COMparison Between All immunoTherapies for Multiple Sclerosis.

Study Overview
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Brief Summary
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The overarching goal of this study is to determine whether rituximab (RTX) offers effectiveness and safety advantages over other commonly used approved Disease-Modifying Drugs (DMT) in the largest real-world population-based structured prospective follow-up cohort of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. The study will include both treatment naïve patients starting their first DMT and patients switching from a previous first line DMT (escalation/second-line).

Detailed Description
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This is a prospective non-intervention observational prospective cohort study assessing the long-term safety and efficacy of RTX treatment in MS compared with other common MS DMTs regarding both clinical and radiological parameters in a real-life population of patients with MS. A number of parameters will be assessed annually. These include baseline demographics, previous drug history and reasons for discontinuation, disability status (expanded disability status scale), relapses, safety and adverse events (AE), contrast enhancing T1 and newly appearing T2 lesions on magnetic resonance imaging, as well as a panel of patient reported outcome measures: Symbol Digit Modalities Test (SDMT); MS impact scale-29 (MSIS-29) Fatigue Scale for Motor and Cognitive Functions (FSMC), EuroQol-5 Dimensions (EQ-5D), the MS check scale and Treatment Satisfaction Questionnaire 9 (TSQM-9). Retrospective data entered in medical charts and the Swedish MS registry will be included together with prospective annual structured follow up from inclusion into the study for a minimum of three years (three to nine years). In a substudy - Covid Enhancement study - analyses will be performed regarding the effect of COVID-19 on people with MS as compared to non-MS individuals and also if there is any indication that a particular DMD is associated with a risk to contract a more severe COVID-19. The analyses will primarily be performed in official health care databases.

Official Title
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COMparison Between All immunoTherapies for Multiple Sclerosis. An Observational Long-term Prospective Cohort Study of Safety, Efficacy and Patient's Satisfaction of MS Disease Modulatory Treatments in Relapsing-remitting Multiple Sclerosis

Conditions
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Relapsing-remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: The study population consists of all patients with Clinically Isolated Syndrome (CIS) or RRMS who; Initiate a first MS DMT (treatment naïve), or Initiate a second ever DMT, of a different drug class than the first, regardless of time between drugs or reason for discontinuation(switchers) from 1st Jan 2011 to 30st June 2018, and Are followed at any of the University clinics of Sweden, and Consent to participation in COMBAT-MS core, and Are expected to be capable to follow study assessments. EXCLUSION CRITERIA: - Patients with progressive forms of MS at start of therapy are not eligible

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Rituximab|Comparisons of efficacy and safety between rituximab and all other frequently used immunomodulating drugs against multiple sclerosis|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed disease progression in patients with Expanded Disability Status Scale (EDSS) ≤2.5 at baseline | - Proportion of patients with baseline EDSS ≤2.5 progressing to 12 months confirmed EDSS ≥3 among those over 3 years of follow up | 3 years | 
| Confirmed disease progression in patients with EDSS ≥2.5 at baseline | - Proportion of patients with baseline EDSS ≥2.5 experiencing 6 months confirmed EDSS increase of 1 point among those over 3 years of follow up | 3 years | 
| Disease-related impact on daily life | - Change in MSIS-29 over 3 years of follow up (change from baseline; mean value ±SD) | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Risk and side effect assessments | - Rate of malignancy, cardiovascular disease, serious infections and all-cause mortality in populations on therapy and ever treated, respectively | 3-9 years | 
| Occurence of Serious Adverse Reactions | - The occurrence of serious adverse events (SAE) of all types that are possibly or likely related to DMT treatment | 3-9 years | 
| Annual relapse rate | - Comparison of mean number of relapses per year between the different treatments | 3-9 years | 
| Number of Contrast-enhancing lesions (CEL) | - Comparison of mean number of CEL on yearly MRI between the different treatments | 3-9 years | 
| Increase in EDSS | - Comparison of yearly increase in mean and median EDSS between the different treatments | 3-9 years | 
| Proportion of patients with at least 1 step increase in EDSS | - Comparison of yearly proportion of patients with at least 1 step increase in EDSS between the different treatments | 3-9 years | 
| Proportion of patients with No Evidence of Disease Activity (NEDA) -2 | - Comparison of early proportion of patients with No Evidence of Disease Activity (NEDA) -2 (free of exacerbations, new/enlarged T2-lesions and occurrence of CEL) between the treatments | 3-9 years | 
| Proportion of patients with NEDA-3 | - Comparison of early proportion of patients with NEDA-3 (NEDA-2 plus no worsening of EDSS from baseline) between the treatments | 3-9 years | 
| Levels of Neurofilament-Light chain (NFL) in serum | - Comparison of mean levels of Neurofilament-Light chain (NFL) in serum between the different treatments | 3-9 years | 
| Brain atrophy rate | - Comparison of yearly brain atrophy rate measured as per cent brain parenchymal fraction (BPF) loss in relation to baseline values between the different treatments | 3-9 years | 
| Time on drug | - Comparison of time to drug discontinuation between the different treatments. Separate analyses will be performed depending on reason to drug discontinuation, mainly side effects and lack of efficacy | 3-9 years | 
| Treatment satisfaction | Comparison of patient satisfaction with their treatment using the Treatment Satisfaction Questionnaire (TSQ) between the treatments | 3-9 years | 
| Quality of life assessments | - Comparison of health related QoL measured by EQ-5D between the treatments | 3-9 years | 
| Fatigue | Comparison of fatigue measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC) between the treatments | 3-9 years | 
| Health economy | - Estimation of total societal costs per year after initiating treatment | 3-9 years | 
| Occurrence of Anti-drug antibodies (ADA) | - Proportion of patients treated with RTX developing high-titer anti-RTX ADA | 3-9 years | 
| Employment rate | - Comparison of mean number of working hours per week between the treatments. | 3-9 years | 
| Severity assessments of COVID-19 in MS | Number of hospital and ICU admittance in people with MS compared to population | 1-2 years after COVID-19 epidemic | 
| Severity assessments of COVID-19 in MS in relation to DMD | Number of hospital and ICU admittance in people with MS in relation to DMD | 1-2 years after COVID-19 epidemic | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fingolimod, Immunomodulating treatment, Cohort study, Dimethyl fumarate, Interferon-beta, Natalizumab, Rituximab, Glatiramer acetate