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-of-life 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-to-treat basis. The Epworth
Sleepiness Scale score was reduced more with
pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; 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).