title: Efficacy and safety evaluation of HSD-1 inhibitor ABT-384 in Alzheimer's disease.
abstract: BACKGROUND
  In this study we assessed increased cortisol in Alzheimer's disease (AD) patients. The selective 11-β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor ABT-384 blocked regeneration of active cortisol and this tests the hypothesis that intracellular hypercortisolism contributes to cognitive impairment.
  
  
  METHODS
  In this double-blind, placebo- and active-controlled phase II study we examine the efficacy and safety of ABT-384 given 10 mg or 50 mg once daily, donepezil 10 mg once daily, or placebo for 12 weeks in subjects with mild-to-moderate AD. The primary efficacy end point was the change from baseline to final evaluation on the 13-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score.
  
  
  RESULTS
  The study was terminated for futility after randomization of 267 subjects. ABT-384 did not improve ADAS-Cog scores or any secondary end point; however, donepezil significantly improved both cognition and functional end points. Overall incidence of adverse events was similar among treatment groups.
  
  
  CONCLUSIONS
  ABT-384, when tested at doses associated with complete brain HSD-1 inhibition, did not produce symptomatic improvement in AD.
authors.affiliation: Global Pharmaceutical R&D, AbbVie, Inc., North Chicago, IL, USA. Electronic address: gerard.marek@abbvie.com.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Marek
authors.affiliation: Global Pharmaceutical R&D, AbbVie, Inc., North Chicago, IL, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Katz
authors.affiliation: Global Pharmaceutical R&D, AbbVie, Inc., North Chicago, IL, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meier
authors.affiliation: Global Pharmaceutical R&D, AbbVie, Inc., North Chicago, IL, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Greco
authors.affiliation: Global Pharmaceutical R&D, AbbVie, Inc., North Chicago, IL, USA.
authors.forename: Wuyan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Global Pharmaceutical R&D, AbbVie, Inc., North Chicago, IL, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Global Pharmaceutical R&D, AbbVie, Inc., North Chicago, IL, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lenz
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy*; D000077265:Donepezil; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D007189:Indans; C584004:N-(5-(aminocarbonyl)tricyclo(3.3.1.13,7)dec-2-yl)-alpha,alpha-dimethyl-4-(5-(trifluoromethyl)-2-pyridinyl)-1-piperazineacetamide; D018697:Nootropic Agents; D010879:Piperazines; D010880:Piperidines; D000077265:Donepezil; D000218:Adamantane
keywords: 11-β-hydroxysteroid dehydrogenase; Alzheimer's disease; Clinical trial; Cognition; Cortisol; Dementia; Donepezil; Enzyme inhibitor; Glucocorticoids; Hypothalamic–pituitary–adrenal axis