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Clinical Trial
. 2025 Jun;34(3):e14373.
doi: 10.1111/jsr.14373. Epub 2024 Oct 8.

Pitolisant 40 mg for excessive daytime sleepiness in obstructive sleep apnea patients treated or not by CPAP: Randomised phase 3 study

Yves Dauvilliers  1 , Sonya Elizabeth Craig  2 , Maria R Bonsignore  3 , Ferran Barbé  4 , Johan Verbraecken  5 , Jerryl Asin  6 , Ognian Georgiev  7 , Rumen Tiholov  8 , Christian Caussé  9 , Jeanne-Marie Lecomte  9 , Jean-Charles Schwartz  9 , Philippe Lehert  10   11 , Winfried Randerath  12 , Jean-Louis Pépin  13 ; HAROSA III Study Group
Collaborators, Affiliations
Clinical Trial

Pitolisant 40 mg for excessive daytime sleepiness in obstructive sleep apnea patients treated or not by CPAP: Randomised phase 3 study

Yves Dauvilliers et al. J Sleep Res. 2025 Jun.

Abstract

Obstructive sleep apnea (OSA) syndrome commonly leads to excessive daytime sleepiness (EDS). Pitolisant, a selective histamine-3 receptor antagonist, is efficacious at doses up to 20 mg once daily in OSA treated or not with continuous positive airway pressure (CPAP). We assessed the efficacy and safety of pitolisant at doses up to 40 mg once daily in patients with moderate to severe OSA treated or not with CPAP therapy. In this phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trial, patients with OSA were assigned 2:1 to receive pitolisant (according to an individual up-titration scheme, 10, 20 or 40 mg once daily) or placebo for 12 weeks. The primary endpoint was a change in the Epworth Sleepiness Scale (ESS) score from baseline to week 12. Secondary endpoints included a change in reaction time using the Oxford Sleep Resistance test (OSleR), Clinical Global Impression of Change (CGI-C), and Patient's Global Opinion of the Effect (PGOE) of study treatment. Overall, 361 patients (mean age 52.4 years, 77.3% male; mean apnea-hypopnea index [AHI] 27.0 events/h) were randomised to receive pitolisant (n = 242; 50% received CPAP) or placebo (n = 119; 48.7% CPAP). After the dose-adjustment phase (week 3), 88.8% of patients received pitolisant 40 mg. Compared with placebo, pitolisant produced a significant reduction in the ESS score at week 12 (least square mean difference -2.6 (95% CI: -3.4; -1.8; p < 0.001)) irrespective of CPAP use; and improved the reaction time on OSleR, CGI-C, and PGOE at week 12. Pitolisant was well tolerated; no new safety signals were identified. In conclusion, pitolisant up to 40 mg once daily was an effective treatment for EDS in patients with moderate to severe OSA irrespective of CPAP use.

Keywords: continuous positive airway pressure; excessive daytime sleepiness; obstructive sleep apnea; pitolisant.

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Conflict of interest statement

JLP has received personal consulting fees, board engagements, and travel to conferences from Bioprojet, Jazz Pharmaceutical, and Idorsia. SC has received board engagements, honoraria for a lecture and travel to conferences from Bioprojet. MRB has received board engagements and travel to conferences from Bioprojet; seminars and travel to conferences from Jazz Pharmaceutical; consulting fees from Takeda Pharmaceuticals. FB has participated on a Data Safety Monitoring Board or Advisory Board for Bioprojet. JV has received funds for seminars, board engagements, and travel to conferences from Air Liquide, Atos Medical, Bioprojet, DEME, Desitin, Ectosense, Idorsia, Inspire Medical Systems, Jazz Pharmaceuticals, Löwenstein Medical, Medidis, Mediq Tefa, MSD, OSG, Philips, ProSomnus, ResMed Narval, SD Worx, Sefam, Somnolog, SomnoMed, Vemedia, Vivisol, and ZOLL Itamar. JA has attended advisory board meetings for Bioprojet; is a Board Member of the Dutch Sleep Medicine Association (SVNL); is a Board Member of the section SRBD (SAS) Dutch Pulmonary Association (NVALT). OG has no conflict of interest. RT has no conflict of interest. CC is an employee of Bioprojet Pharma. JML is the founder and current employee of Bioprojet Pharma. JCS is the co‐founder of Bioprojet. PL has received personal consulting fees from Bioprojet. WR has received personal fees/payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Heinen & Löwenstein, Habel Medizintechnik, Jazz Pharmaceuticals, Inspire, Philips Respironics, Bioprojet, and Westfalen Medical; personal fees of support for attending meetings and/or travel from: Heinen & Löwenstein, Jazz Pharmaceuticals, Philips Respironics, Habel Medizintechnik, and Bioprojet; personal fees for participation on a Data Safety Monitoring Board or Advisory Board from Bioprojet, Jazz Pharmaceuticals, Philips Respironics, Procter & Gamble; has had a leadership or fiduciary role in another board, society, committee or advocacy group, unpaid from European Respiratory Society Head Assembly 4, Sleep Disordered Breathing. YD has received funds for seminars, board engagements and travel to conferences from Jazz, Orexia, Idorsia, Takeda, Avadel, and Bioprojet.

Figures

FIGURE 1
FIGURE 1
CONSORT Diagram: Patient disposition. *In the pitolisant group, 241 patients took at least one tablet of pitolisant (safety population). CPAP, continuous positive airway pressure.
FIGURE 2
FIGURE 2
Mean ESS total scores by treatment at each assessment time in the double‐blind period – FAS (N = 361). ESS, Epworth Sleepiness Scale; FAS, full analysis set; N, number of patients in the FAS; n, number of patients in each group; SD, standard deviation; V, visit.
FIGURE 3
FIGURE 3
Line graph showing heart rate, systolic blood pressure, and diastolic blood pressure in the pitolisant and placebo groups over the 12 week double‐blind phase. DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure.
See this image and copyright information in PMC

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