Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy

Summary

Idiopathic Membranous nephropathy (IMN) is an auto-immune glomerular disease. Recent studies suggest that circulating auto-antibodies against the podocyte surface antigens phospholipase A2 receptor1 (PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A) cause the disease in the majority of the patients. Additional autoantibodies, directed to podocyte neo-expressed cytoplasm proteins have been described, including aldose reductase (AR), Mn-superoxide dismutase (SOD2) and alpha-enolase (alpha-ENO).

The commonest presentation of IMN is nephrotic syndrome. Data from placebo arms of interventional studies show that 30-40% of the untreated patients with persistent nephrotic syndrome (NS) progress to end-stage renal disease (ESRD).

The best-validated treatment regimen of IMN is combination therapy with steroids and cyclophosphamide, capable to induce remission of protenuria in two-third of the patients.

Despite this evidence of efficacy, there are concerns about the use of cyclophosphamide, since it may be associated with adverse events, including bone marrow suppression, gonadal toxicity, infections and oncogenic effects. Thus, the availability of alternative therapies highly effective but with a greater safety profile is desirable.

Given the key role of IgG antibodies in IMN, B cell depletion may favourably impact the glomerular disease. The anti-CD20 monoclonal antibody Rituximab is a selective B cell depleting agent. There is evidence that Rituximab is effective in the treatment of other diseases in which B cells play a key role, such as ANCA-related vasculitis. Observational studies in IMN provided encouraging data; in addition, the drug seems well tolerated.

Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized clinical trials are missing.

The investigators propose this study in order to test, in a randomized controlled trial, the hypothesis that Rituximab is more effective than cyclical steroid/alkylating-agent therapy in inducing remission in patients with IMN and NS undergoing the initial treatment. In addition, the levels of the above-mentioned pathogenetic autoantibodies will be measured at baseline and during treatment. Finally, the study will compare the safety profile of steroid plus cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events

Conditions

• Glomerulonephritis, Membranous

Interventions

DRUG

Rituximab

Rituximab,1 g IV, day 1 and day 15

DRUG

Methylprednisolone

Methylprednisolone 1 g IV daily for 3 doses, then oral methylprednisolone (0.4 mg/kg/day) or oral prednisone (0.5mg/kg/day) for 27 days during Month 1, 3, 5.

DRUG

Cyclophosphamide

Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day) for 30 days

Sponsors & Collaborators

• University of Bari

  collaborator OTHER

• Azienda Ospedaliera Brotzu

  collaborator OTHER

• University of Messina

  collaborator OTHER

• University of Milan

  collaborator OTHER

• Universita di Verona

  collaborator OTHER

• University of Chieti

  collaborator OTHER

• University of Bologna

  collaborator OTHER

• Azienda Sanitaria Locale Roma E

  collaborator OTHER

• IRCCS Azienda Ospedaliero-Universitaria di Bologna

  collaborator OTHER

• Regione Piemonte

  collaborator OTHER

• University of Modena and Reggio Emilia

  collaborator OTHER

• University of Pisa

  collaborator OTHER

• University of Milano Bicocca

  collaborator OTHER

• Humanitas Hospital, Italy

  collaborator OTHER

• Azienda Ospedaliera Universitaria Policlinico

  collaborator OTHER

• Fondazione Salvatore Maugeri

  collaborator OTHER

• University of Bern

  collaborator OTHER

• University of Alberta

  collaborator OTHER

• Istituto Giannina Gaslini

  collaborator OTHER

• Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

  lead OTHER

Principal Investigators

• FRANCESCO SCOLARI, MD · Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2012-01-31

Primary Completion

2019-12-31

Completion

2019-12-31

Countries

• Italy

Study Locations