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-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).

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

Figure 1.

Study design. D = day; DB = double-blind; ESS = Epworth Sleepiness Scale; SB = single blind; TC = telephone call; WO = wash out.

Figure 2.

Study flowchart. Causes of noneligibility were as follows: 10 due to patient decision and 20 due to exclusion criteria (6 significant cardiovascular disease or abnormality, 3 Epworth Sleepiness Scale score <12, 2 severe insomnia not associated with obstructive sleep apnea, 2 apnea–hypopnea index <15 events/h, 2 positive serological test [HIV], 1 severe depression [Beck Depression Inventory score >16], 1 substance abuse [opioids], 1 significant periodic limb movement disorder and central sleep apnea, 1 age <18 yr, and 1 adhering to continuous positive airway pressure therapy). AE = adverse event; D = day; DB = double-blind; ITT = intention to treat; LF = lost to follow-up; OL = open label; PD = patient decision; PP = per protocol; SAF = safety.

Figure 3.

Changes in Epworth Sleepiness Scale (ESS) score during treatment.