MEmbranous Nephropathy Trial Of Rituximab (MENTOR)

This study is currently recruiting participants.
Verified April 2014 by Mayo Clinic
Sponsor:
Information provided by (Responsible Party):
Fernando Fervenza, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01180036
First received: August 10, 2010
Last updated: April 9, 2014
Last verified: April 2014
  Purpose

The primary outcome of this study is to determine whether or not the B cell targeting with Rituximab is more effective than Cyclosporine in inducing long term remission of proteinuria.


Condition Intervention Phase
Idiopathic Membranous Nephropathy
Drug: Rituximab
Drug: Cyclosporine
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: "A Randomized Controlled Trial of Rituximab Versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (IMN)"

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Remission status [ Time Frame: 24 months after randomization ] [ Designated as safety issue: Yes ]
    Complete remission or partial remission at 24 months after randomization will be the primary endpoint.


Secondary Outcome Measures:
  • Remission Status [ Time Frame: 6-24 months after randomization ] [ Designated as safety issue: Yes ]
    Relapse state at month 24 after randomization (Urine Protein) (UP) >3.5 after earlier CR or PR; CR(Complete Remission) or PR (Partial Remission), and CR alone at 6, 12, 18, and 24 after randomization; Time to CR or PR; Anti-PLA2R levels; Quality of life as measured by modified KDQOL; Adverse events; ESRD


Estimated Enrollment: 126
Study Start Date: November 2011
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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 CD19+ B cell count.
Drug: Rituximab
1000 mg, I.V. on Days 1 and 15 and will be retreated at month 6 independent of CD19+ B cell count
Other Name: Rituxan, MabThera
Active Comparator: 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.
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 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.
Other Name: Sandimmune

  Hide Detailed Description

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 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 NS and be safer than any current therapeutic regimen used to treat MN.

Based on this rationale, we 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 <130mmHg. 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 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, we 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. Twenty patients (11 failures to prior therapy) with MN and proteinuria >5g/24h received RTX (375mg/m2 x 4), with retreatment at 6 months regardless of proteinuria response. A detailed PK was conducted simultaneously along with immunological analyses of the adaptive immune compartment (T and B cells) to ascertain the impact of RTX on lymphocyte subpopulations. Baseline proteinuria of 11.9±4.9g/24h decreased to 4.2±3.8g/24h and 2.0±1.7g/24h at 12 and 24 months, respectively (p<0.001) while creatinine clearance increased from 72.4±33 at baseline to 88.4 ±31.5 ml/min/1.73m2 at 24 months (p=0.02).

Of 18 patients who completed 24-months follow up, 4 are in complete remission, 12 are in partial remission (CR + PR = 80%), 1 has a limited response (>50% drop in P but >3.5g/24h) and 1 patient relapsed. When interpreting these results we should take into account that >50% of these patients had failed previous immunosuppressive therapy. This study also emphasizes that proteinuria is reduced gradually and may take several months to reach its nadir an observation that is in agreement with previous reports in patients with MN treated with prednisone in combination with a cytotoxic agent but without the short-term toxicity seen with alkylating agents. Kidney function remained stable or improved in all patients.

Serum RTX levels were similar to those obtained with 2 doses of RTX. Four 4 doses of RTX did result in more effective B cell depletion but proteinuria reduction was basically identical to the results obtained using RTX 1000mg on days 1 and 15. Thus, we believe that this particular dosing regimen with retreatment at 6 months should be used in a randomized-control trial comparing RTX to Cyclosporine (the standard of care for IMN in the US). We believe that RTX will prove equal or superior to Cyclosporine in the treatment of MN and could represent the new standard of care for patients with this disease

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  • ACEi and/or ARB, for >3 months prior to randomization and adequate blood pressure (target BP <130/80 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 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 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, 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/CNI, RTX or alkylating agents with either a CR or PR but relapsed off CSA/CNI after 3 months or relapsed off RTX or alkylating agent after 6 months are eligible.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01180036

Contacts
Contact: Fernando C. Fervenza, MD, PhD 507-266-1045 fervenza.fernando@mayo.edu
Contact: Lori A. Riess 507-266-1047 riess.lori@mayo.edu

