Membranous NephropathyEarly Phase 1NCT00405340
Rituximab in the Treatment of Idiopathic Membranous Nephropathy
A Early Phase 1 study testing Rituximab in people with Membranous Nephropathy, run by Mayo Clinic at 1 site in United States.
Trial summary
Membranous glomerulopathy (MN) is still the most common glomerular disease associated with nephrotic proteinuria (NS). Up to 40% of patients reach end stage renal failure (ESRD), making MN the 2nd or 3rd most common cause of ESRD caused by a primary glomerulopathy. 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
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2006to Apr 2012
- Phase
- Early Phase 1
- 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
- Idiopathic MN with diagnostic biopsy performed within the past 24 months.
- Age > 18 years
- If female, must be post-menopausal, surgically sterile or practicing a medically approved method of contraception
- Patients need to be treated with an ACEI and/or ARB, for at least 4 months prior to rituximab treatment and have adequately controlled blood pressure (BP <130/75 mm Hg in >75% of the readings).
- Proteinuria as measured by urinary proteinuria / urinary creatinine > 5.0 on a spot sample aliquot from a 24-hour urine collection.
- Estimated GFR \≥ 30 ml/min/1.73m2 while taking ACEI/ARB therapy.
Trial locations and contacts
1 site in 1 country.
About this study
Membranous glomerulopathy (MN) is still the most common glomerular disease associated with nephrotic proteinuria (NS). Up to 40% of patients reach end stage renal failure (ESRD), making MN the 2nd or 3rd most common cause of ESRD caused by a primary glomerulopathy. Current treatment options include corticosteroids, alkylating agents, and cyclosporin, but their use is controversial and the associated adverse effects and high cost temper their usage. Experimental data in MN suggests that B cell activation results in immunoglobulin deposition along the glomerular basement membrane causing injury to the membrane and subsequent proteinuria. Drugs that non-selectively inhibit B cells and, these pathogenic antibodies, are closely associated with improved outcomes. Based on the rationale that selective depletion of B cells in humans would prevent the production of ?nephrotoxic? immunoglobulins and subsequent renal injury we recently treated 15 patients with MN with rituximab 1g i.v. twice (day 1 and day 15). Baseline proteinuria of 13.0±5.5g/24h decreased to 9.1±7g, 9.7±8g and 6.5±6 g/24h at 3, 6, and 9 months, respectively (mean ± SD). Analysis of the pharmacokinetic data obtained from this study, however, suggests that in heavily nephrotic patients, rituximab dosed in this fashion results in patients being under-treated. The present study propose to test the hypothesis that rituximab, given in accordance to the standard lymphoma protocol (375mg/m2 x 4), will result in a more effective and profound depletion of B cells, a more complete suppression of pathogenic antibodies, and a higher remission rate of the NS while maintaining a favorable safety profile.
Read the detailed description
- Study Overview: Once a patient with idiopathic MN and proteinuria >5g/24h is identified and meets other entry criteria, he/she will receive a minimum of 4 months of non-immunosuppressive therapy aimed at maximizing Ang II blockade (run-in phase). The target blood pressure (<130 mmHg systolic BP >75% of the readings; but not <100 mmHg systolic) is chosen based on recent recommendations by the JNC VII.(38) 1) The first step will be the administration of an ARB. This is chosen because ARBs are as effective as ACEIs in blocking the AT1 mediated adverse effects of Ang II, while being better tolerated, with minimal cough or angioedema, and less hyperkalemia. Because this part of the study aims to maximize Ang II blockade, ARB dose will continue to be increased every 2 weeks until the maximum tolerated/FDA approved dose is achieved or until intolerable side effects occur (e.g. development of postural hypotension, light headed, hyperkalemia, etc). 2) Once ARB dose has been maximize and there are no observable side-effects, and/or blood pressure is not at target, a long acting ACEi will be added. ACEi dose will be increased every 2 weeks aiming to achieve maximum tolerated or maximum approved dosage. For patients whose blood pressure control is not at target additional medication will be added in the following order: 3) a loop diuretic, 4) a cardioselective \β-blocker, 5) a non-dihydropyridine calcium channel blocker (CCB), and 6) clonidine. The selection of these drugs adheres to the recommendation of the JNC VII.(38) The choice of a non-dihydropyridine CCB was made because of concerns that dihydropyridine-type CCB may obscure the anti-proteinuric effects of the above therapy. In order to further ensure that any potential adverse effect is minimized we have limited CCB to be used as a fifth agent, and to be used only when the combination of ARB/ACEi, diuretic, and \β-blocker have failed to reduce BP to target level. Concomitant Treatment: 1. At the start of the run-in/conservative phase of the study, and as part of the standard of care for patients with NS and severe hyperlipidemia, patients will be started on atorvastatin 10 mg a day (or its equivalent) and if tolerated (no evidence of persistent elevation of liver transaminase >3x upper limit of normal, muscle pain, high CK, or rhabdomyolysis) the dose can be increased according to the recently published KDOQI-dyslipidemia guidelines.(39) The dose should not be increased above the maximum of 40 mg/day. The rationale for not using a higher statin dose is because of the risk of developing proteinuria with the use of statins at high doses. Patients will remain at the highest tolerated dose for the entire duration of the study. Serum lipids will be measured at baseline and every 3 months thereafter. 2. High sodium intake (e.g. >200 mm NaCl/d or 4.6 g sodium/d) can significantly impair the beneficial effects of Ang II blockade.(40) Therefore patients will be instructed to go on a low salt diet (2-3g/day). 3. Patients will receive dietary counseling at enrollment regarding a dietary protein target intake of 0.8 g/kg ideal body weight/day of high quality protein and will be encouraged to maintain the same diet throughout the duration of the study.
