Rituximab in Membranous Nephropathy

February 23, 2011 updated by: Mayo Clinic

The Use of Rituximab in the Treatment of Idiopathic Membranous Nephropathy

Membranous glomerulopathy (MN) is a common immune-mediated glomerular disease and the leading cause of nephrotic syndrome in Caucasian adults. 1 Because of its frequency, it remains the second or third cause of end-stage renal disease caused by a primary glomerulonephritis. 2 At presentation, 70% to 80% of patients have the nephrotic syndrome. 1, 3, 4 Proteinuria greater than 2.0 grams per day is found in > 80% of patients at presentation, with greater than 10 grams found in as many as 30%. 5 The disease affects patients of all ages, but it is most often diagnosed in middle age with the peak incidence during the fourth and fifth decades of life. There is close to a two-to-one predominance of males to females diagnosed with the disease. Idiopathic MN affects all races. Current therapeutic options include corticosteroids alone or in combination with alkylating agents, cyclosporin A, and mycophenolate mofetil. The most widely recognized, and best-validated regimen is combination therapy with corticosteroids and an alkylating agent, but its use is associated with significant adverse effects. Recent meta-analysis confirmed that present day treatments are far from ideal 6 Thus, it should not come as a surprise that the outcome of MN has not substantially improved over the past 30 years, and up to 40% of patients still progress to end-stage renal failure. 7 Like in other glomerular diseases the amount of protein in the urine correlates well with long term prognosis. Thus, this parameter has been used in previous studies, and will be used in this study, as the primary indicator of effectiveness of therapy. We proposed to do a pilot study to test the hypothesis that selective B lymphocyte depletion will result in disappearance of pathogenic antibodies and induction of remission of the nephrotic syndrome in patients with idiopathic membranous nephropathy. Our population will be 10 adults. The study will be conducted between our Nephrology Divisions at Mayo Clinic Rochester, Jacksonville, and Scottsdale. We will enroll patients with a GFR 25 ml/min as estimated by creatinine clearance and proteinuria > 4g/24h, while receiving an ACEI or ARB and with BP controlled of < 130/80 mmHg. Patients will receive Rituximab 1g on Day 1 and 15. Patients followed for 1 years following completion of treatment. The primary outcome will be change in urinary protein excretion at 6 months. Secondary outcomes will be changes in serum albumin, serum lipid?s profile, the number of partial remissions, time to remission, and incidence of relapses. We will also perform a pharmacokinetic study to evaluate the effect of proteinuria on the bio-availability and effects of the drug.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

There is convincing evidence from both experimental and human studies that MN is mediated by the deposition of IgG antibodies in the subepithelial aspect of the GBM. More debatable, is the mechanism(s) of deposition of these antibodies in that location. Given the key role of IgG antibodies in MN, it is reasonable to postulate that suppression of antibody production by depleting B cells and/or plasma cells may improve or even resolve the glomerular pathology as reflected by a reduction in proteinuria. There is evidence that this strategy is effective in the treatment of other antibody-mediated diseases and preliminary studies in MN are promising. Data from animal studies suggest that immune deposition resulting from B cell activation promote injury to the glomerular filtering barrier and proteinuria.103 In humans, as discussed above, there is evidence that therapy directed against B cells, e.g. cyclophosphamide, is effective in MN. Cyclophosphamide has striking direct effects on B cell function, and suppresses the secretion of immunoglobulins.104 Thus, a case could be made for using an agent capable of depleting B cells, and therefore halting the production of nephrotoxic immunoglobulins. This approach could stop the pathogenic events at their initial stages and potentially result in resolution of the pathological process. The rationale for using such an approach can be further substantiated by the fact that Th2 pathway for antibody response is activated and that inhibition of B cells and of pathogenic antibodies is strictly associated with beneficial effects of immunosuppressive drugs in experimental MN.

This is a open-label Phase I/II pilot study. Patients will receive Rituximab at a total dose of 1g on Day 1 and Day 15 according to infusion guidelines. Patient experience complete clinical response (as per response criteria outlined below), AND Patient subsequently experiences clinical relapse, defined as return of proteinuria to 4 g/24h, and in whom CD20+ cell count have normalized, will receive a second course of Rituximab. Patients who relapse but who remain B cell depleted will not be retreated.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
15

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Patients must meet the following inclusion criteria to be eligible for study entry:

  • Membranous Nephropathy with diagnostic biopsy performed within the last 3 years. Renal biopsy slides and electron photomicrographs will be reviewed by study investigators, and must confirm a diagnosis of MN.
  • Age  18 years.
  • Proteinuria as measured via Uprot/UCr ratio > 4.0 on a spot sample of a 24-hour urine collection, despite ACE inhibitor / ARB treatment. The choice of urine protein/creatinine ratios is in accord with recently developed National Kidney Foundation Chronic Kidney Disease (NKF-CKD) guidelines.107 The NKF-CKD guidelines advocate urine protein/creatinine ratios as the preferred method for evaluation of urinary protein excretion in both adults and children.
  • Patients need to be treated with an ACEI and/or ARB, for at least 3 months prior to enrollment with adequately controlled blood pressure (BP <140/80 mm Hg in >75% of the readings).
  • Women must be post-menopausal, surgically sterile or practicing a medically approved method of contraception.
  • Patients with thromboembolic complications and/or clinical signs of NS that are not controlled with conventional medical treatment will enter the immunosuppressive portion of the protocol (Rituxan treatment) without the 3 months of ACE/ARB treatment (high risk patients).
  • Able and willing to give written informed consent and comply with the requirements of the study protocol
  • Adequate renal function as indicated by estimated GFR ≥ 25 ml/min per 1.73m2 and/or or serum creatinine <4.0 mg/dL in the presence of ACE inhibitor/ARB therapy. The GFR will be estimated using the 4 variable MDRD equation as published in the NKF-CKD guidelines. The same NKF-CKD guidelines also promote the use of estimated GFR (GFRest) values rather than serum creatinine levels or creatinine clearance measurements as the preferred non-invasive method of determining glomerular filtration rates.107 We have opted to use this approach rather than the much more expensive and more invasive techniques that employ clearance measurements of exogenous substances (such as inulin or iothalamate) since the likelihood of detecting significant changes in GFR in this short term study is remote - no matter which method is chosen. The inclusion of and/or serum creatinine <4.0 mg/dL is to cover possibility of incomplete 24-hour collection at time baseline creatinine clearance.)
  • Adequate liver function, as indicated by bilirubin, AST, and alkaline phosphatase levels (up to < 2.5 times the upper normal limit).
  • Negative serum pregnancy test (for women of child bearing age)
  • Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months (1 year) after completion of treatment or a period of 21 months for those undergoing retreatment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
1. Change from baseline in proteinuria at six and twelve months following treatment
Toxicity/Safety
PK/bioavailability

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Partial Remission at 6 months
Complete and Partial Remission at 6 months
Time to CR and time to CR or PR
Rates of decline in GFR and UP

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Mayo Clinic

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Genentech, Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 1, 2004

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 1, 2007

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 1, 2007

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 19, 2007

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 19, 2007

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 22, 2007

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 25, 2011

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 23, 2011

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2011

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • IRB 627-04

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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