A Canadian Study Assessing the Utility of the Treatment Optimization Recommendations in Multiple Sclerosis
Condition: Multiple Sclerosis, Relapsing-Remitting
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Study type: Observational

Summary: 
      The Canadian Multiple Sclerosis Working Group (CMSWG) has developed practical recommendations
      on how neurologists can assess the status of subjects on disease modifying drugs (DMDs) and
      decide when it may be necessary to modify treatment in order to optimize outcomes. These
      recommendations are based on relapses, disease progression as measured by the Expanded
      Disability Status Scale (EDSS) or EDSS progression, and magnetic resonance imaging (MRI)
      outcomes. The CMSWG agreed to compare post-treatment relapse rates and severity to baseline
      rates and severity in each individual subject. The recommended minimum baseline reference
      time frame needed to assess relapse rate was 2 years prior to treatment initiation. The
      objective and prospective relapse data should be ideally collected during this reference
      period. The CMSWG recommended that the following should be taken into consideration when
      assessing relapse severity: the effect of the relapse on activities of daily living (ADL),
      the type and number of systems involved (i.e., relapses that are polysymptomatic or that
      affect the cerebellar/motor systems tend to be more severe), and whether or not a course of
      corticosteroids was required. The CMSWG also recommended that, prior to considering treatment
      modification on the basis of progression in disability, progression should be confirmed at 6
      months.

      The CMSWG's Treatment Optimization Recommendations (TORs) have been retrospectively applied
      to the 4 year data set from the PRISMS study. Applying the model to subjects after their
      first year on therapy allowed for accurate prediction of continued disease activity in the
      form of relapses in the majority of subjects who actually experienced ongoing attacks. The
      model was less effective in predicting disability progression, but this may well have been
      due to the low numbers of subjects on treatment progressing over the study period. This
      observational study used the TOR model to identify subjects as either candidates for therapy
      optimization or as candidates to maintain current therapy. All subjects were then followed
      prospectively until re- assessment will be done with this model.
    

Detailed description: 
      Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central
      nervous system (CNS) and is one of the most common causes of neurological disability in young
      adults. The neuropathology of the disease is marked by accumulation of leukocytes in the CNS,
      oligodendrocyte loss, demyelination, axonal atrophy, and neuronal loss. Clinically it is
      characterized by multi-focal recurrent attacks of neurological symptoms and signs with
      variable recovery and eventually, the majority of subjects develop a progressive clinical
      course of MS. The exact cause of MS is unknown, although an autoimmune process has been
      implicated. Genetic susceptibility plays a role in disease initiation but unidentified
      environmental factors may also be involved. Three clinical forms of MS are recognized:
      primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis
      (SPMS) and RRMS. Primary progressive subjects are characterized by slow and steady
      accumulation of neurological deficits from onset without superimposed attacks. Subjects with
      RRMS have exacerbations or relapses with subsequent variable recovery (remission). Secondary
      progressive multiple sclerosis is characterized by the steady accumulation of significant and
      persistent neurological deficit with or without superimposed relapses.

      In approximately 90% of subjects, the first presentation of MS is an acute, usually
      reversible episode of CNS dysfunction, referred to as Clinically Isolated Syndrome (CIS).
      With the advent of MRI, it has become possible to reasonably predict the clinical course of
      CIS subjects presenting with abnormal MRI findings. The first 5 year follow up study of CIS
      subjects presenting with abnormal MRI demonstrated a trend for those with more lesions to
      develop clinically definite MS (CDMS) more frequently, with 92% of those with 4-10 T2 lesions
      developing CDMS compared to 67% of those with 2-3 T2 lesions. It is also well established
      that the vast majority of CIS subjects continue to experience ongoing demyelinating disease
      activity, as evidenced by MRI, even in the absence of a clinical conversion to CDMS.

      The introduction of the disease modifying drugs (DMDs) for MS has had a significant impact on
      the management of those living with this disease. These DMDs are the first agents that have
      been shown to alter the natural course of relapsing MS. Although there is evidence that the
      DMDs significantly reduce disease activity, these agents are not "cures" for MS. Thus, many
      subjects with MS continue to experience disease activity, in spite of treatment with DMDs,
      including continued relapses, progressive impairment, and ongoing accumulation of MRI disease
      burden.

      OBJECTIVES

      Primary objectives:

        -  To assess if application of the TOR influences clinicians' decisions regarding DMD
           treatment in the Canadian clinic setting

        -  To evaluate the perceived utility of the TOR in the DMD treatment decision making
           process in the Canadian clinic setting

      Secondary objective:

        -  To determine the proportion of subjects meeting a medium or high level of concern
           according to the TOR in the Canadian Clinic setting.

      This was a non-interventional, open-label, observational, multicentric, phase IV study.
      Subjects were assessed according to the TOR on two occasions over a prospective 12 month
      observation period. All subjects were assessed according to the TOR at baseline. Subjects
      were subsequently assessed according to the TOR either at a time-point within the 12-month
      period when treatment modification is being considered for reasons other than intolerance or
      at the end of the 12-month observational period. Treatment decisions after each TOR
      assessment was noted, and perceptions on the utility of the TOR in the decision making
      process was captured. Additional feedback on the TOR was collected at the end of the
      observational period through a separate evaluation questionnaire. The assessments that were
      carried out at baseline and subsequent visits included EDSS history/current status, relapse
      history/current status, MRI history/current status, cognitive history/current status (if
      done) and neutralizing antibody (NAb) history/current status (if done).
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Subjects with either relapsing-remitting multiple sclerosis (RRMS) or a CIS were enrolled
        from multiple sites across Canada.
      
Keywords: Multiple sclerosis; Expanded Disability Status Scale; Multiple Sclerosis, Relapsing-Remitting