Rituximab or Cyclophosphamide Combined With Steroids in Idiopathic Membranous Nephropathy

Clinical Study of Rituximab or Cyclophosphamide Combined With Steroids in the Treatment of Idiopathic Membranous Nephropathy

This wasa prospective, multicenter, randomized, controlled trial. Patients with idiopathic membranous nephropathy (IMN) were randomly divided into intervention or control group. Intervention group was given rituximab combined with steroid in induction therapy. After 6 months, patients in the rituximab treatment group who had decreased 24h urinary protein by >25% but did not achieve CR were given rituximab maintenance therapy. Patients in control group were treated with cyclophosphamide combined with prednisolone.The response rate at 24 months (including the proportion of participants with complete and partial responses at 24 months after enrollment) was measured.

Study design A randomized, controlled, multicenter clinical study Outcomes Primary objective To evaluate the efficacy of rituximab or cyclophosphamide combined with steroids in the treatment of idiopathic membranous nephropathy Secondary Objectives The safety of rituximab or cyclophosphamide combined with steroids in idiopathic membranous nephropathy; Primary outcome The response rate at 24 months (including the proportion of participants with complete and partial responses at 24 months after enrollment); Secondary outcomes Response rates at 6 and 12 months (including the proportion of participants with complete response, near-complete response, and partial response at 6 and 12 months after enrollment); The proportion of patients without recurrence at 12 months and 24 months; The median recurrence time; Recurrence frequency; Cumulative dose of glucocorticoid; CD19+ cell count, anti-PLA2R antibody expression level; Incidence of adverse events; Study population 72 patients,male or female, with idiopathic membranous nephropathy (IMN), 36 in each arm. Description of the study intervention Intervention group: rituximab combined with steroid treatment group: 36 cases. The patients were pretreated with diphenhydramine and dexamethasone 30-60 minutes before rituximab infusion. Induction therapy: Rituximab iv infusion 1g, d1, d15, additional glucocorticoid treatment, oral prednisolone, initial dose 0.5mg/(KGD), once a day, after 8 weeks of treatment, reduced by 5mg every 2-4 weeks, until 0.25mg/kg, this dose was maintained for 8 weeks, then reduced by 2.5mg every 2-4 weeks, until drug withdrawal, The course of treatment was about 24 weeks; - Maintenance therapy after 6 months: Patients who achieved CR did not need maintenance therapy; Patients whose 24-hour proteinuria decreased by >25% but did not achieve CR were given an additional course of rituximab 1g, D1, D15 (independent of CD19+ cell count). Patients whose 24-hour proteinuria decreased less than 25% did not need to continue drug treatment, and were considered as treatment failure and withdrawn from the trial. Control group: Treated with Italian protocol, namely cyclophosphamide-steroid alternating cycle treatment,36 cases. - Treatment regimen: Methylprednisolone 0.5-1.0 g/d was given intravenously for the first 3 days of month 1, 3, and 5, followed by oral prednisone 0.5mg/(kg·d) for 27 days, and cyclophosphamide 2.0mg/(kg·d) for 30 days at month 2, 4, and 6. -Maintenance therapy after 6 months: Patients who achieved CR or whose 24h urinary protein decreased by >25% but did not achieve CR did not need maintenance treatment, and were followed up. Patients with 24h proteinuria decreased less than 25% did not need to continue to use drugs, and were considered as treatment failure and withdrawn from the trial. Duration of study: The entire clinical study duration was 36 months from the date of program initiation. Duration of visits: Long-term follow-up

Induction therapy: Rituximab iv infusion 1g, d1, d15, additional glucocorticoid treatment, oral methylprednisolone, initial dose 0.5mg/(KGD), once a day, after 8 weeks of treatment, reduced by 5mg every 2~4 weeks, until 0.25mg/kg, this dose was maintained for 8 weeks, then reduced by 2.5mg every 2~4 weeks, until drug withdrawal, The course of treatment was about 24 weeks; Maintenance therapy after 6 months Patients who achieved CR did not need maintenance therapy; Patients whose 24-hour proteinuria decreased by >25% but did not achieve CR were given an additional course of rituximab 1g, D1, D15 (independent of CD19+ cell count). Patients whose 24-hour proteinuria decreased less than 25% did not need to continue drug treatment, and were considered as treatment failure and withdrawn from the trial.

