title: Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.
abstract: BACKGROUND
  Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients.
  
  
  METHODS
  We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients-those aged 18-55 years with relapsing-remitting multiple sclerosis-to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134.
  
  
  RESULTS
  Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34-0·48) in patients given placebo and 0·21 (0·17-0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40-0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was -0·86 (SD 1·22) for fingolimod 0·5 mg versus -1·28 (1·50) for placebo (treatment difference -0·41, 95% CI -0·62 to -0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61-1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs 0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]).
  
  
  CONCLUSIONS
  Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis.
  
  
  BACKGROUND
  Novartis Pharma AG.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: pcalabr1@jhmi.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.affiliation: Medical Image Analysis Center, University Hospital, Basel, Switzerland.
authors.forename: Ernst-Wilhelm
authors.initials: EW
authors.lastname: Radue
authors.affiliation: Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Goodin
authors.affiliation: The Multiple Sclerosis and Movement Disorders Center, Cornerstone Health Care, Winston-Salem, NC, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Jeffery
authors.affiliation: Department of Neurology, University of Miami, Miami, FL, USA.
authors.forename: Kottil W
authors.initials: KW
authors.lastname: Rammohan
authors.affiliation: Department of Neurology, University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Reder
authors.affiliation: Department of Neurology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Vollmer
authors.affiliation: Department of Neurology, University of California at Davis, Davis, CA, USA; Department of Veterans Affairs Northern California Health Care System (VANCHCS), Mather, CA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Agius
authors.affiliation: Department of Neurology, University Hospital, Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Stites
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Li
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Cappiello
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: von Rosenstiel
authors.affiliation: Department of Neurology, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, NY, USA.
authors.forename: Fred D
authors.initials: FD
authors.lastname: Lublin
mesh_terms: D000293:Adolescent; D000328:Adult; D004185:Disability Evaluation; D018450:Disease Progression; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D010919:Placebos; D011409:Propylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055502:Secondary Prevention; D013110:Sphingosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D010919:Placebos; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine