Hyperarousal features in the sleep architecture of individuals with and without insomnia.

Sleep architecture encodes relevant information on the structure of sleep and has been used to assess hyperarousal in insomnia. This study investigated whether polysomnography-derived sleep architecture displays signs of hyperarousal in individuals with insomnia compared with individuals without insomnia. Data from Phase 3 clinical trials, private clinics and a cohort study were analysed. A comprehensive set of sleep architecture features previously associated with hyperarousal were retrospectively analysed focusing on sleep-wake transition probabilities, electroencephalographic spectra and sleep spindles, and enriched with a novel machine learning algorithm called the Wake Electroencephalographic Similarity Index. This analysis included 1710 individuals with insomnia and 1455 individuals without insomnia. Results indicate that individuals with insomnia had a higher likelihood of waking from all sleep stages, and showed increased relative alpha during Wake and N1 sleep and increased theta power during Wake when compared with individuals without insomnia. Relative delta power was decreased and Wake Electroencephalographic Similarity Index scores were elevated across all sleep stages except N3, suggesting more wake-like activity during these stages in individuals with insomnia. Additionally, sleep spindle density was decreased, and spindle dispersion was increased in individuals with insomnia. These findings suggest that insomnia is characterized by a dysfunction in sleep quality with a continuous hyperarousal, evidenced by changes in sleep-wake architecture.

Integration of Sensor-Based and Self-Reported Metrics in a Sleep Diary: A Pilot Exploration.

OBJECTIVES: Discrepancies between sleep diaries and sensor-based sleep parameters are widely recognized. This study examined the effect of showing sensor-based sleep parameters while completing a daily diary. The provision of sensor-based data was expected to reduce variance but not change the mean of self-reported sleep parameters, which would in turn align better with sensor-based data compared to a control diary. METHOD: In a crossover study, 24 volunteers completed week-long periods of control diary (digital sleep diary without sensor-based data feedback) or integrated diary (diary with device feedback), washout, and then the other diary condition. RESULTS: The integrated diary reduced self-reported total sleep time (TST) by <10 minutes and reduced variance in TST. The integrated diary did not impact mean sleep onset latency (SOL) and, unexpectedly, the variance in SOL increased. The integrated diary improved both bias and limits of agreement for SOL and TST. CONCLUSIONS: Integration of wearable, sensor-based device data in a sleep diary has little impact on means, mixed evidence for less variance, and better agreement with sensor-based data than a traditional diary. How the diary impacts reporting and sensor-based sleep measurements should be explored.

A phase 1 double-blind, placebo-controlled study of zuranolone (SAGE-217) in a phase advance model of insomnia in healthy adults.

OBJECTIVE: To evaluate single zuranolone (SAGE-217) 30 or 45 mg doses in a 5-h phase advance insomnia model. METHODS: In this double-blind, three-way crossover study, healthy adults received placebo (n = 41), zuranolone 30 mg (n = 44), and zuranolone 45 mg (n = 42) across three treatment periods. Sleep was assessed by polysomnography and a postsleep questionnaire. Next-day residual effects and safety/tolerability were evaluated. RESULTS: Compared with placebo, zuranolone resulted in significant improvements in median sleep efficiency (30 mg, 84.6%; 45 mg, 87.6%; placebo, 72.9%; p < 0.001 for both doses), wake after sleep onset (WASO; 30 mg, 55.0 min; 45 mg, 42.5 min; placebo, 113.0 min; p < 0.001 for both doses), duration of awakenings (30 mg, 4.2 min, p < 0.001; 45 mg, 3.7 min, p = 0.001; placebo, 7.4 min), and total sleep time (TST; 30 mg, 406.3 min; 45 mg, 420.3 min; placebo, 350.0 min; p < 0.001 for both doses). Subjective endpoints (WASO, TST, sleep latency, sleep quality) also improved relative to placebo. Zuranolone was generally well tolerated, and the most common adverse events (≥2 participants, any period) were headache and fatigue. CONCLUSION: Zuranolone improved sleep measures versus placebo in a phase advance model of insomnia in healthy adults, supporting future studies in patients with insomnia disorder.

Effects of Weight Loss on Obstructive Sleep Apnea Severity. Ten-Year Results of the Sleep AHEAD Study.

