title: A randomized trial of the efficacy and safety of the H3 antagonist ABT-288 in cognitive impairment associated with schizophrenia.
abstract: BACKGROUND
  ABT-288 is a highly potent histamine-3 receptor antagonist that has demonstrated pro-cognitive effects in preclinical models relevant to schizophrenia. This study evaluated the efficacy and safety of two doses of ABT-288 in the treatment of cognitive impairment associated with schizophrenia.
  
  
  METHODS
  A randomized, double-blind, placebo-controlled, parallel-group 12-week study was conducted at 23 centers in the United States. Clinically stable subjects with schizophrenia were randomized in an equal ratio to ABT-288 10 mg, ABT-288 25 mg, or placebo once daily while continuing their antipsychotic regimen. The primary efficacy measure was the change from baseline to day 84 evaluation on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) composite score vs placebo. Secondary measures included cognitive functioning and psychiatric scales. Safety assessments and sparse pharmacokinetic sampling were also conducted.
  
  
  RESULTS
  A total of 214 subjects were randomized. The mean baseline MCCB composite score was 28.4. Approximately 80% of subjects completed the study. The MCCB composite score mean change from baseline to day 84 was numerically worse for both the 10 mg (1.90, P = .618) and 25 mg (0.64, P = .946) doses of ABT-288 vs placebo (2.19). Results from the secondary measures were consistent with the primary analysis. Subjects' schizophrenia symptoms remained stable throughout the study as evidenced by stable Positive and Negative Syndrome Scale scores. Overall, study medication was tolerated; however, an increased incidence of psychosis-related and sleep-related adverse events was associated with ABT-288.
  
  
  CONCLUSIONS
  Neither dose of ABT-288 resulted in cognitive improvement in clinically stable adults with schizophrenia.
authors: AbbVie Inc., North Chicago, IL; george.haig@abbvie.com.
authors: George M
authors: GM
authors: Haig
authors: AbbVie Inc., North Chicago, IL;
authors: Earle
authors: E
authors: Bain
authors: AbbVie Inc., North Chicago, IL;
authors: Weining
authors: W
authors: Robieson
authors: AbbVie Inc., North Chicago, IL; Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors: Ahmed A
authors: AA
authors: Othman
authors: AbbVie Inc., North Chicago, IL;
authors: Jeffrey
authors: J
authors: Baker
authors: AbbVie Inc., North Chicago, IL; Present address: Amgen, Thousand Oaks, CA.
authors: Robert A
authors: RA
authors: Lenz
mesh_terms: D000328:Adult; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004311:Double-Blind Method; D005260:Female; D054828:Histamine H3 Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy*; D017211:Treatment Failure
chemical_list: C576396:2-(4'-(5-methylhexahydropyrrolo(3,4-b)pyrrol-1-yl)biphenyl-4-yl)-2H-pyridazin-3-one; D054828:Histamine H3 Antagonists; D011724:Pyridazines; D011758:Pyrroles
keywords: cognition disorders; cognitive dysfunction; histamine-3 receptor; humans; therapy