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).
Supplementary Information
The online version contains supplementary material available at 10.1007/s40263-023-01020-9.
Key Points
| Many patients with insomnia disorder spend substantial time in long night-time wake bouts. |
| Compared with placebo, daridorexant improved wake time during the night from Day 1/2 of treatment, mainly by reducing the number of and time spent in long wake bouts. |
| Reductions in long night-time wake bouts were associated with improved daytime functioning for up to 3 months. |
Introduction
Insomnia disorder is a highly prevalent disease with heterogeneous phenotypes that can evolve over time [1, 2]. Insomnia is often associated with objective changes in polysomnography (PSG) parameters [3], including a decrease in total sleep time, longer sleep latency, reduced sleep efficiency, and increased time in wake after sleep onset (WASO). Furthermore, ageing worsens the maintenance of sleep and increases early-morning awakenings [4]. In patients with poor sleep maintenance, long duration wake bouts may be the biggest concern, because shorter bouts may not be remembered [5].
Several approved insomnia treatments with different mechanisms of actions exist. One of the most prescribed classes—the gamma-aminobutyric acid (GABA) receptor agonists—is usually indicated for short-term treatment, because their use is associated with tolerance and dependence, as well as adverse effects related to impaired cognition [6–8]. Because many insomnia medications fail to improve sleep maintenance, a need remains for long-term, efficacious, and safe treatments for people with insomnia disorder [9].
The orexin system has been identified as a target for developing a new class of insomnia medications. Orexins, also known as hypocretins, are hypothalamic neuropeptides that regulate wakefulness and sleep. Specifically, orexins bind to the orexin-1 and orexin-2 receptors to help maintain long periods of wakefulness and suppress rapid eye movement (REM) sleep [10, 11]. The potential of orexin receptor antagonists in inducing sleep was first shown in humans with the dual orexin receptor antagonist (DORA) almorexant [12]. To date, three DORAs (suvorexant, lemborexant, and daridorexant) have been approved in the US for insomnia disorder characterized by difficulties with sleep onset and/or sleep maintenance; daridorexant is the only DORA that has also been approved in the EU [13–15].
Daridorexant has been developed to target an optimal half-life of approximately 8 h [16–18]: long enough to cover the duration of the night but short enough to minimize next-morning residual effects. Phase II studies showed that daridorexant improved objective sleep onset (latency to persistent sleep [LPS]) and maintenance (WASO) as early as after the first two nights of treatment [19, 20]. Two pivotal phase III studies demonstrated the efficacy of daridorexant in improving both WASO and LPS in adults and elderly patients for up to 3 months of treatment [15].
Even though daridorexant reduced WASO in these phase III studies, it did not reduce the total number of self-reported awakenings or objective wake bouts at Months 1 and 3 [15], probably because simple analysis of total wake bouts overlooks key aspects of orexin neurobiology. Specifically, loss of orexin signaling in animal models and in people with narcolepsy results in fewer long wake bouts and more short wake bouts [21], which is in agreement with the role of the orexin system in stabilizing wake time [22–25]. In line with this, the DORA suvorexant (40/30 mg and 20/15 mg) reduced the time spent in longer wake bouts (defined as wake bouts > 2 min), while increasing the number and time spent in shorter wake bouts (defined as ≤ 2 min) in patients with insomnia disorder [26]. Whether this wake bout modulation of suvorexant is replicated with daridorexant has not yet been investigated.
In these exploratory analyses, we analyzed wake bout data from phase II and III studies in adult patients with insomnia to understand if the improvement in WASO observed with daridorexant is due to fewer wake bouts overall or less time spent in longer wake bouts [15, 20]. Data from the daridorexant phase II study were also used to describe any class differences between two different hypnotics: daridorexant and the widely prescribed zolpidem [27].
Methods
The design and results of the phase II and III studies have been published previously [15, 20]. In brief, the phase II study was a multicenter, randomized, double-blind, placebo-controlled, active-reference, parallel-group study (NCT02839200). A total of 360 adults aged 18–64 years with insomnia disorder were randomized (1:1:1:1:1:1), of whom 359 patients received at least one dose of the assigned study drug and were included in the full analysis set (FAS): daridorexant 5 mg (n = 60), 10 mg (n = 58), 25 mg (n = 60), 50 mg (n = 61), placebo (n = 60), or zolpidem 10 mg (n = 60) once daily for 30 days. The phase III study (NCT03545191) was a multicenter, randomized (1:1:1), double-blind, placebo-controlled, parallel-group trial of adults aged ≥ 18 years with insomnia disorder; 930 patients were randomized to receive the assigned study drug once daily for 3 months and were included in the FAS: daridorexant 25 mg (n = 310), daridorexant 50 mg (n = 310) or placebo (n = 310). Both studies were approved by the appropriate health authority, ethics committee, or institutional review board for each participating site and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments [28]. Informed consent was obtained from all individual participants included in the studies.
