Trials of Novel Therapies Specifically for Progressive MS

  • R. S. NicholasEmail author
  • A. Nandoskar
  • M. Hutchinson
  • T. Friede


This chapter reviews randomised placebo-controlled trials conducted over three decades to demonstrate slowing of disability accrual in progressive multiple sclerosis (PMS). A total of 43 randomised placebo-controlled trials were identified in PMS out of which 11 utilised treatments licensed for RMS. These are not discussed here but of the remaining 32 trials 28% reached their primary outcome.

Over 28 years the population entering PMS trials has changed with a 21% reduction in the proportion of patients experiencing a worsening in trial of the extended disability status score (EDSS). The use of the EDSS, an outcome known to be impacted by relapses but favoured by regulators, could indicate the removal of the RMS population from PMS trials as RMS therapies have become the standard. This may have increased the relevance of the EDSS worsening. Thus the majority of those progressing in the latter studies are experiencing true progression rather than relapse driven disability change.

Eighty-one percent of trials targeted inflammatory processes with the remainder targeting non-inflammatory processes. Two studies that have been successful recently have used molecules targeting the immune system. The, as yet unknown, question is whether targeting the immune system is all that will be needed to halt MS progression. Although only 19% of the trials involved molecules which did not target the immune system directly, there have been some notable successes. These approaches, using neuroprotective therapies, offer some novel insights into MS and need to continue as the imperfect efficacy of purely immune-targeted treatments becomes clear.

Much remains to be done to improve the effectiveness of therapy. To this end not only are better treatments are required, but also the way they are used need to be improved. It could be argued that an approach, using combined immunomodulatory and neuroprotective therapies, will be needed. Trial designs need to be improved by considering other endpoints and design approaches and we need to design studies that enable us to confirm that we are maximising the treatments’ effectiveness. This means targeting early in the disease and running potentially longer studies so that we can confirm a long-term treatment regimen is effective with acceptable adverse effects.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • R. S. Nicholas
    • 1
    Email author
  • A. Nandoskar
    • 1
  • M. Hutchinson
    • 2
    • 3
  • T. Friede
    • 4
  1. 1.Centre for Neuroinflammation and NeurodegenerationImperial College LondonLondonUK
  2. 2.St Vincent’s University HospitalDublinIreland
  3. 3.Newman Clinical ResearchUniversity College DublinDublinIreland
  4. 4.Department of Medical StatisticsUniversity Medical Center GöttingenGöttingenGermany

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