Francesco Scolari1,2, Elisa Delbarba2, Domenico Santoro3, Loreto Gesualdo4, Antonello Pani5, Nadia Dallera6, Laila-Yasmin Mani7, Marisa Santostefano8, Sandro Feriozzi9, Marco Quaglia10, Giuliano Boscutti11, Angelo Ferrantelli12, Carmelita Marcantoni13, Patrizia Passerini14, Riccardo Magistroni15, Federico Alberici16,2, Gian Marco Ghiggeri17, Claudio Ponticelli18, Pietro Ravani19. 1. Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy francesco.scolari@unibs.it. 2. Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili of Brescia, Brescia, Italy. 3. Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. 4. Nephrology Unit, Department of Emergency and Transplant Organs, University Aldo Moro of Bari, Bari, Italy. 5. Division of Nephrology and Dialysis, G. Brotzu Hospital, Cagliari, Italy. 6. Nephrology Unit, Montichiari Hospital, ASST Spedali Civili of Brescia, Brescia, Italy. 7. Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 8. Division of Nephrology, Dialysis and Hypertension, Policlinico S.Orsola-Malpighi Hospital, Bologna, Italy. 9. Division of Nephrology, Belcolle Hospital, Viterbo, Italy. 10. Division of Nephrology, University of Piemonte Orientale, Novara, Italy. 11. Division of Nephrology, University Hospital of Udine, Udine, Italy. 12. Division of Nephrology, Cervello Hospital, Palermo, Italy. 13. Division of Nephrology, Policlinico di Catania Hospital, Catania, Italy. 14. Division of Nephrology, Policlinico Hospital, Milano, Italy. 15. Division of Nephrology, Policlinico of Modena Hospital, Modena, Italy. 16. Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. 17. Division of Nephrology, Dialysis and Transplantation, Scientific Institute for Research and Health Care, IRCCS Istituto Giannina Gaslini, Genoa, Italy. 18. Independent Researcher, Past Director of the Division of Nephrology of the Policlinico Hospital, Milano, Italy. 19. Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
Abstract
BACKGROUND: A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. METHODS: We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. RESULTS: At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. CONCLUSIONS: This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.
BACKGROUND: A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. METHODS: We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. RESULTS: At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. CONCLUSIONS: This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.
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