title: Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study.
abstract: OBJECTIVE
  Early treatment following a first clinical demyelinating event (FCDE) delays further disease activity in patients with multiple sclerosis (MS). This study determined the effects of early versus delayed treatment (DT) with subcutaneous interferon (sc IFN) β-1a 44 μg in patients with an FCDE up to 60 months postrandomisation.
  
  
  METHODS
  Patients who completed the 24-month double-blind REFLEX (REbif FLEXible dosing in early MS) study entered an extension (REFLEXION, REbif FLEXible dosing in early MS extensION): patients initially randomised to sc IFN β-1a and not reaching clinically definite MS (clinically definite MS, CDMS (second attack or sustained Expanded Disability Status Scale (EDSS) score increase)) continued original treatment (three times weekly (tiw) or once weekly (qw)); placebo patients switched to tiw (DT); patients with CDMS switched to tiw. Clinical, MRI and adverse event data up to month 60 are reported.
  
  
  RESULTS
  402/517 (77.8%) REFLEX patients entered REFLEXION (DT, n=133; tiw, n=127; qw, n=142). At month 60, cumulative probability of CDMS was: DT 44.6%; qw 40.7% (nominal p=0.084 vs DT); tiw 39.2% (nominal p=0.032 vs DT). Cumulative probability of McDonald MS conversion (CDMS or new MRI activity) at month 60 was also reduced for tiw versus DT (nominal p<0.001). At month 60, mean cumulative numbers of new T2, gadolinium-enhancing and T1 hypointense lesions were lower with sc IFN β-1a qw (nominal p<0.05) and tiw versus DT (nominal p<0.001); T2 and T1 hypointense lesion volume change was lower for sc IFN β-1a tiw versus DT (nominal p<0.01). Treatment was well tolerated; fewer patients receiving tiw versus qw were positive for neutralising or binding antibodies.
  
  
  CONCLUSIONS
  Over 5 years in patients presenting with an FCDE, early sc IFN β-1a tiw administration versus DT prolonged time to CDMS and McDonald MS, and reduced overall MRI activity.
  
  
  BACKGROUND
  NCT00813709; Results.
authors.affiliation: Department of Neurology, Scientific Institute H.S. Raffaele, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Stefano
authors.affiliation: Department of Medicine (Neurology), University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.affiliation: Department of Diagnostic Radiology, VU University Medical Center, Amsterdam, The Netherlands.|The Institutes of Neurology and Healthcare Engineering, UCL, London, UK.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Bernard M J
authors.initials: BM
authors.lastname: Uitdehaag
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marlieke
authors.initials: M
authors.lastname: de Vos
authors.affiliation: Global Medical Affairs, Merck GmbH, Vienna, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Marhardt
authors.affiliation: Global Biostatistics, EMD Serono Inc., Billerica, Massachusetts, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Cytel Inc., Geneva, Switzerland.
authors.forename: Delphine
authors.initials: D
authors.lastname: Issard
authors.affiliation: Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital Basel, Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
mesh_terms: D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D061345:Early Medical Intervention; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007279:Injections, Subcutaneous; D000068556:Interferon beta-1a / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000188:drug therapy*; D009460:Neurologic Examination / Q000187:drug effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000068556:Interferon beta-1a