In both studies, all patients were diagnosed with insomnia disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [29], and were required to have a self-reported history of ≥ 30 min to fall asleep, ≥ 30 min of WASO, and a total sleep time of ≤ 6.5 h. In the phase II study, PSG assessments were performed on two consecutive nights at baseline, then on Days 1 and 2, 15 and 16, and 28 and 29. In the phase III study, PSG assessments were performed on two consecutive nights during baseline, Month 1, and Month 3.
According to the American Academy of Sleep Medicine manual for scoring sleep, there are four sleep stages: three stages of non-REM sleep (N1, N2 and N3, the latter of which is characterized by slow-wave sleep) and one stage of REM sleep [30]. In these analyses, the wake-bout period was defined as the period after the onset of persistent sleep (i.e., 20 consecutive 0.5-min epochs scored as ‘non-wake’ [N1, N2, N3 or REM]). The minimum duration for a wake bout was defined as 0.5 min (i.e., 1 epoch) and the (potential) maximum duration as 470 min (= 8 [h] × 60 [min] − 10 [min] for the minimal duration of LPS) during an 8-h PSG night. Wake time refers to the total time awake from the onset of persistent sleep to lights on.
This exploratory analysis focuses on PSG nights at baseline, Day 1/2, and Day 28/29 of the phase II study, as well as baseline, Month 1, and Month 3 of the phase III study. Patients from the FAS for the phase II and III studies were included in the current analyses. The daridorexant 5-mg and 10-mg groups were not included in the current analysis because these doses were either not further evaluated or did not show a relevant improvement in the phase III program and do not represent the approved doses [31].
Statistical Methods
Threshold Derivation
Previous groups, including Svetnik et al. [26], have proposed threshold derivations that distinguish between short and long wake bouts. This analysis includes a new proposal for calculating a derivation that is based on the current patient population. To ensure a robust sample population with minimal variability in sleep parameters, data for all patients from the phase II study (all of whom were aged 18–64 years) and for patients aged 18–64 years from the phase III study were included; all subsequent analyses of phase III study data included all randomized patients, irrespective of age.
The derivation of the threshold assumes that patients with insomnia are more likely to remember and report longer awakenings for each PSG night [5]. We therefore linked self-reported number of awakenings (NOA; collected daily via a sleep diary throughout the phase II and III studies) with wake-bout data collected during PSG nights, to determine a threshold that would represent long or likely memorable wake bouts for this population. To achieve this, NOA data were matched with the longest wake bouts during the same PSG night; for example, if a patient reported 10 subjective awakenings in one night, these would be matched with the 10 longest objective wake bouts in their PSG data from the same night. For each patient, the shortest of these objective wake bouts was selected. The mean of those shortest wake bouts was then calculated across all patients and PSG nights at baseline (independent of treatment assignment), and the lower boundary of the 95% confidence interval (CI) was considered to be the threshold distinguishing long from short wake bouts. The threshold was derived for both phase II and III studies separately and pooled for the adult population.
Statistical Analyses
The cumulative time in wake bouts was derived in 0.5-min increments over the whole 8-h PSG night and presented as a step function, with 95% CIs and p-values comparing active treatments versus placebo, based on t tests for independent samples (i.e., 960 t tests in total; one for each of the 0.5-min steps of a 480-min PSG night). The mean cumulative time in wake bouts was calculated across treatment groups and visits (displayed on the y-axis) over the 8-h PSG night (displayed on the x-axis). The rationale behind using t tests was that the number of parameters to be estimated via mixed models would have been too large, producing unreliable estimates. Significant p-values of the t tests (at a 0.05 level) are provided underneath the step function in bar graphs.
Logistic regression models for repeated measurements were fitted to compare the odds of subjects having long wake bouts (> 6-min threshold) across active treatment groups and placebo. The logistic regressions included the binary variable of subjects with long wake bouts (yes vs no) as response variable, treatment group, visit, and subjects with long wake bouts at baseline (yes vs no) as factors, and the interactions of treatment by visit and baseline by visit. The resulting odds ratios (ORs) were expressed separately by PSG night.
The time spent in short and long wake bouts was derived for baseline and post-baseline visits based on the new threshold definition, as proposed above. Statistical comparisons were made for the time spent in short and long wake bouts via mixed models for repeated measurements (MMRMs), with the time spent in short/long wake bouts as response variable, treatment group and visit as factors, baseline as covariate, and the interactions of treatment group by visit, and baseline by visit.
