Latency To Persistent Sleep Research Articles

Efficacy and safety of insomnia treatment with lemborexant in older adults: analyses from three clinical trials.

Insomnia is more common as people age. Several common hypnotics used to treat insomnia often do not adequately alleviate sleep issues in older adults and may be associated with negative residual effects such as an increased risk of falls, cognitive impairment, automobile accidents, and lack of response to auditory stimuli. The objective of these analyses of three clinical studies was to investigate the efficacy and safety of the dual orexin-receptor antagonist lemborexant (LEM) in older adults. Study E2006-G000-304 (Study 304; NCT02783729) was a randomized, double-blind, placebo (PBO)-controlled, active-comparator trial where subjects with insomnia disorder received LEM 5 mg (LEM5), LEM 10 mg (LEM10), zolpidem tartrate extended-release 6.25 mg (ZOL), or PBO for 30 days. In crossover Study E2006-E044-106 (Study 106; NCT02583451), healthy subjects (good sleepers) received LEM 2.5 mg, LEM5, LEM10, or PBO for eight nights or zopiclone on days 1 and 8 (and PBO on days 2-7). In crossover Study E2006-A001-108 (Study 108; NCT03008447), healthy subjects received a single dose of LEM5, LEM10, PBO, or ZOL. Sleep assessments included polysomnography-based latency to persistent sleep (LPS), wake after sleep onset (WASO), WASO in the second half of the night (WASO2H), sleep efficiency, postural stability, middle-of-the-night and next-day cognitive performance, middle-of-the-night auditory awakening threshold and return-to-sleep latency, and driving performance. Overall, 453 of 1006 (45%; Study 304), 24 of 48 (50%; Study 106), and 28 of 56 (50%; Study 108) subjects were aged ≥ 65years. In Study 304, LEM decreased (improved) LPS, WASO, and WASO2H from baseline more than ZOL and PBO; subjects treated with LEM had greater increases in sleep efficiency (improved) than with ZOL or PBO. In both Studies 304 and 108, postural stability was not impaired at waketime in subjects who received LEM compared with PBO. At waketime, LEM did not impair memory compared with PBO. In Study 108, following middle-of-the-night awakening, LEM and ZOL did not affect subjects' ability to awaken to auditory stimuli; LEM did not affect tests of memory and attention. In Study 106, LEM did not impair next-day driving performance in healthy elderly compared with PBO. LEM was well tolerated in subjects aged ≥ 65years. LEM provided benefits on sleep variables without next-morning residual effects in subjects aged ≥ 65years, supporting LEM as a treatment option for older adults with insomnia. Study 304: ClinicalTrials.gov identifier, NCT02783729, date of registration, 26 May 2016. Study 106: ClinicalTrials.gov identifier, NCT02583451, date of registration, 22 October 2015. Study 108: ClinicalTrials.gov identifier, NCT03008447, date of registration, 2 January 2017.

Dose-response of daridorexant in insomnia disorder: An analysis of Phase 2 and 3 studies

ObjectiveDaridorexant is approved for the treatment of insomnia at two dose levels (25 and 50 mg). Dose-efficacy and -safety response relationships were evaluated using Phase 2 and 3 data. MethodsData (N = 2153) from one Phase 2 (daridorexant 5, 10, 25, 50 mg, placebo once daily for 1 month) and two Phase 3 studies (daridorexant 10 and 25 or 25 and 50 mg, placebo once daily for 3 months) were pooled. Dose-response analyses at 1 month of double-blind treatment were performed using a linear regression and a two-stage meta-analysis approach. Efficacy endpoints were polysomnography-derived wake after sleep onset, latency to persistent sleep (LPS), self-reported total sleep time and the Insomnia Daytime Symptoms and Impacts Questionnaire total score (only Phase 3 data for the latter). Safety endpoints were the incidence of total adverse events (AEs) and AEs corresponding to somnolence/fatigue. ResultsDose-responses for all efficacy endpoints were significant in the observed dose range (both statistical approaches, p < 0.01). All dose-response relationships were linear except for LPS (two-stage meta-analysis) which showed a change in slope above 10 mg without reaching a plateau. No significant dose-response was observed for any AE (both approaches, p > 0.05). The incidence of AEs corresponding to somnolence/fatigue was low at all doses and, without linear assumption (two-stage meta-analysis) there was no dose-dependency (p = 0.369). ConclusionsThe data support the use of 50 mg as the preferred daridorexant dose in patients with insomnia disorder to provide the greatest opportunity for efficacy with no increased risk for AEs, including somnolence/fatigue, compared to lower doses.

