title: The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis.
abstract: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function.
  
  
  
  To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment.
  
  
  
  Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm ( n = 215) data, we analyzed disability progression using a novel progression endpoint, "EDSS-Plus," defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT.
  
  
  
  Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors' times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone.
  
  
  
  The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Cadavid
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Cohen
authors.affiliation: University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.affiliation: University of Virginia, Charlottesville, VA, USA.
authors.forename: Myla D
authors.initials: MD
authors.lastname: Goldman
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich- Heine University, Düsseldorf, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: Charles University in Prague, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Havrdova
authors.affiliation: Piedmont HealthCare, Huntersville, NC, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Jeffery
authors.affiliation: National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Raj
authors.initials: R
authors.lastname: Kapoor
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Miller
authors.affiliation: Danish Multiple Sclerosis Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Finn
authors.initials: F
authors.lastname: Sellebjerg
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kinch
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Lee
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Shulian
authors.initials: S
authors.lastname: Shang
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mikol
mesh_terms: D000328:Adult; D004185:Disability Evaluation; D006233:Persons with Disabilities / Q000534:rehabilitation; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000175:diagnosis / Q000503:physiopathology*; D012720:Severity of Illness Index; D013997:Time Factors; D034941:Upper Extremity / Q000503:physiopathology; D016138:Walking / Q000502:physiology
keywords: Disability evaluation; disease progression; endpoint determination; secondary progressive multiple sclerosis