Number, Duration, and Distribution of Wake Bouts in Patients with Insomnia Disorder: Effect of Daridorexant and Zolpidem

Abstract

Background: Daridorexant, a dual orexin receptor antagonist approved in early 2022, reduces wake after sleep onset without reducing the number of awakenings in patients with insomnia. The objective of this post hoc analysis was to explore the effect of daridorexant on the number, duration, and distribution of night-time wake bouts, and their correlation with daytime functioning.

Methods: Adults with insomnia disorder were randomized 1:1:1:1:1:1 to placebo, zolpidem 10 mg, or daridorexant 5, 10, 25, or 50 mg in a phase II dose-finding study, and 1:1:1 to placebo or daridorexant 25 or 50 mg in a pivotal phase III study. We analyzed polysomnography data for daridorexant 25 and 50 mg, zolpidem 10 mg, and placebo groups. Polysomnography was conducted at baseline, then on Days 1/2, 15/16, and 28/29 in the phase II study, and Months 1 and 3 in the phase III study. The number, duration, and distribution of wake bouts (≥ 0.5 min) were assessed.

Results: Data from 1111 patients (phase II study: daridorexant 50 mg [n = 61], zolpidem 10 mg [n = 60], placebo [n = 60]; phase III study: daridorexant 25 mg [n = 310], daridorexant 50 mg [n = 310], placebo [n = 310]) were analyzed. Long wake bouts were defined as > 6 min. Compared with placebo, daridorexant 50 mg reduced overall wake time (p < 0.05; all time points, both studies), the odds of experiencing long wake bouts (p < 0.001; Months 1 and 3, phase III study), and the cumulative duration of long wake bouts (p < 0.01; all time points, both studies). Reductions in long wake bouts were sustained through the second half of the night and correlated with improvements in daytime functioning. An increase in the cumulative duration of short wake bouts was observed with daridorexant 50 mg (p < 0.01 vs placebo, Months 1 and 3, phase III study); this was uncorrelated with daytime functioning.

Conclusion: Daridorexant reduced the number and duration of longer wake bouts throughout the night compared with placebo, corresponding with improved daytime functioning.

Clinical trials: Clinicaltrials.gov NCT02839200 (registered July 20, 2016), NCT03545191 (registered June 4, 2018).

Fig. 1

Mean cumulative time in wake bouts across the sleep period with daridorexant 50 mg. The figures show the progression of the mean cumulative time spent in wake bouts (y-axis) over the 8-h PSG night (x-axis). The area around the mean time lines represent the 95% CI. The blue (daridorexant 50 mg) and green (zolpidem 10 mg) bars at the bottom of the figures indicate when the cumulative time in wake bouts was statistically significant when compared with placebo (p < 0.05). The black lines at the bottom of the figures display when the cumulative time in wake bouts on daridorexant 50 mg was statistically significant when compared with zolpidem 10 mg (p < 0.05). PSG data were recorded over two consecutive nights at each timepoint; data for each timepoint represent the mean of the two recordings. Subjects with ≥ 1 night of PSG data at each timepoint were included. CI confidence interval, n number of subjects, PSG polysomnography

Fig. 2

Mean cumulative time in long and short wake bouts with daridorexant 50 mg. Mean cumulative time spent in short and long wake bouts over the entire 8-h PSG night, at baseline, Day 1/2, and Day 28/29 in the phase II study, and baseline, Month 1, and Month 3 in the phase III study. The asterisks compare treatment groups to placebo; *p < 0.05, **p < 0.01, ***p < 0.001. Daggers indicate the comparison with zolpidem; ^†p < 0.05, ^††p < 0.01, ^†††p < 0.001. The absence of asterisks or daggers shows the lack of significant difference between the groups. PSG data were recorded over two consecutive nights at each timepoint; data for each timepoint represent the mean of the two recordings. Subjects with ≥ 1 night of PSG data at each timepoint were included. n number of subjects, PSG polysomnography

Fig. 3

Association of long (> 6 min) and short (≤ 6 min) wake bouts to next-day daytime functioning (IDSIQ sleepiness domain) with daridorexant 50 mg. Change from baseline in long and short wake bouts plotted versus change from baseline in IDSIQ sleepiness domain score for daridorexant 50 mg and placebo. The slope indicates the change in IDSIQ score for every 1-min change in time spent in long or short wake bouts, per treatment group. The shaded area around the mean score indicates the 95% CI. The p-value compares the mean difference in IDSIQ scores between daridorexant and placebo; values < 0.05 are considered statistically significant. PSG data were recorded over two consecutive nights at each timepoint; data for each timepoint represent the mean of the two recordings. Subjects with ≥ 1 night of PSG data at each timepoint were included. CI confidence interval, IDSIQ Insomnia Daytime Symptoms and Impacts Questionnaire, n number of subjects with available data at given timepoint, PSG polysomnography