LPS and its relationship with subjective–objective discrepancies of sleep onset latency in patients with psychiatric disorders

Subjective–objective discrepancies in sleep onset latency (SOL), which is often observed among psychiatric patients, is attributed partly to the definition of sleep onset. Recently, instead of SOL, latency to persistent sleep (LPS), which is defined as the duration from turning out the light to the first consecutive minutes of non-wakefulness, has been utilized in pharmacological studies. This study aimed to determine the non-awake time in LPS that is most consistent with subjective sleep onset among patients with psychiatric disorders. We calculated the length of non-awake time in 30-s segments from lights-out to 0.5–60 min. The root mean square error was then calculated to determine the most appropriate length. The analysis of 149 patients with psychiatric disorders showed that the optimal non-awake time in LPS was 12 min. On the other hands, when comorbid with moderate or severe obstructive sleep apnea (OSA), the optimal length was 19.5 min. This study indicates that 12 min should be the best fit for the LPS non-awake time in patients with psychiatric disorders. When there is comorbidity with OSA, however, a longer duration should be considered. Measuring LPS minimizes discrepancies in SOL and provides important clinical information.

P.054 Older subjects with insomnia disorder and comorbid pain at baseline: response to Lemborexant

Background: There is a well-established reciprocal relationship between pain and poor sleep. Therefore, we evaluated whether an approved sleep-promoting drug, lemborexant (LEM), could improve sleep in older adults who reported both insomnia and pain. Methods: Study E2006-G000-304 (NCT02783729) was a 1-month, placebo (PBO)- and active-controlled study in subjects (age ≥55y) with insomnia disorder. Those reporting some/severe pain on the pain/discomfort dimension of the EQ-5D-3L at baseline were included. Subjects were randomized to placebo (PBO), LEM 5mg (LEM5), 10mg (LEM10) or zolpidem (not reported here). Changes from baseline (CFB) in objective sleep parameters latency-to-persistent sleep (LPS) and total-sleep-time (TST) were analyzed in paired polysomnograms. Results: 183/743 (24.6%) subjects in the PBO (n=55/208[26.4%]), LEM5 (n=78/266[29.3%]) and LEM10 (n=50/269[18.6%]) treatment groups reported some/extreme pain at baseline, with median LPS (minutes): 31.0, 29.4, 42.1, respectively. Respective median CFB for LPS at the beginning (Nights[NT]1/2: +2.5, –8.4, –15.8; P&lt;0.005) was significantly larger/decreased for LEM5/LEM10 versus PBO and LEM5 at treatment end (NT29/30: –7.1, –9.9, –9.0; P=0.031). Mean baseline TST (minutes) was 335.3 (PBO), 336.3 (LEM5), 324.3 (LEM10), and mean CFB was significantly larger/increased (P&lt;0.001) for LEM5/LEM10 versus PBO at NT1/2 and NT29/30. Conclusions: Results suggest LEM may effectively treat insomnia in older adults with comorbid pain.Support: Eisai Inc.

0364 The Effect of Lemborexant on Polysomnographic Sleep Parameters in Adults with Mild, Moderate, or Severe Obstructive Sleep Apnea

