Different Immunosuppressive Treatment in iMN

Official title

Different Immunosuppressive Treatment in Idiopathic Membranous Nephropathy: a Prospective Cohort

Overview

The primary objective of this study is to compare the 24 month remission of different immunosuppressive therapies in the treatment of idiopathic membranous nephropathy (iMN)

Detailed description

To date, the first-line immunosuppressive immunosuppressive therapy of iMN includes corticosteroids combined with cyclophosphamide or rituximab (RTX). In recent randomized trials (MENTOR, GEMRITUX), the long-term remission rate of RTX is about 60%, which is similar to the remission rate of cyclophosphamide combined with corticosteroids in early studies. But there is only one published randomized trial (STARMEN) comparing the efficacy of the two protocols head-to-head. In STRAMEN trial, the long-term remission rate of cyclophosphamide+corticosteroids group was 83%, which was significantly higher than the that (58%) of the tacrolimus-RTX group. But in STRAMEN trial, only one single dose of RTX was given which might influence the efficacy of the tacrolimus-RTX arm. Therefore, head-to-head comparison of RTX (more than one dose) and cyclophosphamide+corticosteroid is needed. The optimal dose of RTX in the treatment of iMN is unclear. In MENTOR trial, RTX was given 1g on D1 and D15, and the rate of complete remission at 6 month was 0, so RTX was repeated at 6 month. Based on the experience of our center, most patients need at least one repeated dose of RTX at 6 month.

Based on the previous rationale, the investigators designed this study to compare the efficacy of cyclophosphamide plus corticosteroids with RTX in the treatment of iMN.

Interventions

• Drug Prednisone
  1mg/kg/d p.o.which will be tapered after 2 months and discontinued over a 6-12 month period.
• Drug Cyclophosphamide
  1-2mg/kg/d p.o. with a target accumulated dose of 12g.
• Drug Rituximab
  1000mg I.V. on D1 and at 6 month. After 6 month, in patients with response but not complete remission, Rituximab could be stopped or repeated with a 6 month-interval (12 month, 18 month, 24 month) until complete remission. Rituximab 1000mg I.V. will be repeated on the 15th day of each Rituximab infusion if CD19+ B cell count\>5/ul.

Primary outcome measures

• complete or partial remission on 24 month [Time frame: 24 months]

Secondary outcome measures (9)

• complete or partial remission on 6, 12 and 18 month [Time frame: 6, 12 and 18 months]
• complete remission on 6, 12, 18 and 24 month [Time frame: 6, 12, 18 and 24 months]
• time to complete or partial remission [Time frame: from date of treatment until the date of first documented remission, up to 24 months]
• change of estimated glomerular filtration rate (eGFR) [Time frame: 24 months]
• serum creatinine increase ≥50 percent from baseline [Time frame: 24 months]
• rate of relapse [Time frame: 12, 18, 24 months]
• anti-PLA2R levels [Time frame: baseline and 3, 6, 9, 12, 18, 24 months]
• CD19+ B cell count [Time frame: baseline and 3, 6, 9, 12, 18, 24 months]
• Adverse events [Time frame: through the study completion until 24 months]

Eligibility criteria

Inclusion criteria

• idiopathic membranous nephropathy
• Female, must be post-menopausal, sterile or have effective contraception
• must be off steroid or mycophenolate mofetil for >1 month and alkylating agents for or RTX> 6 months
• Angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for ≥ 3 months with controlled blood pressure prior to beginning of immunosuppressive therapy or if patients are intolerant to ACEI/ARB.
• proteinuria ≥4g/24h and decreased ≤ 50% from baseline

Exclusion criteria

• presence of active infection or a secondary cause of membranous nephropathy
• proteinuria associated with diabetic nephropathy
• pregnancy or breast feeding
• history of resistance to rituximab or alkylating agents or corticosteroid
• Patients who previously achieved remission after treatment of rituximab or alkylating agents but relapsed off rituximab or alkylating agents after 6 months are eligible.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking Union Medical College Hospital — Beijing

Publications

• 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 PMID 20110379
• Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A, Wakselman L, Michel PA, Mihout F, Dussol B, Matignon M, Mousson C, Simon T, Ronco P; GEMRITUX Study Group. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up. J Am Soc Nephrol. 2017 Jan;28(1):348-358. doi: 10.1681/ASN.2016040449. Epub 2016 Jun 27. PMID 27352623
• Fervenza FC, Appel GB, Barbour SJ, Rovin BH, Lafayette RA, Aslam N, Jefferson JA, Gipson PE, Rizk DV, Sedor JR, Simon JF, McCarthy ET, Brenchley P, Sethi S, Avila-Casado C, Beanlands H, Lieske JC, Philibert D, Li T, Thomas LF, Green DF, Juncos LA, Beara-Lasic L, Blumenthal SS, Sussman AN, Erickson SB, Hladunewich M, Canetta PA, Hebert LA, Leung N, Radhakrishnan J, Reich HN, Parikh SV, Gipson DS, L PMID 31269364
• van den Brand JAJG, Ruggenenti P, Chianca A, Hofstra JM, Perna A, Ruggiero B, Wetzels JFM, Remuzzi G. Safety of Rituximab Compared with Steroids and Cyclophosphamide for Idiopathic Membranous Nephropathy. J Am Soc Nephrol. 2017 Sep;28(9):2729-2737. doi: 10.1681/ASN.2016091022. Epub 2017 May 9. PMID 28487395
• Fernandez-Juarez G, Rojas-Rivera J, Logt AV, Justino J, Sevillano A, Caravaca-Fontan F, Avila A, Rabasco C, Cabello V, Varela A, Diez M, Martin-Reyes G, Diezhandino MG, Quintana LF, Agraz I, Gomez-Martino JR, Cao M, Rodriguez-Moreno A, Rivas B, Galeano C, Bonet J, Romera A, Shabaka A, Plaisier E, Espinosa M, Egido J, Segarra A, Lambeau G, Ronco P, Wetzels J, Praga M; STARMEN Investigators. The STA PMID 33166580
• Dahan K, Johannet C, Esteve E, Plaisier E, Debiec H, Ronco P. Retreatment with rituximab for membranous nephropathy with persistently elevated titers of anti-phospholipase A2 receptor antibody. Kidney Int. 2019 Jan;95(1):233-234. doi: 10.1016/j.kint.2018.08.045. No abstract available. PMID 30606419

Identifiers

NCT: NCT04745728 · iMN cohort

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