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Treatment trials in progressive MS—current challenges and future directions

Nature Reviews Neurology volume 9, pages 496–503 (2013)Cite this article

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Abstract

The introduction of immunomodulatory treatments has transformed the management of patients with relapsing–remitting multiple sclerosis (MS), but has had no consistent benefit in progressive MS. Patients with primary or secondary progressive MS, therefore, are faced with relentless functional decline that remains without treatment. Clinical trials in progressive MS are clearly needed, but their design and conduct is challenging, and different from that of trials in relapsing–remitting MS. Challenges to reliable measurement of clinical progression, uncertainties about the natural history of progressive MS, and the unclear role of imaging outcomes all impede optimal trial design. Clinical trials in progressive MS have used time to a predefined change on the Expanded Disability Status Scale as their main outcome measure, which has had important consequences for trial duration and has led to inclusion of only a highly selected minority of patients. Here, we review the current approach to clinical trial design in progressive MS, outline key ongoing challenges, and suggest strategies to overcome such hurdles.

Key Points

  • During the course of multiple sclerosis, most patients are affected by a progressive disease course (PMS), for which effective treatments are lacking

  • Treatment targets in PMS are speculative, but could include remyelination, cytoprotection and inhibition of microglial activation

  • Reliable measurement of clinical progression in PMS is challenging, and alternatives to the current outcome measure of change on the Expanded Disability Status Scale are needed

  • Brain atrophy measured on MRI is an attractive potential trial outcome, but its relationship to disease progression remains to be established

  • Stringent inclusion criteria used in current trials in PMS lead to exclusion of the majority of patients with PMS

  • New trial models, such as adaptive and seamless phase II–III designs and the Simon-2-stage model, could help to accelerate development of treatments for PMS

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Figure 1: Key pathological differences between RRMS and PMS.
Figure 2: Possible strategies for the treatment of progressive multiple sclerosis include neuroprotection and myelin repair.

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Authors and Affiliations

  1. Multiple Sclerosis Clinic, Foothills Hospital, AC137A, SSB, 1403–29 ST NW, Calgary, AB, T2N 2T9, Canada

    Marcus W. Koch & Luanne M. Metz

  2. Ryals Public Health Building, 1665 University Boulevard, Birmingham, 35294-0022, AL, USA

    Gary Cutter

  3. 3330 Hospital Drive NW, Calgary, T2N 4N1, AB, Canada

    Peter K. Stys & V. Wee Yong

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M. W. Koch researched data for the article. All authors made substantial contributions to discussion of the article content, writing of the article, and to review and/or editing of the manuscript before submission.

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Koch, M., Cutter, G., Stys, P. et al. Treatment trials in progressive MS—current challenges and future directions. Nat Rev Neurol 9, 496–503 (2013). https://doi.org/10.1038/nrneurol.2013.148

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