Rationale: Weight loss is recommended to treat obstructive sleep apnea (OSA).Objectives: To determine whether the initial benefit of intensive lifestyle intervention (ILI) for weight loss on OSA severity is maintained at 10 years.Methods: Ten-year follow-up polysomnograms of 134 of 264 adults in Sleep AHEAD (Action for Health in Diabetes) with overweight/obesity, type 2 diabetes mellitus, and OSA were randomized to ILI for weight loss or diabetes support and education (DSE).Measurements and Main Results: Change in apnea-hypopnea index (AHI) was measured. Mean ± SE weight losses of ILI participants of 10.7 ± 0.7, 7.4 ± 0.7, 5.1 ± 0.7, and 7.1 ± 0.8 kg at 1, 2, 4, and 10 years, respectively, were significantly greater than the 1-kg weight loss at 1, 2, and 4 years and 3.5 ± 0.8 kg weight loss at 10 years for the DSE group (P values ≤ 0.0001). AHI was lower with ILI than DSE by 9.7, 8.0, and 7.9 events/h at 1, 2, and 4 years, respectively (P values ≤ 0.0004), and 4.0 events/h at 10 years (P = 0.109). Change in AHI over time was related to amount of weight loss, baseline AHI, visit year (P values < 0.0001), and intervention independent of weight change (P = 0.01). OSA remission at 10 years was more common with ILI (34.4%) than DSE (22.2%).Conclusions: Participants with OSA and type 2 diabetes mellitus receiving ILI for weight loss had reduced OSA severity at 10 years. No difference in OSA severity was present between ILI and DSE groups at 10 years. Improvement in OSA severity over the 10-year period with ILI was related to change in body weight, baseline AHI, and intervention independent of weight change.

Daridorexant, a New Dual Orexin Receptor Antagonist to Treat Insomnia Disorder.

OBJECTIVE: To evaluate the dose-response relationship of daridorexant, a new dual orexin receptor antagonist, on sleep variables in subjects with insomnia disorder. METHODS: Adults (≤64 years) with insomnia disorder were randomized (1:1:1:1:1:1) to receive daily oral placebo, daridorexant (5, 10, 25, or 50mg), or 10mg zolpidem for 30 days. The primary efficacy outcome was the change in wake time after sleep onset from baseline to days 1 and 2. Secondary outcome measures were change in latency to persistent sleep from baseline to days 1 and 2, change in subjective wake time after sleep onset, and subjective latency to sleep onset from baseline to week 4. Safety was also assessed. RESULTS: Of 1,005 subjects screened, 359 (64% female) were randomized and received ≥1 dose. A significant dose-response relationship (multiple comparison procedure-modeling, 2-sided p < 0.001) was found in the reduction of wake after sleep onset and latency to persistent sleep from baseline to days 1 and 2 with daridorexant. These reductions were sustained through to days 28 and 29 (p = 0.050 and p = 0.042, respectively). Similar dose-dependent relationships were observed for subjective wake after sleep onset and subjective latency to sleep onset. The incidence of treatment-emergent adverse events was 35%, 38%, 38%, and 34% in subjects treated with 5, 10, 25, and 50mg daridorexant, respectively, compared with 30% for placebo, and 40% for 10mg zolpidem. There were no clinically relevant treatment-related serious adverse events. Four subjects withdrew due to adverse events. INTERPRETATION: Daridorexant induced a dose-dependent reduction in wake time after sleep onset in subjects with insomnia disorder (Clinicaltrials.gov NCT02839200). Ann Neurol 2020;87:347-356.

Respiratory safety of lemborexant in healthy adult and elderly subjects with mild obstructive sleep apnea: A randomized, double-blind, placebo-controlled, crossover study.

