Clinical trial NCT01180036: MEmbranous Nephropathy Trial Of Rituximab
Official title: "A Randomized Controlled Trial of Rituximab Versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (IMN)"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Idiopathic Membranous Nephropathy
Keywords: Membranous Nephropathy
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: Columbia University
name: University of British Columbia
name: Ohio State University
name: Stanford University
name: University of Washington
name: University of Michigan
name: University of Alabama at Birmingham
name: Case Western Reserve University
name: The Cleveland Clinic
name: University of Kansas Medical Center
name: University of Manchester
name: University Health Network, Toronto
name: University of Toronto
name: CHU de Quebec-Universite Laval
name: Washington University School of Medicine
name: Florida International University
name: University of Mississippi Medical Center
name: NYU Langone Health
name: Medical College of Wisconsin
name: University of Arizona
name: Sunnybrook Health Sciences Centre
name: Applied Health Research Centre
name: Fulk Family Foundation
First posted: 2010-08-11
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Remission Status
timeFrame: 24 months after randomization
Secondary outcomes:
measure: Remission Status
timeFrame: 12 months after randomization
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Tucson
country: United States
facility: University of Arizona, Tucson
state: Arizona
city: San Francisco
country: United States
facility: Stanford University
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Miami
country: United States
facility: University of Miami Hospital and Clinics
state: Florida
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: New York University
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cleveland
country: United States
facility: MetroHealth System (Case Western Reserve University)
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin, Froedtert Hospital
state: Wisconsin
city: Vancouver
country: Canada
facility: St. Paul's Hospital, Providence Health Care
state: British Columbia
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Quebec
country: Canada
facility: Centre hospitalier universitaire de Quebec - Hotel-Dieu de Quebec
Study officials:
affiliation: Mayo Clinic
name: Fernando C. Fervenza, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Fervenza FC, Appel GB, Barbour SJ, Rovin BH, Lafayette RA, Aslam N, Jefferson JA, Gipson PE, Rizk DV, Sedor JR, Simon JF, McCarthy ET, Brenchley P, Sethi S, Avila-Casado C, Beanlands H, Lieske JC, Philibert D, Li T, Thomas LF, Green DF, Juncos LA, Beara-Lasic L, Blumenthal SS, Sussman AN, Erickson SB, Hladunewich M, Canetta PA, Hebert LA, Leung N, Radhakrishnan J, Reich HN, Parikh SV, Gipson DS, Lee DK, da Costa BR, Juni P, Cattran DC; MENTOR Investigators. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. N Engl J Med. 2019 Jul 4;381(1):36-46. doi: 10.1056/NEJMoa1814427.
citation: Fervenza FC, Canetta PA, Barbour SJ, Lafayette RA, Rovin BH, Aslam N, Hladunewich MA, Irazabal MV, Sethi S, Gipson DS, Reich HN, Brenchley P, Kretzler M, Radhakrishnan J, Hebert LA, Gipson PE, Thomas LF, McCarthy ET, Appel GB, Jefferson JA, Eirin A, Lieske JC, Hogan MC, Greene EL, Dillon JJ, Leung N, Sedor JR, Rizk DV, Blumenthal SS, Lasic LB, Juncos LA, Green DF, Simon J, Sussman AN, Philibert D, Cattran DC; Mentor Consortium group. A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR). Nephron. 2015;130(3):159-68. doi: 10.1159/000430849. Epub 2015 Jun 12.