Excessive daytime sleepiness (EDS) in individuals with obstructive sleep apnea syndrome persisting despite good adherence to continuous positive airway pressure (CPAP) is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects.Is pitolisant efficacious and safe in reducing daytime sleepiness in individuals presenting moderate to severe OSA adhering to CPAP treatment but having residual EDS?In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/day and taken over 12 weeks. The primary endpoint was change in the Epworth Sleepiness Scale (ESS) score in intention to treat. Key secondary endpoints were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test (OSleR), clinical global impressions of severity, the patient's global opinion, EQ-5D quality-of-life, Pichot Fatigue questionnaire scores and safety.244 OSA participants (82.8% male; mean age: 53.1 years, mean apnea+hypopnea index under CPAP: 4.2/hour, baseline ESS score: 14.7, were randomized to pitolisant (n=183) or placebo (n=61). ESS significantly decreased with pitolisant compared to placebo -2.6 (95%CI: [-3.9;-1.4]) (p<0.001) and the rate of responders to therapy (ESS≤10 or ΔESS≥3) was significantly higher with pitolisant (71.0% vs 54.1%; p=0.013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared to the placebo group (47.0% and 32.8%, p=0.03). No cardiovascular or other significant safety concerns were reported.Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduces subjective and objective sleepiness and improves participant-reported outcomes and physician-reported disease severity.