The MultiSCRIPT trial: personalized medicine in Multiple SClerosis – pRagmatIc Platform Trial embedded within the Swiss MS Cohort

Multiple sclerosis (MS) is a chronic, progressive and disabling disease of the central nervous system where the immune system attacks the myelin sheet of the axons. MS is also the most common non-traumatic cause of disability in young adults. The most common form of the disease is relapsing-remitting MS (RRMS). It is characterized by attacks with new or exacerbating old neurological symptoms followed by remissions. Patients with RRMS increasingly use disease modifying therapies to modulate/suppress the pathogenic

activity of the immune system. The most effective therapies almost completely suppress acute disease activity. However, higher efficacy increases the risk for infectious diseases. No consensus exists on how to adapt such therapies to treat patients as little as possible but as much as necessary. More personalized treatment and care strategies in MS are urgently needed. The Swiss MS Cohort study (SMSC) was established in 2012 and has 8 centers across Switzerland. In September 2021, the SMSC included >1300 of the estimated 15,000 patients living with MS in Switzerland. Every 6 to 12 months patients come for standardized evaluations of relapses and disability status, blood sampling and magnetic resonance imaging (MRI) to detect disease activity in the brain or spinal cord. The applicants have critical expertise in standardizing and integrating high-quality clinical, imaging and

biomarker assessments within the SMSC and conducted extensive research on the novel biomarker serum neurofilament light chain (sNfL). NfL is a neuroaxonal protein released in the cerebrospinal fluid and then the blood when neurons are damaged. Higher levels of sNfL are associated with disease activity and higher risk of relapses; conversely, patients under effective treatment have lower levels of sNfL. sNfL offers a novel way to monitor and even predict disease activity, and to personalize MS therapy. We believe that intensive

sNfL monitoring in addition to usual care could 1) improve patients’ quality of life by reducing their treatment burden (e.g., by reducing the drug dose) and risk for side effects (e.g., infections) and 2) result in fewer patients with disease activity by early and more sensitive biomarker-guided treatment escalation. We propose the Multiple SClerosis pRagmatIc Platform Trial (MultiSCRIPT) embedded in the SMSC. We aim to evaluate new personalized care strategies that ensure no evidence of disease activity, while achieving

better patient outcomes, fewer adverse events and improved care. By using the procedures and high-quality real-world data collection of the SMSC usual care, MultiSCRIPT avoids almost all burden for participants that traditional clinical trials would require. This innovative approach will make clinical research part of usual care in MS. All RRMS patients in the SMSC for at least a year will be eligible. We expect to include 915 patients. One half of the patients will be randomly allocated to intensive sNfL monitoring every 6 months, plus the established clinical and MRI evaluation used in the SMSC, and the other half will be treated as usual with no added sNfL monitoring. We will consider intensive biomarker monitoring strategy better than usual care if either more patients have no evidence of disease activity, or more patients have a better health-related quality of life. MultiSCRIPT aims to be a continuous learning system. Each comparison of a new personalized strategy is one learning cycle, which ends with a decision whether the strategy is better and should be implemented in usual care, or not. This project is the first cycle. It is designed to lay the foundation for subsequent cycles, in which a new strategy, based on the learnings of this first cycle, will be evaluated. The continuous evaluation in MultiSCRIPT initiates an evolutionary process that systematically develops, improves and personalizes treatment and care of patients living with MS in Switzerland and beyond.