MAIN STUDY: SWITCH SUB-STUDY: SWITCH-JCV
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 4

Summary: 
      MAIN STUDY: The purpose of this study is to determine if teriflunomide will be safe and
      effective to prevent relapses in patients with relapsing types of MS when switching from
      natalizumab to teriflunomide in patients at risk for PML. This is a two center interventional
      study of patients who have had 12 or more continuous infusions of natalizumab , who are
      anti-JCV-ab positive, and who had been free of clinical relapses during prior 12 months of
      natalizumab therapy who will be switching to teriflunomide.

      SUB-STUDY: To study the number of patients experiencing a reduction in the anti-JCV antibody
      Index value in patients who had received at least one dose of teriflunomide during
      participation in the SWITCH protocol (main study).
    

Detailed description: 
      MAIN STUDY: Teriflunomide (TFM) is the primary metabolite of leflunomide, which is marketed
      worldwide for the treatment of rheumatoid arthritis. Teriflunomide inhibits dihydroorotate
      dehydrogenase( DHODH), the forth enzyme in the de novo synthesis pathway of pyrimidines.
      Activated T-lymphocytes utilize both the de novo pyrimidine and salvage pathways of
      pyrimidines ribonucleotide synthesis.After mitogen stimulation, teriflunomide inhibits in
      vitro T cell proliferation, DNA and RNA synthesis and expression of cell surface and nuclear
      antigens that are directly involved in T-cell activation and proliferation.

      Natalizumab (NTZ) is a FDA approved treatment for relapsing-forms of multiple sclerosis (MS)
      with pivotal studies showing an annualized relapse-rate (ARR) reduction of 68%, a reduction
      of new Gadolinium "enhancing" (Gd+) lesions by 92% and a reduction of disability of 42%
      compared to placebo. NTZ is highly effective in controlling MS but the risk of developing
      progressive multifocal leukoencephalopathy (PML) increases with the duration of the use of
      natalizumab. It can have a serious and life threatening complication in about 1 in 500 to 1
      in 250 patients who have had more that 18 infusions due PML and who have a detected antibody
      (Ab) for the JC virus. The risk of PML is much greater in patients who have had prior
      immunosuppressive (IS) treatment. The combination of detected anti-JCV Ab , duration of NTZ
      treatment of greater than 24 months and prior IS increases the risk of development PML to an
      incidence of 11 per 1000 treated patients. So there is a need to have an alternative MS
      disease modifying treatment (DMT) to use for patients at risk to develop PML from NTZ
      treatment that might be sufficiently effective for MS so as not to have the patients' MS
      worsen while lowering or eliminating the risk of PML.

      SUB-STUDY: John Cunningham virus (JCV) is the responsible organism for the development of
      progressive multifocal encephalopathy (PML). Multiple sclerosis (MS) patients treated with
      natalizumab (NTZ), who have evidence of exposure to JCV have a significantly elevated risk,
      as high as 12/1000 patients, of developing PML, necessitating the elective transition of
      patients off NTZ.

      JCV is a member of the polyoma virus family, and closely related to BK virus. BK virus has
      been found to be a significant threat to destroy transplanted kidneys and there is growing
      evidence that treatment with leflunomide, the pro-drug of teriflunomide (TFM) clears BKV from
      the kidney.

      Main study assessed the clinical efficacy of TFM in MS patients transitioned off NTZ solely
      because they have evidence of exposure to JCV, as determined by the presence of serum
      anti-JCV immunoglobulin G (IgG). Previous work by other investigators has demonstrated a
      close correlation between positive anti-JCV antibody titers and the presence of active JCV
      infection.

      There is evidence that JCV is closely related to its fellow polyoma virus BKV, and that BKV
      is cleared by treatment with the TFM pro-drug leflunomide, we propose to determine if
      treatment of the JCV antibody positive patients currently enrolled in the approved protocol
      results in reduction in, or reversion to negative, of the anti-JCV antibody titer as measured
      by the JCV antibody Index, a commercially available assay which is used internationally as
      the standard for evidence of JCV exposure in NTZ-treated patients.
    

Intervention name(s): teriflunomide
Intervention type(s): Drug
Intervention description(s): 14 mg oral teriflunomide daily
Other intervention name(s): Aubagio
Intervention MeSH terms: Teriflunomide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: teriflunomide; natalizumab; relapsing multiple sclerosis