Clinical Trial: Rituximab in the Treatment of Idiopathic Membranous Nephropathy

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Rituximab in the Treatment of Idiopathic Membranous Nephropathy

Brief Summary: Membranous glomerulopathy (MN) is still the most common glomerular disease associated with nephrotic proteinuria (NS). Up to 40% of patients reach end stage renal failure (ESRD), making MN the 2nd or 3rd most common cause of ESRD caused by a primary glomerulopathy. Current treatment options include corticosteroids, alkylating agents, and cyclosporin, but their use is controversial and the associated adverse effects and high cost temper their usage. Experimental data in MN suggests that B cell activation results in immunoglobulin deposition along the glomerular basement membrane causing injury to the membrane and subsequent proteinuria. Drugs that non-selectively inhibit B cells and, these pathogenic antibodies, are closely associated with improved outcomes. Based on the rationale that selective depletion of B cells in humans would prevent the production of ?nephrotoxic? immunoglobulins and subsequent renal injury we recently treated 15 patients with MN with rituximab 1g i.v. twice (day 1 and day 15). Baseline proteinuria of 13.0±5.5g/24h decreased to 9.1±7g, 9.7±8g and 6.5±6 g/24h at 3, 6, and 9 months, respectively (mean ± SD). Analysis of the pharmacokinetic data obtained from this study, however, suggests that in heavily nephrotic patients, rituximab dosed in this fashion results in patients being under-treated. The present study propose to test the hypothesis that rituximab, given in accordance to the standard lymphoma protocol (375mg/m2 x 4), will result in a more effective and profound depletion of B cells, a more complete suppression of pathogenic antibodies, and a higher remission rate of the NS while maintaining a favorable safety profile.

Detailed Summary:

a. Study Overview: Once a patient with idiopathic MN and proteinuria >5g/24h is identified and meets other entry criteria, he/she will receive a minimum of 4 months of non-immunosuppressive therapy aimed at maximizing Ang II blockade (run-in phase). The target blood pressure (<130 mmHg systolic BP >75% of the readings; but not <100 mmHg systolic) is chosen based on recent recommendations by the JNC VII.(38) 1) The first step will be the administration of an ARB. This is chosen because ARBs are as effective as ACEIs in blocking the AT1 mediated adverse effects of Ang II, while being better tolerated, with minimal cough or angioedema, and less hyperkalemia. Because this part of the study aims to maximize Ang II blockade, ARB dose will continue to be increased every 2 weeks until the maximum tolerated/FDA approved dose is achieved or until intolerable side effects occur (e.g. development of postural hypotension, light headed, hyperkalemia, etc). 2) Once ARB dose has been maximize and there are no observable side-effects, and/or blood pressure is not at target, a long acting ACEi will be added. ACEi dose will be increased every 2 weeks aiming to achieve maximum tolerated or maximum approved dosage. For patients whose blood pressure control is not at target additional medication will be added in the following order: 3) a loop diuretic, 4) a cardioselective &#946;-blocker, 5) a non-dihydropyridine calcium channel blocker (CCB), and 6) clonidine. The selection of these drugs adheres to the recommendation of the JNC VII.(38) The choice of a non-dihydropyridine CCB was made because of concerns that dihydropyridine-type CCB may obscure the anti-proteinuric effects of the above therapy. In order to further ensure that any potential adverse effect is minimized we have limited CCB to be used as a fifth agent, and to be used only when the combination of ARB/ACEi, diuretic, and &#946;-blocker have failed to reduce B
Sponsor: Mayo Clinic

Current Primary Outcome: Primary endpoint. [ Time Frame: 12 months ]

Original Primary Outcome: Primary endpoint.

Current Secondary Outcome:

  • Complete and partial remission rates at 6, 9, and 12 months [ Time Frame: 6, 9, and 12 months ]
  • Pharmacokinetics/bioavailability [ Time Frame: 12 months ]
  • Rate of decline in urinary protein [ Time Frame: 12 months ]
  • Frequency of relapse after CR [ Time Frame: 12 months ]
  • Toxicity [ Time Frame: 12 months ]


Original Secondary Outcome:

  • . Complete and partial remission rates at 6, 9, and 12 months
  • Pharmacokinetics/bioavailability
  • Rate of decline in urinary protein
  • Frequency of relapse after CR
  • Toxicity


Information By: Mayo Clinic

Dates:
Date Received: November 29, 2006
Date Started: October 2006
Date Completion:
Last Updated: October 23, 2015
Last Verified: October 2015