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.
OBJECTIVE
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 1h 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 < or = .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%).


CONCLUSIONS
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.
Merck Sharp and Dohme Corp., Whitehouse Station, NJ, USA. Electronic address: william.herring@merck.com.
W Joseph
WJ
Herring
Kenneth
K
Liu
Jill
J
Hutzelmann
Duane
D
Snavely
Ellen
E
Snyder
Paulette
P
Ceesay
Christopher
C
Lines
David
D
Michelson
Thomas
T
Roth
D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage; D003131:Combined Modality Therapy; D045422:Continuous Positive Airway Pressure; D018592:Cross-Over Studies; D006970:Disorders of Excessive Somnolence / Q000188:drug therapy* / Q000628:therapy; D004311:Double-Blind Method; D005260:Female; D017442:Histamine Agonists / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D011597:Psychomotor Performance / Q000187:drug effects*; D052999:Quinazolinones / Q000008:administration & dosage*; D020181:Sleep Apnea, Obstructive / Q000188:drug therapy* / Q000628:therapy; D016896:Treatment Outcome; D014851:Wakefulness / Q000187:drug effects*; D064690:Wakefulness-Promoting Agents / Q000008:administration & dosage; D055815:Young Adult
D001559:Benzhydryl Compounds; D017442:Histamine Agonists; C574738:MK-0249; D052999:Quinazolinones; D064690:Wakefulness-Promoting Agents; D000077408:Modafinil
Excessive daytime sleepiness; Histamine subtype-3 receptor; MK-0249; Modafinil; Obstructive sleep apnea; Randomized trial