In addition, each 8-h PSG night was divided into four quarters (of 2 h each) to compare the mean number of long wake bouts across treatments and visits for each quarter of the night.
For the time spent in short and long wake bouts, and the distribution of short and long wake bouts throughout the sleep period, additional analyses using the threshold proposed by Svetnik et al. (≤ 2 min for short and > 2 min for long wake bouts) were performed, to allow comparisons with existing literature [26]. The odds of subjects having long wake bouts were not analyzed using this threshold, because almost all patients had wake bouts > 2 min.
To explore the correlation between wake-bout outcomes and a clinical outcome scale, we used the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) data from the phase III study, which compared daridorexant with placebo (IDSIQ data were not captured in the phase II study). IDSIQ is a validated questionnaire used to assess daytime functioning in subjects with insomnia [32]. We analyzed IDSIQ total score, as well as the alert/cognition, mood, and sleepiness domains, with a focus on the sleepiness domain (given that this was a key secondary endpoint in the phase III study). Another MMRM was fitted, with the change from baseline in corresponding IDSIQ score as response, treatment group and visit as factors, corresponding baseline IDSIQ score and change of time in short/long wake bouts as covariates, and all four interactions of the variables treatment group, visit and change of time in short/long wake bouts, and a baseline by visit interaction. Two MMRMs were fitted, analyzing the change in time of short and long wake bouts separately.
All statistical analyses were performed with SAS® 9.4 (SAS® Institute Inc., Cary, NC, USA).
Results
Patient Characteristics
Data for a total of 1111 patients were included in these analyses: 181 from the phase II study (60 patients in each of the placebo and zolpidem arms and 61 in the daridorexant 50-mg arm) and 930 from the phase III study (310 patients in each of the placebo and daridorexant 25-mg and 50-mg arms) [15, 20]. As published previously [15, 20], patient characteristics and baseline sleep parameters were similar across groups; these are summarized in Supplementary Appendix 1, with sleep parameters at baseline shown in Table S1 (see electronic supplementary material [ESM]).
Key Sleep Parameter Outcomes
The effects of daridorexant 25 mg and 50 mg on key sleep parameters have been published previously [15, 20] and are summarized in Table S1 (see ESM). In summary, in the phase II study, significant dose–response relationships were observed between daridorexant and WASO and LPS reduction, as well as the magnitude of total sleep time (TST) increase (all p < 0.001 through Days 28 and 29); a significant dose-dependent increase in subjective TST (sTST) through Week 4 was also observed (p = 0.006). In the phase III study, daridorexant 25 mg and 50 mg led to significant improvements versus placebo in WASO, LPS, and sTST at Months 1 and 3 (all p < 0.05); increases in TST compared with baseline were higher in the daridorexant than placebo groups, with the highest increase observed in the daridorexant 50-mg group.
Defining Long and Short Wake Bouts
In these analyses, results from the phase II study showed a mean duration of derived ‘perceived’ awakenings of 6.38 min (95% CI 5.89–6.91; Table 1). The analysis was repeated in the population of patients aged 18–64 years in the phase III study and results were similar, with a mean duration of derived ‘perceived’ awakenings of 6.69 min (95% CI 6.26–7.15). To re-derive the threshold from the largest possible population, the analysis was repeated on all adult subjects aged 18–64 years from the phase II and III studies, resulting in a mean duration of derived ‘perceived’ awakenings of 6.57 min (95% CI 6.24–6.91). Based on these findings, we defined short wake bouts as all wake bouts that differ significantly from the shortest derived wake bout, that is, all wake bout durations being shorter than the lower 95% CI of 6.24 min. Thus, short wake bouts were defined as ≤ 6 min, while long wake bouts were defined as > 6 min. This newly defined threshold for long wake bouts was used in subsequent analyses, irrespective of age restrictions. The > 2-min threshold for long wake bouts proposed by Svetnik et al. [26] was also used in some analyses to allow comparisons with existing literature.
Table 1.
