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Objective To evaluate the dose–response relationship of daridorexant, a new dual orexin receptor antagonist, on sleep variables in subjects with insomnia disorder. Methods Adults (≤64 years) with insomnia disorder were randomized (1:1:1:1:1:1) to receive daily oral placebo, daridorexant (5, 10, 25, or 50mg), or 10mg zolpidem for 30 days. The primary efficacy outcome was the change in wake time after sleep onset from baseline to days 1 and 2. Secondary outcome measures were change in latency to persistent sleep from baseline to days 1 and 2, change in subjective wake time after sleep onset, and subjective latency to sleep onset from baseline to week 4. Safety was also assessed. Results Of 1,005 subjects screened, 359 (64% female) were randomized and received ≥1 dose. A significant dose–response relationship (multiple comparison procedure‐modeling, 2‐sided p < 0.001) was found in the reduction of wake after sleep onset and latency to persistent sleep from baseline to days 1 and 2 with daridorexant. These reductions were sustained through to days 28 and 29 (p = 0.050 and p = 0.042, respectively). Similar dose‐dependent relationships were observed for subjective wake after sleep onset and subjective latency to sleep onset. The incidence of treatment‐emergent adverse events was 35%, 38%, 38%, and 34% in subjects treated with 5, 10, 25, and 50mg daridorexant, respectively, compared with 30% for placebo, and 40% for 10mg zolpidem. There were no clinically relevant treatment‐related serious adverse events. Four subjects withdrew due to adverse events. Interpretation Daridorexant induced a dose‐dependent reduction in wake time after sleep onset in subjects with insomnia disorder (http://clinicaltrials.gov NCT02839200). Ann Neurol 2020;87:347–356

ObjectiveTo assess the dose-response of daridorexant, a new dual orexin receptor antagonist, on wake after sleep onset (WASO).MethodsElderly (≥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.ResultsOf 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).ConclusionsDaridorexant 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 evidenceThis study provides Class I evidence that, for elderly people with insomnia, daridorexant reduced WASO.