Safety and efficacy of combined B-cell depleting therapy and daratumumab in patients with autoimmune encephalitis (RADIA): study protocol for a multicenter, randomized trial

Background Anti-NMDA receptor encephalitis (NMDARE) is the most common autoimmune encephalitis, involving an immune response against NMDA receptors on neurons. Despite standard immunotherapy, approximately 30% of critically ill patients require long-term intensive care. Current management strategies are mainly based on retrospective studies and expert opinions, with limited high-quality evidence. This study aims to evaluate the efficacy and safety of B-cell depleting agents followed by daratumumab as a second-line treatment for severe autoimmune encephalitis (AE) with NMDARE as the primary target population. Objective To describe the study protocol for the RADIA study. Study design This multicenter, open-label, randomized controlled trial is conducted across 58 tertiary hospitals in China. Eligible participants are patients with severe AE especially NMDARE (mRS ≥ 3 points and neuropsychiatric manifestations inadequate to symptomatic treatment) post first-line immunotherapy. A total of 200 patients will be randomized at a 2:2:1 ratio into three groups. 80 patients will receive B-cell depleting agent (anti-CD20 mAb ofatumumab) followed by anti-CD38 mAb daratumumab, 80 patients will receive B-cell depleting agent ofatumumab alone, and 40 receive repeated IVIG or plasmapheresis. Main outcome measures The primary endpoint is the proportion of patients with an mRS score ≤ 2, assessed at 16 weeks after treatment initiation. The secondary outcomes include scores on the Clinical Assessment Scale for Autoimmune Encephalitis (CASE), neurocognitive function, antibody status, ICU stay, and hospitalization duration up to 48 weeks. Adverse events will be monitored continuously. Conclusion This trial aims to provide robust data on the efficacy of B cell depleting agents followed by daratumumab in patients with severe AE, with a primary focus on the NMDARE subgroup. This combined regimen may provide a new treatment option for NMDARE. Clinical trial registration https://clinicaltrials.gov/study/NCT06867991 , identifier (NCT06867991).