title: A randomized, double-blind, placebo-controlled, 16-week study of the H3 receptor antagonist, GSK239512 as a monotherapy in subjects with mild-to-moderate Alzheimer's disease.
abstract: BACKGROUND
  Histaminergic H3 receptors may play a role in modulating cholinergic and monoaminergic neurotransmission. This Phase II study evaluated the efficacy and safety of GSK239512, a highly potent, brain penetrant H3 receptor antagonist as monotherapy treatment for subjects with mild-to-moderate probable Alzheimer's disease (AD).
  
  
  METHODS
  In this 16-week, double-blind, randomized, parallel group study, 196 currently untreated subjects with mild-tomoderate AD (Mini Mental State Examination [MMSE] 16-24) received GSK239512 (n=97); or placebo (n=99) administered orally each morning. After a two-week placebo run-in period GSK239512 was up-titrated over 4 weeks in a flexible manner (10-20-40-80 microgram [µg]) followed by a 12-week Maintenance Phase. Co-primary efficacy endpoints were change from baseline in Episodic Memory and Executive Function/Working Memory composite scores from the CogState neuropsychological test battery (NTB) at Week 16.
  
  
  RESULTS
  Compared to placebo, GSK239512 improved Episodic Memory at Week 16 (Effect Size [ES] =0.35; p=0.0495). No statistically significant differences were observed on other cognitive domains or on clinical measures including the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADASCog). GSK239512 treatment was associated with mild to moderate adverse events with headache, dizziness and events related to sleep disturbances being the most common and more pronounced in the early titration period when subjects were first being exposed to GSK239512 at the lower 10µg and 20µg doses. There were no clinically relevant changes in other safety parameters.
  
  
  CONCLUSIONS
  GSK239512, at doses up to 80µg/day, improved Episodic Memory in patients with mildto- moderate AD. However, no improvements were observed on Executive Function/Working Memory or other domains of cognition. No changes were observed on any of the clinical measures included as secondary endpoints (including ADAS-Cog) indicating that GSK239512 failed to show benefit in this population. GSK239512 had an acceptable safety and tolerability profile. These findings suggest that H3 antagonists may, at most, have modest and selective effects on cognitive function in patients with mild-to-moderate AD.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Grove
authors.forename: Conn M
authors.initials: CM
authors.lastname: Harrington
authors.forename: Andreas
authors.initials: A
authors.lastname: Mahler
authors.forename: Isabel
authors.initials: I
authors.lastname: Beresford
authors.forename: Paul
authors.initials: P
authors.lastname: Maruff
authors.forename: Martin T
authors.initials: MT
authors.lastname: Lowy
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Nicholls
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Boardley
authors.forename: Alienor C
authors.initials: AC
authors.lastname: Berges
authors.forename: Pradeep J
authors.initials: PJ
authors.lastname: Nathan
authors.affiliation: Neurosciences Therapeutic Area, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC, 27709, USA. conn.m.harrington@gsk.com.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Horrigan
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy*; D001552:Benzazepines / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D056344:Executive Function / Q000187:drug effects; D005260:Female; D006633:Histamine Antagonists / Q000627:therapeutic use; D006801:Humans; D008297:Male; D055118:Medication Adherence; D061212:Memory, Episodic; D008570:Memory, Short-Term / Q000187:drug effects; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D001552:Benzazepines; C584220:GSK239512; D006633:Histamine Antagonists; D018697:Nootropic Agents