title: Long-term efficacy and safety of fingolimod in Japanese patients with relapsing multiple sclerosis: 3-year results of the phase 2 extension study.
abstract: BACKGROUND
  The low level of disease activity and manageable safety profile seen with fingolimod versus placebo in a 6-month, phase 2, randomized controlled trial in Japanese patients with relapsing multiple sclerosis (MS; ClinicalTrials.gov Identifier NCT00537082) were maintained in the initial 6-month observational study extension. Here, we report long-term safety and efficacy results of the 3-year follow-up to the phase 2 study extension.
  
  
  METHODS
  The 6-month core study was completed by 147 patients, of whom 143 entered the extension and took at least one dose of fingolimod. Those originally randomized to placebo were re-randomized to fingolimod 1.25 mg (n = 23) or 0.5 mg (n = 27). During the extension, the patients taking fingolimod 1.25 mg (n = 46) were switched to open-label fingolimod 0.5 mg, and those originally randomized to fingolimod 0.5 mg (n = 47) continued with open-label fingolimod 0.5 mg.
  
  
  RESULTS
  Continuous fingolimod treatment was associated with a sustained low level of MRI and relapse activity for the duration of the extension phase; 75-100% (range across all assessment time points up to end of study) of patients remained free of Gd-enhanced T1 lesions, 88-100% remained free of new/newly enlarged T2 lesions, and 45-62% remained relapse-free. In patients who switched to the active treatment, a 79.5% decrease in annualized relapse rate (ARR; from 1.131 before switch to 0.232 6-months after switch) was observed in the first 6 months of the extension phase and thereafter remained low until the end of study (0.16-0.31 across all assessment time points after switch up to end of study). The mean number of Gd-enhanced T1 and new/newly enlarged T2 lesions decreased up to month 9 and thereafter remained low until the end of study (0.0-0.1 and 0.0-0.3, respectively, across all assessment time points after switch up to end of study). Fingolimod was generally well-tolerated and the safety profile was consistent with the core and 6-month extension. Serious adverse events were reported in 13.3% of patients during the extension study, with the range in the continuous fingolimod and placebo-fingolimod switch groups (3.7-21.7%) being similar to that reported in the core study for the placebo and fingolimod groups (5.3-20.4%).
  
  
  CONCLUSIONS
  Continuous fingolimod treatment over 36 months was associated with maintained efficacy and a manageable safety profile with no new safety signals. These results indicate that fingolimod provides long-term treatment benefit for Japanese patients with relapsing MS.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00670449 (April 28, 2008).
authors.affiliation: Institute of Multiple Sclerosis Therapeutics, Nishinokyo-Kasugacho 16-44-409, Nakakyo-ku, Kyoto, 604-8453, Japan. saida_takahiko@maia.eonet.ne.jp.|Kyoto Min-Iren-Central Hospital, Kyoto, Japan. saida_takahiko@maia.eonet.ne.jp.|Kyoto University Hospital, Kyoto, Japan. saida_takahiko@maia.eonet.ne.jp.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Saida
authors.affiliation: International University of Health and Welfare, 1-7-4 Momochihama, Sawara, Fukuoka City, Fukuoka, 814-0001, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Itoyama
authors.affiliation: Hokkaido Medical Center, National Hospital Organization, 1-1 Yamanote 5-jo 7-chome, Sapporo, 063-0005, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kikuchi
authors.affiliation: Institute of Multiple Sclerosis Therapeutics, Nishinokyo-Kasugacho 16-44-409, Nakakyo-ku, Kyoto, 604-8453, Japan.
authors.forename: Qi
authors.initials: Q
authors.lastname: Hao
authors.affiliation: Novartis Pharma KK, 1-23-1, Toranomon, Minato-ku, Tokyo, 105-6333, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kurosawa
authors.affiliation: Novartis Pharma KK, 1-23-1, Toranomon, Minato-ku, Tokyo, 105-6333, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Novartis Pharma AG, Fabrikstrasse 12, 4002, Basel, Switzerland.
authors.forename: Lixin Zhang
authors.initials: LZ
authors.lastname: Auberson
authors.affiliation: Novartis Pharma KK, 1-23-1, Toranomon, Minato-ku, Tokyo, 105-6333, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Tsumiyama
authors.affiliation: Mitsubishi Tanabe Pharma Corporation, 17-10, Nihonbashi-Koamicho, Chuo-ku Tokyo, 103-8405, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagato
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Kira
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007564:Japan; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D017063:Outcome Assessment, Health Care; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride
keywords: Aquaporin 4; Fingolimod; Multiple sclerosis; Phase 2 study extension; Relapse