Abstract Introduction Several commonly prescribed hypnotics may worsen respiratory function, especially in the elderly. Lemborexant (LEM) is a dual-orexin-receptor-antagonist approved to treat adults with insomnia. In Studies 102 (NCT03471871) and 113 (NCT04647383), LEM demonstrated respiratory safety in subjects with mild, moderate, or severe obstructive sleep apnea (OSA) who did not report insomnia. The current analyses evaluated sleep variables from these studies. Methods Studies 102 and 113 were double-blind, placebo (PBO)-controlled, crossover studies in adults with untreated mild (apnea-hypopnea-index [AHI] ≥5 to &amp;lt; 15), moderate (AHI≥15 to &amp;lt; 30), or severe (AHI≥30) OSA, without insomnia. Subjects were randomized to two 8-night periods (separated by ≥14 days) treated with LEM 10mg (LEM10) or PBO. Latency to persistent sleep (LPS), sleep efficiency (SE), and wake after sleep onset (WASO) were assessed using polysomnography on Days 1 (D1) and 8 (D8). Results The analysis set comprised 39, 13, and 20 subjects with mild, moderate, or severe OSA, respectively. On both days, LPS was not statistically different from PBO in any group. Compared with PBO, SE was significantly greater on D1 in subjects with mild (LEM10, 90.43; PBO, 80.31; P&amp;lt; 0.0001), moderate (LEM10, 88.83; PBO, 84.02; P=0.016), and severe (LEM10, 87.76; PBO, 77.84; P&amp;lt; 0.0001) OSA. On D8, SE was significantly greater in subjects with mild (LEM10, 86.65; PBO, 80.59; P=0.003) and moderate (LEM10, 88.45; PBO, 80.70; P=0.004) OSA, with a trend towards significance in subjects with severe (LEM10, 85.60; PBO, 80.63; P=0.055) OSA. WASO was significantly lower (improved) on D1 in subjects with mild (LEM10, 33.30; PBO, 76.76; P&amp;lt; 0.0001), moderate (LEM10, 44.26; PBO, 64.71; P=0.008), and severe (LEM10, 42.03; PBO, 91.49; P&amp;lt; 0.0001) OSA. On D8, WASO was significantly lower in subjects with mild (LEM10, 51.74; PBO, 70.52; P=0.015) and moderate (LEM10, 49.16; PBO, 75.15; P=0.008) but not severe (LEM10, 59.85; PBO, 74.46; P=0.161) OSA. LEM was well-tolerated. Conclusion In untreated OSA subjects without insomnia, irrespective of OSA severity, LEM improved sleep maintenance versus PBO. LPS did not differ between treatments since such patients may not report sleep onset difficulties. These findings support the use of LEM for patients with comorbid insomnia and sleep apnea (COMISA). Support (if any) Eisai, Inc.

0411 Long-term efficacy of lemborexant on objective sleep measures in clinical practice

Abstract Introduction In the treatment of insomnia, both subjective and objective evaluations are essential. The orexin receptor antagonist, lemborexant, has a favorable profile in terms of efficacy, acceptability, and tolerability for adults diagnosed with insomnia. To date, the long-term efficacy of lemborexant has been evaluated solely on a subjective basis, with no long-term objective measures under natural sleeping conditions. Therefore, a small, lightweight sleep electroencephalograph monitor was used to evaluate sleep objectively at home after 4 and 12 weeks of lemborexant treatment. Methods Adults and elderly subjects with insomnia disorder per DSM-5 were enrolled in an open-label, single-arm, single-center trial. Participants took lemborexant (5/10 mg) at bedtime for 12 weeks. In addition, they underwent a home-based sleep study at baseline and weeks 4 and 12. Sleep ­efficiency (SE), total sleep time (TST), latency to persistent sleep (LPS), and wake after sleep onset (WASO) were ­evaluated at home. Sleep disturbance (Pittsburgh sleep quality index: PSQI), ­sleepiness (Epworth sleepiness scale: ESS), and depressive symptoms (Beck depression index: BDI) were examined. Results 31 subjects completed the 4-week and 29 completed the 12-week assessments. Subjects showed significant improvements in objective SE at weeks 4 and 12 of treatment compared to untreated baseline. Objective TST tended to increase with the treatment at week 12. Mixed-effects linear analysis revealed that the poorer the sleep measures (SE, TST, LPS, and WASO) were at baseline, the more these measures improved with lemborexant. Scores of PSQI, ESS, and BDI significantly decreased (improved) with lemborexant treatment compared to those at baseline. Conclusion The findings from the analyses demonstrate objective improvement of SE with lemborexant treatment across 12 weeks and support the previously reported benefit of lemborexant using polysomnography. Support (if any)

Dual orexin receptor antagonists for the treatment of insomnia: systematic review and network meta-analysis.

