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MEmbranous Nephropathy Trial Of Rituximab (MENTOR)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 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: September 25, 2014
Last verified: September 2014

August 10, 2010
September 25, 2014
November 2011
January 2016   (final data collection date for primary outcome measure)
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.
Remission status [ Time Frame: After 27 months ] [ Designated as safety issue: Yes ]
The primary outcome is to determine whether or not the B cell targeting with Rituximab is more effective than Cyclosporine in inducing long term remission of proteinuria.
Complete list of historical versions of study NCT01180036 on ClinicalTrials.gov Archive Site
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
Remission Status [ Time Frame: 6-27 months ] [ Designated as safety issue: Yes ]
CR(Complete Remission) or PR (Partial Remission), and CR alone at 6, 12, 18, 24, and 27 months Frequency of and time to relapse Rate of change in urinary protein at 6 and 12 months and beyond Time to CR or PR and to CR alone. Toxicity Quality of life as measured by SF-36 Frequency of PRA2 antibodies and its relation to therapy and proteinuria response
Not Provided
Not Provided
 
MEmbranous Nephropathy Trial Of Rituximab
"A Randomized Controlled Trial of Rituximab Versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (IMN)"

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.

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

Interventional
Phase 2
Phase 3
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Idiopathic Membranous Nephropathy
  • 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
  • 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
  • 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.
    Intervention: Drug: Rituximab
  • 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.
    Intervention: Drug: Cyclosporine
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
126
June 2016
January 2016   (final data collection date for primary outcome measure)

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.
Both
18 Years to 80 Years
No
Contact: Fernando C. Fervenza, MD, PhD 507-266-1045 fervenza.fernando@mayo.edu
Contact: Lori A. Riess 507-266-1047 riess.lori@mayo.edu
United States,   Canada
 
NCT01180036
10-003372
Yes
Fernando Fervenza, Mayo Clinic
Mayo Clinic
Not Provided
Principal Investigator: Fernando C. Fervenza, M.D., Ph.D. Mayo Clinic
Mayo Clinic
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP