title: Suitability of the Clinical Dementia Rating-Sum of Boxes as a single primary endpoint for Alzheimer's disease trials.
abstract: BACKGROUND
  Clinical measures continue to be used as primary endpoints for disease-modifying trials for Alzheimer's disease (AD). Currently, two co-primary endpoints must be specified, which measure cognitive and functional impairments. Generally, the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is one of the co-primary endpoints, but high variability in this measure results in large sample sizes. We evaluated the psychometric properties of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) to assess its suitability as a single primary endpoint as an alternative to the traditional co-primary approach.
  
  
  METHODS
  Internal consistency, structural and convergent validity, and 2-year internal and external responsiveness of the CDR-SB were assessed in 667 very mild to moderate (global Clinical Dementia Rating, 0.5-2) AD patients from the REAL.FR (Réseau sur la Maladie d'Alzheimer Français) study.
  
  
  RESULTS
  The CDR-SB showed good internal consistency (Cronbach's alpha = 0.88), and acceptable structural (separate "cognitive" and "functional" factors) and convergent validity. Variability in mean changes over time was low, leading to excellent internal responsiveness (effect size = 1.2; standardized response mean = 1.17 at 2 years) and smaller sample sizes as compared with the ADAS-Cog. External responsiveness was acceptable when compared with "clinically meaningful" changes on the Activities of Daily Living scale but only borderline acceptable when compared with the ADAS-Cog and Instrumental Activities of Daily Living. Levels of missing data and floor/ceiling effects were low.
  
  
  CONCLUSIONS
  The CDR-SB measures cognitive and functional impairment simultaneously, and has excellent 2-year internal responsiveness. This makes it a promising candidate as a sole primary endpoint for AD trials, although more work is required to determine the clinical relevance of CDR-SB changes, and its usefulness as an endpoint at other disease stages.
authors: University of Toulouse III, France. coley@cict.fr
authors: Nicola
authors: N
authors: Coley
authors: Sandrine
authors: S
authors: Andrieu
authors: Mark
authors: M
authors: Jaros
authors: Michael
authors: M
authors: Weiner
authors: Jesse
authors: J
authors: Cedarbaum
authors: Bruno
authors: B
authors: Vellas
mesh_terms: D000203:Activities of Daily Living; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D015337:Multicenter Studies as Topic; D011594:Psychometrics / Q000379:methods*; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D002800:Cholinesterase Inhibitors