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

Interviewer: What was the main objective of your study?

Tobias Di Marco: The main objective was to evaluate the effect of daridorexant, a dual orexin receptor antagonist (DORA), on sleep architecture in patients with chronic insomnia disorder. Specifically, we investigated whether daridorexant can reduce electroencephalogram (EEG) features associated with hyperarousal by assessing the effect on sleep–wake transitions, changes to EEG spectral power content, and changes to sleep spindle features. The analysis used data from two randomized phase 3 clinical studies (Clinicaltrials.gov: NCT03545191 and NCT03575104) investigating 3 months of daridorexant treatment.

Interviewer: Please explain what hyperarousal is and why focus the analysis on the effect of daridorexant on EEG features of hyperarousal?

Tobias Di Marco: While hyperarousal lacks a universal definition, it is typically described as a persistent state of cognitive, emotional, physical, or cortical activity in patients suffering from chronic insomnia. One of the leading hypotheses in insomnia research is that hyperarousal is likely the main factor contributing to the poor sleep quality and reduced sleep duration in patients with chronic insomnia. EEG measures, including spectral analyses or quantification of sleep microarchitecture (e.g. spindle-derived metrics), can provide insights into the level of hyperarousal in the brain. For example, during spectral analyses, increased beta and alpha EEG activity during the night can be a marker of a higher aroused brain state.

Interviewer:  Could you describe the study design and methods?

Tobias Di Marco: We analysed polysomnograms (PSGs) from two phase 3, placebo-controlled randomized studies that evaluated the safety and efficacy of daridorexant vs placebo in adult patients with chronic insomnia disorder (ClinicalTrials.gov identifier NCT03545191 and NCT03575104). All study patients randomized in the two studies to daridorexant 25 mg, 50 mg, or placebo for 3 months and with PSG data available at baseline, 1 month and 3 months, were included in the analysis. Study participants had insomnia disorder as per DSM-5 criteria, defined as problems with sleep onset, sleep maintenance, or early morning awakenings for at least 3 months, with associated daytime functioning impairments.

Interviewer: Could you describe the main outcomes of your study? 

Tobias Di Marco:  Our analysis demonstrated that daridorexant 50 mg had a significant impact on sleep transitions and brain activity patterns. Specifically, it decreased transitions from sleep to wake and increased transitions from wake to NREM and REM sleep stages over three months, compared to placebo. Additionally, we observed a reduction in relative alpha and beta power (markers commonly associated with wakefulness) and an increase in delta power during wake at both Months 1 and 3. No significant effects were seen on spectral power in deeper sleep stages like N2, N3, and REM or on sleep spindle properties.

Overall, this suggests that daridorexant not only supports quicker transitions into sleep but also reduces features of hyperarousal, a hallmark of chronic insomnia. The effects were dose-dependent, with the 50 mg dose showing more pronounced benefits compared to the 25 mg dose.

Interviewer: Are there any study limitations?

Tobias Di Marco: While the results are exciting, we still have to acknowledge the limitations of our study. This is an exploratory analysis, and as such,h all results are considered hypothesis-generating only. Despite this limitation, we consistently observed significant differences between treatment groups across multiple measures.

Interviewer: What does this study add to the field of research on chronic insomnia?

Tobias Di Marco:. Together with our companion paper (J Sleep Res  2024 Jun 9:e14256.  doi: 10.1111/jsr.14256) the findings in this paper add to the ongoing research on hyperarousal as a key factor in the pathophysiology of chronic insomnia. Our analysis demonstrated how daridorexant reduces EEG markers of hyperarousal, thus addressing one of the root causes of chronic insomnia. Together with the ESRS insomnia guidelines, these insights can inform physicians in their discussions with patients on the most appropriate pharmacological options for treating chronic insomnia.