Lemborexant is a dual orexin receptor antagonist indicated for the treatment of adult and elderly individuals with insomnia. Some current pharmacologic treatments for insomnia cause respiratory depression, a serious safety concern, particularly for individuals with obstructive sleep apnea (OSA). This phase 1, randomized, double-blind, placebo-controlled, two-period crossover study examined respiratory safety parameters in individuals with mild OSA following treatment with lemborexant. Participants (n = 39) were randomized to one of two treatment sequences, including placebo and lemborexant 10 mg. Each treatment period lasted 8 days and was separated by a washout of at least 14 days. Following single or multiple doses, there were no significant differences in mean apnea-hypopnea index for lemborexant 10 mg versus placebo (least squares mean [LSM] difference [95% confidence interval {CI}]: day 1, -0.03 [-2.22, 2.17]; day 8, -0.06 [-1.95, 1.83]) or peripheral capillary oxygen saturation during sleep (LSM difference [95% CI]: day 1, 0.07 [-0.31, 0.46]; day 8, 0.25 [-0.11, 0.61]). There were no significant differences versus placebo for the percentage of total sleep time during which peripheral capillary oxygen saturation was <80% (LSM difference [95% CI]: day 1, 0.002 [-0.019, 0.023]; day 8, 0.006 [-0.015, 0.026]), <85% (LSM difference [95% CI]: day 1, 0.067 [-0.124, 0.258]; day 8, 0.056 [-0.117, 0.228]) or <90% (LSM difference [95% CI]: day 1, 0.312 [-0.558, 1.181]; day 8, 0.088 [-0.431, 0.607]). The incidence of treatment-emergent adverse events was low and similar for lemborexant and placebo. Lemborexant demonstrated respiratory safety in this study population and was well tolerated.

Solriamfetol for Excessive Sleepiness in Obstructive Sleep Apnea (TONES 3). A Randomized Controlled Trial.

Rationale: Primary treatment of obstructive sleep apnea can be accompanied by a persistence of excessive sleepiness despite adherence. Furthermore, effectiveness of sleep apnea treatment is limited by poor adherence. Currently available pharmacologic options for the treatment of sleepiness in this population are limited. Objectives: To evaluate the efficacy and safety of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, for the treatment of excessive sleepiness in participants with obstructive sleep apnea with current or prior sleep apnea treatment. Methods: This was a double-blind, randomized, placebo-controlled, parallel-group, 12-week trial comparing solriamfetol, 37.5, 75, 150, and 300 mg, with placebo. Measurements and Main Results: Of 476 randomized participants, 459 were included in the prespecified efficacy analyses. Coprimary endpoints (Maintenance of Wakefulness Test sleep latency and Epworth Sleepiness Scale score) were met at all solriamfetol doses (P < 0.05), with dose-dependent effects observed at Week 1 maintained over the study duration. All doses except 37.5 mg resulted in higher percentages of participants reporting improvement on Patient Global Impression of Change (key secondary endpoint; P < 0.05). Adverse events were reported in 47.9% of placebo- and 67.9% of solriamfetol-treated participants; five participants experienced serious adverse events (two [1.7%] placebo, three [0.8%] solriamfetol); none were deemed related to study drug. The most common adverse events with solriamfetol were headache (10.1%), nausea (7.9%), decreased appetite (7.6%), anxiety (7.0%), and nasopharyngitis (5.1%). Conclusions: Solriamfetol significantly increased wakefulness and reduced sleepiness in participants with obstructive sleep apnea and excessive sleepiness; most adverse events were mild or moderate in severity. Clinical trial registered with www.clinicaltrials.gov (NCT02348606) and www.eudract.ema.europa.eu (EudraCT 2014-005514-31).

Efficacy of SM-1 in a transient insomnia model.

OBJECTIVES: The objectives of this study were primarily to assess the efficacy and safety of SM-1 in a circadian challenge model of transient insomnia and secondarily, to assess the contribution of diphenhydramine to the combination. METHODS: Randomized, double-blind, placebo-controlled three-way cross-over study with a 5-hr phase advance. Subjects were 39 healthy adults reporting a history of transient insomnia. All treatments (SM-1, SM-1 without diphenhydramine, or placebo) were administered to all subjects in a randomly assigned sequence, with at least 1 week between treatments. The primary endpoint was total sleep time (TST) determined by polysomnography. Secondary endpoints included wakefulness after sleep onset (WASO), latency to persistent sleep, number of awakenings (NAW), subjective TST (sTST) and sleep latency (sSL), TST, and NAW by quarters of the night and sleep quality. Safety endpoints included adverse events, Karolinska Sleepiness Scale digit symbol substitution test, and subject-reported alertness level. RESULTS: SM-1 provided an increase of 126.7 min in TST over placebo (p < .001). WASO, sTST, sleep quality, and sSL also showed significant improvement. Diphenhydramine demonstrated a significant (p = .014) contribution of 43.7 min to TST. SM-1 was well-tolerated with type and frequency of adverse events comparable with placebo, and no residual sleepiness upon awakening after 8 hr. CONCLUSIONS: SM-1 provided a robust and statistically significant increase in TST compared with placebo in a circadian model of transient insomnia, without evidence of next-day impairment. Diphenhydramine contributed to the effect.

