Clinical Trial: Eculizumab Therapy for Dense Deposit Disease and C3 Nephropathy

Study Status: Withdrawn
Recruit Status: Unknown status
Study Type: Interventional

Official Title: Eculizumab Therapy for Dense Deposit Disease and C3 Nephropathy

Brief Summary:

This is an open label, non-blinded, proof of concept efficacy and safety study of eculizumab in patients with biopsy proven DDD or C3 nephropathy. The trial will consist of adult patients with these diseases who have > 1 gram of proteinuria or a decreased glomerular filtration rate (GFR), both predictors of a poor long-term outcome in many glomerular diseases. They will be treated with eculizumab for one year. The goals will be to determine whether treatment leads to an improvement in kidney function, defined by remissions of proteinuria and improvements in estimated GFR (measured by serum creatinine), and to improvement in histologic parameters, including percentage of non-affected glomeruli, interstitial fibrosis, intensity of C3 staining of immunofluorescence, and amount of electron dense deposits by electron microscopy.

All enrolled subjects will receive eculizumab treatment for one year. There will be 29 study visits over 53 weeks. The goal is to determine whether this treatment will improve kidney function, as evidenced by less protein in the urine and improved lab results.

An EXTENSION TREATMENT PHASE has been added. After completing the study, patients are followed with labs every four weeks as per standard of care. If labs suggest a relapse, they will be allowed to continue on therapy at the previous dosage until this drug receives FDA approval for this indication. Treatment intervals and dosage are identical to the original study.


Detailed Summary:

The purpose of the study is to evaluate the efficacy and safety of eculizumab in adult patients with dense deposit disease and C3 nephropathy.

Dense deposit disease (DDD), also called membranoproliferative glomerulonephritis (MPGN) type II, is a rare form of glomerulonephritis named because of the characteristic appearance of electron-dense material in the glomerular basement membrane observed on kidney biopsy. The principle immune defect in DDD is excessive activation of the alternative complement pathway, with deposition of complement components in the glomerular basement membrane. Hence, by immunofluorescence microscopy, there is heavy C3 deposited along the basement membrane. Some patients have been found to have deficiencies of Factor H or Factor I, inhibitors of C3 activation. Others have a C3 nephritic factor, an antibody that activates the alternative complement cascade. It has recently been recognized that C3 nephropathy, a rare glomerular disease with mesangial cell proliferation and C3 deposition by immunofluorescence microscopy, is associated with similar over-activation of the alternative complete cascade.

While DDD affects mostly children and young adults, in the series of 32 patients from Columbia with DDD whose biopsies were read from 1977-2007, 18 patients (56%) were older than 16 years of age at the time of diagnosis, and about 40% of patients were over 30 years old. The age division is important for two reasons. First, in the Columbia series, children appeared to have better clinical outcomes than adults. While 25.9% of all patients had a complete remission, there was a significant distinction between adults, of whom only 7.1% achieved complete remission, and children, of whom 46.1% achieved complete remission. Of the remaining patients who did not achieve remission, 42.9% of adults, compared to only 7.7
Sponsor: Columbia University

Current Primary Outcome: Number of subjects with complete remission of proteinuria [ Time Frame: Up to 1 year after therapy ]

The primary end point is complete remission, defined as remission of proteinuria to <500 mg/day with normal renal function.


Original Primary Outcome: Complete remission [ Time Frame: after 1 year of therapy ]

The primary end point is complete remission, defined as remission of proteinuria to <500 mg/day with normal renal function.


Current Secondary Outcome: Change in proteinuria level [ Time Frame: Up to 1 year after therapy ]

Partial remission, a secondary endpoint, will be defined as reduction in proteinuria by at least 50% and to <2 g/day with stable renal function (i.e. no more than a 20% increase in serum creatinine).


Original Secondary Outcome:

  • Partial remission [ Time Frame: after 1 year of therapy ]
    Partial remission, a secondary endpoint, will be defined as reduction in proteinuria by at least 50% and to <2 g/day with stable renal function (i.e. no more than a 20% increase in serum creatinine).
  • Improvement in histologic parameters [ Time Frame: after 1 year of therapy ]
    Improvement in histologic parameters, including percentage of non-affected glomeruli, interstitial fibrosis, intensity of C3 staining of immunoflourescence, and amount of electron dense deposits by electron microsopy.


Information By: Columbia University

Dates:
Date Received: October 13, 2010
Date Started: August 2010
Date Completion: December 2015
Last Updated: February 5, 2014
Last Verified: February 2014