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Randomized Controlled Trial
. 2025 Feb 1;82(2):123-131.
doi: 10.1001/jamaneurol.2024.4164.

Discontinuation of First-Line Disease-Modifying Therapy in Patients With Stable Multiple Sclerosis: The DOT-MS Randomized Clinical Trial

Eline M E Coerver  1 , Wing Hee Fung  1 , Janet de Beukelaar  2 , Willem H Bouvy  3 , Leo R Canta  4 , Oliver H H Gerlach  5   6 , Elske Hoitsma  7 , Erwin L J Hoogervorst  8 , Brigit A de Jong  1 , Nynke F Kalkers  9 , Zoé L E van Kempen  1 , Harry Lövenich  10 , Caspar E P van Munster  11 , Bob W van Oosten  1 , Joost Smolders  12 , Anke Vennegoor  13 , Esther M P E Zeinstra  14 , Mar Barrantes-Cepas  15 , Gijs Kooij  16 , Menno M Schoonheim  15 , Birgit I Lissenberg-Witte  17 , Charlotte E Teunissen  18 , Bastiaan Moraal  19 , Frederik Barkhof  19   20 , Bernard M J Uitdehaag  1 , Jop Mostert  21 , Joep Killestein  1 , Eva M M Strijbis  1
Affiliations
Randomized Controlled Trial

Discontinuation of First-Line Disease-Modifying Therapy in Patients With Stable Multiple Sclerosis: The DOT-MS Randomized Clinical Trial

Eline M E Coerver et al. JAMA Neurol. .

Abstract

Importance: Increasing numbers of people with multiple sclerosis (MS) use disease-modifying therapy (DMT). Long-term stable disease while taking such medications provides a rationale for considering DMT discontinuation given patient burden, costs, and potential adverse effects of immunomodulating therapy.

Objective: To investigate whether first-line DMT can be safely discontinued in patients with long-term stable MS.

Design, setting, and participants: This multicenter, rater-blinded, noninferiority randomized clinical trial was conducted between July 1, 2020, and March 20, 2023, at 14 Dutch centers. Data analysis was performed between July 2023 and January 2024. Key inclusion criteria were relapse-onset MS, aged 18 years or older, without relapses, and without substantial magnetic resonance imaging (MRI) activity in the previous 5 years under first-line DMT. Participants were randomized 1:1 to discontinue or continue first-line DMT.

Intervention: Discontinuation of first-line DMT.

Main outcome and measure: The primary outcome was significant inflammatory disease activity, defined as relapse and/or 3 or more new T2 lesions or 2 or more contrast-enhancing lesions on brain MRI.

Results: Of 163 potentially eligible participants, 89 participants were included in the trial at the moment of early termination. Forty-four participants (49.4%) were assigned to the continue group and 45 participants (50.6%) were assigned to the discontinue group. Median (IQR) age was 54.0 (49.0-59.0) years, and 60 participants (67.4%) were female. Two participants in the continue group were lost to follow-up. After a median (IQR) follow-up time of 15.3 (11.4-23.9) months, the trial was prematurely terminated because of inflammatory disease activity recurrence above the predefined limit. In total, 8 of 45 participants in the discontinue group (17.8%) vs 0 of 44 participants in the continue group reached the primary end point and had recurrent, mostly radiological inflammation. Two of these 8 participants had a clinical relapse. Median (IQR) time to disease activity was 12.0 (6.0-12.0) months.

Conclusions and relevance: In this randomized clinical trial, even in patients with long-term MS stable for over 5 years, first-line DMT discontinuation can lead to recurrence of inflammatory disease activity. Although this study cohort was relatively small, the recurrence of inflammation in the discontinue group was significantly higher than in the continue group and also higher than in the previously published DISCOMS trial, which only included individuals aged 55 years or older. This study provides additional data, especially in a younger population and including longitudinal biomarker measurements, for informed decision-making in cases when treatment discontinuation is considered.

