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.

Journal Article (Journal Article;Multicenter Study)

INTRODUCTION: 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. CONCLUSION: 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.

Full Text

Duke Authors

Cited Authors

  • Grove, RA; Harrington, CM; Mahler, A; Beresford, I; Maruff, P; Lowy, MT; Nicholls, AP; Boardley, RL; Berges, AC; Nathan, PJ; Horrigan, JP

Published Date

  • January 2014

Published In

Volume / Issue

  • 11 / 1

Start / End Page

  • 47 - 58

PubMed ID

  • 24359500

Electronic International Standard Serial Number (EISSN)

  • 1875-5828

Digital Object Identifier (DOI)

  • 10.2174/1567205010666131212110148

Language

  • eng

Conference Location

  • United Arab Emirates