0407 ACT-541468, A Dual Orexin Receptor Antagonist, For The Treatment Of Insomnia Disorder: A Randomized, Double-Blind, Placebo-Controlled, 5-Period, 5-Treatment Crossover Dose-Response Phase 2 Study In The Elderly. (12th April 2019)

• Record Type: Journal Article
• Authors: Zammit, Gary; Dauvilliers, Yves; Pain, Scott; Kinter, Dalma Seboek; Kunz, Dieter
• Is Part Of: Sleep. Volume 42(2019)Supplement 1
• Page Start: A165
• Page End: A165
• Publication Date: 2019-04-12
• Subjects: Sleep -- Physiological aspects -- Periodicals; Sleep disorders -- Periodicals; Sommeil -- Aspect physiologique -- Périodiques; Sommeil, Troubles du -- Périodiques; Sleep disorders; Sleep -- Physiological aspects; Sleep -- physiological aspects; Sleep Wake Disorders; Psychophysiology; Electronic journals; Periodicals; 616.8498
• DOI: 10.1093/sleep/zsz067.406
• Languages: English
• ISSNs: 0161-8105

Abstract

Abstract: Introduction: Most hypnotic treatments for insomnia disorder negatively impact next-day functioning in the elderly. ACT-541468 is a potent and selective dual orexin receptor antagonist that has shown minimal residual next-day effects in Phase 2. We present data from a polysomnography (PSG) dose-response study of ACT-541468 in elderly subjects with insomnia disorder. Methods: Eligible elderly (≥65 years) subjects with insomnia disorder (Diagnostic and Statistical Manual of Mental Disorders, 5 th edition criteria) had wake after sleep onset (WASO) ≥30 min, latency to persistent sleep (LPS) ≥30 min, total sleep time <6.5 h and were randomly allocated to 1 of 5 treatment sequences (Latin square design). Treatment (5 mg, 10 mg, 25 mg, 50 mg ACT-541468 and placebo) was administered on Days1&2 of each of the five treatment periods, followed by a 5-12-day washout. The main efficacy endpoints were the change from baseline (placebo run-in) in WASO (primary) and LPS (secondary) to Days1&2 (mean of PSG on Days1&2). The dose-response of ACT-541468 on WASO and LPS was evaluated using generalized MCP-Mod methodology. Self-reported next-day functioning (daytime alertness, morning sleepiness, daytime ability to function) was assessed by a visual analog scale. Results: Of 149 subjects screened, 58 (67% female; median age 69 years [range 65-85]) were randomized. A dose-response relationship was demonstrated for WASO (p≤0.0001) and LPS (p≤0.025). Observed mean reductions from baseline to Days1&2 for ascending doses for WASO were; (placebo, −14.13), −18.43, −32.37, −44.20, and −61.11 min and for LPS were; (placebo, −33.88), −37.92, −44.61, −44.81, and −44.88 min. Self-reported next-day functioning was improved across all groups. The most frequent treatment-emergent adverse events were fatigue, nasopharyngitis, gait disturbance, and headache (all ≤7%), with no apparent relationship to dose (except fatigue [50 mg], 7%). Conclusion: A significant dose-response was established for ACT-541468 in the reduction of WASO and LPS, with no dose-limiting safety events. No increase in next-day excessive sleepiness related to treatment was reported. Further long-term studies of ACT-541468 are warranted. Support (If Any): None