A Comparative Clinical Effectiveness Trial of Rituximab Versus Ravulizumab, Inebilizumab, Satralizumab, and Eculizumab to Prevent Relapses in Neuromyelitis Optica Spectrum Disorder (NMOSD)
Philippe-Antoine Bilodeau1, Anastasia Vishnevetsky1, Michael Devlin2, Shamik Bhattacharyya3, Rebecca Salky1, Juan Sebastian Mendoza4, Tim Friede5, Jeffrey Bennett6, Bruce Cree7, Jacqueline Palace8, Michael Levy9, Kazuo Fujihara10, Ho Jin Kim11, Eoin Flanagan12, Marcelo Matiello13, Friedemann Paul14
1Massachusetts General Hospital, 2The Sumaira Foundation, 3Brigham and Women's Hospital, 4Charite-Berlin, 5University Medical Center Göttingen, 6University of Colorado School of Medicine, 7UCSF, Multiple Sclerosis Center, 8John Radcliff Hospital Oxford Univeristy Hospitals Trust, 9Massachusetts General Hospital/Harvard Medical School, 10Fukushima Medical University School of Medicine, 11National Cancer Center, 12Mayo Clinic, 13Massachusetts General Hospital, Brigham, Harvard, 14Charite Universitatsmedizin in Berlin
Objective:
To compare the effectiveness and safety of rituximab versus complement inhibitors, inebilizumab, and satralizumab (CIS) in AQP4-IgG-positive NMOSD patients
Background:
Neuromyelitis 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/Methods:
BEST-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.
Results:
Regulatory approvals and ClinicalTrials.gov registration were obtained in May 2025. First patient-in is planned for March 1st, 2025. Target accrual is 540 participants. No clinical outcome data are yet available
Conclusions:
BEST-NMOSD is the first comparative effectiveness trial comparing all approved NMOSD DMTs to rituximab. The primary endpoint combines efficay and safety, allowing for a holistic comparison of treatments. This reflects real-world decisions and this study will deliver actionable results for patients, physicians, and regulatory authorities.
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