Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
Condition: Nephrotic Syndrome
MeSH terms: Nephrotic Syndrome; Nephrosis; Glomerulosclerosis, Focal Segmental; Nephrosis, Lipoid; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      Background. Patients, especially children, with steroid-dependent or multirelapsing nephrotic
      syndrome (NS) secondary to minimal change disease (MCD) or idiopathic focal and segmental
      glomerulosclerosis (FSGS) on continuous treatment with steroids and/or other
      immunosuppressive agents to limit or prevent recurrences are at increased risk of severe
      drug-related adverse events. Case reports suggest that Rituximab, a B cell depleting
      monoclonal antibody, could be a safe and effective alternative to steroid or
      immunosuppressants to achieve and maintain remission in this population.

      Objectives. The study is primarily aimed at evaluating whether Rituximab may maintain stable
      NS remission after tapering and withdrawal of steroid and immunosuppressive therapy in
      patients with MCD or FSGS and steroid-dependent or multirelapsing NS. Secondarily, the study
      will assess whether Rituximab allows reducing maintenance doses of steroids and other
      immunosuppressants (in those who relapse), thus limiting treatment related side effects and
      costs.

      Methods. This prospective, sequential, open, study will include 20 patients with histology
      evidence of MCD or FSGS and steroid-dependant or multirelapsing NS, who are on stable
      complete or partial remission since at least 1 month and, based on their previous history,
      are expected to invariably relapse after steroid/immunosuppression withdrawal. After baseline
      evaluation of clinical, laboratory and kidney function parameters [including glomerular
      filtration rate (GFR), renal plasma flow (RPF), albumin and sodium fractional clearance and
      the glomerular albumin permeability assay (Palb)], patients will receive one Rituximab
      infusion that will be repeated 1 week later if CD20 cells are not fully depleted from the
      circulation. Then ongoing immunosuppression will be progressively tapered up to complete
      withdrawal over 6 to 9 months. 24h proteinuria will be monitored monthly and spot urine will
      be tested daily by albustix to early detect disease relapses. Baseline evaluations will be
      repeated at study end (1 year). Relapses will be treated with high-dose steroids as per
      center practice and the last immunosuppressive therapy effective in preventing disease
      reactivation will be reintroduced.

      Expected results. Rituximab is expected to prevent NS recurrence following tapering and
      discontinuation of steroid and other immunosuppressants. Maintaining remission without
      chronic immunosuppression is expected to minimize risks and costs of therapy and to
      remarkably improve patient outcomes.
    

Detailed description: 
      BACKGROUND Nephrotic syndrome (NS)affects 2 every 100,000 children younger than 16 years.
      Minimal change disease (MCD) accounts for around 90 percent of cases and most of the
      remaining ones are associated with focal segmental glomerulosclerosis (FSGS). Patients with
      NS are at increased risk for life-threatening infections and thromboembolic episodes, and are
      often affected by dyslipidemia and osteoporosis. Glucocorticoids are first-line treatment and
      may achieve remission in about 90% of patients with MCD and in 20 to 60% of those with FSGS.
      In about 20% to 60% of those achieving remission, however, steroid withdrawal is followed by
      a recurrence of the disease. These patients require chronic steroid therapy
      (steroid-dependent cases): this prevents relapses in most cases but is invariably associated
      with severe adverse effects including growth retardation, infections, malignancies,
      hypertension, impaired glucose tolerance, weight gain and somatic changes. In a small
      proportion of patients, recurrences occur even under chronic steroid therapy (multirelapsing
      cases). In these cases, several approaches have been used to control disease activity
      including plasmapheresis and add-on therapy with cyclophosphamide, cyclosporine,
      mycophenolate mofetil and other immunosuppressants. Chronic immunosuppression, however,
      seldom achieves persistent remission and is invariably burdened by serious adverse effects
      including gonadotoxicity and sterility, opportunistic infections, malignancies, bone marrow
      depression and renal toxicity. Thus, safer and more effective treatments are urgently needed
      for these patients.

      Rituximab, a chimeric monoclonal antibody targeted to the CD20 antigen of B cells able to
      induce antibody-dependent and complement-mediated lysis of these cells, has been reported to
      be effective in children with NS secondary to MCD or FSGS unresponsive to other
      immunosuppressive treatments. Rituximab achieved persistent NS remission in a patient with
      MCD diagnosed at age of 30 yrs who had a history of frequent relapses refractory to treatment
      with other immunosuppressants. Thus, chronic MCD persisting into adult-years may respond to
      rituximab and sustained remissions are possible despite long-term disease and after other
      treatments have failed. Along the same line, rituximab achieved prompt and persistent
      remission in an adult with steroid and mycophenolate mofetil-resistant MCD and in two
      patients with FSGS and steroid-resistant NS.

      The above findings suggest that rituximab may have a role in the treatment of patients who
      require chronic exposure to steroids and/or other immunosuppressants to prevent or limit
      disease reactivation. Thus, main goal of the present study is to assess whether rituximab
      administration may allow tapering and withdrawing ongoing treatment without exposing the
      patients to the risk of disease recurrence.

      AIMS Primary

        -  To evaluate whether Rituximab therapy is able to prevent NS recurrence after complete
           withdrawal of steroids and other immunosuppressive treatments in patients with
           steroid-dependant or multirelapsing NS on sustained remission for at least 1 month.

      Secondary

        -  To assess whether Rituximab therapy may reduce the need for steroids and other
           immunosuppressive agents to prevent and treat further disease relapses;

        -  To evaluate whether tapering or withdrawal of immunosuppressant therapy is associated
           with regression of the related toxicities, such as growth retardation, hypertension,
           impaired glucose tolerance and dyslipidemia;

        -  To assess whether persistent NS remission is associated with an improvement of kidney
           function and of renal hemodynamics;

        -  To study whether proteinuria remission is associated with the disappearance of albumin
           permeability factor(s) from patient's sera;

        -  To assess the safety profile of the rituximab treatment;

        -  To evaluate the cost/effectiveness of the study treatment.
    

Intervention name(s): Rituximab
Intervention type(s): Drug
Intervention description(s): Rituximab (375 mg/m2) will be given as a single intravenous infusion after reconstitution in normal saline to a concentration of 1 mg/ml given though a 0.22 micron in line filter. The initial infusion rate will be 1 ml/kg/h and will be progressively increased up to 4 ml/kg/h according to drug tolerability. Pre-medication with steroids and/or antihistaminic agents will be done according to per-center's practice.Rituximab administration will be repeated in those patients > 5 B cells/mm3 in the peripheral blood on the day after first Rituximab administration.
Intervention MeSH terms: Rituximab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment