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Clinical Research
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Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial

Francesco Scolari, Elisa Delbarba, Domenico Santoro, Loreto Gesualdo, Antonello Pani, Nadia Dallera, Laila-Yasmin Mani, Marisa Santostefano, Sandro Feriozzi, Marco Quaglia, Giuliano Boscutti, Angelo Ferrantelli, Carmelita Marcantoni, Patrizia Passerini, Riccardo Magistroni, Federico Alberici, Gian Marco Ghiggeri, Claudio Ponticelli, Pietro Ravani and for the RI-CYCLO Investigators
JASN April 2021, 32 (4) 972-982; DOI: https://doi.org/10.1681/ASN.2020071091
Francesco Scolari
1Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
2Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili of Brescia, Brescia, Italy
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Elisa Delbarba
2Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili of Brescia, Brescia, Italy
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Domenico Santoro
3Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
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Loreto Gesualdo
4Nephrology Unit, Department of Emergency and Transplant Organs, University Aldo Moro of Bari, Bari, Italy
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Antonello Pani
5Division of Nephrology and Dialysis, G. Brotzu Hospital, Cagliari, Italy
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Nadia Dallera
6Nephrology Unit, Montichiari Hospital, ASST Spedali Civili of Brescia, Brescia, Italy
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Laila-Yasmin Mani
7Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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Marisa Santostefano
8Division of Nephrology, Dialysis and Hypertension, Policlinico S.Orsola-Malpighi Hospital, Bologna, Italy
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Sandro Feriozzi
9Division of Nephrology, Belcolle Hospital, Viterbo, Italy
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Marco Quaglia
10Division of Nephrology, University of Piemonte Orientale, Novara, Italy
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Giuliano Boscutti
11Division of Nephrology, University Hospital of Udine, Udine, Italy
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Angelo Ferrantelli
12Division of Nephrology, Cervello Hospital, Palermo, Italy
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Carmelita Marcantoni
13Division of Nephrology, Policlinico di Catania Hospital, Catania, Italy
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Patrizia Passerini
14Division of Nephrology, Policlinico Hospital, Milano, Italy
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Riccardo Magistroni
15Division of Nephrology, Policlinico of Modena Hospital, Modena, Italy
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Federico Alberici
1Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
2Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili of Brescia, Brescia, Italy
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Gian Marco Ghiggeri
16Division of Nephrology, Dialysis and Transplantation, Scientific Institute for Research and Health Care, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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Claudio Ponticelli
17Independent Researcher, Past Director of the Division of Nephrology of the Policlinico Hospital, Milano, Italy
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Pietro Ravani
18Department of Medicine, University of Calgary, Calgary, Alberta, Canada
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Significance Statement

A cyclic regimen of corticosteroid and cyclophosphamide is the first-line therapy for membranous nephropathy. Rituximab is superior to conservative treatment and noninferior to cyclosporine in inducing remission; it also may have a more favorable safety profile compared with cyclic therapy, but a head-to-head comparison of rituximab versus cyclic therapy is lacking. Using a multisite design, the authors designed a pilot randomized trial to obtain estimates of the effects of the two therapies and to assess the recruitment potential of a noninferiority trial. They found rituximab and cyclophosphamide may have comparable effects on disease remission and a similar short-term safety profile. These data suggest that, although rituximab may be a valid alternative to cyclic therapy for patients with membranous nephropathy, a head-to-head pragmatic comparison would require a large, global, noninferiority trial.

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

  • membranous nephropathy
  • glomerulonephritis
  • nephrotic syndrome
  • Copyright © 2021 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 32 (4)
Journal of the American Society of Nephrology
Vol. 32, Issue 4
April 2021
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Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial
Francesco Scolari, Elisa Delbarba, Domenico Santoro, Loreto Gesualdo, Antonello Pani, Nadia Dallera, Laila-Yasmin Mani, Marisa Santostefano, Sandro Feriozzi, Marco Quaglia, Giuliano Boscutti, Angelo Ferrantelli, Carmelita Marcantoni, Patrizia Passerini, Riccardo Magistroni, Federico Alberici, Gian Marco Ghiggeri, Claudio Ponticelli, Pietro Ravani, for the RI-CYCLO Investigators
JASN Apr 2021, 32 (4) 972-982; DOI: 10.1681/ASN.2020071091

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Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial
Francesco Scolari, Elisa Delbarba, Domenico Santoro, Loreto Gesualdo, Antonello Pani, Nadia Dallera, Laila-Yasmin Mani, Marisa Santostefano, Sandro Feriozzi, Marco Quaglia, Giuliano Boscutti, Angelo Ferrantelli, Carmelita Marcantoni, Patrizia Passerini, Riccardo Magistroni, Federico Alberici, Gian Marco Ghiggeri, Claudio Ponticelli, Pietro Ravani, for the RI-CYCLO Investigators
JASN Apr 2021, 32 (4) 972-982; DOI: 10.1681/ASN.2020071091
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  • glomerulonephritis
  • nephrotic syndrome

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