Disease Control in RRMS Transferring Treatment From Natalizumab to Fingolimod
Condition: Relapsing Remitting Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Study type: Observational

Summary: 
      This is an observational study to develop new hypothesis regarding the dynamic and safety of
      switching from natalizumab to fingolimod:

        -  Comparison of disease activity (clinical and MRI) during the year after change of
           therapy in comparison to the year before change

        -  Dynamic of onset of disease activity after having stopped treatment with natalizumab

        -  Change of immunological parameters during treatment change from natalizumab to
           fingolimod in comparison to clinical and MRI measures
    

Detailed description: 
      The risk of progressive multifocal leukoencephalopathy (PML) upon treatment with natalizumab
      increases over time, at least into the 3rd year of therapy. Many Multiple Sclerosis (MS)
      patients who are currently being treated with natalizumab, as well as their physicians, are
      looking for alternative MS treatments, fingolimod being one. In transferring patients from
      natalizumab to fingolimod, it is not known if their co-administration leads to an increased
      risk of adverse effects due to a shared feature that both have immunomodulation as a
      mechanism of action. Therefore a sufficient washout period after natalizumab discontinuation
      and fingolimod initiation is desirable. However, this has to be balanced with the increasing
      risk over time of recurring disease activity while patients are untreated.

      This study prospectively evaluates how safe it is to switch patients from natalizumab to
      fingolimod treatment following cessation of natalizumab treatment, in a cohort of RRMS
      patients.

      Safety of the proposed transition paradigms is defined as both traditional safety measures
      but also recurrence of disease activity during a washout period of 8 weeks after the
      cessation of natalizumab treatment followed by fingolimod treatment initiation. An interim
      analysis of the first 15 patients revealed a clinical and MRI activity in 38.5 and 64.3%
      respectively. Therefore a shorter interval was defined for any subject entering into this
      study after october 2013: the interval was defined to be 4 weeks for those patients.

      Overall, the study aims to provide guidance to physicians on the management of
      natalizumab-treated patients for whom a transition to fingolimod treatment is considered an
      appropriate treatment alternative.

      An evidence based rationale for changing to a 4 or 8 week wash out period is not possible due
      to missing evidence. Due to the known risk of PML for patients being treated with natalizumab
      for more than 2 years, starting fingolimod during natalizumab therapy seems to be
      inappropriate, as an elevated risk for JC Virus (JCV) manifestation could be expected in this
      constellation. On the other hand considerable shortening of the 8-weeks interval could be
      favorable to prevent clinical and MRI activity. An interval of 4 weeks between last dose of
      natalizumab and first dose of fingolimod seemed to be an appropriate compromise to balance
      risks and benefits of this treatment transition.

      Fingolimod and Natalizumab are influencing the immune system in completely different ways. It
      is therefore highly interesting not only to monitor clinical disease activity and MRI
      activity, but also to study immunological responses during the switching phase of both drugs.

      The change of therapy from natalizumab to fingolimod poses possible risks. On the one hand MS
      could reactivate if the start of fingolimod is delayed too long, on the other hand infectious
      problems could emerge if fingolimod is started early and the patient is treated with two
      concomitant immunomodulators. Analyzing the immune response during the critical Switch period
      may help to identify markers that predict recrudescence of disease activity or a severe
      suppression of the immune response. It is known that natalizumab can block migration of
      lymphocytes via endothelial cells by interaction with integrins. More recently, it has been
      described that natalizumab influences also gene expression profiles in lymphocytes and that
      the blockade of migration over endothelial cells might not be as constant as the clinical
      effect predicts.

      In contrast to natalizumab, fingolimod blocks egress of lymphocytes from secondary lymphoid
      organs (SLO) such as lymph nodes. This effect is mediated by functional antagonization
      sphingosine-1-phosphate (S1P) receptors on lymphocytes by fingolimod. Due to a different
      expression of lymph node homing receptors naïve and central memory T-cells regularly
      circulate to SLO and are consequently more prone to sequestration to SLO than effector memory
      cells that do not circulate to SLO on a regular basis. This is reflected by a decrease of
      naïve and central memory cells and a relative increase of effector memory cells in peripheral
      blood of fingolimod treated patients. So far, the effect of a concomitant treatment of
      natalizumab and fingolimod on the immune system has not been studied.

      The different aspects of immune modulation of both drugs will be studied. At baseline and
      then at early follow-up visit (8, 12, 16, 20 weeks) we aim to:

        -  assess alterations of the composition of myeloid cells and lymphocyte subpopulations
           (i.e. naïve, central memory and effector memory and regulatory T cells, B cells) and
           adhesion molecule expression in peripheral blood

        -  measure autoantigen specific T cell proliferation and Interferon gamma (IFNγ) production

        -  characterize transcriptomics alterations (including messenger ribonucleic acid (mRNA)
           and small non-coding RNA expression) in lymphocytes of MS-patients

        -  assess changes in plasma cytokine, chemokine, and Matrix metalloproteinase levels

        -  assess the migratory capacity of peripheral blood mononuclear cells (PBMCs)

      For the patients being recruited after october 2013 with a shorter wash out period, the
      neuroimmunological analysis has been omitted.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients with relapsing remitting multiple sclerosis, who are planned to change treatment
        from natalizumab to fingolimod
      
Biospecimen description: 
      -  assess alterations of the composition of myeloid cells and lymphocyte subpopulations
           (i.e. naïve, central memory and effector memory and regulatory T cells, B cells) and
           adhesion molecule expression in peripheral blood

        -  measure autoantigen specific T cell proliferation and IFNγ production

        -  characterize transcriptomic alterations (including mRNA and small non-coding RNA
           expression) in lymphocytes of MS-patients

        -  assess changes in plasma cytokine, chemokine, and Matrix metallo-proteinase levels

        -  assess the migratory capacity of PBMCs
    
Keywords: RRMS; Natalizumab; Fingolimod; Treatment Change; Disease Activity