Derivation of long and short wake bouts by studies at baseline
| Study | Mean | 95% CI |
|---|---|---|
| Overall—Age: < 65 years (N = 924) | 6.57 | 6.24–6.91 |
| Phase II study—Age: < 65 years (n = 358) | 6.38 | 5.89–6.91 |
| Phase III study—Age: < 65 years (n = 566) | 6.69 | 6.26–7.15 |
Mean and 95% CI for the derived wake-bout duration of the phase II and III studies for subjects aged < 65 years. To ensure a robust sample population with minimal variability in sleep parameters for this derivation activity, data for all patients from the phase II study (all of whom were 18–64 years old) and for patients 18–64 years old from the phase III study were included. Patients with missing PSG data at baseline were excluded from the derivation analysis. CI confidence interval, n number of subjects included in analysis, PSG polysomnography
Mean Cumulative Wake Time Across the Sleep Period
In the phase II study, the mean cumulative wake time was similar between daridorexant 50-mg, zolpidem, and placebo groups at baseline (Fig. 1). On Day 1/2, the curves of active treatments and placebo started to separate early during the night, with daridorexant 50 mg showing a constant reduction in wake time compared with placebo during the course of the night. At the end of the night, the decrease in wake time with daridorexant 50 mg was 45.5 min compared with baseline, with a placebo-corrected decrease of 26 min. Zolpidem showed similar efficacy early in the night, but the curves of both active treatments started to separate after approximately 210 min. Daridorexant 50 mg was significantly different from zolpidem 10 mg after 390 min (p < 0.05). Approximately 390 min after the beginning of the recording, zolpidem 10 mg no longer differed from placebo. In contrast, daridorexant 50 mg differed from placebo from around 60 min up until the end of the night. On Day 28/29, the reduction in time spent in wake bouts was not significantly different between patients receiving zolpidem 10 mg and patients receiving placebo at the beginning of the night (up to approximately 150 min) or toward the end of the night (after 300 min). For patients receiving daridorexant 50 mg, the reduction in the time spent in wake bouts was significantly greater compared with patients receiving placebo from approximately 150 min up to the end of the night, and significantly greater compared with patients receiving zolpidem 10 mg after 410 min; these results were similar to those observed on Day 1/2.
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
The analysis was repeated for the phase III study (Fig. 1, Fig. S1 [see ESM]). At baseline, the mean cumulative wake time was similar between treatment groups. After 1 and 3 months of treatment with daridorexant 50 mg, the mean cumulative time in wake bouts was significantly lower compared with placebo from 90 min onwards at Month 1, and from 140 min onwards at Month 3 (both p < 0.05). The effect was similar with daridorexant 25 mg, with treatment leading to significant reductions in the amount of time spent in wake bouts from approximately 150 min to the end of the night at Month 1, and from approximately 115 min to the end of night at Month 3.
Occurrence of Short and Long Wake Bouts
In the phase II study, the distribution of subjects with long wake bouts (> 6 min) was similar across all treatment groups at baseline (Table 2). The odds of having long wake bouts were higher for subjects in the placebo group than for those in the daridorexant 50-mg group for each PSG night (OR in the range of 1.86–4.11 across PSG nights), with significant results on Day 1 and Day 29 (p < 0.05). Similarly, subjects treated with zolpidem 10 mg had increased odds (2.15–4.80 across PSG nights) of having long wake bouts when compared with daridorexant 50 mg. Subjects receiving placebo had lower odds of having long wake bouts when compared with zolpidem 10 mg on Day 2 and Day 28/29 (OR 0.42–0.92). Only on Day 1 were the odds of having long wake bouts lower for zolpidem 10 mg compared with placebo.
Table 2.
Percentage of subjects with long wake bouts (> 6 min) by treatment group and visits (phase II study)
| Visit | Patients n/N (%) | Patients n/N (%) | Difference in % | Logistic regression | ||
|---|---|---|---|---|---|---|
| Odds ratio | 95% CI | |||||
| Daridorexant 50 mg (active) | Zolpidem 10 mg (comparator) | |||||
| Baseline | 1st night | 59/61 (96.72) | 58/60 (96.67) | 0.05 | ||
| 2nd night | 58/61 (95.08) | 56/60 (93.33) | 1.75 | |||
| Day 1/2 | 1st night | 35/60 (58.33) | 46/60 (76.67) | − 18.33 | 2.37* | [1.07–5.24] |
| 2nd night | 36/61 (59.02) | 52/60 (86.67) | − 27.65 | 4.80*** | [1.92–12.02] | |
| Day 28/29 | 1st night | 37/57 (64.91) | 47/59 (79.66) | − 14.75 | 2.15 | [0.93–4.98] |
| 2nd night | 34/57 (59.65) | 49/59 (83.05) | − 23.40 | 3.44** | [1.44–8.22] | |
| Visit | Patients n/N (%) | Patients n/N (%) | Difference in % | Logistic regression | ||
|---|---|---|---|---|---|---|
