- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00405340
Rituximab in the Treatment of Idiopathic Membranous Nephropathy
Study Overview
Detailed Description
a. 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.
1. 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 Type
Enrollment (Actual)
Phase
- Early Phase 1
Contacts and Locations
Study Locations
-
-
Minnesota
-
Rochester, Minnesota, United States, 55905
- Mayo Clinic
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Drug
Rituximab
|
Patients will received rituximab 4 weekly doses of rituximab 375 mg/m2 at baseline.
Patients will be retreated at 6 months.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Primary endpoint.
Time Frame: 12 months
|
12 months
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Toxicity
Time Frame: 12 months
|
12 months
|
Complete and partial remission rates at 6, 9, and 12 months
Time Frame: 6, 9, and 12 months
|
6, 9, and 12 months
|
Pharmacokinetics/bioavailability
Time Frame: 12 months
|
12 months
|
Rate of decline in urinary protein
Time Frame: 12 months
|
12 months
|
Frequency of relapse after CR
Time Frame: 12 months
|
12 months
|
Collaborators and Investigators
Sponsor
Collaborators
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 06-004833
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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