Several randomized clinical trials (RCTs) have shown that dual orexin receptor antagonists (DORAs) are effective in the treatment of chronic insomnia. However, the superiority of one particular DORA over the others remains unclear. To perform a network meta-analysis to evaluate the efficacy of different DORAs in patients with chronic insomnia. The Medline, Embase, and Cochrane Central databases were searched for RCTs that compared DORA with placebo in patients ≥ 18 years of age with a diagnosis of insomnia disorder. We pooled outcomes for wake time after sleep onset (WASO), latency to persistent sleep (LPS), total sleep time (TST), and adverse events (AEs). We included 10 RCTs with 7,806 patients, 4,849 of whom received DORAs as the intervention. Overall, we found that DORAs were associated with the improvement of all analyzed efficacy outcomes. Concerning TST, an apparent dose-dependent pattern was noticed, with higher doses relating to a longer TST. Lemborexant 10mg provided the largest reduction in WASO (at month 1) in minutes (standardized mean difference [SMD] = -25.40; 95% confidence interval [95%CI] = -40.02--10.78), followed by suvorexant 20/15mg (SMD = -25.29; 95%CI = -36.42--14.15), which also appeared to provide the largest decrease in long-term WASO (SMD = -23.70; 95%CI = -35.89--11.51). The most frequent AEs were somnolence, nasopharyngitis, and headache, with rates of up to 14.8%. Our results suggest that DORAs are associated with greater efficacy when compared with placebo in the treatment of insomnia, a complex 24-hour sleep disorder. Additionally, dosing might play an important role in the management of chronic insomnia.

Daridorexant: Comprehensive Review of A New Oral Agent for the Treatment of Insomnia.

To review the current pharmacology, pharmacokinetics/pharmacodynamics, safety, and efficacy of daridorexant in patients with insomnia. A literature search of PubMed (March 1, 2018, to October 19, 2022) and ClinicalTrials.gov search was conducted using the following terms: daridorexant and ACT-541468. Additional articles were identified by hand from references. We included English-language articles evaluating daridorexant pharmacology, efficacy, or safety in humans for the management of insomnia. Daridorexant has a peak plasma concentration of 1-2 hours, terminal half-life of 8 hours, and absolute bioavailability of 61%. Wake after sleep onset (WASO) significantly decreased from baseline to months 1 and 3 in daridorexant 25 (-18.40 and -22.97 min, P < 0.0001) and 50 mg (-28.98 and -29.41 min, P < 0.0001) groups compared with placebo. Latency to persistent sleep (LPS) significantly decreased from baseline to months 1 and 3 for daridorexant 25 mg (-28.17 and -30.73 min, P = 0.0005 and P = 0.0015) and 50 mg (-31.20 and -34.80 min, P < 0.0001). Daridorexant can be administered in diverse patient populations because of its tolerability and favorable safety profile. However, due to the lack of large scale studies that directly compare dual orexin receptor antagonists (DORAs), there is not enough data to recommend 1 DORA over another. Daridorexant is well tolerated and has demonstrated significant reductions in LPS and WASO in the treatment of insomnia in adult patients.

Efficacy and Safety of Daridorexant in Older and Younger Adults with Insomnia Disorder: A Secondary Analysis of a Randomised Placebo-Controlled Trial.

