title: Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder.
abstract: BACKGROUND
  Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD).
  
  
  METHODS
  This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score.
  
  
  RESULTS
  Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2-2016) with the HAM-A psychic subscale score for the entire cohort at baseline (FDR-adjusted P=.015).
  
  
  CONCLUSIONS
  Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment.
authors.affiliation: Bristol-Myers Squibb Company, Neuroscience Global Clinical Research, Wallingford, Connecticut 06492, USA. vlad.coric@bms.com
authors.forename: Vladimir
authors.initials: V
authors.lastname: Coric
authors.forename: Howard H
authors.initials: HH
authors.lastname: Feldman
authors.forename: Dan A
authors.initials: DA
authors.lastname: Oren
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
authors.forename: Joseph
authors.initials: J
authors.lastname: Pultz
authors.forename: Randy C
authors.initials: RC
authors.lastname: Dockens
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wu
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Gentile
authors.forename: Shu-Pang
authors.initials: SP
authors.lastname: Huang
authors.forename: Eileen
authors.initials: E
authors.lastname: Emison
authors.forename: Terrye
authors.initials: T
authors.lastname: Delmonte
authors.forename: Bernadette B
authors.initials: BB
authors.lastname: D'Souza
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Zimbroff
authors.forename: Jack A
authors.initials: JA
authors.lastname: Grebb
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Goddard
authors.forename: Elyse G
authors.initials: EG
authors.lastname: Stock
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001008:Anxiety Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D015283:Citalopram / Q000627:therapeutic use*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011594:Psychometrics; D011720:Pyrazoles / Q000627:therapeutic use*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012720:Severity of Illness Index; D014227:Triazines / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D014151:Anti-Anxiety Agents; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D015283:Citalopram; C542342:pexacerfont