MEmbranous Nephropathy Trial Of Rituximab
- Conditions
- Idiopathic Membranous Nephropathy
- Interventions
- Registration Number
- NCT01180036
- Lead Sponsor
- Mayo Clinic
- Brief Summary
The primary outcome of this study is to determine whether or not the B cell targeting with Rituximab is non-inferior or more effective than Cyclosporine in inducing long term remission of proteinuria.
- Detailed Description
In IMN, experimental data suggests that B cells are involved in the pathogenesis of the disease. To date, the best proven therapy for patients with MN consists of the combined use of corticosteroids and cyclophosphamide (CYC). Since the mechanism of action of CYC includes suppression of various stages of the B cell cycle including B cell activation, proliferation, and differentiation and inhibition of immunoglobulin (IgG) secretion, it lends credence to the hypothesis that B cells abnormalities are involved in the pathogenesis of MN. Given the key role of IgG antibodies in MN, it is reasonable to postulate that suppression of antibody production by depleting B cells may improve or even resolve the glomerular pathology and be reflected by a reduction in proteinuria. Thus, a case could be made for using an agent capable of selectively depleting B cells, and therefore halting the production of immunoglobulins against antigens potentially present in the glomeruli. This approach could stop the initiating sequence of pathogenic events and result in resolution of the. The P.I. believes that the application of selective B cell targeting with Rituximab (RTX) will prove at least equal, or even superior, both in the production of short term and long term control of the nephrotic syndrome (NS) and be safer than any current therapeutic regimen used to treat MN.
Based on this rationale, the investigators conducted a pilot trial in 15 newly-biopsied patients (\<3 years) with IMN and proteinuria \>5g/24h despite ACEi/ARB use for \>3months and systolic BP \<130 millimeter of mercury (mmHg). Mean baseline creatinine was 1.4 mg/dl. Thirteen males and 2 females, median age 47 (range 33-63), were treated with RTX (1g) on days 1 and 15. At six months, patients who remained with proteinuria \>3g/24 received a second identical course of RTX. Baseline proteinuria of 13.0±5.7g/24h (range 8.4-23.5) decreased to 6.0±7.0 g/24h (range 0.2-20) at 12 months (mean ± SD). In the fourteen patients who completed a 12 months follow-up complete remission (proteinuria \<0.3g/24h) was achieved in 2 patients and partial remission (\<3g/24h) in 7 patients. In 5 of these 7 patients, proteinuria was \<1.5g/24h and follow up at 18 months showed that 3 of these 7 patients on PR achieved CR of proteinuria. Five patients did not respond. The mean drop in proteinuria from baseline to 12 months was 6.2± 5.1g (p=.002, paired t-test). There were a limited number of minor side-effects. Initial cluster of differentiation 20 (CD20)+ B cell depletion was seen in all patients. However, at 3 months, CD20+ B cells were starting to recover with five patients \>35 cells/µl (range 35-152).(50) These data contrasts with previous work by Ruggenenti et al. using RTX given weekly (375 mg/m2) for 4 weeks. Pharmacokinetic (PK) analysis showed that RTX levels in this 2-dose regimen were 50% lower compared to non-proteinuric patients, which could potentially result in undertreatment.
Based on these results, the investigators recently conducted a study postulating that in patients with MN, 4 weekly doses of RTX would result in more effective B cell depletion, a higher remission rate and maintaining of the same safety profile compared to patients treated with RTX dosed at 1g x 2.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 130
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Rituximab Treatment Arm Rituximab Patients randomized to the RTX arm will receive 1000 mg IV on Days 1 and 15. Patients who achieve complete remission at 6 months will not be retreated. A second course of RTX 1000 mg IV will be administered at study month 6 for individuals who have not achieved a complete remission, but have achieved a minimum of \>25% reduction in Time 0 proteinuria. Dosing at study month 6 will be independent of cluster of differentiation (CD) 19+ B cell count. Cyclosporine Treatment Arm Cyclosporine Patients randomized to the Cyclosporine arm will be started at a dose of CsA = 3.5 mg/kg/day p.o. divided into 2 equal doses given at 12 hour intervals. Target trough CsA blood levels are 125 to 175 ng/ml. Patients will have their doses adjusted according to their blood levels of CSA as monitored every 2 weeks until the target trough level is reached. If a complete remission is achieved by 6 months, CSA will be tapered and discontinued over a three-month period. If after 6 months there has not been a reduction in proteinuria of at least 25% of baseline values, the drug will also be discontinued. If there has been a \>25% reduction in baseline proteinuria (but not complete remission) the CSA will be continued for an additional 6 months.
- Primary Outcome Measures
Name Time Method Remission Status 24 months after randomization The number of subjects to reach the composite of maintaining complete remission or partial remission at 24 months after randomization will be the primary endpoint.
- Secondary Outcome Measures
Name Time Method Remission Status 12 months after randomization The number of subjects to reach either complete remission or partial remission at 12 months after randomization.
Trial Locations
- Locations (21)
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Ohio State University
🇺🇸Columbus, Ohio, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Mayo Clinic Jacksonville
🇺🇸Jacksonville, Florida, United States
Mayo Clinic Scottsdale
🇺🇸Scottsdale, Arizona, United States
MetroHealth System (Case Western Reserve University)
🇺🇸Cleveland, Ohio, United States
University of Arizona, Tucson
🇺🇸Tucson, Arizona, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
University of Miami Hospital and Clinics
🇺🇸Miami, Florida, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
New York University
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
Medical College of Wisconsin, Froedtert Hospital
🇺🇸Milwaukee, Wisconsin, United States
Centre hospitalier universitaire de Quebec - Hotel-Dieu de Quebec
🇨🇦Quebec, Canada
St. Paul's Hospital, Providence Health Care
🇨🇦Vancouver, British Columbia, Canada
Stanford University
🇺🇸San Francisco, California, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States