"A Randomized Controlled Trial of Rituximab Versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (IMN)"
Rochester, Minn., Jacksonville, Fla., Phoenix/Scottsdale, Ariz.
Open for Enrollment
Why is this study being done?
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
Who can I contact for additional information about this study?
Rochester: Lori A Riess 507-266-1047
Shirley A Jennison 507-255-0231
Scottsdale: Leslie F. Thomas, M.D. 480-342-0161
Andrea L. Francone, R.N. 480-342-1258
Jacksonville: Nabeel Aslam, MD 904-953-7259
Jonathan J. Wright, MHSc, CCRP 904-953-7521