MEmbranous Nephropathy Trial Of Rituximab (MENTOR)

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

Columbia University, University of British Columbia, Ohio State University, Stanford University, University of Washington, University of Michigan, University of Alabama at Birmingham, Case Western Reserve University, The Cleveland Clinic, University of Kansas Medical Center, University of Manchester, University Health Network, Toronto, University of Toronto, CHU de Quebec-Universite Laval, Washington University School of Medicine, Florida International University, University of Mississippi Medical Center, NYU Langone Health, Medical College of Wisconsin, University of Arizona, Sunnybrook Health Sciences Centre, Applied Health Research Centre, Fulk Family Foundation

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.

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.

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.

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.

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

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.

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.

The number of subjects to reach either complete remission or partial remission at 12 months after randomization.

Inclusion Criteria Idiopathic MN with diagnostic biopsy Female, must be post-menopausal, surgically sterile or practicing a medically approved method of contraception(no birth-control pill) Must be off prednisone or mycophenolate mofetil for >1 month and alkylating agents for >6 months. angiotensin-converting-enzyme inhibitor (ACEi) and/or Angiotensin II receptor blockers (ARB), for >3 months prior to randomization and adequate blood pressure (target BP <130/80 millimeter of mercury (mmHg) in >75% of the readings, but subjects with BP <140/80 mmHg in >75% of the readings will be eligible). Patients with documented evidence of >3 months treatment with maximal angiotensin II blockade, on an 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA) reductase inhibitor, and BP control (BP <140/80 mmHg in >75% of the readings) who remain with proteinuria >5g/24h may enter and be randomized to RTX/CSA without the need of the run-in/conservative phase of the study. Proteinuria >5g/24h on two 24-hour urine collection collected within 14 days of each other Estimated glomerular filtration rate (GFR) ≥40 ml/min/1.73m2 while taking ACEi/ARB therapy OR quantified endogenous creatinine clearance >40 ml/min/1.73m2 based on a 24-hour urine collection. Exclusion Criteria Presence of active infection or a secondary cause of MN (e.g. hepatitis B, systemic lupus erythematosus (SLE), medications, malignancies). Testing for HIV, Hepatitis B and C should have occurred <2 years prior to enrollment into the study. Type 1 or 2 diabetes mellitus: to exclude proteinuria secondary to diabetic nephropathy. Patients who have recent history of steroid induced diabetes but no evidence on renal biopsy performed within 6 months of entry into the study are eligible for enrollment. Pregnancy or breast feeding for safety reasons History of resistance to CSA (or other calcineurin inhibitors, e.g. tacrolimus), RTX or alkylating agents (e.g. Cytoxan). Patients who previously responded to CSA/Calcineurin Inhibitor (CNI), RTX or alkylating agents with either a complete remission (CR) or partial remission (PR) but relapsed off CSA/CNI after 3 months or relapsed off RTX or alkylating agent after 6 months are eligible.

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