Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01180036
Other study ID # 10-003372
Secondary ID
Status Completed
Phase Phase 2/Phase 3
First received
Last updated
Start date November 2011
Est. completion date October 1, 2017

Study information

Verified date April 2019
Source Mayo Clinic
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 130
Est. completion date October 1, 2017
Est. primary completion date October 1, 2017
Accepts healthy volunteers No
Gender All
Age group 18 Years to 80 Years
Eligibility 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.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
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
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.

Locations

Country Name City State
Canada Centre hospitalier universitaire de Quebec - Hotel-Dieu de Quebec Quebec
Canada Toronto General Hospital Toronto Ontario
Canada St. Paul's Hospital, Providence Health Care Vancouver British Columbia
United States University of Michigan Ann Arbor Michigan
United States University of Alabama at Birmingham Birmingham Alabama
United States Cleveland Clinic Cleveland Ohio
United States MetroHealth System (Case Western Reserve University) Cleveland Ohio
United States Ohio State University Columbus Ohio
United States University of Mississippi Medical Center Jackson Mississippi
United States Mayo Clinic Jacksonville Jacksonville Florida
United States University of Kansas Medical Center Kansas City Kansas
United States University of Miami Hospital and Clinics Miami Florida
United States Medical College of Wisconsin, Froedtert Hospital Milwaukee Wisconsin
United States Columbia University Medical Center New York New York
United States New York University New York New York
United States Mayo Clinic Rochester Rochester Minnesota
United States Washington University School of Medicine Saint Louis Missouri
United States Stanford University San Francisco California
United States Mayo Clinic Scottsdale Scottsdale Arizona
United States University of Washington Medical Center Seattle Washington
United States University of Arizona, Tucson Tucson Arizona

Sponsors (24)

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

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type Measure Description Time frame Safety issue
Primary Remission Status 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. 24 months after randomization
Secondary Remission Status The number of subjects to reach either complete remission or partial remission at 12 months after randomization. 12 months after randomization
See also
  Status Clinical Trial Phase
Recruiting NCT06245707 - the Effects of Different Treatment Schemes on Cognitive Function of Patients With Idiopathic Membranous Nephropathy N/A
Recruiting NCT03864250 - Tacrolimus Monotherapy for Idiopathic Membranous Nephropathy N/A
Completed NCT01845688 - Clinical Study of QingReMoShen Granule to Treat Idiopathic Membranous Nephropathy N/A
Withdrawn NCT01093781 - Aliskiren in Patients With Idiopathic Membranous Nephropathy N/A
Completed NCT00362531 - Tacrolimus Combined With Prednisone Treatment of Idiopathic Membranous Nephropathy and Nephrotic Syndrome Phase 2/Phase 3
Recruiting NCT05839314 - Effect of Huaier Granule on the Treatment of Idiopathic Membranous Nephropathy Phase 4
Completed NCT00302523 - Tacrolimus Treatment of Patients With Idiopathic Membranous Nephropathy N/A
Terminated NCT03466801 - The Efficacy of Prednisone and Combination Therapy With Methylprednisolone and Cyclophosphamide on IMN in Stage I. N/A
Terminated NCT03475602 - Membranous Nephropathy-associated Serological Antibody Predict the Prognosis of Idiopathic Membranous Nephropathy
Not yet recruiting NCT05850845 - Study on the Application of Hyperspectral Imaging Technique in CTX Treatment of IMN
Not yet recruiting NCT05667896 - Prognostic Model of GC/TAC in the Treatment of MN
Not yet recruiting NCT05667922 - Prognostic Model of TAC in the Treatment of MN
Not yet recruiting NCT05667883 - Prognostic Model of GC/CTX in the Treatment of MN
Not yet recruiting NCT05667909 - Prognostic Model of Rituximab in the Treatment of MN
Recruiting NCT02173106 - A Controlled Study of Steroids Plus Cyclosporin Therapy for Patients of Idiopathic Membranous Nephropathy Phase 2
Completed NCT01161459 - Treatment of Idiopathic Membranous Nephropathy With Tripterygium Wilfordii Plus Steroid vs Tacrolimus Plus Steroid N/A
Recruiting NCT03549663 - Tacrolimus Monotherapy for Idiopathic Membranous Nephropathy (IMN) N/A
Not yet recruiting NCT05845762 - Obinutuzumab in the Management of Idiopathic Membranous Nephropathy
Completed NCT00694863 - Treatment With Synthetic ACTH in High Risk Patients With Membranous Nephropathy Phase 2
Recruiting NCT03170323 - Mycophenolate Mofetil Plus Steroid in the Treatment Of Patients With Progressive Idiopathic Membranous Nephropathy Phase 4

External Links