MultiSCRIPT-Cycle 1- A Pragmatic trial embedded within the Swiss Multiple Sclerosis Cohort (SMSC) on neurofilament light chain monitoring to inform personalized treatment decisions in Multiple Sclerosis: a study protocol for a randomized clinical trial

Background: Treatment decisions for persons with relapsing-remitting multiple sclerosis (RRMS) rely on clinical and radiological disease activity, the benefit-harm profile of drug therapy, and preferences of patients and physicians. However, there is limited evidence to support evidence-based personalized decision-making on how to adapt disease modifying therapies treatments targeting no evidence of disease activity, while achieving better patient-relevant outcomes, fewer adverse events and improved care. Serum neurofilament light chain (sNfL) is a sensitive measure of disease activity that captures and prognosticates disease worsening in RRMS. sNfL might therefore be instrumental for a patient-tailored treatment adaptation. We aim to assess whether 6-monthly sNfL monitoring in addition to usual care improves patient-relevant outcomes compared to usual care alone. Methods: Pragmatic multicenter, 1:1 randomized, platform trial embedded in the Swiss MS Cohort (SMSC). All patients with RRMS in the SMSC for ≥1 year are eligible. We plan to include 915 patients with RRMS, randomly allocated to two groups with different care strategies, one of them new (group A), one of them usual care (group B). In group A, 6-monthly monitoring of sNfL will together with information on relapses, disability and magnetic resonance imaging (MRI) inform personalized treatment decisions (e.g., escalation or de-escalation) supported by pre-specified algorithms. In group B, patients will receive usual care with their usual 6- or 12-monthly visits. Two primary outcomes will be used: 1) evidence of disease activity (EDA3: occurrence of relapses, disability worsening, or MRI activity) and 2) quality of life (MQoL-54) using 24-month follow-up. The new treatment strategy with sNfL will be considered superior to usual care if either more patients have no EDA3, or their health-related quality of life increases. Data collection will be embedded within the SMSC using established trial-level quality procedures. Discussion: MultiSCRIPT aims to be a platform where research and care are optimally combined to generate evidence to inform personalized decision-making in usual care. This approach aims to foster better personalized treatment and care strategies, at low cost and with rapid translation to clinical practice. Trial registration: [NCT06095271][1]  ### Competing Interest Statement PJ, PB, SS, AO, LD, AM, DL, GD, LR declares no conflict of interest; OF, MU, MJL, MS declared none; Ente Ospedaliero Cantonale, employer of CZ, received grants and/or compensation for Zecca as lecturer and consultant activities and/or grants from Abbvie, Almirall, Biogen Idec, Bristol Meyer Squibb, Genzyme, Lilly, Lundbeck, Merck, Mylan, Novartis, Pfizer, Teva Pharma, Roche, Sanofi; AS received speaker honoraria for activities with Bristol Myers Squibb, CSL Behring, Novartis, and Roche, and research support by the Baasch Medicus Foundation, the Medical Faculty of the University of Bern and the Swiss MS Society, all not related to this work; The University Hospital Basel (USB) and the Research Center for Clinical neuroimmunology and Neuroscience (RC2NB), as the employers of CG, have received the following fees which were used exclusively for ( research support from Siemens, GeNeuro, Genzyme-Sanofi, Biogen, Roche. They also have received advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro, Merck, Biogen and Roche; as well as speaker fees from Genzyme-Sanofi, Novartis, GeNeuro, Merck, biogen and Roche; JO received research support by the Swiss MS Society and served on advisory boards for Roche and Merck; TD has served on scientific advisory boards, steering committees, and data safety monitoring boards for Alexion, Actelion, Biogen, Celgene, Genzyme, GeNeuro, Merck, Mitsubishi Pharma, Novartis, Roche, Octapharma, and MedDay; has received travel