Effects of a lifestyle intervention on REM sleep-related OSA severity in obese individuals with type 2 diabetes.

The aim of this study was to determine if an intensive lifestyle intervention (ILI) reduces the severity of obstructive sleep apnea (OSA) in rapid-eye movement (REM) sleep, and to determine if longitudinal changes in glycaemic control are related to changes in OSA severity during REM sleep over a 4-year follow-up. This was a randomized controlled trial including 264 overweight/obese adults with type 2 diabetes (T2D) and OSA. Participants were randomized to an ILI targeted to weight loss or a diabetes support and education (DSE) control group. Measures included anthropometry, apnea-hypopnea index (AHI) during REM sleep (REM-AHI) and non-REM sleep (NREM-AHI) and glycated haemoglobin (HbA1c) at baseline and year 1, year 2 and year 4 follow-ups. Mean baseline values of REM-AHI were significantly higher than NREM-AHI in both groups. Both REM-AHI and NREM-AHI were reduced significantly more in ILI versus DSE, but these differences were attenuated slightly after adjustment for weight changes. Repeated-measure mixed-model analyses including data to year 4 demonstrated that changes in HbA1c were related significantly to changes in weight, but not to changes in REM-AHI and NREM-AHI. Compared to control, the ILI reduced REM-AHI and NREM-AHI during the 4-year follow-up. Weight, as opposed to REM-AHI and NREM-AHI, was related to changes in HbA1c. The findings imply that weight loss from a lifestyle intervention is more important than reductions in AHI for improving glycaemic control in T2D patients with OSA.

A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia.

The antidepressant mirtazapine is an alternative to classical hypnotics, and this study investigated the efficacy and safety of esmirtazapine (Org 50081, the maleic acid salt of S-mirtazapine) in patients given a diagnosis of primary insomnia after acute (2-day) treatment. Patients aged 18 to 65 years with primary insomnia were randomized to receive placebo or 1.5-, 3.0-, or 4.5-mg esmirtazapine in a balanced 4-way crossover study; 2 sleep laboratory nights with polysomnography were separated by 5-day, single-blind placebo washout periods. Polysomnography-determined total sleep time (primary end point) and patient-reported total sleep time improved by at least 25 minutes with all 3 doses of esmirtazapine (P ≤ 0.001 vs placebo). Polysomnography-measured wake time after sleep onset (P ≤ 0.0001) and latency to persistent sleep also improved vs placebo (P ≤ 0.01, 3.0 and 4.5 mg). Patient-reported sleep quality improved with 3.0- and 4.5-mg esmirtazapine (P ≤ 0.01 and P ≤ 0.05, respectively, vs placebo). Morning alertness and contentment were not altered after esmirtazapine, and calmness increased with 4.5-mg esmirtazapine vs placebo. Evening questionnaires showed no difference in duration of daytime naps but reduced energy and ability to work/function after esmirtazapine treatment periods vs placebo (P < 0.05), although this effect was limited to the first night of each 2-night period. There were few adverse events, no serious adverse events, or clinically relevant treatment differences in vital signs, laboratory values, or electrocardiogram. Esmirtazapine doses of 1.5 to 4.5 mg/day significantly improved quantity and quality of sleep and were generally well tolerated, with no evidence of safety concerns or consistent pattern of residual effects.

The sleep effects of lurasidone: a placebo-controlled cross-over study using a 4-h phase-advance model of transient insomnia.

BACKGROUND: Lurasidone, an atypical antipsychotic, is a potent 5-HT7 antagonist and D2 , 5-HT2A antagonist, and 5-HT1A partial agonist. As such, lurasidone would be expected to modulate sleep and circadian function but there have been no human studies of the sleep effects of a 5-HT7 antagonist. The purpose of this study was to assess effects of lurasidone on sleep. METHODS: This was a cross-over, polysomnographic study involving 54 healthy volunteers who underwent two treatment periods (order randomized) each consisting of two nights in the laboratory: Night 1-lights out at usual bedtime; Night 2-4-h advance of sleep phase and randomization to either lurasidone 40 mg or placebo. The next morning impairment testing was carried out. RESULTS: Lurasidone significantly (p < 0.05) increased total sleep time by an average of 28.4 min versus placebo, decreased wake time after sleep onset and wake time after the final awakening, and increased sleep efficiency. No other effects were found. CONCLUSIONS: Lurasidone had a sleep maintenance effect without effects on sleep onset, rapid eye movement, or slow-wave sleep. Lurasidone is likely to be beneficial to patients with disturbed sleep, particularly those with sleep maintenance problems. Copyright © 2016 John Wiley & Sons, Ltd.

