Measuring Silent Disease Progression in Multiple Sclerosis With a Multimodal Approach

The goal of this observational prospective, observational, multicenter proof of concept study is to identify silent disease progression in people with multiple sclerosis (MS) that are treated with monoclonal antibodies.

Progression independent of relapse activity (PIRA) refers to disability progression unrelated to relapses. Treatment with disease-modifying agent shifts the primary cause of disability towards PIRA, likely due to the prevention of relapses during therapy. In order to promptly identify these patients in the future, newer biomarkers are needed that can detect disease activity more sensitively. Digital health technologies (DHTs), such as connected wearables, offer the capability of continuously collecting real-life data. As they can capture movement patterns, sleep behavior, and cognition, DHTs can document silent disease progression in MS patients and have the potential to enhance our understanding of disease activity.

The goal of the 360 PMS (progressive Multiple Sclerosis) study is to evaluate various widely available smartwatch-derived digital metrics and blood-based analyses as well as imaging tools for monitoring silent disease activity in MS patients at two study centres. Patients with relapsing remitting or primary progressive MS that are treated with monoclonal antibodies and do not have an Expanded Disability Status Scale (EDSS) of more than 7,0 will be included in this study.

Clinical evaluations will be conducted every 6 months, as well as blood-based measurements that include serum neurofilament-light-chain (sNfL), glial fibrillary acidic protein (GFAP) and proteomic data. Data captured by smartwatches (Withings Scanwatch) include activity-related data (step count, minutes in certain intensity levels), basic cardiovascular measurements such as heart rate, and sleep-related data (total time asleep, sleep efficiency and quality etc.). Additionally, disease progression can be optionally evaluated by monitoring fine motor skills while typing on the smartphone by a smartphone application (Neurokeys).

The study will initially start at the core centre at the University Clinic Düsseldorf and plans to enrol further sites in the months following initiation. Further centers might not include optical coherence tomography (OCT) or MRI measurements. At the core facility additional examinations will be conducted: Structural MRI examinations will be conducted at baseline and in month 12 and 24. OCT measurements will examine retinal morphology and be conducted every 6 months.

The investigators will attempt to closely analyze MS patients under treatment with monoclonal antibodies with these methods. Data will be collected for a 24-month prospective period.

• EDSS: Change From Baseline in Expanded Disability Status Scale (EDSS) Score [Time frame: Baseline up to 24 months (after 6 months, 12 months, 18 months, 24 months)]
• Change From Baseline in World Health Organization Quality of Life Brief Version (WHOQOL-BREF) Score [Time frame: Baseline up to 24 months (after 6 months, 12 months, 18 months, 24 months)]
• Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score - Component Paced Auditory Serial Addition Test [Time frame: Baseline up to 24 months (after 6 months, 12 months, 18 months, 24 months)]
• Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score - Component 9-hole peg test [Time frame: Baseline up to 24 months (after 6 months, 12 months, 18 months, 24 months)]
• Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score - Component Timed 25-foot walk (T25FW) [Time frame: Time Frame: Baseline up to 24 months (after 6 months, 12 months, 18 months, 24 months)]
• Change in Pittsburgh Sleep Quality Index (PSQI) [Time frame: Time Frame: Baseline up to 24 months (after 6 months, 12 months, 18 months, 24 months)]
• Change From Baseline in Fatigue Severity Scale (FSS) [Time frame: Time Frame: Baseline up to 24 months (after 6 months, 12 months, 18 months, 24 months)]
• Change in blood-based serum filament lightchain (sNFL) levels [Time frame: Time Frame: Baseline up to 24 months (after 6 months, 12 months, 18 months, 24 months)]
• Change in blood-based glial fibrillary acidic protein(GFAP) levels [Time frame: Time Frame: Baseline up to 24 months (after 6 months, 12 months, 18 months, 24 months)]
• Change in proteomic signatures [Time frame: Time Frame: Baseline up to 24 months (after 6 months, 12 months, 18 months, 24 months)]
• Questionnaire about smartwatch usage (System Usability Score) [Time frame: After 6 months and 24 months of use]]
• Changes in fine motor skills composite as calculated by Neurokeys [Time frame: Through study completion, up to two years]