Efficacy and safety of pitolisant in residual excessive daytime sleepiness for patients with obstructive sleep apnea adhering to continuous positive airway pressure therapy in the HAROSA studies: An individual patient meta-analytical approach

Purpose: Obstructive sleep apnea (OSA) is typically treated with continuous positive airway pressure (CPAP) therapy. Some patients experience residual excessive daytime sleepiness (EDS) under CPAP. Pitolisant demonstrated effectiveness in reducing EDS. An individual patient meta-analysis was conducted assessing the efficacy and safety of pitolisant 20 mg and 40 mg versus placebo to treat EDS in patients with OSA using CPAP. Methods: A study-patient, hierarchical, random-effects model was used. Epworth Sleepiness Scale (ESS) and Oxford Sleep Resistance test (OSLER) were co-primary endpoints. Secondary endpoints included EDS-Z scores, fatigue, clinical global impression, and quality of life (QoL). Results: The searches identified three randomized controlled trials. Individual patient data were derived from 423 patients (placebo: n = 120, pitolisant 20 mg: n = 183, pitolisant 40 mg: n = 120). Treatment effects on ESS were -3.20 (95 % confidence interval [CI]: 4.37, -2.00; P < 0.001) and -3.57 (95 % CI: 4.87, -2.80); P < 0.001) for the 20 mg and 40 mg doses, with corresponding standardized mean differences (SMD) of -0.71 (95 % CI: 0.45, -0.97) and -0.79 (95 % CI: 0.51, -1.08). Treatment effects in minutes for OSLER were 1.24 (95 % CI: 0.60, 1.10, SMD = 0.61; P = 0.001) and 1.21 (95 % CI: 0.06, 1.38, SMD = 0.51; P = 0.006). Pitolisant 40 mg was superior to the 20-mg dose for older age (>= 50 years) and higher baseline apnea-hypopnea index values (>= 15). No significant differences were observed for safety outcomes. Conclusion: Pitolisant 20 mg and 40 mg were significantly therapeutically superior to placebo in treating residual EDS in patients with OSA who received CPAP on the outcomes for ESS, OSLER, and QoL.