Pitolisant for Residual Excessive Daytime Sleepiness in OSA Patients Adhering to CPAP

Abstract

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.

Current Management of Residual Excessive Daytime Sleepiness Due to Obstructive Sleep Apnea: Insights for Optimizing Patient Outcomes

“…• Most frequently reported TEAEs with pitolisant versus placebo: headache (14.8% vs. 11.5%), insomnia (9.3% vs. 3.3%) [ 98 ]…”

“…• Similar frequencies of severe treatment-related TEAEs and treatment-related TEAEs (headache, insomnia, diarrhea) with pitolisant and placebo [ 98 ]…”

“…• Post-dose QTcF > 450 ms and QTcF elongation ≥ 60 ms observed in several patients with pitolisant and placebo [ 97 , 98 ]…”

Residual excessive daytime sleepiness in patients treated for obstructive sleep apnea: guidance for assessment, diagnosis, and management

“…Pitolisant (Wakix ® ; Harmony Biosciences, LLC, Plymouth Meeting, PA) is a histamine-3 receptor antagonist approved in the United States to improve wakefulness and cataplexy in adults with narcolepsy and in the European Union for the treatment of narcolepsy with or without cataplexy in adults [81,102]. Recent phase 3 RCTs suggest pitolisant may reduce EDS in patients with OSA [86,103], but it is not currently approved for use in OSA [81,102]. Amphetamines (e.g.…”

“…Modafinil and armodafinil have been associated with a trend toward reduction in CPAP use, although both short-and longterm data suggest that adherence remains stable during treatment with solriamfetol [96,99,109]. It is unknown whether pitolisant impacts primary OSA therapy adherence [103]. Sometimes, despite best efforts by clinician and patient, patients remain nonadherent to primary OSA therapy.…”