B-cell immunosuppresion or pulsed immune reconstitution therapy as Efficient and Active Treatment for Multiple Sclerosis

Multiple sclerosis (MS) is a demyelinating and neurodegenerative inflammatory disease of the central nervous system, affecting more than 13 000 patients in Norway and more than 2.2 mill patients worldwide. Oral cladribine is one of the first choices for highly efficient disease modulatory treatment (DMT), while Rituximab is used off-label as DMT in relapsing MS. Large observational studies indicate good tolerance and treatment effect of rituximab in MS and studies from other diseases indicate a good safety profile. However, no phase 3 studies have been performed to test whether rituximab is as efficient as established highly efficient MS treatments. Formal safety data is also lacking for the treatment with rituximab in MS. We perform a prospective randomized open-label blinded endpoint multicenter non-inferiority study. The primary objective is to test whether rituximab is non-inferior to oral cladribine in the treatment of relapsing MS. 264 MS patients aged 18-65 years with relapsing MS have been recruited from 10 centers during 2019-2022 and will be followed for 96 weeks. The primary endpoint is difference in new T2 lesions between the groups. Furthermore, we will test novel blood sample and MRI biomarkers to provide tools for personalized MS treatments. Finally, the health economic consequences of these treatment options will be evaluated. This study will guide clinicians and patients in future treatment choices for MS and can potentially make a huge impact on the costs of future MS treatment.

Multiple sclerosis (MS) is a serious and prevalent central nervous system disease with no curative treatment. Recent research indicates that B-cell immunosuppression and pulsed immune reconstitution therapy both are promising treatment strategies for this devastating disease. The choice of therapy in MS is a challenge to both patients and clinicians in the absence of comparative pharmaceutical studies and valid biomarkers. Modern MS treatment has also high direct costs, which is an obstacle to treatment availability in many parts of the world. This study will answer the yet unaddressed research question of whether to recommend B-cell immunosuppression or pulsed immune reconstitution therapy to MS patients with highly active disease. This will be the first prospective open-label blinded endpoint (PROBE) multi-centre non-inferiority study of MS treatment in Norway, comparing a recently introduced choice of treatment in highly active MS disease (cladribine) with a promising off-label therapy (rituximab). Neurologists in Norway will recruit MS patients who are in need of highly effective disease modulatory treatment. Consenting patients will be randomized to cladribine or rituximab. A total of 288 patients will be recruited during the first two years, each followed for 96 weeks with a total trial period of four years. The primary endpoint is difference in numbers of new magnetic resonance imaging (MRI) T2 lesions after 96 weeks of treatment, and secondary outcomes are disease activity and disability progression assessed by clinical and MRI assessments, neurofilament analysis, patient reported outcome measures and health economy analyses. Using this strategy, the study aims to identify the overall differences between these two therapies and also study the role of new biomarkers, in order to guide clinical practice towards an improved evidence-based, cost-effective personalized MS treatment.