Abstract
Objective To assess the dose-response of daridorexant, a new dual orexin receptor antagonist, on wake after sleep onset (WASO). Methods Elderly (≥65 years) participants (n = 58) with insomnia were randomly allocated (Latin square design) to receive 5 treatments (5, 10, 25, and 50 mg daridorexant and placebo) during 5 treatment periods, each consisting of 2 treatment nights followed by a 5- to 12-day washout period. Main efficacy endpoints were the absolute change from baseline in WASO (primary) and latency to persistent sleep (LPS; secondary) to days 1 and 2 (mean of 2 treatment nights assessed by polysomnography) in each period. Safety and tolerability were also assessed. Results Of 58 participants included, 67% were female, and the median age was 69 years (range 65–85 years). WASO and LPS were dose-dependently reduced from baseline to days 1 and 2 after daridorexant administration (multiple comparison procedure modeling, p < 0.0001 and p = 0.004, respectively); reductions were statistically significant for doses ≥10 mg compared with placebo (WASO: −32.0, −45.1, −61.4 minutes; LPS: −44.9, −43.8, −45.4 minutes for 10, 25, and 50 mg, respectively, p ≤ 0.025). Treatment-emergent adverse events were similar for daridorexant and placebo; the most frequent were fatigue, nasopharyngitis, gait disturbance, and headache (≤7% in any group). Conclusions Daridorexant was well tolerated. Dose-dependent improvements in WASO and LPS were statistically significant (dose range 10–50 mg) in elderly people with insomnia disorder. ClinicalTrials.gov identifier: NCT02841709. Classification of evidence This study provides Class I evidence that, for elderly people with insomnia, daridorexant reduced WASO.