title: Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial.
abstract: BACKGROUND
  Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS.
  
  
  METHODS
  Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985.
  
  
  RESULTS
  Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p<0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p<0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group.
  
  
  CONCLUSIONS
  Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS.
  
  
  BACKGROUND
  Merck Serono SA Geneva, a subsidiary of Merck KGaA, Darmstadt, Germany.
authors: Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: thomas.leist@jefferson.edu.
authors: Thomas P
authors: TP
authors: Leist
authors: Department of Neurology and Institute of Experimental Neurology, University Vita-Salute IRCCS, San Raffaele Hospital, Milan, Italy.
authors: Giancarlo
authors: G
authors: Comi
authors: University of California, San Francisco, CA, USA.
authors: Bruce A C
authors: BA
authors: Cree
authors: Stony Brook University Medical Center, Stony Brook, NY, USA.
authors: Patricia K
authors: PK
authors: Coyle
authors: University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors: Mark S
authors: MS
authors: Freedman
authors: Department of Neurology and Center for Neuropsychiatry, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany.
authors: Hans-Peter
authors: HP
authors: Hartung
authors: University of Lille-Nord de France, Hôpital Roger Salengro, Lille, France.
authors: Patrick
authors: P
authors: Vermersch
authors: EMD Serono, Inc,(†) Rockland, USA.
authors: Florence
authors: F
authors: Casset-Semanaz
authors: EMD Serono, Inc,(†) Rockland, USA.
authors: Matthew
authors: M
authors: Scaramozza
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D017338:Cladribine / Q000008:administration & dosage*; D003711:Demyelinating Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis* / Q000188:drug therapy* / Q000453:epidemiology; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D017338:Cladribine