title: Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial.
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.
  
  
  RESULTS
  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%]).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK; Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London, London, UK; UCL Institute of Neurology, University College London, London, UK; Imperial College Healthcare NHS Trust, London, UK; Imperial College, London, UK. Electronic address: jeremy.chataway@uclh.nhs.uk.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chataway
authors.affiliation: UCL Institiute of Ophthalmology, University College London, London, UK.
authors.forename: Nadine
authors.initials: N
authors.lastname: Schuerer
authors.affiliation: Imperial College Healthcare NHS Trust, London, UK.
authors.forename: Ali
authors.initials: A
authors.lastname: Alsanousi
authors.affiliation: Brighton and Sussex Medical School, Brighton, UK.
authors.forename: Dennis
authors.initials: D
authors.lastname: Chan
authors.affiliation: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London, London, UK; UCL Institute of Neurology, University College London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: MacManus
authors.affiliation: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London, London, UK; UCL Institute of Neurology, University College London, London, UK.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Hunter
authors.affiliation: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London, London, UK; UCL Institute of Neurology, University College London, London, UK.
authors.forename: Val
authors.initials: V
authors.lastname: Anderson
authors.affiliation: Imperial College, London, UK.
authors.forename: Charles R M
authors.initials: CR
authors.lastname: Bangham
authors.affiliation: UCL Institute of Neurology, University College London, London, UK.
authors.forename: Shona
authors.initials: S
authors.lastname: Clegg
authors.affiliation: UCL Institute of Neurology, University College London, London, UK.
authors.forename: Casper
authors.initials: C
authors.lastname: Nielsen
authors.affiliation: National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK; UCL Institute of Neurology, University College London, London, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Imperial College, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Wilkie
authors.affiliation: Imperial College Healthcare NHS Trust, London, UK; Imperial College, London, UK; London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Nicholas
authors.affiliation: UCL Institiute of Ophthalmology, University College London, London, UK.
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Calder
authors.affiliation: UCL Institiute of Ophthalmology, University College London, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Greenwood
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Frost
authors.affiliation: Imperial College Healthcare NHS Trust, London, UK; Imperial College, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Nicholas
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D001284:Atrophy / Q000517:prevention & control; D001921:Brain / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D006233:Persons with Disabilities; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy* / Q000473:pathology; D019821:Simvastatin / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin