Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment. A Randomized Trial

Abstract

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome. Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment. Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-oflife questionnaire, and Pichot fatigue questionnaire. Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-totreat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (22.8; 95% confidence interval, 24.0 to 21.5; P , 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns. Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure. Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

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

“…Procedures were similar to those of the companion study. 16 Randomization was centralized and performed via a website (Arone Projection; https://www.bioprojet-studies.org/). Randomization was on a 3:1 (three pitolisant for one placebo) basis (e-Appendix 1).…”

“…[13][14][15] We recently reported that pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in the specific phenotype of sleepy individuals with OSA who decline CPAP or are nonadherent to CPAP therapy. 16 The evaluation of pitolisant needs to be completed in the different subgroup of OSA individuals: those exhibiting residual sleepiness, despite good adherence to CPAP treatment. The objectives of the present study were to demonstrate the efficacy and safety of pitolisant given at 5 mg, 10 mg, or 20 mg once daily vs placebo over 12 weeks for the treatment of residual EDS in individuals undergoing well-managed CPAP therapy for moderate to severe OSA.…”

Histaminergic neurons in the tuberomammillary nucleus as a control centre for wakefulness

“…H 3 receptor negatively controls histamine synthesis and release as an autoreceptor and also regulates the release of other neurotransmitters such as dopamine, ACh, noradrenaline, adrenaline, glutamate and GABA (Nieto-Alamilla et al, 2016). Although expression levels of HRH3 in peripheral tissues are low (Lovenberg et al, 1999) (Dauvilliers et al, 2020;Liguori et al, 2020), Prader-Willi syndrome (Pullen et al, 2019) and anorexia nervosa (Scolnick, 2019 Fukui et al (1994). b Inoue et al (1996).…”

Pitolisant and Other Histamine-3 Receptor Antagonists—An Update on Therapeutic Potentials and Clinical Prospects

“…Only one clinical study assessing the efficacy of pitolisant in OSA has been published [38]. In the phase III, double-blind, placebo-controlled, parallel-group, multicenter trial, 268 patients with moderate to severe obstructive sleep apnea, who had refused treatment with CPAP were randomized and given placebo or pitolisant.…”