To Örebro University

Introduction: In the RIFUND-MS trial (NCT02746744), we demonstrated a superior effect of rituximab (RTX) compared with dimethyl fumarate (DMF) for prevention of relapses and focal MRI activity in relapsing-remitting multiple sclerosis (RRMS). However, the optimal dosing regimen of RTX for optimization of the benefit-to-risk balance is not known.

Objectives/Aims: To compare the effect and safety of a standard RTX dosing interval of 6 months with dose interval extension to 12 months, with proportions fulfilling No Evidence of Disease Activity-3 (NEDA-3) during year 2 – 4 as primary endpoint (non-inferiority).

Methods: The RIDOSE-MS trial (NCT03979456) is a rater-blinded randomized phase 3 trial comparing 500 mg RTX given 12-monthly with 500 mg 6-monthly over a 3-year period after an initial common 1-year with 6-monthly dosing. We used the following definition of NEDA-3: no relapses, no new or enlarging T2 MRI lesions and no confirmed disability worsening. Secondary outcomes included soluble biomarkers reflecting immunological side effects, particularly decrease in immunoglobulin G (IgG) levels, and rate of infections.

Results: A total of 207 individuals were randomized to each treatment arm; 104 to the extended dosing, and 103 to the standard dosing arm. The last patient completed the trial in December 2024, and site closure is ongoing. We expect database lock in May 2025 and results of primary and key secondary endpoints available for presentation at the ECTRIMS meeting 2025. There were in total reported 12 protocol-defined relapses over the entire trial period of 4 years, yielding an annual relapse rate of 0.015 for both arms combined. This is the same relapse rate as in the RTX arm of the previous RIFUND-MS trial, comparing RTX with DMF. No new serious safety concerns emerged.

Conclusion: The overall relapse rate was very low in the RIDOSE-MS trial, in which half of the participants were treated with an extended dosing regimen of RTX regardless of individual dynamics in the re-population of B cells. Since long-term safety mainly is related to the immunosuppressive properties of anti-CD20 therapies, it is important to investigate whether increased intervals between RTX infusions reduce risks while maintaining the efficacy of treatment. Primary endpoint data will be presented as well as key secondary endpoints.