Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial

• Published in: Lancet neurology 2014-06, Vol.13 (6), p.545-556
• Main Authors: Calabresi, Peter A, Dr, Radue, Ernst-Wilhelm, Prof, Goodin, Douglas, MD, Jeffery, Douglas, MD, Rammohan, Kottil W, MD, Reder, Anthony T, MD, Vollmer, Timothy, MD, Agius, Mark A, MD, Kappos, Ludwig, Prof, Stites, Tracy, PhD, Li, Bingbing, PhD, Cappiello, Linda, MD, von Rosenstiel, Philipp, MD, Lublin, Fred D, MD
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Disability Evaluation; Disease Progression; Double-Blind Method; Drug Administration Schedule; Drug dosages; Drug therapy; Female; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacology; Infections; Magnetic Resonance Imaging; Male; Middle Aged; Multiple sclerosis; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Neurology; Patients; Placebos; Propylene Glycols - administration & dosage; Propylene Glycols - adverse effects; Propylene Glycols - pharmacology; Regulatory approval; Secondary Prevention; Sphingosine - administration & dosage; Sphingosine - adverse effects; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Studies; Treatment Outcome; Young Adult
• ISSN: 1474-4422; 1474-4465
• DOI: 10.1016/S1474-4422(14)70049-3

Summary 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. Findings 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