Journal Article

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

Wilkie, David, Nicholas, Jennifer M, Schuerer, Nadine, Greenwood, John, Frost, Chris, Fox, Nick C, Anderson, Val, Bangham, Charles R M, MacManus, David, Hunter, Kelvin, Clegg, Shona, Nielsen, Casper, Chan, Dennis, Alsanousi, Ali, Calder, Virginia L, Nicholas, Richard, Chataway, Jeremy

2014

Overview

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. 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. 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%]). 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. 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.

• Publisher: Elsevier Ltd,Elsevier,Elsevier Limited
• Subject: Administration, Oral / Adolescent / Adult / Adult and adolescent clinical studies / Aged / Atrophy - prevention & control / Autoimmune diseases / Biological and medical sciences / Brain - pathology / Clinical outcomes / Clinical trials / Cytokines - metabolism / Disabled Persons / Dose-Response Relationship, Drug / Double-Blind Method / Drug dosages / Drug therapy / Female / General aspects / Humans / Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage / Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects / Internal Medicine / Male / Medical sciences / Middle Aged / Multiple sclerosis / Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis / Multiple Sclerosis, Chronic Progressive - drug therapy / Multiple Sclerosis, Chronic Progressive - pathology / Neurology / Organic mental disorders. Neuropsychology / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Simvastatin - administration & dosage / Simvastatin - adverse effects / Statins / Vascular diseases / Young Adult