A generalized estimating equation approach to analysis of maintenance of wakefulness testing in a study of lisdexamfetamine dimesylate, armodafinil, and placebo in sleep-deprived adults.

In a study of acute sleep deprivation in healthy male volunteers randomized to double-blind treatment with lisdexamfetamine dimesylate (20, 50, or 70 mg), placebo control, or an active control (armodafinil 250 mg), Maintenance of Wakefulness Test data were compared using a generalized estimating equation analysis to eliminate the need for unequivocal sleep latency imputation. Compared with placebo across all Maintenance of Wakefulness Tests, all active treatments were associated with lower risk of falling asleep (risk ratio [95% confidence interval]): 0.45 (0.27-0.76; P = 0.0026), 0.10 (0.05-0.20; P < 0.0001), and 0.05 (0.02-0.14; P < 0.0001) for 20, 50, and 70 mg lisdexamfetamine dimesylate, respectively, and 0.11 (0.06-0.21; P < 0.0001) for the active control. Sleep-risk ratios were similar for lisdexamfetamine dimesylate 50 or 70 mg and for the active control, but lisdexamfetamine 20 mg was associated with a greater risk of falling asleep compared with the active control (4.13 [1.97-8.67]; P = 0.0002). Generalized estimating equation analysis detected wake-promoting effects of active treatments and eliminating data imputation, suggesting model utility in future studies.

Maintenance of wakefulness with lisdexamfetamine dimesylate, compared with placebo and armodafinil in healthy adult males undergoing acute sleep loss.

This study evaluated daytime alertness and performance with lisdexamfetamine dimesylate during acute sleep loss. In a randomized, double-blind study in healthy adult men (n = 135) undergoing 24-hour sleep loss, the alerting effects of single oral lisdexamfetamine dimesylate doses (20, 50, or 70 mg) were compared with a placebo and an active control (armodafinil 250 mg). Primary end point was mean unequivocal sleep latency on the 30-minute maintenance of wakefulness test taken every 2 hours from midnight to 8:00 A.M. Secondary end points included the Karolinska sleepiness scale and psychomotor vigilance task. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. Least squares mean (SE) maintenance of wakefulness test unequivocal sleep latency (in minutes) was longer with lisdexamfetamine dimesylate 20, 50, and 70 mg, or armodafinil 250 mg (23.3 [1.10], 27.9 [0.64], 29.3 [0.44], or 27.6 [0.63], respectively) versus placebo (15.3 [1.00]; P < 0.0001). Longer mean unequivocal sleep latency was seen with lisdexamfetamine dimesylate 70 mg versus armodafinil (P = 0.0351) and armodafinil versus lisdexamfetamine dimesylate 20 mg (P = 0.0014). On Karolinska sleepiness scale, lisdexamfetamine dimesylate 50 and 70 mg improved estimated sleepiness versus placebo (P ≤ 0.0002) and armodafinil (P ≤ 0.03). Active treatments improved psychomotor vigilance task performance versus placebo (P < 0.0001). The TEAEs were mild/moderate. No serious adverse events occurred. The most common TEAE was headache with lisdexamfetamine dimesylate and armodafinil (7.4% each) versus placebo (3.7%). Small mean increases in vital signs were observed with lisdexamfetamine dimesylate and armodafinil. In sleep-deprived healthy men, alertness was greater with lisdexamfetamine dimesylate and armodafinil versus placebo on the primary end point. Studies are needed in clinical populations and using longer durations of administration.

Hypoglossal nerve stimulation improves obstructive sleep apnea: 12-month outcomes.