| Daridorexant 50 mg (active) | Placebo (comparator) | Odds ratio | 95% CI | |||
| Baseline | 1st night | 59/61 (96.72) | 58/60 (96.67) | 0.05 | ||
| 2nd night | 58/61 (95.08) | 58/60 (96.67) | − 1.58 | |||
| Day 1/2 | 1st night | 35/60 (58.33) | 51/60 (85.00) | − 26.67 | 4.11** | [1.70–9.92] |
| 2nd night | 36/61 (59.02) | 44/59 (74.58) | − 15.56 | 2.02 | [0.92–4.42] | |
| Day 28/29 | 1st night | 37/57 (64.91) | 44/57 (77.19) | − 12.28 | 1.86 | [0.81–4.26] |
| 2nd night | 34/57 (59.65) | 47/57 (82.46) | − 22.81 | 3.16** | [1.32–7.52] | |
| Visit | Visit | Patients n/N (%) | Patients n/N (%) | Difference in % | Logistic regression | |
|---|---|---|---|---|---|---|
| Zolpidem 10 mg (active) | Placebo (comparator) | Odds ratio | 95% CI | |||
| Baseline | 1st night | 58/60 (96.67) | 58/60 (96.67) | 0.00 | ||
| 2nd night | 56/60 (93.33) | 58/60 (96.67) | − 3.33 | |||
| Day 1/2 | 1st night | 46/60 (76.67) | 51/60 (85.00) | − 8.33 | 1.73 | [0.68–4.41] |
| 2nd night | 52/60 (86.67) | 44/59 (74.58) | 12.09 | 0.42 | [0.16–1.10] | |
| Day 28/29 | 1st night | 47/59 (79.66) | 44/57 (77.19) | 2.47 | 0.86 | [0.36–2.10] |
| 2nd night | 49/59 (83.05) | 47/57 (82.46) | 0.59 | 0.92 | [0.35–2.42] | |
Percentage of subjects with at least one wake bout > 6 min on each night for all treatment groups. Odds ratios > 1 benefit the active group; odds ratios < 1 benefit the comparator group
CI confidence interval, n number of subjects with long wake bouts, N patients with available PSG data on the night in question, PSG polysomnography
*p < 0.05 for active vs comparator group. **p < 0.01 for active vs comparator group. ***p < 0.001 for active vs comparator group
In the phase III study, the odds of having long wake bouts were higher in subjects treated with placebo compared with subjects treated with daridorexant 50 mg after 1 and 3 months of treatment (OR 2.53–4.41 across PSG nights) (Table 3). Results were statistically significant (p < 0.05) at all timepoints. Subjects treated with daridorexant 25 mg had similar results, although the effect of daridorexant versus placebo on Night 2 of Month 1 did not reach significance (Table 3).
Table 3.
Percentage of subjects with long wake bouts (> 6 min) by treatment group and visits (phase III study)
| Visit | Patients n/N (%) |
Patients n/N (%) |
Difference in % | Logistic regression | ||
|---|---|---|---|---|---|---|
| Odds ratio | 95% CI | |||||
| Daridorexant 25 mg (active) | Placebo (comparator) | |||||
| Baseline | 1st night | 303/310 (97.74) | 300/309 (97.09) | 0.65 | ||
| 2nd night | 294/310 (94.84) | 296/309 (95.79) | − 0.95 | |||
| Month 1 | 1st night | 244/297 (82.15) | 279/297 (93.94) | − 11.78 | 3.44** | [1.96–6.05] |
| 2nd night | 252/297 (84.85) | 269/300 (89.67) | − 4.82 | 1.52 | [0.93–2.48] | |
| Month 3 | 1st night | 236/288 (81.94) | 260/282 (92.20) | − 10.25 | 2.64* | [1.56–4.47] |
| 2nd night | 219/289 (75.78) | 251/284 (88.38) | − 12.60 | 2.44** | [1.56–3.82] | |
| Visit | Patients n/N (%) |
Patients n/N (%) |
Difference in % | Logistic regression | ||
|---|---|---|---|---|---|---|
| Daridorexant 50 mg (active) | Placebo (comparator) | Odds ratio | 95% CI | |||
| Baseline | 1st night | 298/309 (96.44) | 300/309 (97.09) | − 0.65 | ||
| 2nd night | 298/309 (96.44) | 296/309 (95.79) | 0.65 | |||
| Month 1 | 1st night | 247/305 (80.98) | 279/297 (93.94) | − 12.96 | 3.68** | [2.10–6.46] |
| 2nd night | 229/302 (75.83) | 269/300 (89.67) | − 13.84 | 2.78** | [1.76–4.39] | |
| Month 3 | 1st night | 209/287 (72.82) | 260/282 (92.20) | − 19.38 | 4.41** | [2.66–7.33] |
| 2nd night | 213/284 (75.00) | 251/284 (88.38) | − 13.38 | 2.53** | [1.61–3.95] | |
Percentage of subjects with at least one wake bout > 6 min on each night for all treatment groups. Odds ratios > 1 benefit the active group; odds ratios < 1 benefit the comparator group
CI confidence interval, n number of subjects with long wake bouts, N patients with available PSG data on the night in question, PSG polysomnography
*p < 0.001 for active vs comparator group. **p < 0.0001 for active vs comparator group
Contribution of Short and Long Wake Bouts to Cumulative Wake Time, and Distribution of Long Wake Bouts Throughout the Sleep Period
At baseline in the phase II study, the total amount of time spent in long wake bouts (> 6 min) was almost double the total amount of time spent in short bouts in all three treatment groups (Fig. 2). On Day 1/2, the total time spent awake in bouts > 6 min decreased in all groups and was significantly lower in subjects treated with daridorexant 50 mg compared with placebo (p < 0.001) and with zolpidem 10 mg (p < 0.01) up to Day 28/29. The daridorexant 50-mg group was the only group in which long wake bouts contributed less to the cumulative wake time (17.7 min) than short wake bouts (30.8 min) on Day 1/2. The effect was maintained on Day 28/29. The zolpidem group did not significantly differ from placebo in reducing the time spent in long and short wake bouts on Day 1/2 and on Day 28/29.
