Noellie , Duman Taskin , Kilic Erhan , Tutuncu Melih , Uygunoglu Ugur , Destan Sena , Sen Sedat , Friedli Christoph , Wagner Franca , Weber Lea , Tchoubar Annaig , Dumont Emilie , Eryilmaz Asli , Roman Tanguy , Pelletreau Christopher , Grateau Aurélie , Mathieu Yanica , Yaiche Sarhan , Rintelen Felix , Firmino Isabel , De Chastenier Aymeric , Gheribenblidia Amel , Zeydan Burcu 
Published: August 2023

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: NCT03122652