Rituximab: If at the end of this period the patient still meets entry criteria he/she will be treated with rituximab, 375 mg/m2 i.v. on days 1, 8, 15 and 22, with subsequent follow-up of at least one year. Patients will be retreated at month 6th once B-cells return to circulation and will be independent of the clinical status of the patient. B-cell return is defined as CD19+B cell count > 15/microliter or >5% of baseline count. There will be a +/- 3 day window for each study visit, to account for weekends, holidays, and scheduling conflicts.
Figure 3. Schematic time-line for the study. Primary endpoint.
- Change in proteinuria from baseline to 12 months. This approach was selected taking in consideration that B cell recovery following administration of rituximab usually begins at 6 months after the last infusion, but it is not complete until 9-12 months later, (complete recovery is defined as normalization of CD19+ B cell counts; normal CD19+ count is 71-567 cells/\μl).
Secondary endpoints.
- Complete and partial remission rates at 6, 9, and 12 months (see definitions in Table 3)
- Pharmacokinetics/bioavailability
- Rate of decline in urinary protein
- Frequency of relapse after CR
- Toxicity
- 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
Patients will received rituximab 4 weekly doses of rituximab 375 mg/m2 at baseline. Patients will be retreated at 6 months.
| Study group | Role | What they receive |
|---|---|---|
| Drug | Experimental | Rituximab Receives: Drug: Rituximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Primary endpoint.
Measured: 12 months
Secondary outcomes (5)
Complete and partial remission rates at 6, 9, and 12 months
Measured: 6, 9, and 12 months
Pharmacokinetics/bioavailability
Measured: 12 months
Rate of decline in urinary protein
Measured: 12 months
Frequency of relapse after CR
Measured: 12 months
Toxicity
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Nov 2006 (estimated)
- Study startOct 2006
- Primary completionJul 2010
- Study completionApr 2012
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
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mayo Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- Genentech, Inc.
- Responsible party
- Principal investigator, Fernando Fervenza, Mayo Clinic
- Investigators
- Fernando C. Fervenza, M.D., Ph.D., Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00405340
- Sponsor's protocol ID
- 06-004833
- Status last verified
- Oct 2015
- First submitted
- 29 Nov 2006
- Last updated
- 27 Oct 2015
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Rituximab in the Treatment of Idiopathic Membranous Nephropathy
- ClinicalTrials.gov ID
- NCT00405340
- Acronym / sponsor ID
- 06-004833
- Conditions
- Membranous Nephropathy
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Mayo ClinicUniversity, hospital or other
- Collaborators
- Genentech, Inc.
- Study start
- Oct 2006
- Primary completion
- Jul 2010 (actual)
- Study completion
- Apr 2012 (actual)
- First posted
- 30 Nov 2006 (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 still the most common glomerular disease associated with nephrotic proteinuria (NS). Up to 40% of patients reach end stage renal failure (ESRD), making MN the 2nd or 3rd most common cause of ESRD caused by a primary glomerulopathy. Current treatment options include corticosteroids, alkylating agents, and cyclosporin, but their use is controversial and the associated adverse effects and high cost temper their usage. Experimental data in MN suggests that B cell activation results in immunoglobulin deposition along the glomerular basement membrane causing injury to the membrane and subsequent proteinuria. Drugs that non-selectively inhibit B cells and, these pathogenic antibodies, are closely associated with improved outcomes. Based on the rationale that selective depletion of B cells in humans would prevent the production of ?nephrotoxic? immunoglobulins and subsequent renal injury we recently treated 15 patients with MN with rituximab 1g i.v. twice (day 1 and day 15). Baseline proteinuria of 13.0±5.5g/24h decreased to 9.1±7g, 9.7±8g and 6.5±6 g/24h at 3, 6, and 9 months, respectively (mean ± SD). Analysis of the pharmacokinetic data obtained from this study, however, suggests that in heavily nephrotic patients, rituximab dosed in this fashion results in patients being under-treated. The present study propose to test the hypothesis that rituximab, given in accordance to the standard lymphoma protocol (375mg/m2 x 4), will result in a more effective and profound depletion of B cells, a more complete suppression of pathogenic antibodies, and a higher remission rate of the NS while maintaining a favorable safety profile.
