Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives

Abstract

Progressive multiple sclerosis is characterized by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or preceded by a relapsing disease course (secondary progressive). An effective disease modifying treatment for progressive multiple sclerosis has not been identified, and the results of clinical trials to date have been generally disappointing. Ongoing advances in our understanding of pathogenesis, identification of novel targets for neuro-protection, and improved outcome measures have the potential to lead to effective treatments for progressive multiple sclerosis. In this review lessons learned from previous clinical trials and perspectives from current trials in progressive multiple sclerosis are summarized. Promising clinical, imaging, and biological markers will also be reviewed, along with novel clinical trial designs.

Multiple sclerosis, a treatable disease

“…There is an urgent need to develop interim markers for phase II studies. 10 One such parameter is MRI atrophy, for example in the MS-STAT trial (NCT00647348, ClinicalTrials.gov) -using high-dose simvastatin as a neuroprotective agent, the reduction in annualised brain atrophy rate versus placebo was about 40%. 36 This technique and others, such as optical coherence tomography (OCT) and spinal cord atrophy, are starting to be harnessed in more modern trial platforms, eg the phase II multiple sclerosis secondary-progressive multi-arm randomisation trial (MS-SMART; NCT01910259, ClinicalTrials.gov) where three putative neuroprotective agents (amiloride, fluoxetine and riluzole) are being compared with placebo.…”

“…Unfortunately, the results have essentially been negative. 10 This was reinforced by the negative INFORMS trial of fingolimod in PPMS. 33 However, the counter to this may be the recently NHS England has taken on the commissioning of drugs since 2013 and advises that patients must be under the care of a designated MS centre that is registered to take part in the national risk sharing scheme involving the three beta interferon products and glatiramer acetate.…”

“…[7][8][9] Many other MRI indices exist, eg T1 black holes, or are being developed, eg atrophy measures of reduction in brain volume, although these are not yet incorporated fully into standard clinical practice. 3,10 The diagnosis of MS can be further reinforced by paraclinical data in the form of increased latency of evoked potentials, eg visual evoked potentials, and lumbar puncture with the assessment of unmatched oligoclonal immunoglobulin IgG bands in the cerebrospinal fluid (CSF) that are seen in up to 90% of MS patients. 3,5,11 Other disease processes must be considered and actively excluded.…”

Mapping the effects of vitamin D in multiple sclerosis

“…The use of disease modulating drugs (DMD) prevents relapses and postpones the accumulation of disability in the RRMS phase [58] . However, currently registered DMD still cannot protect against disability progression in the SPMS phase [8] .Likewise, vitamin D status is predominantly associated with the disease course in the RR phase of MS. A high vitamin D status has been associated with a lower risk of relapses in RRMS [41] , which may be true particularly for patients at the start of their disease or for younger patients [42,53] . Although negative correlations between disability and vitamin D status have been described in MS cohorts [42,59] , an effect of vitamin D status on disability progression was not found in longitudinal [60][61] and cross-sectional data [59] .…”

“…However, there is no cure available for MS. Most of the MS treatments reduce inflammation and prevent relapses, but to a far lesser extent influence progression of the disease [8] , as reflected by progression on the expanded disability status scale (EDSS) [9] ( Figure 1). Therefore, only patients with active inflammation can benefit from these treatments.…”