Reduced upper airway muscle activity during sleep is a key contributor to obstructive sleep apnea pathogenesis. Hypoglossal nerve stimulation activates upper airway dilator muscles, including the genioglossus, and has the potential to reduce obstructive sleep apnea severity. The objective of this study was to examine the safety, feasibility and efficacy of a novel hypoglossal nerve stimulation system (HGNS; Apnex Medical, St Paul, MN, USA) in treating obstructive sleep apnea at 12 months following implantation. Thirty-one subjects (35% female, age 52.4 ± 9.4 years) with moderate to severe obstructive sleep apnea and unable to tolerate positive airway pressure underwent surgical implantation and activation of the hypoglossal nerve stimulation system in a prospective single-arm interventional trial. Primary outcomes were changes in obstructive sleep apnea severity (apnea-hypopnea index, from in-laboratory polysomnogram) and sleep-related quality of life [Functional Outcomes of Sleep Questionnaire (FOSQ)]. Hypoglossal nerve stimulation was used on 86 ± 16% of nights for 5.4 ± 1.4 h per night. There was a significant improvement (P < 0.001) from baseline to 12 months in apnea-hypopnea index (45.4 ± 17.5 to 25.3 ± 20.6 events h(-1) ) and Functional Outcomes of Sleep Questionnaire score (14.2 ± 2.0 to 17.0 ± 2.4), as well as other polysomnogram and symptom measures. Outcomes were stable compared with 6 months following implantation. Three serious device-related adverse events occurred: an infection requiring device removal; and two stimulation lead cuff dislodgements requiring replacement. There were no significant adverse events with onset later than 6 months following implantation. Hypoglossal nerve stimulation demonstrated favourable safety, feasibility and efficacy.

Effect of daridorexant on sleep architecture in patients with chronic insomnia disorder - A pooled post hoc analysis of two randomized Phase 3 clinical studies.

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<0.05) and increased the probability of transitions from Wake-to-N1 (P<0.05), N2 (P<0.05), and REM sleep (P<0.05), as well as from N1-to-N2 (P<0.05) compared to baseline and placebo. Daridorexant 50 mg decreased relative beta power during Wake (P=0.011) and N1 (P<0.001) compared to baseline and placebo. During Wake, relative alpha power decreased (P<0.001) and relative delta power increased (P<0.001) 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=0.004). Effects with 50 mg were consistent between Month 1 and Month 3 and less pronounced with 25 mg. CONCLUSION: 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.

Comparison of polysomnography in people with Alzheimer's disease and insomnia versus non-demented elderly people with insomnia.

BACKGROUND: We used baseline polysomnography (PSG) data obtained during the clinical program development for suvorexant to compare the PSG profiles of people with Alzheimer's disease and insomnia (ADI) versus age-matched elderly individuals with insomnia (EI). METHODS: Sleep laboratory baseline PSG data from participants age 55-80 years from 2 trials in people with insomnia and a trial in people with ADI were included. ADI participants had dementia of mild-to-moderate severity. Diagnostic criteria for insomnia, exclusion for other sleep problems, PSG recording procedures, and endpoint derivations were similar across the trials. All participants underwent a night of in-laboratory PSG prior to the baseline night to allow for screening/adaptation. Participants in the EI and ADI groups were compared with regard to sleep architecture, sleep micro-structure, and quantitative EEG power spectral endpoints. The analysis was performed on a post hoc basis using propensity score matching to compare sleep parameters separately in women and men while accounting for age group and total sleep time. RESULTS: A total of 837 EI and 239 ADI participants were included, with the majority in each population (∼65%) being women. Compared to EI, those with ADI had a lower percentage of time spent in slow wave sleep (and a corresponding higher percentage of time spent in the lighter N1 sleep), a lower number of spindles per minute of N2 sleep, and lower absolute EEG power during NREM sleep, particularly in the lower-frequency bands. Trends for lower REM sleep percentage in ADI did not reach statistical significance. CONCLUSIONS: Our findings in this large data set, in which the influence of sleep problems was effectively subtracted out (since both groups had insomnia), provide strong confirmatory support of results from previous smaller studies in indicating that AD of mild-to-moderate severity is associated with less slow wave sleep, spindles, and lower-frequency EEG power. TRIAL REGISTRATION: ClinicalTrials.gov, numbers NCT01097616, NCT01097629, NCT02750306.

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

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).

Alterations in sleep architecture in response to experimental sleep curtailment are associated with signs of positive energy balance.

