A Comparative Clinical Effectiveness Trial of Rituximab Versus Ravulizumab, Inebilizumab, Satralizumab, and Eculizumab to Prevent Relapses in Neuromyelitis Optica Spectrum Disorder (NMOSD)

ObjectiveTo compare the effectiveness and safety of rituximab versus complement inhibitors, inebilizumab, and satralizumab (CIS) in AQP4-IgG-positive NMOSD patients. BackgroundNeuromyelitis optica spectrum disorder (NMOSD) can cause severe attacks of inflammation in the optic nerves, spinal cord, and brainstem that often result in blindness, paralysis, or death. Rituximab has long been used off-label, but recent studies suggest higher rates of treatment failure and serious adverse events compared to complement inhibitors (ravulizumab, eculizumab), inebilizumab, and satralizumab (CIS). Treatment decisions remain challenging due to the absence of direct comparative data. Design/MethodsBEST-NMOSD is a multicentre phase 4 trial. Adults (≥18 y) with seropositive NMOSD meeting 2015 IPND criteria are randomised 1:1 to rituximab or pooled CIS, then 1:1:1 to complement inhibitors (ravulizumab, eculizumab), inebilizumab, or satralizumab. The primary endpoint is a composite of (1) time to adjudicated relapse and (2) time to protocol-defined safety or tolerability failure. Suspected attacks are adjudicated by a blinded Adjudication Committee using pre-specified clinical and MRI criteria. Secondary outcomes include Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), treatment satisfaction, vision-related quality of life, pain, depression and fatigue. ResultsRegulatory approvals and ClinicalTrials.gov registration were obtained in May 2025. First patient-in is planned for August 1st, 2025. Target accrual is 540 participants. No clinical outcome data are yet available. ConclusionsBEST-NMOSD is the first comparative effectiveness trial comparing all approved NMOSD DMTs to rituximab. The primary endpoint combines efficacy and safety, allowing for a comprehensive comparison of treatments. This reflects real-world decisions and this study will deliver actionable results for patients, physicians, and regulatory authorities.