Control group (treated with Italian protocol, namely cyclophosphamide-steroid alternating cycle treatment) : - Treatment regimen: Methylprednisolone 0.5-1.0 g/d was given intravenously for the first 3 days of month 1, 3, and 5, followed by oral prednisone 0.5mg/(kg·d) for 27 days, and cyclophosphamide 2.0mg/(kg·d) for 30 days at month 2, 4, and 6. -Maintenance therapy after 6 months: Patients who achieved CR or whose 24h urinary protein decreased by >25% but did not achieve CR did not need maintenance treatment, and were followed up. Patients with 24h proteinuria decreased less than 25% did not need to continue to use drugs, and were considered as treatment failure and withdrawn from the trial.

including the proportion of participants with complete and partial responses at 24 months after enrollment

Including the proportion of participants with complete response, near-complete response, and partial response at 6 and 12 months after enrollment

Inclusion Criteria: Men and women aged 18-75 years; Patients diagnosed as idiopathic membranous nephropathy (IMN) by renal biopsy within 24 months before enrollment; (3) Proteinuria > 3.5g/d for 3 consecutive days (once a week for 3 consecutive weeks); 4, serum albumin < 35 g/L; 5, assess glomerular filtration rate (eGFR) ≥30ml/min/1.73m2(calculated according to CKD-EPI formula); 6, ACEI or ARB treatment for at least 2 months, blood pressure <140/90 MMHG; 7, if female, must be postmenopausal or postoperative infertility or use of medical contraception (considering the potential risk of thromboembolism in patients with kidney disease); 8, the subject voluntarily signed the informed consent; Exclusion Criteria: Patients with type 1 diabetes or type 2 diabetes and diabetic nephropathy; Patients with secondary membranous nephropathy and any active infections (such as hepatitis B and C, systemic lupus erythematosus, drug therapy, malignancy, and other secondary causes, should be tested for HIV, hepatitis B, and C before enrollment); Previous treatment with rituximab, steroids, alkylating agents, calcineurin inhibitors, synthetic ACTH, mycophenolate mofetil (MMF), and azathioprine; Receipt of any other study medication (within the last month); Allergies or a history of allergies to any known interventional drug or any of its components (including excipients); Resistance to rituximab or cyclophosphamide; Presence of active infection; A history of immunodeficiency, including other acquired or congenital immunodeficiency diseases, or organ transplantation; Pregnancy or lactation; 10, a history of mental illness; 11, laboratory tests meeting the following criteria need to be excluded: （1） Hemoglobin <80g/L; （2） Platelet < 80 x 109/ L; （3） Neutrophil < 1.0×109/ L; （4） Aspartate aminotransferase (AST) or amino acid aminotransferase (ALT) >2.5× upper limit of normal except in relation to the primary disease; 12. Any patient judged by the investigator to be ineligible for enrollment in the trial.

Ronco P, Debiec H. Pathophysiological advances in membranous nephropathy: time for a shift in patient's care. Lancet. 2015 May 16;385(9981):1983-92. doi: 10.1016/S0140-6736(15)60731-0.

Polanco N, Gutierrez E, Covarsi A, Ariza F, Carreno A, Vigil A, Baltar J, Fernandez-Fresnedo G, Martin C, Pons S, Lorenzo D, Bernis C, Arrizabalaga P, Fernandez-Juarez G, Barrio V, Sierra M, Castellanos I, Espinosa M, Rivera F, Oliet A, Fernandez-Vega F, Praga M; Grupo de Estudio de las Enfermedades Glomerulares de la Sociedad Espanola de Nefrologia. Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. J Am Soc Nephrol. 2010 Apr;21(4):697-704. doi: 10.1681/ASN.2009080861. Epub 2010 Jan 28.

Kanigicherla DA, Short CD, Roberts SA, Hamilton P, Nikam M, Harris S, Brenchley PE, Venning MC. Long-term outcomes of persistent disease and relapse in primary membranous nephropathy. Nephrol Dial Transplant. 2016 Dec;31(12):2108-2114. doi: 10.1093/ndt/gfv435. Epub 2016 Jan 13.

Ponticelli C, Zucchelli P, Imbasciati E, Cagnoli L, Pozzi C, Passerini P, Grassi C, Limido D, Pasquali S, Volpini T, et al. Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med. 1984 Apr 12;310(15):946-50. doi: 10.1056/NEJM198404123101503.

Ponticelli C, Zucchelli P, Passerini P, Cagnoli L, Cesana B, Pozzi C, Pasquali S, Imbasciati E, Grassi C, Redaelli B, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med. 1989 Jan 5;320(1):8-13. doi: 10.1056/NEJM198901053200102.

Ponticelli C, Altieri P, Scolari F, Passerini P, Roccatello D, Cesana B, Melis P, Valzorio B, Sasdelli M, Pasquali S, Pozzi C, Piccoli G, Lupo A, Segagni S, Antonucci F, Dugo M, Minari M, Scalia A, Pedrini L, Pisano G, Grassi C, Farina M, Bellazzi R. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol. 1998 Mar;9(3):444-50. doi: 10.1681/ASN.V93444.

Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009 Jul 2;361(1):11-21. doi: 10.1056/NEJMoa0810457.