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

• Status: Unknown status
• Trial end date: 2019-12-01
• Target enrollment: 0
• Participant gender: All

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

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Azienda Ospedaliera Spedali Civili di Brescia; Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
• Collaborators: Azienda Ospedaliera Brotzu; Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi; Azienda Ospedaliera Universitaria Policlinico; Azienda Sanitaria Locale Roma E; Fondazione Salvatore Maugeri; Humanitas Hospital, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna; Istituto Giannina Gaslini; Regione Piemonte; Universita di Verona; University of Alberta; University of Bari; University of Bern; University of Bologna; University of Chieti; University of Messina; University of Milan; University of Milano Bicocca; University of Modena and Reggio Emilia; University of Pisa
• Treatments: Cyclophosphamide; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Rituximab

Criteria

Inclusion Criteria:

1. Biopsy-proven diagnosis of idiopathic MN performed within the past 24 months

2. Proteinuria > 3.5 g/24h on three 24-hour urine collection (once a week for 3 weeks)

3. Estimated GFR (MDRD formula) ≥ 30ml/min/1.73m2 under ACEI/ARB therapy

4. Post-menopausal females, or females surgically sterile or practicing a medically approved method of contraception (no birth-control pill)

5. Three months of ACEI and/or ARB therapy before treatment

6. Blood Pressure <130/80 mm Hg

7. HMG-CoA reductase inhibitor therapy

8. Patients remaining with proteinuria >3.5g/24h after 3 months of ACEI and/or ARB therapy and Blood Pressure <130/80 mm Hg may be randomized to RTX / cyclical corticosteroid/alkylating-agent therapy without the need of the run-in/conservative phase of the study.

Exclusion Criteria:

1. serum creatinine >2.5 mg/dl; Estimated GFR < 30 ml/min/1.73m2

2. previous treatment with Rituximab, Steroids, Alkylating Agents, Calcineurin Inhibitors, Synthetic ACTH, MMF, Azathioprine

3. Presence of active infection

4. Secondary cause of MN (e.g. hepatitis B, SLE, medications, malignancies). Testing for HIV, Hepatitis B and C should have occurred < 6 months prior to enrollment into the study

5. Type 1 or 2 diabetes mellitus

6. Pregnancy or nursing for safety reasons

7. Renal vein thrombosis documented prior to entry by renal US or CT scan