on behalf of the HAROSA I Study Group * BACKGROUND: Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects.RESEARCH QUESTION: Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS? STUDY DESIGN AND METHODS: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-totreat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety.RESULTS: Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n ¼ 183) or placebo (n ¼ 61). ESS significantly decreased with pitolisant compared with placebo (À2.6; 95% CI, -3.9 to À1.4; P < .001), and the rate of responders to therapy (ESS # 10 or change in ESS $ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P ¼ .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P ¼ .03). No cardiovascular or other significant safety concerns were reported.INTERPRETATION: Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity.
Auditory event‐related potentials (ERP), multiple sleep latency tests, mini‐mental state exam, and depression tests were studied in 15 patients with obstructive sleep apnea syndrome (OSA). The P3 wave latency of ERP was significantly increased compared with 15 age‐matched control subjects. After 4 weeks and after 1 year of treatment of OSA by nasal continuous positive airway pressure (CPAP), there was no significant improvement in the abnormalities of ERP. These observed changes in ERP were not correlated with excessive daytime sleepiness, depression, nocturnal hypoxemia, and sleep fragmentation. The cause of increased P3 latency has not been elucidated, but a chronic cerebral insult was suspected.
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