Rationale: Excessive daytime sleepiness is a common disabling symptom in 
obstructive sleep apnea syndrome.Objectives: To evaluate the efficacy and safety 
of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting 
effects, for the treatment of daytime sleepiness in patients with moderate to 
severe obstructive sleep apnea refusing continuous positive airway pressure 
treatment.Methods: In an international, multicenter, double-blind, randomized 
(3:1), placebo-controlled, parallel-design trial, pitolisant was individually 
titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in 
the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of 
wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, 
Clinical Global Impression of severity, patient's global opinion, EuroQol 
quality-of-life questionnaire, and Pichot fatigue questionnaire.Measurements and 
Main Results: A total of 268 patients with obstructive sleep apnea (75% male; 
mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) 
were randomized (200 to pitolisant and 68 to placebo) and analyzed on an 
intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more 
with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; 
P < 0.001). Wake maintenance tests were not improved. The Pichot fatigue score 
was reduced with pitolisant. The overall impact of pitolisant was confirmed by 
both physicians' and patients' questionnaires. Adverse event incidence, mainly 
headache, insomnia, nausea, and vertigo, was similar in the pitolisant and 
placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other 
significant safety concerns.Conclusions: Pitolisant significantly reduced 
self-reported daytime sleepiness and fatigue and improved patient-reported 
outcomes and physician disease severity assessment in sleepy patients with 
obstructive sleep apnea refusing or nonadherent to continuous positive airway 
pressure.Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and 
EU Clinical Trials Register (EudraCT 2009-017251-94).