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Clinical Trial
. 2023 Oct 1;80(10):1080-1088.
doi: 10.1001/jamaneurol.2023.2815.

Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial

Christine Lebrun-Frénay  1 , Aksel Siva  2 , Maria Pia Sormani  3   4 , Cassandre Landes-Chateau  1 , Lydiane Mondot  1 , Francesca Bovis  3 , Patrick Vermersch  5 , Caroline Papeix  6 , Eric Thouvenot  7 , Pierre Labauge  8 , Françoise Durand-Dubief  9 , Husnu Efendi  10 , Emmanuelle Le Page  11 , Murat Terzi  12 , Nathalie Derache  13 , Bertrand Bourre  14 , Robert Hoepner  15 , Rana Karabudak  16 , Jérôme De Seze  17 , Jonathan Ciron  18 , Pierre Clavelou  19 , Sandrine Wiertlewski  20   21 , Omer Faruk Turan  22 , Nur Yucear  23 , Mikael Cohen  1 , Christina Azevedo  24 , Orhun H Kantarci  25 , Darin T Okuda  26 , Daniel Pelletier  23 ; TERIS Study Group
Collaborators, Affiliations
Clinical Trial

Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial

Christine Lebrun-Frénay et al. JAMA Neurol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Siva reported receiving consultancy, travel, and registration coverage from F. Hoffmann-La Roche Ltd, Merck-Serono, and Sanofi-Genzyme; consultancy fees from Alexion; and grants from the Turkish Multiple Sclerosis Society outside the submitted work. Dr Sormani reported receiving personal fees from Biogen, Merck, Novartis, Roche, Sanofi, Alexion, and Immunic outside the submitted work. Dr Bovis reported receiving grants from National MS Society 2022 Biostatistic/Informatics Junior Faculty Award outside the submitted work. Dr Vermersch reported receiving personal fees from AB Science, Imcyse, Sanofi-Genzyme, Merck, Novartis, Celgene-BMS, Roche, and Teva and grants from Sanofi-Genzyme, Merck, and Roche outside the submitted work. Dr Thouvenot reported receiving personal fees from Actelion and Teva and grants from Biogen, Merck-Serono, Novartis, and Roche outside the submitted work. Dr Efendi reported receiving personal fees from Sanofi outside the submitted work. Dr Le Page reported receiving personal fees from Biogen Idec, Novartis, Merck, Alexion, and Sanofi outside the submitted work. Dr Derache reported receiving personal fees from Biogen and Sanofi, speaker fees from Janssen, and expert advice from Merck and Novartis outside the submitted work. Dr Hoepner reported receiving speaker honoraria from Merck, Novartis, Roche, Biogen, Alexion, Sanofi, Janssen, Bristol Myers Squibb, Teva, and Almirall; grants from Roche, Merck, Sanofi, Bristol Myers Squibb, Biogen, Chiesi, Swiss MS Society, and SISF University Bern outside the submitted work. Dr De Seze reported receiving personal fees from Sanofi during the conduct of the study. Dr Ciron reported receiving advisory board fees from Biogen, Novartis, Merck, Sanofi, and Roche outside the submitted work. Dr Clavelou reported receiving advisory board and travel fees from Sanofi and Janssen and advisory board fees from Merck during the conduct of the study. Dr Wiertlewski reported receiving advisory board fees from Sanofi outside the submitted work. Dr Cohen reported receiving advisory board fees from Biogen, Merck, Sanofi, Roche, Celgene-BMS, Alexion, Horizon Therapeutics, and Ad Scientiam outside the submitted work. Dr Azevedo reported receiving grants from the National Multiple Sclerosis Society and the National Institutes of Health; personal fees from Horizon Therapeutics, Genentech, Sanofi Genzyme, TG Therapeutics, and EMD Serono; grant review from the Department of Defense and the National Institutes of Health; and continuing medical education activity fees from Efficient LLC, American Academy of Neurology, Spire Learning, and Catamount Medical Education outside the submitted work. Dr Kantarci reported receiving grants from the National Institutes of Health outside the submitted work. Dr Okuda reported receiving personal fees from Alexion, Celgene/Bristol Myers Squibb, Genentech, Genzyme/Sanofi, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, TG Therapeutics, and Viela Bio Inc and grants from Biogen and EMD Serono/Merck outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow Diagram
ITT indicates intention to treat.
Figure 2.
Figure 2.. Kaplan-Meier Estimates of Time From Randomization to the First Demyelinating Event (Unadjusted Analysis)
The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, with a risk reduction of 63% before adjustments and 72% after adjustments relative to placebo in preventing a first clinical event.
See this image and copyright information in PMC

References

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