Membranous NephropathyPhase 2/3NCT00425217
Rituximab in Membranous Nephropathy
A Phase 2/3 study testing Rituximab in people with Membranous Nephropathy, run by Mayo Clinic at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Membranous Nephropathy
- What is being tested?
- Rituximab
- How many people
- 15 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2004to Apr 2007
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Conditions
- Membranous Nephropathy
- Being tested
- Rituximab
- Medical subject headings
- Glomerulonephritis, Membranous
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
1. Change from baseline in proteinuria at six and twelve months following treatment
Toxicity/Safety
PK/bioavailability
Secondary outcomes (4)
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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jan 2007 (estimated)
- Study startAug 2004
- Primary completionApr 2007
- Study completionApr 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Membranous NephropathyStudies of the same condition, open and under way.
- More trials run by Mayo ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mayo Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- Genentech, Inc.
- Investigators
- Fernando C. Fervenza, M.D., Ph.D., Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00425217
- Sponsor's protocol ID
- IRB 627-04
- Status last verified
- Feb 2011
- First submitted
- 19 Jan 2007
- Last updated
- 25 Feb 2011
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Feb 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Use of Rituximab in the Treatment of Idiopathic Membranous Nephropathy
- ClinicalTrials.gov ID
- NCT00425217
- Acronym / sponsor ID
- IRB 627-04
- Conditions
- Membranous Nephropathy
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- Mayo ClinicUniversity, hospital or other
- Collaborators
- Genentech, Inc.
- Study start
- Aug 2004
- Primary completion
- Apr 2007 (actual)
- Study completion
- Apr 2007 (actual)
- First posted
- 22 Jan 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Rituximab | Drug | – |
Primary outcome
1. Change from baseline in proteinuria at six and twelve months following treatment
Toxicity/Safety
PK/bioavailability
4 secondary outcomes
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2011.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Fernando C. Fervenza, M.D., Ph.D. principal investigator
Mayo Clinic
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Rituximab in people with Membranous Nephropathy, run by Mayo Clinic at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Feb 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
1. Change from baseline in proteinuria at six and twelve months following treatment. The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2011.