Trial registration: ClinicalTrials.gov Identifier: NCT04260711.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Coerver reported grants from ZonMW (848043001) and from Stichting Multiple Sclerosis (MS) Research (17-992) during the conduct of the study. Dr Bouvy reported personal fees from Novartis outside the submitted work. Dr Gerlach reported grants from the National MS Foundation and the MS Research Foundation outside the submitted work. Dr Hoitsma reported speaker fees from Biogen, Roche, and Sanofi Genzyme; authorship fees from Sandoz; and study compensation fees paid to her institution for the Calliper, Esteem, and Lemtrada Pass studies. Dr Smolders reported grants from Nationaal MS Fonds (P2021-001, OZ2018-003, and OZ2016-001), the Erasmus Foundation Rogier's droomproject, the Stitchting MOVES Inspiratiebeurs, Stichting MS research (20-490f, 20-490g, and MS22-1168), Roche, and Siemens Healthineers; lecture fees paid to his institution from Biogen, Sanofi-Genzyme, and Merck outside the submitted work. Dr Zeinstra reported the costs of a research nurse, bloodwork, and magnetic resonance imaging from ZonMW during the conduct of the study and advisory fees from Janssen-Cilag, Merck, Novartis, and Sanofi outside the submitted work. Dr Barrantes-Cepas reported research grant support from Atara Biotherapeutics and Merck. Dr Schoonheim reported grants paid to his institution from Amsterdam Neuroscience, ARSEP, Atara Biotherapeutics, Biogen, Celgene/Bristol Myers Squibb, the Dutch MS Research Foundation, EIP, Eurostars-EUREKA, MAGNIMS, MedDay, Merck, and ZonMW Vidi (09150172010056) outside the submitted work; honoraria from Sanofi; and serving on the editorial boards of Neurology, Multiple Sclerosis Journal, and Frontiers in Neurology. Dr Teunissen reported that research of CET was supported by the European Commission (Marie Curie International Training Network, grant agreement 860197 [MIRIADE]), TAME, Innovative Medicines Initiatives 3TR (Horizon 2020, grant 831434), EPND (IMI 2 Joint Undertaking, grant 101034344), and JPND (bPRIDE, CCAD), European Partnership on Metrology, cofinanced from the European Union’s Horizon Europe Research and Innovation Programme and by the Participating States ([22HLT07 NEuroBioStand]; that the CANTATE project was funded by the Alzheimer Association, Alzheimer Drug Discovery Foundation, Alzheimer Netherlands, the Dutch Research Council (ZonMW), Health-Holland, the Michael J. Fox Foundation, and the Selfridges Group Foundation; being the recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health-Holland, Topsector Life Sciences & Health (PPP-allowance #LSHM20106); receiving TAP-dementia, a ZonMW-funded project (#10510032120003) in the context of the Dutch National Dementia Strategy; research contracts with AC-Immune, Acumen, ADx Neurosciences, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, and Vivoryon; serving as editor in chief of Alzheimer Research and Therapy; serving on editorial boards of Molecular Neurodegeneration, Neurology: Neuroimmunology & Neuroinflammation, and Medidact Neurologie/Springer; serving on a committee to define guidelines for cognitive disturbances and a committee for acute neurology in the Netherlands; and consultancy or speaker contracts for Aribio, Beckman-Coulter, Biogen, Cognition Therapeutics, Eli Lilly, Merck, Novo Nordisk, Olink, Roche and Veravas. Dr Barkhof reported consultant fees from Combinostics and IXICO; an educational website research grant from Biogen PML and MRI analysis grant from Roche; and personal fees for serving on a steering committee from Merck outside the submitted work. Dr Uitdehaag reported serving on the adjudication committee for Immunic Therapeutics outside the submitted work. Dr Killestein reported grants from ZonMW (848043001) and from Stichting MS Research (17-992) during the conduct of the study; consulting fees paid to his institution from Biogen, F. Hoffmann-La Roche, Immunic, Merck, Novartis, Sanofi/Genzyme, and TEVA outside the submitted work. Dr Strijbis reported grants from ZonMW and Stichting MS Research during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Profile
aIncludes 2 participants who were lost to follow-up. In addition to the scheduled visits and procedures, there were 17 unscheduled visits: 7 in the continue group due to new complaints and 10 in the discontinue group due to 3 with new complaints, 1 on request, and 6 for follow-up after disease activity.
Figure 2.
Figure 2.. Serum Neurofilament Light (NfL) and Glial Fibrillary Acidic Protein (GFAP) Levels of Participants With Significant Disease Activity and Any Magnetic Resonance Imaging Activity
Cases 1-8 (A-H) are participants (all in the discontinue group) with significant disease activity (relapse and/or ≥3 new T2 lesions or ≥2 contrast-enhancing lesions [CELs]). Cases 9-12 (I-K) are participants with MRI activity (≤2 new T2 lesions, 1 contrast-enhancing lesion, or enlarged T2 lesions) other than the criteria for significant MRI activity. Cases 9 and 10 (I and J) are in the discontinue group and case 12 is (K) in the continue group. Case 11 is not presented, as the blood sample during disease activity was not collected. The gray dashed line represents the baseline NfL level per case.
See this image and copyright information in PMC

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