Alertness and psychomotor performance effects of the histamine-3 inverse agonist mk-0249 in obstructive sleep apnea patients on continuous positive airway pressure therapy with excessive daytime sleepiness: A randomized adaptive crossover study

W. Joseph Herring, Kenneth Liu, Jill Hutzelmann, Duane Snavely, Ellen Snyder, Paulette Ceesay, Christopher Lines, David Michelson, Thomas Roth

Research output: Contribution to journalArticle

Abstract

Objectives: We aimed to evaluate the efficacy of the selective H3 receptor inverse agonist MK-0249 to treat excessive daytime sleepiness (EDS). Methods: In this three-period, double-blind, crossover study, 125 patients (100 men, 25 women; mean age, 48.6. years) with obstructive sleep apnea receiving nasal continuous positive airway pressure therapy who had refractory EDS were randomized to 2. weeks each of daily MK-0249 (5, 8, 10, or 12. mg, adaptively assigned), modafinil 200. mg, and placebo. At baseline and after each treatment period, six maintenance of wakefulness tests (MWT) and Psychomotor Vigilance Tasks (PVT) were conducted at 2-h intervals, beginning 1. h postdose (~09:00). The Epworth sleepiness scale (ESS), Clinical Global Impression of Severity (CGIS) and Digit Symbol Substitution Test (DSST) also were assessed. The primary end point was MWT sleep latency averaged over the first four time points (MWT-early). Results: MWT-early mean change from baseline sleep latency at week 2 was 1.2. min for placebo, 2.1. min for MK-0249 (top two doses pooled; P>. .05 vs placebo), and 5.9. min for modafinil ( P≤. .001 vs placebo). MK-0249 showed improvements vs placebo on secondary and exploratory end points of ESS, CGIS, PVT, and DSST. Insomnia adverse events (AEs) were greater for MK-0249 (combined doses, 17.5%) than for placebo (0.9%) or modafinil (1.8%). Conclusion: MK-0249 did not significantly affect MWT sleep latency. However, the pattern of improvement on subjective ratings and psychomotor performance end points suggested that MK-0249 was associated with changes in aspects of cognition and performance not captured by the MWT.

Original languageEnglish (US)
Pages (from-to)955-963
Number of pages9
JournalSleep Medicine
Volume14
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

Keywords

  • Excessive daytime sleepiness
  • Histamine subtype-3 receptor
  • MK-0249
  • Modafinil
  • Obstructive sleep apnea
  • Randomized trial

ASJC Scopus subject areas

  • Medicine(all)

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