Sleep reduction is associated with increased energy intake and weight gain, though few studies have explored the relationship between sleep architecture and energy balance measures in the context of experimental sleep restriction. Fourteen males and 13 females (body mass index: 22-26 kg/m(2)) participated in a crossover sleep curtailment study. Participants were studied under two sleep conditions: short (4 h/night; 0100-0500 h) and habitual (9 h/night; 2200-0700 h), for 5 nights each. Sleep was polysomnographically recorded nightly. Outcome measures included resting metabolic rate (RMR), feelings of appetite-satiety, and ad libitum food intake. Short sleep resulted in reductions in stage 2 sleep and rapid eye movement (REM) sleep duration (P < 0.001), as well as decreased percentage of stage 2 sleep and REM sleep and increased slow wave sleep (SWS) percentage (P < 0.05). Linear mixed model analysis demonstrated a positive association between stage 2 sleep duration and RMR (P = 0.051). Inverse associations were observed between REM sleep duration and hunger (P = 0.031) and between stage 2 sleep duration and appetite for sweet (P = 0.015) and salty (P = 0.046) foods. Stage 2 sleep percentage was inversely related to energy consumed (P = 0.024). Stage 2 sleep (P = 0.005), SWS (P = 0.008), and REM sleep (P = 0.048) percentages were inversely related to fat intake, and SWS (P = 0.040) and REM sleep (P = 0.050) were inversely related to carbohydrate intake. This study demonstrates that changes in sleep architecture are associated with markers of positive energy balance and indicate a means by which exposure to short sleep duration and/or an altered sleep architecture profile may lead to excess weight gain over time.

Efficacy of the triple-combination SM-1 in a 5-h phase advance transient insomnia model.

Thomas Dahl, PO Box 404, Guilford, CT 06437 USA. Email: tadahl@outlook.com. The objectives of the study were to demonstrate the efficacy and safety of SM-1 in a circadian challenge model of transient insomnia. Randomized, double-blind, placebo-controlled cross-over study utilizing a 5-h phase advance model of transient insomnia. Subjects were 85 healthy adults reporting a history of transient insomnia, with an average age of 38.9 years. Both SM-1 and placebo were administered to all subjects in a randomly assigned sequence, with at least 1 week between treatments. The primary endpoint was total sleep time determined by polysomnography. Secondary endpoints included wakefulness after sleep onset, latency to persistent sleep, number of awakenings, subjective total sleep time and subjective sleep onset latency, total sleep time by quarters of the night, subjective number of awakenings, and sleep quality. Safety endpoints included adverse events, Karolinska Sleepiness Scale, Digit Symbol Substitution Test, and predischarge evaluation (tandem gait and Romberg tests). SM-1 provided an increase of 94.4 min in total sleep time over placebo (p < 0.0001). Wakefulness after sleep onset, subjective total sleep time, subjective sleep onset latency, and total sleep time in the first quarter of the night also showed significant improvement. SM-1 was well-tolerated with both type and frequency of adverse events being comparable to placebo, and no residual sleepiness upon awakening (i.e., after 8 h). SM-1 provided a robust and statistically significant increase in total sleep time compared to placebo in a circadian model of transient insomnia, without evidence of next-day impairment.

Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials.

