Eculizumab Therapy for Dense Deposit Disease and C3 Nephropathy

• ClinicalTrials.gov Identifier: NCT01221181
• Recruitment Status: Completed
• First Posted: October 14, 2010
• Results First Posted: February 19, 2019
• Last Update Posted: February 19, 2019
• Sponsor: Columbia University
• Collaborator: Alexion Pharmaceuticals
• Information provided by (Responsible Party): Gerald B. Appel, Columbia University

Study Description

Brief Summary:

This 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. The patients 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.

Condition or disease	Intervention/treatment	Phase
Dense Deposit Disease; Membranoproliferative Glomerulonephritis	Drug: Eculizumab	Phase 1

Detailed Description:

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 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 micro-thromboses related to activation of the alternative 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 the formation of the membrane attack complex C5-9. Speculatively, this drug could provide effective, targeted therapy for patients with DDD.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Eculizumab Therapy for Dense Deposit Disease and C3 Nephropathy
• Study Start Date: July 2010
• Actual Primary Completion Date: October 2011
• Actual Study Completion Date: October 2011

Arms and Interventions

Arm

Intervention/treatment

Experimental: Eculizumab; Patients will receive Eculizumab and 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. meningitides 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.

Drug: Eculizumab; Dosage/Frequency: 900 mg IV once a week for 4 weeks, 1200 mg IV week 5, then 1200 mg IV every 2 weeks through week 53.; Other Name: Eculizumab (Soliris®)

Outcome Measures

Primary Outcome Measures :

1. Number of Patients With Change in Proteinuria or Serum Creatinine Over Treatment Period [ Time Frame: One year ]
   This is designed to measure response to eculizumab through clinical and histological data, including a reduction in serum creatinine or in proteinuria, or histopathologic improvement. Any reduction in serum creatinine and/or proteinuria was included in our descriptive analysis.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 of 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. meningitides vaccine prior to therapy

Contacts and Locations

Locations

United States, New York

Columbia University Medical Center, Glomerular Center

New York, New York, United States, 10032

Columbia University Medical Center, Nephrology Clinical Research Center

New York, New York, United States, 10032

Sponsors and Collaborators

Columbia University

Alexion Pharmaceuticals

Investigators

• Principal Investigator: Gerald B Appel, MD; Columbia University

More Information

Additional Information:

Eculizumab for dense deposit disease and C3 glomerulonephritis 

Pathology after eculizumab in dense deposit disease and C3 glomerulonephritis 

Publications of Results:

Bomback AS, Smith RJ, Barile GR, Zhang Y, Heher EC, Herlitz L, Stokes MB, Markowitz GS, D'Agati VD, Canetta PA, Radhakrishnan J, Appel GB. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol. 2012 May;7(5):748-56. doi: 10.2215/CJN.12901211. Epub 2012 Mar 8.

• Responsible Party: Gerald B. Appel, Professor of Clinical Medicine, Nephrology, Columbia University
• ClinicalTrials.gov Identifier: NCT01221181
• Other Study ID Numbers: AAAF2403
• First Posted: October 14, 2010
• Results First Posted: February 19, 2019
• Last Update Posted: February 19, 2019
• Last Verified: February 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Gerald B. Appel, Columbia University:

Dense deposit disease; C3 nephropathy; Eculizumab

Additional relevant MeSH terms:

Kidney Diseases; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Urologic Diseases; Nephritis; Immune System Diseases; Eculizumab; Complement Inactivating Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs