Long-Term Maintenance of Mycophenolate Mofetil in Anti-NMDA Receptor Encephalitis (LEARN): A Multicentre, Open-Label, Blinded-Endpoint, Randomized Controlled Trial

Abstract

Background: Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is a severe autoimmune disorder with significant morbidity and mortality. Current first-line treatments have limitations, including relapse rates and heterogeneous responses, necessitating effective maintenance therapy. This study aims to assess the efficacy and safety of adding mycophenolate mofetil (MMF) as long-term adjunctive therapy to first-line treatment compared to first-line treatment alone in newly diagnosed NMDARE patients.

Methods: We did a prospective, randomized, open-label, blinded end point trial at four academic hospital centers in China. Patients aged older than 14 years of age presenting with new acute onset of NMDARE, according to the recent international consensus, who had received one or more first-line treatment options within two weeks and had a modified Rankin scale (mRS) score of 2 or more before assessment, were recruited. Participants were randomly assigned in a 1:1 ratio to receive either first-line treatment plus MMF maintenance (0.5g twice daily for 24 months) or non-MMF maintenance. Randomization was performed by an independent statistician using computer-generated randomization software with permuted blocks of four. The participants were stratified by age, sex, and region. Participants, caregivers, and investigators were aware of treatment group assignment, whereas outcome assessors and site staff were blinded. All analyses were conducted by intention to treat approach, which included all participants with available data. The primary efficacy outcome was the number of patients with relapse and the difference in the time to relapse. Secondary outcomes included response rates, extent of NMDAR1-IgG reduction, duration of prednisone tapering, longitudinal disability profiles, fatigue, cognitive and neuropsychological deficits, and adverse events (AEs). This trial, registered with ClinicalTrials.gov (ChiCTR2100044362), concluded after all participants completed 24 months of follow-up.

Findings: Between Mar, 2021, and June, 2022, 255 participants were continuously screened for eligibility, a total of 100 patients with NMDARE underwent randomization (52.0% female; median age, 27 years [range 14 to 60]) and were followed for at least 2 years after beginning trial treatment. The MMF plus group experienced fewer relapse events (5.9% [3 of 51 patients] vs. 26.5% [13 of 49 patients]; hazard ratio, 4.2; 95%CI, 1.5-11.6; P=0.006) and better treatment response (84.3% patients achieving ≥1 point mRS score improvement within 4 weeks after randomization vs 65.3%; relative risk ratio [RR], 1.8; 95%CI, 1.1-3.4; P=0.03). No significant difference was found between the groups in achieving a better long-term functional prognosis (the proportion of patients having an mRS score ≤ 2 points) at 12 months (92.1% vs. 79.6%; P=0.08) and 24 months (98.0% vs. 89.7%; P=0.11), the time of standard prednisone tapering, NMDAR1-IgG titer reduction, or the median time to achieve a one-point mRS improvement. However, patients in the MMF plus group experienced significantly less fatigue, cognitive impairment, depressive symptoms, and seizure activity during longitudinal follow-up. Most AEs in the MMF plus group were mild or moderate in severity, with no reported deaths or anaphylactic reactions related to MMF.

Interpretation: This study provides Class II evidence that the long-term adjunctive of MMF to first-line treatment of NMDARE resulted in a lower risk of relapsed and was well tolerated beyond the 24 months of treatment.

Trial Registration Details: This trial was a randomized, multicenter, prospective, open-labelled, blinded end point study (LEARN, ChiCTR2100044362).

Funding: This work was supported by the National Key R&D Program of China (Grant No: 2022YFC2503800, JH2023019), the Clinical Research Incubation Project of West China Hospital of Sichuan University (Grant No: 22HXFH022), the Postdoctoral Fellowship Program of CPSF (Grant No: GZC20241130), and the China Postdoctoral Science Foundation (Grant No: 2024M752236)

Declaration of Interest: All authors declare no competing interests.

Ethical Approval: Written informed consent was obtained from all patients or their legal representatives before the study began. The study was done in accordance with the Declaration of Helsinki and Good Clinical Practice. An independent ethics committee at each site approved the study protocol, if required, and any subsequent amendments.

Keywords: Anti-N-methyl-D-aspartate receptor encephalitis, Mycophenolate Mofetil, Adjunctive therapy, Relapse, Outcome