Effect of daridorexant on sleep architecture in patients with chronic insomnia disorder: a pooled post hoc analysis of two randomized phase 3 clinical studies

Abstract Study Objectives Post hoc analysis to evaluate the effect of daridorexant on sleep architecture in people with insomnia, focusing on features associated with hyperarousal. Methods We studied sleep architecture in adults with chronic insomnia disorder from two randomized phase 3 clinical studies (Clinicaltrials.gov: NCT03545191 and NCT03575104) investigating 3 months of daridorexant treatment (placebo, daridorexant 25 mg, daridorexant 50 mg). We analyzed sleep–wake transition probabilities, EEG spectra, and sleep spindle properties including density, dispersion, and slow oscillation phase coupling. The wake EEG similarity index (WESI) was determined using a machine learning algorithm analyzing the spectral profile of the EEG. Results At month 3, daridorexant 50 mg decreased wake-to-wake transition probabilities (p .05) and increased the probability of transitions from wake-to-N1 (p .05), N2 (p .05), and REM sleep (p .05), as well as from N1-to-N2 (p .05) compared to baseline and placebo. Daridorexant 50 mg decreased relative beta power during wake (p = .011) and N1 (p .001) compared to baseline and placebo. During the wake, relative alpha power decreased (p .001) and relative delta power increased (p .001) compared to placebo. Daridorexant did not alter EEG spectra bands in N2, N3, and REM stages or in sleep spindle activity. Daridorexant decreased the WESI score during wake compared to baseline (p = .004). Effects with 50 mg were consistent between months 1 and 3 and less pronounced with 25 mg. Conclusions Daridorexant reduced EEG features associated with hyperarousal as indicated by reduced wake-to-wake transition probabilities and enhanced spectral features associated with drowsiness and sleep during wake and N1. Clinical Trials ClinicalTrials.gov NCT03545191: study to assess the efficacy and safety of ACT-541468 (daridorexant) in adult and elderly participants with insomnia disorder. URL: Study Details | study to assess the efficacy and safety of ACT-541468 (daridorexant) in adult and elderly participants with insomnia disorder | ClinicalTrials.gov ClinicalTrials.gov NCT03575104: study to assess the efficacy and safety of ACT-541468 (daridorexant) in adult and elderly participants who experience difficulties sleeping. URL: study details | study to assess the efficacy and safety of ACT-541468 (daridorexant) in adult and elderly participants who experience difficulties sleeping | ClinicalTrials.gov