IMPORTANCE Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population. OBJECTIVE To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder. DESIGN, SETTING, AND PARTICIPANTS The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67

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Study Objectives: To identify dose(s) of lemborexant that maximize insomnia treatment efficacy while minimizing next-morning residual sleepiness and evaluate lemborexant effects on polysomnography (PSG) measures (sleep efficiency [SE], latency to persistent sleep [LPS], and wake after sleep onset [WASO]) at the beginning and end of treatment. Methods: Adults and elderly subjects with insomnia disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition were enrolled in a multicenter, randomized, double-blind, placebo-controlled, Bayesian, adaptive, parallel-group study, receiving lemborexant (1, 2.5, 5, 10, 15, 25 mg) or placebo for 15 nights. Efficacy assessments included a utility function that combined efficacy (SE) and safety (residual morning sleepiness as measured by Karolinska Sleepiness Scale [KSS]), PSG measures, and sleep diary. Safety assessments included KSS, Digit Symbol Substitution Test, computerized reaction time tests, and adverse events (AEs). Results: A total of 616 subjects were screened; 291 were randomized. Baseline characteristics were similar between lemborexant groups and placebo (~63% female, median age: 49.0 years). The study was stopped for early success after the fifth interim analysis when the 15-mg dose met utility index/KSS criteria for success; 3 other doses also met the criteria. Compared with placebo, subjects showed significant improvements in SE, subjective SE, LPS, and subjective sleep onset latency at the beginning and end of treatment for lemborexant doses ≥ 5 mg (P < .05). WASO and subjective WASO showed numerically greater improvements for doses > 1 mg. AEs, mostly mild to moderate, included dose-related somnolence. Conclusions: Lemborexant doses ranging from 2.5-10 mg provided efficacy for the treatment of insomnia while minimizing next-morning residual sleepiness.

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