Locations
United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Dana Rizk, MD    205-934-9509    drizk@uab.edu   
Contact: Teresa Chacana    205-934-7649    tchacana@uab.edu   
Principal Investigator: Dana Rizk, MD         
United States, Arizona
Mayo Clinic Scottsdale Recruiting
Scottsdale, Arizona, United States, 85054
Contact: Leslie F. Thomas, M.D.    480-342-0161    thomas.leslie@mayo.edu   
Contact: Andrea L. Francone, R.N.    480-342-1258    francone.andrea@mayo.edu   
Principal Investigator: Leslie F. Thomas, MD         
Sub-Investigator: Irvin M. Cohen, MD         
Sub-Investigator: Mira T. Keddis, MD         
University of Arizona, Tucson Recruiting
Tucson, Arizona, United States, 85724
Contact: Amy Sussman, MD    520-626-6371    asussman@deptofmed.arizona.edu   
Contact: Carol Stuehm    520-626-8318    carolsA@email.arizona.edu   
Principal Investigator: Amy Sussman, MD         
Sub-Investigator: Bijin Thajudeen, MD         
United States, California
Stanford University Recruiting
San Francisco, California, United States, 94304
Contact: Richard Lafayette, MD    650-736-1822    czar@stanford.edu   
Contact: Kshama Mehta    650-736-1822    krmehta@stanford.edu   
Principal Investigator: Richard Lafayette, MD         
Sub-Investigator: Neiha Arora, MD         
Sub-Investigator: Preeti Nargund, MD         
United States, Florida
Mayo Clinic Jacksonville Recruiting
Jacksonville, Florida, United States, 32224
Contact: Nabeel Aslam, MD    904-953-7259    aslam.nabeel@mayo.edu   
Contact: Jonathan J. Wright, MHSc, CCRP    904-953-7521    wright.johnathan@mayo.edu   
Principal Investigator: Nabeel Aslam, MD         
Sub-Investigator: Ivan E. Porter, MD         
University of Miami Hospital and Clinics Recruiting
Miami, Florida, United States, 33136
Contact: Dollie Green, MD       Dgreen@med.miami.edu   
Contact: Isabel Jaraba    305-585-7677    Ijaraba@med.miami.edu   
Principal Investigator: Dollie Green, MD         
Sub-Investigator: Adela Mattiazzi, MD         
United States, Kansas
University of Kansas Medical Center Recruiting
Kansas City, Kansas, United States, 66160
Contact: Ellen McCarthy, MD    913-588-7609    emccarthy@kumc.edu   
Contact: Beth Courtney    913-588-7691    bcourtney@kumc.edu   
Principal Investigator: Ellen McCarthy, M.D.         
Sub-Investigator: Sri Yarlagadda, M.D.         
United States, Maryland
Johns Hopkins Medical Center Recruiting
Baltimore, Maryland, United States, 21224
Contact: Duvuru Geetha, MD    410-550-2820    gduvura@jhmi.edu   
Contact: Tanisha Williams, MPH    410-550-7302    tmitch19@jhmi.edu   
Principal Investigator: Duvuru Geetha, MD         
Sub-Investigator: Paul Segal, DO         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Patrick Gipson, MD    734-232-3836    pgipson@med.umich.edu   
Contact: Hailey Turner, MS    734-232-4851    heturner@med.umich.edu   
Principal Investigator: Patrick Gipson, M.D.         
Sub-Investigator: Matthias Kretzler, M.D.         
Sub-Investigator: Brett Plattner, M.D.         
Sub-Investigator: Debbie Gipson, M.D.         
Sub-Investigator: Laura Mariani, MD         
Sub-Investigator: Puneet Garg, MD         
Sub-Investigator: Panduranga Rao, MD         
United States, Minnesota
Mayo Clinic Rochester Recruiting
Rochester, Minnesota, United States, 55905
Contact: Lori A Riess    507-266-1047    riess.lori@mayo.edu   
Contact: Shirley A Jennison    507-255-0231    jennison.shirley@mayo.edu   
Sub-Investigator: John J. Dillon, M.D., PhD         
Sub-Investigator: Stephen B. Erickson, M.D., Ph.D         
Sub-Investigator: Eddie L. Greene, M.D., Ph.D         
Sub-Investigator: LaTonya J. Hickson, M.D., Ph.D         
Sub-Investigator: Marie C. Hogan, M.D., Ph.D         
Sub-Investigator: Nelson Leung, M.D., Ph.D         
United States, Mississippi
University of Mississippi Medical Center Recruiting
Jackson, Mississippi, United States, 39216
Contact: Luis Juncos, MD    601-984-5670    ljuncos@umc.edu   
Contact: Kathryn Roberson    6k01-984-5670    kroberson@umc.edu   
