TY - JOUR
T1 - 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
T2 - A randomized adaptive crossover study
AU - Herring, W. Joseph
AU - Liu, Kenneth
AU - Hutzelmann, Jill
AU - Snavely, Duane
AU - Snyder, Ellen
AU - Ceesay, Paulette
AU - Lines, Christopher
AU - Michelson, David
AU - Roth, Thomas
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
KW - Excessive daytime sleepiness
KW - Histamine subtype-3 receptor
KW - MK-0249
KW - Modafinil
KW - Obstructive sleep apnea
KW - Randomized trial
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U2 - 10.1016/j.sleep.2013.04.010
DO - 10.1016/j.sleep.2013.04.010
M3 - Article
C2 - 23920422
AN - SCOPUS:84883768395
SN - 1389-9457
VL - 14
SP - 955
EP - 963
JO - Sleep Medicine
JF - Sleep Medicine
IS - 10
ER -