Background: Disease modifying therapies (DMTs) offer opportunities to improve the course of multiple sclerosis (MS), but decisions about treatment are difficult. People with multiple sclerosis (pwMS) want more involvement in decisions about DMTs, but new approaches are needed to support shared decision-making (SDM) because of the number of treatment options and the range of outcomes affected by treatment. We designed a patient-centered tool, MS-SUPPORT, to facilitate SDM for pwMS. We sought to evaluate the feasibility and impact of MS-SUPPORT on decisions about disease modifying treatments (DMTs), SDM processes, and quality-of-life., Methods: This multisite randomized controlled trial compared the SDM intervention (MS-SUPPORT) to control (usual care) over a 12-month period. English-speaking adults with relapsing MS were eligible if they had an upcoming MS appointment and an email address. To evaluate clinician perspectives, participants' MS clinicians were invited to participate. Patients were referred between November 11, 2019 and October 23, 2020 by their MS clinician or a patient advocacy organization (the Multiple Sclerosis Association of America). MS-SUPPORT is an online, interactive, evidence-based decision aid that was co-created with pwMS. It clarifies patient treatment goals and values and provides tailored information about MS, DMTs, and adherence. Viewed by patients before their clinic appointment, MS-SUPPORT generates a personalized summary of the patient's treatment goals and preferences, adherence, DMT use, and clinical situation to share with their MS clinician. Outcomes (DMT utilization, adherence, quality-of-life, and SDM) were assessed at enrollment, post-MS-SUPPORT, post-appointment, and quarterly for 1 year., Results: Participants included 501 adults with MS from across the USA (84.6% female, 83% white) and 34 of their MS clinicians (47% neurologists, 41% Nurse Practitioners, 12% Physician Assistants). Among the 203 patients who completed MS-SUPPORT, most (88.2%) reported they would recommend it to others and that it helped them talk to their doctor (85.2%), understand their options (82.3%) and the importance of taking DMTs as prescribed (82.3%). Among non-users of DMTs at baseline, the probability ratio of current DMT use consistently trended higher over one-year follow-up in the MS-SUPPORT group (1.30 [0.86-1.96]), as did the cumulative probability of starting a DMT within 6-months, with shorter time-to-start (46 vs 90 days, p=0.24). Among the 222 responses from 34 participating clinicians, more clinicians in the MS-SUPPORT group (vs control) trended towards recommending their patient start a DMT (9 of 108 (8%) vs 5 of 109 (5%), respectively, p=0.26). Adherence (no missed doses) to daily-dosed DMTs was higher in the MS-SUPPORT group (81.25% vs 56.41%, p=.026). Fewer patients forgot their doses (p=.046). The MS-SUPPORT group (vs control) reported 1.7 fewer days/month of poor mental health (p=0.02)., Conclusions: MS-SUPPORT was strongly endorsed by patients and is feasible to use in clinical settings. MS-SUPPORT increased the short-term probability of taking and adhering to a DMT, and improved long-term mental health. Study limitations include selection bias, response bias, social desirability bias, and recall bias. Exploring approaches to reinforcement and monitoring its implementation in real-world settings should provide further insights into the value and utility of this new SDM tool., Competing Interests: Declaration of Competing Interest Funding for this research was provided by EMD Serono Inc., USA, an affiliate of Merck KGaA, Darmstadt, Germany, through MS-LINK, a scientific consortium with a mission to improve patient outcomes by advancing MS science to generate actionable real-world data and patient-centered solutions. Further research supported by MS-LINK is designed to close existing scientific gaps identified by the MS community to advance discovery, care, and outcomes for patients with MS. NC: reports research grants and payment for participation in Advisory Board from EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany, during the conduct of the study; grants from Pfizer, grants from Biogen, grants from Edwards Lifesciences, LLC, and grants from MSAA (Multiple Sclerosis Association of America). EA: reports consultation or advisory fees for Alexion, Biogen, Celgene/BMS, EMD Serono/Merck, Genentech/Roche, Horizon, Motric Bio, Novartis, Sanofi, and TG Therapeutics; and funding or grants from: Biogen, Genentech/Roche, Novartis, TG Therapeutics, Patient-Centered Outcomes Research Institute, National Multiple Sclerosis Society, National Institutes of Health, and Rocky Mountain MS Center, LP: has nothing to disclose. CI: (Carolina) has received research support from Riccio Neuroscience Fund and compensation from Sanofi Genzyme and Bristol Myers Squibb for advisory board participation. IBM: has nothing to disclose. AJS: reports funding by NIH/NINDS K02NS109340; compensation for consulting or advisory boards from EMD Serono, Genentech, Biogen, Alexion, Celgene, Octave Bioscience, and Greenwich Biosciences, compensation for nonpromotional speaking from EMD Serono, and research support from Biogen; and participated in contracted research with Biogen, Novartis, Actelion, and Genentech. CK: Consultant for EMD Serono, Biogen, Genzyme, BMS, Amgen, Teva, and Alexion. TL: is an employee of EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, JC: reports personal fees from EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany, Biogen, Allergan, and Biohaven, CIw (Crystal): has nothing to disclose. HC: has nothing to disclose. LN: has nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)