Safety and Tolerability of Rituximab in Neuromyelitis Optica
Condition: Neuromyelitis Optica
MeSH terms: Neuromyelitis Optica
Study type: Interventional
Phase: Phase 1

Summary: 
      The goal of this research study is to investigate whether Rituximab is safe to use in
      patients suffering from NMO, or who are at high risk for developing NMO. It is thought that
      NMO is caused by the immune system reacting against the optic nerves and spinal cord. B cells
      are a part of the immune system that may contribute to the illness. Rituximab is an antibody
      that depletes B cells. Depletion of these B cells with Rituximab may induce remission of the
      disease. Because pathological and serological studies suggest that NMO appears to be, at
      least in part, a B-cell mediated disease Rituximab, is an attractive treatment candidate for
      this disease.
    

Detailed description: 
      Rituximab is a genetically engineered, chimeric, murine/human monoclonal antibody directed
      against the CD20 antigen found on the surface of normal and malignant pre-B and mature B
      cells. The antibody is an IgG1 immunoglobulin containing murine light- and heavy chain
      variable region sequences and human constant region sequences. Rituximab is composed of two
      heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA
      analysis) and has an approximate molecular mass of 145 kD. Rituximab has a binding affinity
      for the CD20 antigen of ~8.0 nM.

      Rituximab was developed by Biogen Idec and Genentech, Inc. It was approved by the FDA in 1997
      for the treatment of relapsed or refractory low grade or follicular, CD20+, B-cell
      non-Hodgkin's lymphoma (NHL).

      Rituximab has also been studied in a variety of non-malignant autoimmune disorders where B
      cells and auto antibodies appear to play a role in pathophysiology. Rituximab has been
      reported to relieve signs and symptoms of rheumatoid arthritis , lupus , immune
      thrombocytopenia , autoimmune anemia , autoimmune neuropathy , and paraneoplastic
      opsoclonus/myoclonus .

      A Phase II study (WA16291) has been completed in patients with rheumatoid arthritis (RA) . A
      total of 161 patients were randomized to 4 treatment arms: Methotrexate, Rituximab alone,
      Rituximab and Methotrexate, Rituximab and Cyclophosphamide. Two doses of Rituximab, 1 gm
      each, were administered IV two weeks apart. Infusion reactions were observed in 36% of
      patients during their first infusion of Rituximab compared to 30% for placebo . Four
      Rituximab-treated patients developed serious infections, for a rate of 4.6 per 100 patient
      years. For context, the rate of infections requiring hospital admission was 9.57 per 100
      patient years in a community based epidemiologic study in RA.

      We treated 8 patients with NMO with Rituximab and observed that Rituximab appears to be well
      tolerated with 0/8 of the patients suffering serious adverse reactions that could be directly
      related to Rituximab administration. Moreover, 7/8 patients experienced decrease in
      neurological disability following treatment, suggesting that B-cell depletion may enhance
      neurological recovery from attacks. 7/8 of the patients remained attack-free within a period
      of 18 months of follow-up on average (range 3 to 12 months) following treatment. We observed
      one attack following treatment in a single patient, whereas 14 attacks would have been
      predicted by the pre-treatment attack rate (p=0.012, paired t test comparing pre- and
      post-treatment attack rates). Nevertheless, the observed impact of treatment on recovery is
      more than what would be expected from spontaneous recovery and deserves further
      investigation. If B cells are essential for pathogenesis of recurrent attacks in NMO, B cell
      depletion may induce sustained remission. We also observed in one case, a dramatic recovery
      of electrophysiological conduction in the optic nerves (visual evoked potentials), which
      implies that in this case, rituxan did not impair repair mechanisms, for example,
      demyelination following the acute attack.
    

Intervention name(s): Rituximab
Intervention type(s): Drug
Intervention description(s): Rituximab is a highly purified, 1328-amino acid antibody with an approximate molecular mass of 145 kD. Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) administration. Rituximab is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. In this single arm study all subjects are treated with two cycles of rituximab. Each cycle consists of two 1000 mg infusions administered two weeks apart. The cycles of rituximab treatment are administered at baseline and at 9 months.
Other intervention name(s): Rituxan
Intervention MeSH terms: Rituximab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Neuromyelitis Optica; acute transverse myelitis