title: Composite end points to assess delay of disability progression by MS treatments.
abstract: BACKGROUND
  The Expanded Disability Status Scale (EDSS) has low sensitivity and reliability for detecting sustained disability progression (SDP) in multiple sclerosis (MS) trials.
  
  
  OBJECTIVE
  This study evaluated composite disability end points as alternatives to EDSS alone.
  
  
  METHODS
  SDP rates were determined using 96-week data from the Olympus trial (rituximab in patients with primary progressive MS). SDP was analyzed using composite disability end points: SDP in EDSS, timed 25-foot walk test (T25FWT), or 9-hole peg test (9HPT) (composite A); SDP in T25FWT or 9HPT (composite B); SDP in EDSS and (T25FWT or 9HPT) (composite C); and SDP in any two (EDSS, T25FWT, and 9HPT) (composite D).
  
  
  RESULTS
  Overall agreements between EDSS and other disability measures in defining SDP were 66%-73%. Composite A showed similar treatment effect estimate versus EDSS alone with much higher SDP rates. Composite B, C, and D all showed larger treatment effect estimate with different or similar SDP rates versus EDSS alone. Using composite A (24-week confirmation only), B, C, or D could reduce sample sizes needed for MS trials.
  
  
  CONCLUSIONS
  Composite end points including multiple accepted disability measures could be superior to EDSS alone in analyzing disability progression and should be considered in future MS trials.
authors.affiliation: Department of Biostatistics, Genentech Inc, USA zhang.jiameng@gene.com.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, UCSF Multiple Sclerosis Center, USA.
authors.forename: E
authors.initials: E
authors.lastname: Waubant
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, USA.
authors.forename: G
authors.initials: G
authors.lastname: Cutter
authors.affiliation: Department of Neurology, University of Texas Health Science Center at Houston, USA.
authors.forename: Js
authors.initials: J
authors.lastname: Wolinsky
authors.affiliation: Pharmaceuticals Division - PDN, F Hoffmann-La Roche Ltd, Switzerland Department of Neurology, University Hospital Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Leppert
mesh_terms: D004185:Disability Evaluation; D006233:Persons with Disabilities; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D013997:Time Factors; D016138:Walking / Q000502:physiology*
keywords: 9HPT; EDSS; Multiple sclerosis; PPMS; T25WT; composite end point; disability progression; rituximab