MEmbranous Nephropathy Trial Of Rituximab
Condition: Idiopathic Membranous Nephropathy
MeSH terms: Kidney Diseases; Glomerulonephritis, Membranous
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

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 (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.
    

Intervention name(s): Rituximab; Cyclosporine
Intervention type(s): Drug; Drug
Intervention description(s): 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; 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.
Other intervention name(s): Rituxan, MabThera; Sandimmune
Intervention MeSH terms: Cyclosporine; Rituximab; Cyclosporins
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Membranous Nephropathy