Overview

This trial is active, not recruiting.

Conditions dense deposit disease, membranoproliferative glomerulonephritis
Treatment eculizumab
Phase phase 1
Target C5
Sponsor Columbia University
Collaborator Alexion Pharmaceuticals
Start date August 2010
End date December 2015
Trial size 6 participants
Trial identifier NCT01221181, AAAF2403

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Eculizumab 900 mg IV one a week for 4 weeks, 1200 mg IV week 5, then 1200 mg IV every 2 weeks through week 53.
eculizumab Eculizumab (Soliris®)
900 mg IV once a week x 4 weeks, 1200 mg IV week 5, then 1200 mg IV every 2 weeks through week 53. Patients will be observed for 60 minutes after the first 5 infusions, then 30 minutes after all subsequent infusions. Patients will not be allowed to take other immunomodulatory therapies during the study period but will continue on their other non-immunomodulatory therapies (e.g. ACE inhibitors, -statins, aspirin) without modifications unless clinically indicated. All patients, if unvaccinated, will be given N. meningitidis vaccine at least two weeks prior to first eculizumab exposure. All female patients of childbearing potential will be asked to use adequate contraception methods during treatment and up to 5 months following discontinuation of eculizumab treatment.

Primary Outcomes

Measure
Number of subjects with complete remission of proteinuria
time frame: Up to 1 year after therapy

Secondary Outcomes

Measure
Change in proteinuria level
time frame: Up to 1 year after therapy

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: - Adult patients with biopsy proven DDD or C3 nephropathy, at least 18 years of age - 24-hour urine protein > 1000 mg/day, urine protein:creatinine ratio > 1.0, or acute renal failure (defined as > 50% increase in serum creatinine from baseline) - Willing and able to sign informed consent - Patients of childbearing age must agree to use birth control - Patients must be willing to be vaccinated against meningococcal disease or have documentation of previous vaccination against meningococcal disease Exclusion Criteria: - Patients under 18 years of age - Patients unable to sign informed consent - Patients having received rituximab or another monoclonal antibody within 6 months of the trial - Patients currently taking and unable to discontinue other immunomodulatory therapies (e.g. cyclosporine, high-dose steroids, mycophenolate mofetil) unless these other therapies are indicated for prophylaxis against transplant rejection (e.g. stable doses of mycophenolate mofetil and/or calcineurin inhibitor). Patients on chronic steroid therapy who are unable to taper down to <10 mg/day will be excluded. - Patients of childbearing age who refuse to use birth control - Patients with a baseline estimated GFR less than 30 ml/min/1.73m2 - Patients with other renal diseases (e.g. diabetic nephropathy, renal vascular disease) that would interfere with interpretation of the study. - Patients with comorbid conditions that would interfere with completion of the trial (malignancies, congestive heart failure (CHF), recent myocardial infarction). - Patients with known contraindications to the use of eculizumab, including refusal to receive N. meningitidis vaccine prior to therapy

Additional Information

Official title Eculizumab Therapy for Dense Deposit Disease and C3 Nephropathy
Principal investigator Gerald B Appel, MD
Description 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% of children, progressed to end stage renal disease (ESRD) over a mean follow-up of over 5 years. Second, as there are no large clinical trials to guide specific interventions for DDD and the role of immunomodulatory therapies still remains controversial, many nephrologists (including those at our center) advocate using immunomodulatory therapy only in selected adult patients. Immunomodulatory therapies not specifically targeted to DDD, such as corticosteroids, cyclophosphamide, and calcineurin inhibitors, have either been unsuccessful or not studied in a meaningful number of patients to warrant routine use. However, as the principal defect underlying DDD is excessive activation of the alternative complement pathway, with deposition of complement components in the glomerular basement membrane, a therapy that directly targets the alternative complement pathway may prove particularly beneficial for this disease. Eculizumab is a humanized monoclonal antibody that binds with high affinity to C5. The drug is FDA-approved for the treatment of paroxysmal nocturnal hemoglobinuria (in which mutations of complement regulatory proteins on hematopoietic cells lead to alternative complement pathway-mediated hemolysis). It is currently being studied for use in atypical hemolytic uremic syndrome, a rare disease marked by diffuse microthromboses related to activation of the alternate complement system. Eculizumab prevents cleavage of C5, thereby precluding formation of C5a, which has been implicated in glomerular inflammation in animal models of DDD. Moreover, by inhibiting the activation of C5, it prevents formation of the membrane attack complex C5-9. Speculatively, this drug could provide effective, targeted therapy for patients with DDD. Eculizumab was studied unsuccessfully in the past in patients with membranous nephropathy, a disease in which the alternate complement pathway is not over-activated. Despite the negative findings of this study, experience with the medication was gained at Columbia University Medical Center; in fact, we were one of the largest recruiting sites for this placebo controlled randomized blinded trial. The primary end point is complete remission, defined as remission of proteinuria to <500 mg/day with normal renal function. 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). Other secondary endpoints will be based on histologic parameters from renal biopsies performed after 1 year of therapy and compared to pre-treatment (baseline) biopsies; these include change in intensity of C3 staining on immunofluorescence, change in percentage of non-affected glomeruli, change in percentage of interstitial fibrosis and tubular atrophy, and changes in electron dense deposits by electron microscopy. No response will be defined as failure to meet criteria for either complete or partial remission, including patients with unremitting proteinuria, progressive chronic kidney disease, or progression to ESRD.
Trial information was received from ClinicalTrials.gov and was last updated in February 2014.
Information provided to ClinicalTrials.gov by Columbia University.