BACKGROUND: Daytime functioning is impaired in people with insomnia disorder. Currently available dual orexin receptor antagonists have shown efficacy in insomnia disorder, but do not address all aspects of this disease. We aimed to assess safety and efficacy of daridorexant, a novel orexin receptor antagonist, on night-time and daytime symptoms of insomnia. METHODS: We did two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials at 156 sites in 17 countries. Adults (aged ≥18 years) with insomnia disorder were randomly assigned using interactive response technology (1:1:1) to receive daridorexant 50 mg, 25 mg, or placebo (study 1) or daridorexant 25 mg, 10 mg, or placebo (study 2) every evening for 3 months. Participants, investigators, and site personnel were masked to treatment allocation. The primary endpoints were change from baseline in wake time after sleep onset (WASO) and latency to persistent sleep (LPS), measured by polysomnography, at months 1 and 3. The secondary endpoints were change from baseline in self-reported total sleep time and the sleepiness domain score of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) at months 1 and 3. Study-wise type I error rate (5%) was controlled for all pairwise comparisons. Efficacy was analysed in all randomly assigned participants, and safety in all participants who received at least one dose of treatment. The studies are registered at ClinicalTrials.gov, NCT03545191 (study 1) and NCT03575104 (study 2). FINDINGS: Between June 4, 2018 and Feb 25, 2020, 930 participants were randomly assigned to receive daridorexant 50 mg (n=310), daridorexant 25 mg (n=310), or placebo (n=310) in study 1. Between May 29, 2018, and May 14, 2020, 924 participants were randomly assigned to receive daridorexant 25 mg (n=309), daridorexant 10 mg (n=307), or placebo (n=308) in study 2. In study 1, WASO and LPS were significantly reduced among participants in the daridorexant 50 mg group compared with participants in the placebo group at month 1 (least squares mean [LSM] difference -22·8 min [95% CI -28·0 to -17·6], p<0·0001 for WASO; -11·4 min [-16·0 to -6·7], p<0·0001 for LPS) and month 3 (-18·3 min [-23·9 to -12·7], p<0·0001 for WASO; -11·7 min [-16·3 to -7·0], p<0·0001 for LPS). WASO and LPS were significantly reduced among participants in the daridorexant 25 mg group compared with the placebo group at month 1 (LSM difference -12·2 min [-17·4 to -7·0], p<0·0001 for WASO; -8·3 min [-13·0 to -3·6], p=0·0005 for LPS) and month 3 (-11·9 min [-17·5 to -6·2], p<0·0001 for WASO; -7·6 min [-12·3 to -2·9], p=0·0015 for LPS). Compared with placebo, participants in the daridorexant 50 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 22·1 min [14·4 to 29·7], p<0·0001) and month 3 (19·8 min [10·6 to 28·9], p<0·0001), and IDSIQ sleepiness domain scores at month 1 (-1·8 [-2·5 to -1·0], p<0·0001) and month 3 (-1·9 [-2·9 to -0·9], p=0·0002). Compared with the placebo group, participants in the daridorexant 25 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 12·6 min [5·0 to 20·3], p=0·0013) and month 3 (9·9 min [0·8 to 19·1], p=0·033), but not IDSIQ sleepiness domain scores (-0·8 [-1·5 to 0·01], p=0·055 at month 1; -1·0 [-2·0 to 0·01], p=0·053 at month 3). In study 2, WASO was significantly reduced among participants in the daridorexant 25 mg group compared with participants in the placebo group at month 1 (LSM difference -11·6 min [-17·6 to -5·6], p=0·0001) and month 3 (-10·3 min [-17·0 to -3·5], p=0·0028), whereas no significant differences in LPS were observed at month 1 (-6·5 min [-12·3 to -0·6], p=0·030) or month 3 (-9·0 [-15·3 to -2·7], p=0·0053). Compared with the placebo group, participants in the daridorexant 25 mg group had significant improvement in self-reported total sleep time at month 1 (LSM difference 16·1 min [8·2 to 24·0], p<0·0001) and month 3 (19·1 [10·1 to 28·0], p<0·0001), but not in IDSIQ sleepiness domain scores (-0·8 [-1·6 to 0·1], p=0·073 at month 1; -1·3 [-2·2 to -0·3], p=0·012 at month 3). Compared with the placebo group, no significant differences were observed among participants in the daridorexant 10 mg group for WASO (LSM difference -2·7 min [-8·7 to 3·2], p=0·37 at month 1; -2·0 [-8·7 to 4·8], p=0·57 at month 3), LPS (-2·6 min [-8·4 to 3·2], p=0·38 at month 1; -3·2 min [-9·5 to 3·1], p=0·32 at month 3), self-reported total sleep time (13·4 min [5·5 to 21·2], p=0·0009 at month 1; 13·6 min [4·7 to 22·5], p=0·0028 at month 3), nor IDSIQ sleepiness domain scores (-0·4 [-1·3 to 0·4], p=0·30 at month 1; -0·7 [-1·7 to 0·2], p=0·14 at month 3). Overall incidence of adverse events was comparable between treatment groups (116 [38%] of 308 participants in the daridorexant 50 mg group, 117 [38%] of 310 in the daridorexant 25 mg group, and 105 [34%] of 309 in the placebo group in study 1; 121 [39%] of 308 participants in the daridorexant 25 mg group, 117 [38%] of 306 in the daridorexant 10 mg group, and 100 [33%] of 306 in the placebo group). Nasopharyngitis and headache were the most common adverse events in all groups. One death (cardiac arrest) occurred in the daridorexant 25 mg group in study 1, which was not deemed to be treatment-related. INTERPRETATION: Daridorexant 25 mg and 50 mg improved sleep outcomes, and daridorexant 50 mg also improved daytime functioning, in people with insomnia disorder, with a favourable safety profile. FUNDING: Idorsia Pharmaceuticals.