Detailed description
- Study Overview: Once a patient with idiopathic MN and proteinuria >5g/24h is identified and meets other entry criteria, he/she will receive a minimum of 4 months of non-immunosuppressive therapy aimed at maximizing Ang II blockade (run-in phase). The target blood pressure (<130 mmHg systolic BP >75% of the readings; but not <100 mmHg systolic) is chosen based on recent recommendations by the JNC VII.(38) 1) The first step will be the administration of an ARB. This is chosen because ARBs are as effective as ACEIs in blocking the AT1 mediated adverse effects of Ang II, while being better tolerated, with minimal cough or angioedema, and less hyperkalemia. Because this part of the study aims to maximize Ang II blockade, ARB dose will continue to be increased every 2 weeks until the maximum tolerated/FDA approved dose is achieved or until intolerable side effects occur (e.g. development of postural hypotension, light headed, hyperkalemia, etc). 2) Once ARB dose has been maximize and there are no observable side-effects, and/or blood pressure is not at target, a long acting ACEi will be added. ACEi dose will be increased every 2 weeks aiming to achieve maximum tolerated or maximum approved dosage. For patients whose blood pressure control is not at target additional medication will be added in the following order: 3) a loop diuretic, 4) a cardioselective \β-blocker, 5) a non-dihydropyridine calcium channel blocker (CCB), and 6) clonidine. The selection of these drugs adheres to the recommendation of the JNC VII.(38) The choice of a non-dihydropyridine CCB was made because of concerns that dihydropyridine-type CCB may obscure the anti-proteinuric effects of the above therapy. In order to further ensure that any potential adverse effect is minimized we have limited CCB to be used as a fifth agent, and to be used only when the combination of ARB/ACEi, diuretic, and \β-blocker have failed to reduce BP to target level. Concomitant Treatment: 1. At the start of the run-in/conservative phase of the study, and as part of the standard of care for patients with NS and severe hyperlipidemia, patients will be started on atorvastatin 10 mg a day (or its equivalent) and if tolerated (no evidence of persistent elevation of liver transaminase >3x upper limit of normal, muscle pain, high CK, or rhabdomyolysis) the dose can be increased according to the recently published KDOQI-dyslipidemia guidelines.(39) The dose should not be increased above the maximum of 40 mg/day. The rationale for not using a higher statin dose is because of the risk of developing proteinuria with the use of statins at high doses. Patients will remain at the highest tolerated dose for the entire duration of the study. Serum lipids will be measured at baseline and every 3 months thereafter. 2. High sodium intake (e.g. >200 mm NaCl/d or 4.6 g sodium/d) can significantly impair the beneficial effects of Ang II blockade.(40) Therefore patients will be instructed to go on a low salt diet (2-3g/day). 3. Patients will receive dietary counseling at enrollment regarding a dietary protein target intake of 0.8 g/kg ideal body weight/day of high quality protein and will be encouraged to maintain the same diet throughout the duration of the study.
Rituximab: If at the end of this period the patient still meets entry criteria he/she will be treated with rituximab, 375 mg/m2 i.v. on days 1, 8, 15 and 22, with subsequent follow-up of at least one year. Patients will be retreated at month 6th once B-cells return to circulation and will be independent of the clinical status of the patient. B-cell return is defined as CD19+B cell count > 15/microliter or >5% of baseline count. There will be a +/- 3 day window for each study visit, to account for weekends, holidays, and scheduling conflicts.
Figure 3. Schematic time-line for the study. Primary endpoint.
- Change in proteinuria from baseline to 12 months. This approach was selected taking in consideration that B cell recovery following administration of rituximab usually begins at 6 months after the last infusion, but it is not complete until 9-12 months later, (complete recovery is defined as normalization of CD19+ B cell counts; normal CD19+ count is 71-567 cells/\μl).
Secondary endpoints.
- Complete and partial remission rates at 6, 9, and 12 months (see definitions in Table 3)
- Pharmacokinetics/bioavailability
- Rate of decline in urinary protein
- Frequency of relapse after CR
- Toxicity
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Drug | Experimental | Drug: RituximabRituximab |
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 |
|---|---|---|
| RituximabPatients will received rituximab 4 weekly doses of rituximab 375 mg/m2 at baseline. Patients will be retreated at 6 months. | Drug | Drug |
Primary outcome
Primary endpoint.
Time frame: 12 months
5 secondary outcomes
Complete and partial remission rates at 6, 9, and 12 months
Time frame: 6, 9, and 12 months
Pharmacokinetics/bioavailability
Time frame: 12 months
Rate of decline in urinary protein
Time frame: 12 months
Frequency of relapse after CR
Time frame: 12 months
Toxicity
Time frame: 12 months
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 27 Oct 2015.
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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 Early Phase 1 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 27 Oct 2015. 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 phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
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?
Primary endpoint. (time frame: 12 months). 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 27 Oct 2015.