• Jean-Louis Pépin, Ognian Georgiev, Rumen Tiholov, Valérie Attali, Johan Verbraecken, Bertien Buyse, Markku Partinen, Ingo Fietze, Georgi Belev, Dejan Dokic, Renaud Tamisier, Patrick Lévy, Isabelle Lecomte, Jeanne-Marie Lecomte, Jean-Charles Schwartz, Yves Dauvilliers, and HAROSA I Study Group.
• HP2 Laboratory, INSERM U1042, University Grenoble Alpes, and EFCR Laboratory, Grenoble Alpes University Hospital, Grenoble, France. Electronic address: JPepin@chu-grenoble.fr.
• Chest. 2021 Apr 1; 159 (4): 1598-1609.

BackgroundExcessive 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 QuestionIs 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 MethodsIn 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-to-treat 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.ResultsTwo 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 = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; 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 = .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 = .03). No cardiovascular or other significant safety concerns were reported.InterpretationPitolisant 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.Trial RegistryClinicalTrials.gov; No.: NCT01071876; URL: www.clinicaltrials.gov; EudraCT N°: 2009-017248-14; URL: eudract.ema.europa.eu.Copyright © 2020. Published by Elsevier Inc.

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