Randomized Clinical Trial to Compare Efficacy and Safety of Maintenance Mycophenolate-Mofetil to Cyclosporine After Repeated Courses of Rituximab in Children With Steroid Resistant Nephrotic Syndrome

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Background: Approximately 10% of children with children with idiopathic nephrotic syndrome will not achieve complete remission after 6-8 weeks therapy with corticosteroid and have steroid resistant nephrotic syndrome (SRNS). Rituximab (RTX), a B cell depleting monoclonal antibody followed by maintenance mycophenolate-mofetil (MMF) or cyclosporine (CYC) has been shown to be efficacious in children with SRNS. Controlled trial comparing the efficacy and safety of treatment with CYC to MMF after RTX induction is lacking. Methods: A total of 55 children with SRNS were randomized to receive 12 months MMF 1.0 g/m2/day (n=28) or CYC 5 mg/kg/day (n=27) following RTX infusions (375 mg/m2 intravenously) to maintain persistent B cell depletion. The primary outcome was complete remission rate at 12 months and secondary outcome consisted of incidence of treatment-related adverse events among all intention-to-treat population. Results: RTX/MMF therapy was associated with a significantly higher relapse-free survival (complete remission rate) at 12-month [23(82% vs. [15(56%)]; p<0·01). Among patients who experienced relapse; median time to first relapse was significantly longer for patients treated with RTX/MMF (10·3 months) than patients receiving RTX/CYC (7·1 months) (P<0·01). Only 3 patients in the RTX/MMF group had more than 1 relapse during the study period compared with 8 in the RTX/CYC group (p<0·01). Overall, the response to therapy was greater in patients with the FSGS who were receiving RTX/MMF regimen (p<0·01). Moderate to severe infections were twice as common in the RTX/CYC than in RTX/MMF (P=0·05). Interpretation: The study found a superiority of MMF over CYC after RTX in terms of relapse -free survival and adverse events. The findings suggest that MMF therapy following RTX may be considered first line corticosteroid-sparing therapy in the treatment of SRNS. Trial Registration: The study was registered with the WHO International Clinical Trials Registry Platform (ICTRP) and Iranian Registry of Clinical Trials (IRCT20150421021894N; https://irct.ir), registration date 25 March 2019. Funding Statement: None. Declaration of Interests: The authors declare they have no financial competing interests for the overall trial and the study site. Ethics Approval Statement: The study protocol and consent documents were approved (IR.ZAUMS.REC.1397.491) by the Ethics committee (Institutional Review Board) of Zahedan University of Medical Sciences, Iran following approval of institute scientific committee. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research where the study was conducted and with the 1964 Helsinki Declaration and its later amendments as revised in 2013 and confirmed to the CONSORT 2010 checklist guidelines for reporting the randomized clinical trial. Informed written parental consent was obtained from all subjects prior to study.