and/or speaker honoraria from Biogen, Genzyme, Merck, Novartis, Roche, and Merck-Serono; has received research support from Alexion, Biogen, Novartis, Roche, the Swiss MS Society, the European Union and the Swiss National Foundation. LA served on scientific advisory boards for Celgene, Novartis Pharmaceuticals, Merck, Biogen, Sanofi Genzyme, Roche, and Bayer; received funding for travel and/or speaker honoraria from Celgene, Biogen, Sanofi Genzyme, Novartis, Merck Serono, Roche, Teva, and the Swiss MS Society; and research support from Biogen, Sanofi, Genzyme, and Novartis; PR has received honoraria for lectures or advisory board participation from Alexion, Bristol-Myers Squibb, Boehringer Ingelheim, Debiopharm, Merck Sharp and Dohme, Laminar, Midatech Pharma, Novocure, QED, Roche, and Sanofi and research support from Merck Sharp and Dohme and Novocure; PR reports that the Geneva University Hospital received honoraria for speaking from Biogen, Merck, Roche; consulting fees from Biogen, Merck , Novartis, Roche; research grants from Biogen, Merck, Novartis; SM received honoraria for travel, honoraria for lectures/consulting and/or grants for studies from Almirall, Alexion, Bayer, Biogen, Bristol-Myers Squibb SA/Celgene, Genzyme, Merck-Serono, Teva, Novartis and Roche; CP reports that the Lausanne University Hospital received speaker honoraria, travel grants and consulting services for her activities with Novartis, Roche, Biogen, Merck, Sanofi-Aventis none related to this work; RH received speaker/advisor honorary from Merck, Novartis, Roche, Biogen, Alexion, Sanofi, Janssen, Bristol-Myers Squibb, Teva/Mepha and Almirall. He received research support within the last 5 years from Roche, Merck, Sanofi, Biogen, Chiesi, and Bristol-Myers Squibb. He also received research grants from the Swiss MS Society, the SITEM Insel Support Fund and is a member of the Advisory Board of the Swiss and International MS Society. He also serves as deputy editor in chief for Journal of Central Nervous System disease. All conflicts are not related to this work; Ente Ospedaliero Cantonale, employer of CG, received grants and/or compensation for Gobbi as lecturer and consultant activities and/or grants from Almirall, Biogen Idec, Bristol Meyer Squibb, Genzyme, Lilly, Lundbeck, Merck, Mylan, Novartis, Teva Pharma, Roche, Sanofi. Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Lugano, Switzerland; LK has received no personal compensation. His institutions (University Hospital Basel/Stiftung Neuroimmunology and Neuroscience Basel) have received and used exclusively for research support payments for steering committee and advisory board participation, consultancy services, and participation in educational activities from: Actelion, Bayer, BMS, df-mp Molnia & Pohlmann, Celgene, Eli Lilly, EMD Serono, Genentech, Glaxo Smith Kline, Janssen, Japan Tobacco, Merck, MH Consulting, Minoryx, Novartis, F. Hoffmann-La Roche Ltd, Senda Biosciences Inc, Sanofi, Santhera, Shionogi BV, TG Therapeutics, and Wellmera, and license fees for Neurostatus-UHB products; grants from Novartis, Innosuisse, and Roche; OY received grants from ECTRIMS/MAGNIMS, University of Basel, Pro Patient Stiftung, University of Basel, Free Academy Basel, Swiss Multiple Sclerosis Society, Swiss National Science Foundation and advisory board/lecture and consultancy fees from Roche, Sanofi Genzyme, Allmirall, Biogen and Novartis; RC2NB is supported by Foundation Clinical Neuroimmunology and Neuroscience Basel. RC2NB has a contract with Roche for a steering committee participation of LGH. ### Clinical Trial NCT06095271 ### Funding Statement This project is supported by the Swiss National Science Foundation as part of the Investigator Initiated Clinical Trial program (33IC30_205806/1). The funder had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Ethikkommission Nordwest- und Zentralschweiz (EKNZ) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present studywill be available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT06095271&atom=%2Fmedrxiv%2Fearly%2F2024%2F03%2F24%2F2024.03.22.24304720.atom