Background and ObjectiveThe dual orexin receptor antagonist daridorexant, studied in two phase III trials, dose-dependently improved objective and subjective sleep variables and daytime functioning in adults with insomnia. Because treatment of insomnia in older adults is challenging and has limited options, the purpose of the current analysis was to further analyse the phase III trial studying the higher doses of daridorexant, those that showed efficacy (daridorexant 50 mg, daridorexant 25 mg and placebo, nightly for 3 months), and compare the safety and efficacy of daridorexant in patients aged ≥ 65 (‘older adults’) to those aged < 65 years (‘younger adults’).MethodsAnalyses by age (≥ 65 years, n = 364; < 65 years, n = 566) were performed on data from the randomised, double-blind, placebo-controlled Trial 1 in adult patients with insomnia (NCT03545191). Efficacy endpoints included a change from baseline at month 1 and month 3 in polysomnography-measured wake after sleep onset (WASO) and latency to persistent sleep (LPS), self-reported total sleep time (sTST) and daytime functioning assessed using the validated Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). Safety endpoints included adverse events and the Visual Analog Scale for morning sleepiness.ResultsAt baseline, mean [standard deviation] WASO was numerically greater (110 [39] vs 92 [38] min) in older than younger adults, while LPS was comparable (~ 65 min). Mean baseline IDSIQ total and all domain scores were numerically lower (i.e. better) in older adults. Daridorexant caused similar reductions in WASO and LPS, and similar increases in sTST, from baseline, in both age groups; improvements were numerically greater with daridorexant 50 mg than 25 mg. At month 3, daridorexant 50 mg, compared with placebo, decreased WASO by a least-squares mean of 19.6 (95% confidence interval 9.7, 29.5) in older patients versus 17.4 min (10.7, 24.0) in younger patients and decreased LPS by a least-squares mean of 14.9 (7.5, 22.3) in older patients versus 9.7 min (3.7, 15.7) in younger patients. Daridorexant 50 mg increased sTST from baseline to month 3 by a least-squares mean of 59.9 (49.6, 70.3) in older patients versus 57.1 min (48.9, 65.3) in younger patients. Daridorexant 50 mg progressively improved IDSIQ total and domain scores from week 1 onwards similarly in both groups; daridorexant 25 mg improved IDSIQ scores, but only in younger adults. In both age groups, in comparison with placebo, the overall incidence of adverse events was comparable, and there were fewer falls on daridorexant. Daridorexant improved Visual Analog Scale morning sleepiness in both groups; daridorexant 50 mg increased the mean (standard deviation) Visual Analog Scale morning sleepiness score by 15.9 (20.7) in older adults and by 14.9 (18.7) in younger adults from baseline to month 3. In older adults, there was one case of sleep paralysis, and no cases of narcolepsy, cataplexy, or complex sleep behaviour.ConclusionsIn older patients with insomnia, as in younger patients, the efficacy of daridorexant is maximal on night-time and daytime variables at the higher dose of 50 mg. Older patients particularly require this dose to improve daytime functioning. Older patients are not at an increased risk of adverse events or residual effects the next morning after night-time administration of daridorexant, even at 50 mg. The dose of daridorexant does not need to be decreased for older patients.Clinical Trial RegistrationClinicalTrials.gov (NCT03545191) [first posted: 4 June, 4 2018], https://clinicaltrials.gov/ct2/show/NCT03545191.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40266-022-00977-4.

Daridorexant for the treatment of insomnia disorder: findings and implications.

The involvement of the orexin system in the physiopathology of insomnia has been rapidly increasing in understanding. In this sense, daridorexant was the third orexin receptor antagonist approved by the FDA in January 2022. This review aims to summarize the chemistry, pharmacodynamics, pharmacokinetics, efficacy, safety, and tolerability profile of daridorexant for the treatment of insomnia disorder. We performed a review of daridorexant for the treatment of insomnia disorder. The search was carried out in Medline via PubMed, Embase, and clinical trials, up to March 2022. Daridorexant 25 and 50mg had more significant improvement for the wake after sleep onset (WASO), latency to persistent sleep (LPS), and subjective total sleep time (sTST) than placebo. In addition, daridorexant 50mg was better for Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) than placebo. The most common adverse events were nasopharyngitis and headache. Daridorexant was efficacious and safe. Studies that evaluate the long-term safety and compare daridorexant with benzodiazepines, benzodiazepine receptor agonists, sedative antidepressants, and other orexin receptor antagonists are required.

0451 Effect of Lemborexant Treatment on Polysomnographic Sleep Measures in Older Adults with Insomnia and Objective Short Sleep

