Efficacy of Three Neuroprotective Drugs in Secondary Progressive Multiple Sclerosis
abstract
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Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.
METHODS
We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.
FINDINGS
Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.
INTERPRETATION
The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.
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Additional Info
Disclosure statements are available on the authors' profiles:
Efficacy of Three Neuroprotective Drugs in Secondary Progressive Multiple Sclerosis (MS-SMART): A Phase 2b, Multiarm, Double-Blind, Randomised Placebo-Controlled Trial
Lancet Neurol 2020 Mar 01;19(3)214-225, J Chataway, F De Angelis, P Connick, RA Parker, D Plantone, A Doshi, N John, J Stutters, D MacManus, F Prados Carrasco, F Barkhof, S Ourselin, M Braisher, M Ross, G Cranswick, SH Pavitt, G Giovannoni, CA Gandini Wheeler-Kingshott, C Hawkins, B Sharrack, R Bastow, CJ Weir, N Stallard, S ChandranFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Multiple sclerosis (MS) treatment has made tremendous headway during the last couple of years. Nevertheless, we are still not able to fully halt continuous decline during the progressive phases of the disease in most of the patients, although the development of ocrelizumab for primary-progressive (PP) MS and siponimod for secondary-progressive (SP) MS have been substantial steps forward. Chataway and colleagues addressed this unmet need in the multi-arm phase IIb clinical trial MS-SMART using three compounds with axonoprotective and neuroprotective properties: amiloride, fluoxetine, and riluzole. The primary endpoint was MRI-based and consisted of percent brain volume change (PBVC) after 96 weeks. The study team randomized 445 patients with SPMS and an EDSS of 4.0 to 6.5. At the end of the trial, there was unfortunately no difference regarding PBVC for all groups.
Although the primary endpoint was not met, this trial is an important contribution to the field. First, using three therapeutic arms and one placebo group is a novel way to design a trial, which allows testing of several substances together, thereby reducing effort, time, and money needed for a clinical trial. Moreover, the study team demonstrates that it is feasible to translate generic medications without support from entities into a clinical trial—a challenge known as translational gap, since there is a plethora of therapeutics with potential for progressive MS due to their mechanism of action that are not tested in a clinical trial due to aforementioned limitations. Whether PBVC is the best way to evaluate a treatment effect or whether a clinical endpoint might be more appropriate remains a matter of debate.1
Summarizing, although not having met its primary endpoint, the MS-SMART trial is a substantial contribution to the MS community and might serve as blueprint for further clinical trials in progressive MS.
Reference