Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder.
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.
Coric
Vladimir
V
Bristol-Myers Squibb Company, Neuroscience Global Clinical Research, Wallingford, Connecticut 06492, USA. vlad.coric@bms.com
Feldman
Howard H
HH
Oren
Dan A
DA
Shekhar
Anantha
A
Pultz
Joseph
J
Dockens
Randy C
RC
Wu
Xiaoling
X
Gentile
Kimberly A
KA
Huang
Shu-Pang
SP
Emison
Eileen
E
Delmonte
Terrye
T
D'Souza
Bernadette B
BB
Zimbroff
Daniel L
DL
Grebb
Jack A
JA
Goddard
Andrew W
AW
Stock
Elyse G
EG
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
D014151:Anti-Anxiety Agents; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D015283:Citalopram; C542342:pexacerfont