Idiopathic Membranous Nephropathy Clinical Trial
Official title:
"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 non-inferior or 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 (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.
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