Abstract Introduction In Phase 3 Study 304 (NCT02783729), lemborexant (LEM) provided significant benefit versus placebo (PBO) on polysomnographic (PSG) and sleep diary-based sleep onset and maintenance outcomes over 1mo in subjects with insomnia disorder. Based on evidence that patients with insomnia and objective short sleep (ISS [total sleep time; TST] &amp;lt;6hrs) may respond less well to interventions such as cognitive behavioral therapy for insomnia (CBT-I) than patients with insomnia and objective long sleep (TST ≥6hrs), we conducted post-hoc analyses of LEM efficacy in the ISS subgroup (subjects with PSG TST&amp;lt;6hrs). Methods Study 304 was a 1mo, randomized, double-blind, PBO- and active-controlled, parallel-group study in female (age ≥55y) and male (age ≥65y) subjects (n=1006). Subjects received PBO, LEM 5mg (LEM5), LEM 10mg (LEM10), or zolpidem tartrate extended-release 6.25mg (ZOL). Latency to persistent sleep (LPS) and wake after sleep onset (WASO) were assessed at Nights (NT) 1/2 and NT29/30 using PSG and averaged; change from baseline (paired PSGs during single-blind PBO run-in) were analyzed using mixed-effect model repeated measurement analysis. Results The ISS subgroup comprised 710/1006 (70.58%) subjects. Mean (SD) baseline LPS was similar across treatments: PBO=52.80(35.73); ZOL=54.77(40.93); LEM5=54.28(39.30); LEM10=53.31(34.45). On NT1/2, LEM5/10 led to statistically significantly greater (P&amp;lt;0.05) decreases from baseline (PBO=−9.65[36.52]; ZOL=−17.78[36.34]; LEM5=−22.02[31.62]; LEM10=−25.42[34.73]) versus PBO and ZOL. On NT29/30, LEM5/10 led to statistically significantly greater (P&amp;lt;0.0005) decreases from baseline (PBO=−11.88[35.09]; ZOL=−12.57[38.50]; LEM5=−25.37[37.06]; LEM10=−28.20[34.75] versus PBO. ZOL was not different from PBO. Mean (SD) baseline WASO was similar: PBO=123.79(37.21); ZOL=128.37(38.94); LEM5=128.14(37.52); LEM10=129.07(37.98). On NT1/2, LEM5/10 led to statistically significantly greater (P&amp;lt;0.0001) decreases from baseline (LSM[SE]: PBO=−23.52[2.74]; ZOL=−54.74[2.47]; LEM5=−60.58[2.45]; LEM10=−69.35[2.41] versus PBO. LEM10 was significantly different than ZOL (P&amp;lt;0.0001). On NT29/30, LEM5/10 led to statistically significantly greater (P&amp;lt;0.0001) decreases from baseline (PBO=−29.62[3.09]; ZOL=−46.86[2.80]; LEM5=−52.67[2.74]; LEM10=−55.37[2.70] versus PBO. LEM10 was significantly different than ZOL (P&amp;lt;0.05). Conclusion The data support LEM as an effective therapy for older adult patients with ISS and suggest LEM may be more beneficial than ZOL, particularly for patients with ISS and sleep onset difficulties. These findings suggest that LEM may be a reasonable therapy to consider for treating older patients with ISS where CBT-I may have relatively limited efficacy. Support (If Any) Eisai Inc.

Effects of TS-142, a novel dual orexin receptor antagonist, on sleep in patients with insomnia: a randomized, double-blind, placebo-controlled phase 2 study

RationaleNovel compound with potent antagonistic activity against orexin receptors may be new treatment option for patients with insomnia.ObjectiveThe aim was to investigate the efficacy and safety of single oral doses of the dual orexin receptor antagonist TS-142 in patients with insomnia.MethodsThis multicenter, double-blind, crossover randomized clinical trial included non-elderly patients with insomnia. Patients were randomized to receive single doses of placebo and TS-142 at doses of 5, 10, and 30 mg in one of four different sequences, with a 7-day washout period between treatments. Primary efficacy endpoints were latency to persistent sleep (LPS) and wake time after sleep onset (WASO) measured by polysomnography.ResultsTwenty-four patients were included (mean age 50.3 ± 10.5 years; mean duration of insomnia 5.71 ± 8.68 years). Least-squares mean differences (95% confidence interval) from placebo in LPS with 5, 10, and 30 mg TS-142 were − 42.38 (− 60.13, − 24.63), − 42.10 (− 60.02, − 24.17), and − 44.68 (− 62.41, − 26.95) minutes, respectively (all p < 0.001). Least-squares mean differences (95% confidence interval) from placebo in WASO with 5, 10, and 30 mg TS-142 were − 27.52 (− 46.90, − 8.14), − 35.44 (− 55.02, − 15.87), and − 54.69 (− 74.16, − 35.23) minutes, respectively (all p < 0.01). Self-reported aspects of sleep initiation and sleep quality, determined using the Leeds Sleep Evaluation Questionnaire (LSEQ), were also improved with TS-142 administration versus placebo. TS-142 was well tolerated; all adverse events were mild or moderate and none were serious.ConclusionSingle-dose TS-142 was well tolerated and had clinically relevant effects on objective and subjective sleep parameters in patients with insomnia.Clinical Trial registrationJapicCTI173570 (www.clinicaltrials.jp); NCT04573725 (www.clinicaltrials.gov).