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
To analyze the distribution of wake bouts across the night, the 8-h test period was divided into four quarters of 2 h each. In the phase II study, the baseline distribution of long wake bouts (> 6 min) was similar across treatment groups, with long wake bouts becoming more numerous as the night progressed (Fig. S2, see ESM). In all treatment groups, the mean number of long wake bouts decreased on Day 1/2 and Day 28/29 when compared with baseline, with the strongest effects observed in the second and third quarters of the night. This relative reduction in the second half of the night appeared greatest in the daridorexant 50-mg group, with the mean number of long wake bouts (> 6 min) decreasing in all four quarters of the night.
A similar pattern of cumulative time spent in long (> 6 min) wake bouts was observed in the phase III study (Fig. 2), with significant reductions in long wake bouts in the daridorexant 50-mg group compared with placebo (mean cumulative duration 31.5 vs 59.7 min at Month 1; and 31.3 vs 54.8 min at Month 3; both p < 0.01). In this study, the time spent in short wake bouts was significantly increased with daridorexant 50 mg when compared with placebo at both timepoints (p < 0.01). Although less pronounced than with the 50-mg dose, the effect of daridorexant 25 mg was similar, with significant reductions in cumulative time spent in long wake bouts compared with placebo after 1 and 3 months (p < 0.001), and significant increases in time spent in short wake bouts compared with placebo after 1 month (p < 0.01) and 3 months (p < 0.05) (Fig. S3, see ESM).
The distribution of long wake bouts throughout the sleep period in the phase III study was also comparable to the phase II study, in which daridorexant 50 mg had fewer long wake bouts (> 6 min) in all quarters of the night when compared with baseline; these results were maintained for up to 3 months. The effect of daridorexant 25 mg was similar to, although less pronounced than, daridorexant 50 mg (Fig. S2, see ESM).
When analyzing the cumulative contributions of wake bouts using the 2-min threshold proposed by Svetnik et al. [26], the overall patterns of results were similar to those with the newly devised 6-min thresholds for the phase II and phase III studies, with two notable exceptions in the phase II study: firstly, the contributions of the short versus long wake bouts on Days 1/2 and 28/29 were similar (approximately 20 min each), and secondly, the increase in cumulative duration of short (≤ 2 min) wake bouts was significant for the daridorexant 50-mg group (mean cumulative duration 22.9 min) compared with the placebo group (mean cumulative duration 19.1 min) at Day 28/29; this statistical significance was not present when the 6-min threshold was used.
When analyzing the distribution of wake bouts throughout the sleep period using the 2-min threshold proposed by Svetnik et al. [26], the overall distribution of long wake bouts throughout the night, and overall treatment effects remained the same for the phase II and III studies as when using the 6-min threshold, albeit with higher numerical frequencies (Fig. S2, see ESM).
Correlation Between Time in Long and Short Wake Bouts and Next-Day Daytime Functioning
Changes in IDSIQ domain scores were measured in the phase III study only and have been reported previously [15]. The relationship between change in time spent in long and short wake bouts and change in IDSIQ scores (overall and subscales) with daridorexant and placebo can be seen in Fig. 3, as well as in Figs. S4, S5, and S6 in the ESM. The slopes indicate the change in IDSIQ score for every 1-min change in time spent in long or short wake bouts. Here we focus on results for the sleepiness domain score, which was a key secondary outcome in the phase III study.
