NCT01180036

MEmbranous Nephropathy Trial Of Rituximab

"A Randomized Controlled Trial of Rituximab Versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (IMN)"

• Status: Completed
• Phase: Phase 2 / Phase 3
• Study type: Interventional
• Enrollment: 130 (actual)
• Sponsor: Mayo Clinic · Academic / Other
• Sex: All
• Age: 18 Years – 80 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Idiopathic Membranous Nephropathy

Interventions

Type	Name	Description
DRUG	Rituximab	1000 mg, I.V. on Days 1 and 15 and will be retreated at month 6 independent of cluster of differentiation (CD) 19+ B cell count
DRUG	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 doses for 12 months). Target trough CsA blood levels, as determined in whole blood by High Performance Liquid Chromatography (HPLC), are 125 to 175 ng/ml. A persistent and otherwise unexplained increase in serum creatinine \>30% would prompt an approximate 25% dose reduction of CSA, aiming for a corresponding 25% reduction in CSA trough level. If with this dose reduction the creatinine does not return to within 30% of baseline levels within 3 weeks, then a second dose reduction of approximately 25% with similar reduction in CSA trough level will be used. If the creatinine does not fall to baseline values with this second dose reduction, the drug will be discontinued. At the end of 12 months, Cyclosporine will be tapered by 1/3 of the maintenance dose monthly and hence discontinued after 3 months.

Timeline

• Start date: 2011-11-01
• Primary completion: 2017-10-01
• Completion: 2017-10-01
• First posted: 2010-08-11
• Last updated: 2019-04-30
• Results posted: 2019-04-30

Locations

21 sites across 2 countries: United States, Canada