Rituximab Treatment of Focal Segmental Glomerulosclerosis
Condition: Focal Segmental Glomerulosclerosis (FSGS)
MeSH terms: Glomerulosclerosis, Focal Segmental
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine whether the approved drug, rituximab, is effective
      in the treatment of focal segmental glomerulosclerosis (FSGS)
    

Detailed description: 
      Focal segmental glomerulosclerosis (FSGS) remains an enigmatic disease despite many years of
      study. There has been a recent increased incidence of FSGS particularly in African Americans
      in whom the outcome tends to be worse. In about 30% of patients transplanted for FSGS, the
      disease recurs and often results in severe nephrotic syndrome and accelerated graft loss.
      FSGS is a common cause of nephrotic disease accounting for 10-20% of cases of idiopathic
      nephrotic syndrome in children and 35% of cases in adults. Most cases are refractory to
      current therapy resulting in the ultimate progression to end stage renal disease. Overall,
      FSGS accounts for about 15% of pediatric and 5% of adult cases of end stage renal disease.
      With the frequent post transplant recurrence, the morbidity and mortality of FSGS is
      increased. Thus, FSGS is a disease that is associated with a large cost to society and
      long-term morbidity to the individual patient. A treatment that could induce permanent
      remission and reverse organ damage would make a major contribution to society by reduction of
      these expenses. A circulating Permeability Factor (PF, Savin Factor) has been suspected as
      central to the pathogenesis of recurrent disease but its identity has been difficult to
      discern. The molecular weight has reported to be between 30 and 100 kDa. Although, PF has
      been reported to adhere to protein A columns and such columns can be part of the treatment of
      FSGS, this molecular weight would exclude PF being an intact antibody. Immunosuppressive
      agents have been the only therapy demonstrating efficacy, albeit partial, suggesting that at
      least some cases of FSGS are immune mediated. While high dose steroids are the first line of
      treatment for FSGS, cyclosporine has been efficacious in randomized trials and has been used
      for steroid resistant FSGS but is associated with substantial toxicity. If cyclosporine
      fails, cyclophosphamide, plasmapheresis, protein A immunoabsorption, and most recently
      mycophenolate mofetil (MMF) have been used with variable efficacy.

      Rituximab, primarily indicated for treatment of lymphoma, has become a first line agent in
      the treatment of post transplant lymphoma. However, it has been used with increased frequency
      to treat various autoimmune diseases including those such as rheumatoid arthritis that have
      been thought to be primarily T-cell mediated and others such as immune thrombocytopenia
      purpura that have been thought to be primarily B-cell mediated. In a trial being conducted by
      the Immune Tolerance Network, ANCA positive vasculitis is being treated with rituximab and it
      appears that a short course of rituximab leads to tolerance in this autoimmune disease.
      Rituximab's mechanism of action in the various autoimmune diseases for which has efficacy has
      been variously suggested to result from elimination of either circulating autoantibody, by
      elimination of B-cell produced cytokines, or by interference with the antigen presentation
      provide by B cells.

      We have recently had a case of immediate post transplant recurrence of FSGS in a child that
      failed to respond to MMF, steroids, long-term plasmapheresis and conversion from tacrolimus
      to cyclosporine. The FSGS associated proteinuria however completely resolved at about 6
      months after treatment of post transplant lymphoma with 6 doses of rituximab. A similar case
      that also resolved after treatment of PTLD with rituximab was recently reported. While the
      mechanism of action of both cyclosporine and MMF is unknown in FSGS, both drugs have been
      shown to have activity against B cells. The response seen in these two recent cases following
      treatment with a B cell specific agent leads to the hypothesis that at least some cases of
      FSGS have an autoimmune mechanism in which B cells play a central role. We propose to test
      this hypothesis by the treatment of patients with recurrent or primary persistent FSGS with
      rituximab.

      This study will be a single center, single-arm, pilot trial. As the study will be registered
      at clintrials.gov, subjects may be referred from outside physicians. However, all treatment
      will be done at IU in the GCRC. After meeting inclusion/exclusion criteria and signing the
      consent, serum for PF levels, and blood for B cell flow cytometry will be obtained. Rituximab
      (375 mg/m2) will be administered intravenously as per current package label in a facility
      capable of handling infusion reactions. Subjects would be pre dosed with diphenhydramine and
      acetaminophen. Solu-Medrol, 1.5 mg/kg would be dosed 1 hour prior to the first dose of
      rituximab. Three subsequent doses of rituximab will be given at weekly intervals. Study
      visits will then be conducted monthly thereafter for the 6 months and then every 3 months, at
      which time, assessments of safety will be made. Efficacy will be determined by monitoring
      first AM Uprotein/C ratio. Flow cytometry, PF factor, urine proteomics and general blood work
      including CBC, Chemistry, electrolytes, serum immunoglobulin will also be done. During the
      second year, subjects would be followed every three months. The primary endpoint will be
      resolution of proteinuria defined as a Up/C ratio of <0.2. Secondary endpoints will be the
      number of subjects who achieve partial remission defined at a fall of 50% or more in the Up/C
      ratio from the pre-treatment baseline; the number of patients who develop a recurrence or
      increase of proteinuria on samples obtained at least 4 weeks apart; effect of treatment on PF
      levels; safety as measured by infections and drug infusion reactions. Consideration will be
      given to a plan of redosing in subjects who relapse after initial response.
    

Intervention name(s): rituximab
Intervention type(s): Drug
Intervention description(s): 375 mg/m2 intravenously for 4 doses
Other intervention name(s): Rituxan
Intervention MeSH terms: Rituximab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Focal segmental glomerulosclerosis; FSGS; Proteinuria; rituximab; B cell; autoimmune; CD20; treatment; children