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
The MMRM showed a significant treatment effect of daridorexant 50 mg and placebo on the IDSIQ sleepiness domain at Month 1 and Month 3 for both short and long wake bouts (Fig. 3; all p-values < 0.05). In both placebo and daridorexant 50-mg arms, a decrease from baseline in the time spent in long wake bouts was associated with an improvement (reduction) in the IDSIQ sleepiness domain score, as can be seen from the upward curve in both treatment arms in Fig. 3. However, the treatment effect size observed for daridorexant 50 mg was greater when compared with placebo, exemplified by the larger slope value for daridorexant 50 mg compared with placebo at Month 1 (0.020 vs 0.016) and at Month 3 (0.033 vs 0.023). To calculate the increase or decrease in IDSIQ score relative to no change in wake bout duration, the slope value was multiplied by the change in time spent in wake bouts. For example, at Month 3, a 50-min decrease in cumulative long wake bout duration with daridorexant 50 mg was associated with a 1.65-point improvement in IDSIQ sleepiness domain score, relative to no change in wake bout duration (i.e., 0.033 × − 50 min = − 1.65 points; therefore, 1.65 points less when compared with no change in wake bout duration). Analogously, in the placebo group, a 50-min decrease in cumulative long wake bout duration at Month 3 resulted in a 1.15-point improvement (reduction) in IDSIQ sleepiness domain score relative to no change in long wake bout duration. The change in the time spent in short (≤ 6 min) wake bouts had a less pronounced association with change in IDSIQ sleepiness domain score when compared with change in time spent in long wake bouts, as indicated by the nearly flat curve in both treatment arms (slope values for daridorexant 50 mg and placebo at Month 1: 0.014 and 0.015, respectively, and at Month 3: 0.012 and − 0.010, respectively) (Fig. 3). Therefore, the treatment effect size observed for daridorexant 50 mg for change in time spent in long wake bouts was greater when compared with change in time spent in short wake bouts (slope values for daridorexant 50 mg for change in time spent in long versus short wake bouts at Month 1: 0.020 vs 0.014, respectively, and at Month 3: 0.033 vs 0.012, respectively). At Month 3, an increase of 10 min in short wake bouts resulted in a worsening (increase) of the IDSIQ sleepiness domain score by 0.12 points with daridorexant 50 mg and an improvement of 0.10 points with placebo relative to no change in short wake bout duration. Similar analyses on the association of change in time spent in long and short wake bouts for IDSIQ total score, alert/cognition score, and mood score all showed similar results (Fig. S4, see ESM). The association between change in long and short wake-bout duration and IDSIQ scores in subjects treated with daridorexant 25 mg were similar to those with daridorexant 50 mg (Figs. S5 and S6 in the ESM).
Discussion
In contrast to other insomnia phenotypes, sleep maintenance insomnia is often characterized by long bouts of wakefulness during the night; we developed a new working definition of long wake bouts (> 6 min) based on adult patients’ perception of awakenings. The threshold for long wake bouts was consistent when replicated in the populations of the phase II and III studies. This derivation is independent of treatment effects because it is assessed at baseline. The derivation assumed that longer awakenings are more likely to be remembered, in line with previous studies that reported that wake bouts ≥ 5 min are more likely to be remembered by subjects and are thus clinically meaningful [5, 33].
Our results for the derivation of long and short wake bouts support the observation that patients with insomnia often report a mismatch between perceived time asleep and duration of awakenings and actual sleep time, where longer uninterrupted sleep is required in order to be perceived as sleep [34–36]. However, it remains unclear how this impacts sleep perception in people with insomnia, with theories ranging from distorted time estimation ability, confirmation bias, and elevated cortical arousals [37].
Daridorexant at 25 mg and 50 mg once nightly reduced the mean number of long wake bouts (> 6 min in duration) across the entire night. This reduction in longer wake bouts resulted in a large decrease in cumulative wake time. Patients treated with zolpidem experienced a steep increase in cumulative wake time as the night progressed, starting from the third quarter of the night onwards, suggesting a rebound-like increase in wake time, which is likely related to its short half-life (2.4 h) [38]. The waning effect through the last part of the night observed with zolpidem may be partly overcome with the controlled-release formulation, which has a slightly longer half-life of 2.8 h [39]; the lack of comparison with this formulation is a limitation of this study and may warrant future investigation. However, zolpidem controlled release is not approved globally [40–42] and was therefore not available as a comparator in the phase II study, which was conducted in the US, Israel, and four countries in Europe [20].