Principal Investigator: Luis Juncos, MD         
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Jai Radhakrishnan, MD    212-305-5020    jr55@columbia.edu   
Contact: Irma Orbe    212-305-5038    io67@columbia.edu   
Principal Investigator: Jai Radhakrishnan, MBBS, MD, MSc         
Sub-Investigator: Andrew Bomback, MD         
Sub-Investigator: Pietro Canetta, MD         
Sub-Investigator: Jonathan Hogan, MD         
New York University Recruiting
New York, New York, United States, 10016
Contact: Lada Beara Lasic, M.D., M.Sc.    212-263-2922    lada.bearalasic@nyumc.org   
Contact: Emily Tavarez    212-263-6411    emily.tavarez@nyumc.org   
Principal Investigator: Lada Beara Lasic, MD, MSc         
Sub-Investigator: Olga Zhdanova, MD         
United States, Ohio
MetroHealth System (Case Western Reserve University) Recruiting
Cleveland, Ohio, United States, 44109
Contact: John Sedor, MD    216-778-4993    john.sedor@case.edu   
Contact: Cindy Newman    216-778-3237    cnewman@metrohealth.org   
Principal Investigator: John Sedor, M.D.         
Sub-Investigator: John O'Toole, M.D.         
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: James Simon, MD    216-445-4891    simonj2@ccf.org   
Contact: Sue Saunders    216-444-4552    SAUNDES2@ccf.org   
Principal Investigator: James Simon, MD         
Sub-Investigator: Surafel Gebreselassie, MD         
Ohio State University Recruiting
Columbus, Ohio, United States, 43210
Contact: Brad H. Rovin, M.D.    614-293-4997    Brad.Rovin@osumc.edu   
Contact: Sarah Hasselbach    614-293-3942    sarah.hasselbach@osumc.edu   
Principal Investigator: Brad H. Rovin, M.D.         
Sub-Investigator: Samir Parikh, M.D.         
United States, Washington
University of Washington Medical Center Recruiting
Seattle, Washington, United States, 98195
Contact: Jonathan Ashley Jefferson, M.D.    206-685-8661    jjefferson@Nephrology.washington.edu   
Contact: Laura Curtin    206-221-3938    LCurtin@Nephrology.washington.edu   
Principal Investigator: Jonathan Ashley Jefferson, M.D.         
Sub-Investigator: Peter J. Nelson, M.D.         
United States, Wisconsin
Medical College of Wisconsin, Froedtert Hospital Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Samuel Blumenthal, MD    414-384-2000    ssblumen@mcw.edu   
Contact: Charlotte Klis    414-805-9075    cklis@mcw.edu   
Principal Investigator: Samuel Blumenthal, M.D.         
Sub-Investigator: Hariprasad Trivedi, M.D.         
Canada, British Columbia
St. Paul's Hospital, Providence Health Care Recruiting
Vancouver, British Columbia, Canada, V6Z1Y6
Contact: Sean Barbour, MD, MSc    604-875-5950    Sean.Barbour@vch.ca   
Contact: Naama Rozen    604-682-2344 ext 62281    nrozen@providencehealth.bc.ca   
Principal Investigator: Sean Barbour, M.D.         
Sub-Investigator: Adeera Levin, M.D.         
Canada, Ontario
Toronto General Hospital Recruiting
Toronto, Ontario, Canada, M5G2C4
Contact: Daniel Cattran, MD    416-340-4187    daniel.cattran@uhn.ca   
Contact: Paul Ling    416-340-3514    pling@uhnresearch.ca   
Principal Investigator: Daniel Cattran, MD, FRCPC         
Sub-Investigator: Michelle Hladunewich, MD         
Sub-Investigator: Heather Reich, MD         
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Fernando C. Fervenza, M.D., Ph.D. Mayo Clinic
  More Information

No publications provided

Responsible Party: Fernando Fervenza, M.D., Ph.D, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01180036     History of Changes
Other Study ID Numbers: 10-003372
Study First Received: August 10, 2010
Last Updated: April 9, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Mayo Clinic:
Membranous Nephropathy

Additional relevant MeSH terms:
Glomerulonephritis, Membranous
Kidney Diseases
Glomerulonephritis
Nephritis
Urologic Diseases
Autoimmune Diseases
Immune System Diseases
Cyclosporins
Cyclosporine
Rituximab
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents
Antineoplastic Agents

ClinicalTrials.gov processed this record on April 17, 2014