Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial.


Type
Article
Change log
Authors
Chataway, Jeremy 
Schuerer, Nadine 
Alsanousi, Ali 
MacManus, David 
Abstract

BACKGROUND: Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profile, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive multiple sclerosis. METHODS: We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18-65 years with secondary progressive multiple sclerosis were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. Patients, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00647348. FINDINGS: 140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was significantly lower in patients in the simvastatin group (0·288% per year [SD 0·521]) than in those in the placebo group (0·584% per year [0·498]). The adjusted difference in atrophy rate between groups was -0·254% per year (95% CI -0·422 to -0·087; p=0·003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]). INTERPRETATION: High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing. FUNDING: The Moulton Foundation [charity number 1109891], Berkeley Foundation [268369], the Multiple Sclerosis Trials Collaboration [1113598], the Rosetrees Trust [298582] and a personal contribution from A Pidgley, UK National Institute of Health Research (NIHR) University College London Hospitals/UCL Biomedical Research Centres funding scheme.

Description
Keywords
Administration, Oral, Adolescent, Adult, Aged, Atrophy, Brain, Cytokines, Disabled Persons, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Multiple Sclerosis, Chronic Progressive, Simvastatin, Young Adult
Journal Title
Lancet
Conference Name
Journal ISSN
0140-6736
1474-547X
Volume Title
383
Publisher
Elsevier BV