Daridorexant 50 mg reduced long wake bouts compared with placebo, yet it increased the time spent in short wake bouts. When defining short wake bouts as ≤ 6 min, a nominal increase in wake time versus placebo was observed in the phase II study, with significance reached in the phase III study. When the threshold for short versus long wake bouts was set at 2 min, as proposed by Svetnik et al. [26], the increase in time spent in short wake bouts in the phase II study also became significant on Days 28/29. These increases are similar to those observed with suvorexant [26]. Although this increase in short wake bouts could be interpreted as an increase in sleep fragmentation and arousal [34, 43], it is unlikely that these wake bouts have a negative impact on subjects’ perception of their sleep, given that these patients reported an improvement in sleep quality [15, 20] as well as daytime functioning [15]. To test this hypothesis, we analyzed the change from baseline in long and short wake bouts versus the change from baseline in IDSIQ domain scores, with a focus on the sleepiness domain, as this was a key secondary outcome in the phase III study. These analyses were conducted for daridorexant versus placebo only, as the phase II study did not assess IDSIQ domain scores, meaning the following conclusions cannot be expanded to comparisons with zolpidem. The reduction in time spent in long wake bouts was associated with a greater improvement in IDSIQ sleepiness domain score and the improvement was clinically significant (≥ 4-point improvement) across the entire range of cumulative time spent in long wake bouts [15]. Notably, the greater the reduction in the time spent in long wake bouts, the greater the improvement observed on the IDSIQ sleepiness domain score. Conversely, the change from baseline in short wake bouts was not associated with a substantial change in the IDSIQ sleepiness domain score. Despite the lack of association of short wake bouts and change in the IDSIQ sleepiness domain score, the daridorexant group maintained lower scores suggesting that there are other parameters affected by the drug that are independent of the time spent in short wake bouts, which can also contribute to the observed improvement in daytime function. It can be hypothesized that longer periods of wakefulness are likely accompanied by higher levels of arousal and frustration, impaired psychological well-being, a decrease in quality of life, and reduced sleep quality [26, 44, 45], and that besides improving the total sleep time, the structure of sleep is modulated as well [43].
Brief wake bouts during the night may be important to help connect sleepers to their surroundings [46, 47] and may be part of physiological sleep, as they occur in healthy adults, with percentages increasing as the sleep cycles progress. Patients with insomnia do not seem to differ much in the number of wake bouts when compared with normal sleepers; instead, the time awake is increased in people with insomnia [47].
This analysis provides new insights into the dynamics of sleep physiology in insomnia disorder and the role of orexin signaling that go beyond the observations made from recording more traditional sleep parameters, such as WASO, LPS, TST, and sTST (reported in the parent studies). However, some limitations should be considered when interpreting the results. First, this is an exploratory analysis, and analyses from the phase II study were based on data from approximately 60 patients per treatment arm; therefore, the results must be considered as hypothesis-generating only. However, the reproducibility of similar results in an independent clinical trial provides credibility to the findings. Second, our ability to understand the relevance of the increase in smaller wake bouts in a clinical context is limited by the analysis of daridorexant only and by the absence of a comparison with people without insomnia. Third, although daridorexant appears to reduce long wake bouts, we did not assess if there is a difference between different age groups and sexes and which stages of sleep (N1, N2, N3, or REM) preceded these bouts. Fourth, the threshold used to define ‘shorter versus longer’ wake bouts was derived using a dataset of patients aged < 65 years (potentially limiting its applicability to those aged 65 years and above) and was based on subjective patient recall of awakenings. The underlying assumption that duration of wake bouts is the only driver of subjective perception of awakening may be insufficient because other factors may also contribute to this perception and it might be influenced by age.
Conclusion
This analysis suggests that daridorexant reduces cumulative wake time at night, primarily by reducing the number and duration of long night-time wake bouts while slightly increasing shorter wake bouts throughout the whole night. The implications of these findings should be further explored together with the impact of age and sex.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
Medical writing and editorial support in late stages of manuscript revision was provided by AXON Communications, funded by Idorsia Pharmaceuticals Ltd.
Declarations
Funding
These analyses (and the studies on which they are based) were funded by Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Conflict of interest
Financial disclosures: YD reports board membership, consultancy, and lecture activity with Idorsia Pharmaceuticals Ltd. TES and AND report consultancy and lecture activity with Idorsia Pharmaceuticals Ltd, Neurocrine, Epilog, Angelini Pharma and Jazz Pharmaceuticals. GZ is an employee of Clinilabs Drug Development Corporation, a company that has received grants from Idorsia Pharmaceuticals Ltd and reports consultancy activity with Idorsia Pharmaceuticals Ltd. TDM and MM are employees of Idorsia Pharmaceuticals Ltd. DSK was an employee of Idorsia Pharmaceuticals Ltd at the time the research was conducted. Non-financial disclosures: none.
Ethics approval
Both the phase II and phase III studies were approved by the appropriate health authority, ethics committee, or institutional review board for each participating site and performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.
Consent to participate
Informed consent was obtained from all individual participants included in the studies.
Consent for publication
Not applicable.
Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Code availability
Not applicable.
Author contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Michael Meinel, Tobias Di Marco and Yves Dauvilliers. The first draft of the manuscript was written by Tobias Di Marco and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript and agree to be accountable for the work.
Footnotes
Affiliation for Dalma Seboek Kinter while research conducted.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.