MEmbranous Nephropathy Trial Of Rituximab

NCT ID: NCT01180036

Last Updated: 2019-04-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 130 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-11-30
• Study Completion Date: 2017-10-01

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.

Conditions

Idiopathic Membranous Nephropathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Rituximab Treatment Arm

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.

Group Type: ACTIVE_COMPARATOR

Rituximab

Intervention Type: DRUG

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

Cyclosporine Treatment Arm

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.

Group Type: ACTIVE_COMPARATOR

Cyclosporine

Intervention Type: DRUG

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.

Interventions

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

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Rituxan, MabThera; Sandimmune

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Columbia University

OTHER

Sponsor Role: collaborator

University of British Columbia

OTHER

Sponsor Role: collaborator

Ohio State University

OTHER

Sponsor Role: collaborator

Stanford University

OTHER

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: collaborator

University of Michigan

OTHER

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: collaborator

Case Western Reserve University

OTHER

Sponsor Role: collaborator

The Cleveland Clinic

OTHER

Sponsor Role: collaborator

University of Kansas Medical Center

OTHER

Sponsor Role: collaborator

University of Manchester

OTHER

Sponsor Role: collaborator

University Health Network, Toronto

OTHER

Sponsor Role: collaborator

University of Toronto

OTHER

Sponsor Role: collaborator

CHU de Quebec-Universite Laval

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

Florida International University

OTHER

Sponsor Role: collaborator

University of Mississippi Medical Center

OTHER

Sponsor Role: collaborator

NYU Langone Health

OTHER

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: collaborator

University of Arizona

OTHER

Sponsor Role: collaborator

Sunnybrook Health Sciences Centre

OTHER

Sponsor Role: collaborator

Applied Health Research Centre

OTHER

Sponsor Role: collaborator

Fulk Family Foundation

UNKNOWN

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

Fernando Fervenza

M.D., Ph.D

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Fernando C. Fervenza, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Mayo Clinic Scottsdale

Scottsdale, Arizona, United States

University of Arizona, Tucson

Tucson, Arizona, United States

Stanford University

San Francisco, California, United States

Mayo Clinic Jacksonville

Jacksonville, Florida, United States

University of Miami Hospital and Clinics

Miami, Florida, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

University of Michigan

Ann Arbor, Michigan, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

Washington University School of Medicine

St Louis, Missouri, United States

New York University

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

MetroHealth System (Case Western Reserve University)

Cleveland, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

Ohio State University

Columbus, Ohio, United States

University of Washington Medical Center

Seattle, Washington, United States

Medical College of Wisconsin, Froedtert Hospital

Milwaukee, Wisconsin, United States

St. Paul's Hospital, Providence Health Care

Vancouver, British Columbia, Canada

Toronto General Hospital

Toronto, Ontario, Canada

Centre hospitalier universitaire de Quebec - Hotel-Dieu de Quebec

Québec, , Canada

Countries

United States; Canada

References

von Groote TC, Williams G, Au EH, Chen Y, Mathew AT, Hodson EM, Tunnicliffe DJ. Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2021 Nov 15;11(11):CD004293. doi: 10.1002/14651858.CD004293.pub4.

Reference Type: DERIVED

PMID: 34778952 (View on PubMed)

Xie J, Liu L, Mladkova N, Li Y, Ren H, Wang W, Cui Z, Lin L, Hu X, Yu X, Xu J, Liu G, Caliskan Y, Sidore C, Balderes O, Rosen RJ, Bodria M, Zanoni F, Zhang JY, Krithivasan P, Mehl K, Marasa M, Khan A, Ozay F, Canetta PA, Bomback AS, Appel GB, Sanna-Cherchi S, Sampson MG, Mariani LH, Perkowska-Ptasinska A, Durlik M, Mucha K, Moszczuk B, Foroncewicz B, Paczek L, Habura I, Ars E, Ballarin J, Mani LY, Vogt B, Ozturk S, Yildiz A, Seyahi N, Arikan H, Koc M, Basturk T, Karahan G, Akgul SU, Sever MS, Zhang D, Santoro D, Bonomini M, Londrino F, Gesualdo L, Reiterova J, Tesar V, Izzi C, Savoldi S, Spotti D, Marcantoni C, Messa P, Galliani M, Roccatello D, Granata S, Zaza G, Lugani F, Ghiggeri G, Pisani I, Allegri L, Sprangers B, Park JH, Cho B, Kim YS, Kim DK, Suzuki H, Amoroso A, Cattran DC, Fervenza FC, Pani A, Hamilton P, Harris S, Gupta S, Cheshire C, Dufek S, Issler N, Pepper RJ, Connolly J, Powis S, Bockenhauer D, Stanescu HC, Ashman N, Loos RJF, Kenny EE, Wuttke M, Eckardt KU, Kottgen A, Hofstra JM, Coenen MJH, Kiemeney LA, Akilesh S, Kretzler M, Beck LH, Stengel B, Debiec H, Ronco P, Wetzels JFM, Zoledziewska M, Cucca F, Ionita-Laza I, Lee H, Hoxha E, Stahl RAK, Brenchley P, Scolari F, Zhao MH, Gharavi AG, Kleta R, Chen N, Kiryluk K. The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis. Nat Commun. 2020 Mar 30;11(1):1600. doi: 10.1038/s41467-020-15383-w.

Reference Type: DERIVED

PMID: 32231244 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31269364 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26087670 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://www.mayo.edu/research/clinical-trials

Mayo Clinic Clinical Trials

Other Identifiers

10-003372

Identifier Type: -

Identifier Source: org_study_id