Effects of daridorexant on sleep and daytime functioning in older adults with insomnia

Introduction Insomnia affects older adults more than younger adults, and comorbidities more prevalent in older populations can add to symptom burden and reduce therapeutic options. Drugs that improve insomnia symptoms with limited safety risks are needed to treat this patient group. We report older adult subgroup analyses from a Phase-3 registration trial with daridorexant. Methods In this multi-center, double-blind trial (NCT03545191), adults (18–64y) and older adults (≥65y) with insomnia were randomized (1:1:1) to receive oral daridorexant 25mg, 50mg or placebo every evening for 3 months. Month 3 endpoints were: change from baseline in polysomnography-measured wake-after-sleep-onset (WASO) and latency-to-persistent-sleep (LPS) (both primary endpoints), subjective total sleep time (sTST), and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire [IDSIQ] – sleepiness domain; with a lower score indicating improved daytime functioning). Safety endpoints included treatment emergent adverse events (TEAE), AEs of special interest (AESI; symptoms related to excessive daytime sleepiness or complex sleep behavior, and suicidal ideation/self-injury) and withdrawal effects upon treatment cessation (assessed by the Benzodiazepine Withdrawal Symptom Questionnaire total score and relevant AEs). Results Of the 930 patients randomized, 364 (39.1%) were ≥65y: daridorexant 25mg (n=121), 50mg (n=121) and placebo (n=122). In this subgroup, at Month 3, the placebo-corrected least-square mean of change from baseline [95%CL] for daridorexant 25mg and 50mg were: WASO -17.0[-27.0,-7.0] and -19.6[-29.5,-9.7] mins; LPS -7.8[-15.2,-0.4] and -14.9[-22.3,-7.5] mins; sTST 18.7[4.1,33.2] and 30.6[16.1,45.2] mins; IDSIQ sleepiness domain -0.6[-2.2,0.9] and -2.6[-4.1,-1.0], all respectively. Conclusions Daridorexant is efficacious in the older adults for improvements in sleep and daytime functioning. No significant safety concerns in this vulnerable population were identified at either dose. This research was funded by Funded by Idorsia Pharmaceuticals Ltd. Fietze I, Bassetti C, Mayleben D, et al, 347. Daridorexant is Safe and Improves Both Sleep and Daytime Functioning in Elderly Patients with Insomnia, Sleep 2021; 44 (Suppl_2): A138-A139, https://doi.org/10.1093/sleep/zsab072.346 © Sleep Research Society 2021. Published by OUP on behalf of the Sleep Research Society. Insomnia affects older adults more than younger adults, and comorbidities more prevalent in older populations can add to symptom burden and reduce therapeutic options. Drugs that improve insomnia symptoms with limited safety risks are needed to treat this patient group. We report older adult subgroup analyses from a Phase-3 registration trial with daridorexant. In this multi-center, double-blind trial (NCT03545191), adults (18–64y) and older adults (≥65y) with insomnia were randomized (1:1:1) to receive oral daridorexant 25mg, 50mg or placebo every evening for 3 months. Month 3 endpoints were: change from baseline in polysomnography-measured wake-after-sleep-onset (WASO) and latency-to-persistent-sleep (LPS) (both primary endpoints), subjective total sleep time (sTST), and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire [IDSIQ] – sleepiness domain; with a lower score indicating improved daytime functioning). Safety endpoints included treatment emergent adverse events (TEAE), AEs of special interest (AESI; symptoms related to excessive daytime sleepiness or complex sleep behavior, and suicidal ideation/self-injury) and withdrawal effects upon treatment cessation (assessed by the Benzodiazepine Withdrawal Symptom Questionnaire total score and relevant AEs). Of the 930 patients randomized, 364 (39.1%) were ≥65y: daridorexant 25mg (n=121), 50mg (n=121) and placebo (n=122). In this subgroup, at Month 3, the placebo-corrected least-square mean of change from baseline [95%CL] for daridorexant 25mg and 50mg were: WASO -17.0[-27.0,-7.0] and -19.6[-29.5,-9.7] mins; LPS -7.8[-15.2,-0.4] and -14.9[-22.3,-7.5] mins; sTST 18.7[4.1,33.2] and 30.6[16.1,45.2] mins; IDSIQ sleepiness domain -0.6[-2.2,0.9] and -2.6[-4.1,-1.0], all respectively. Daridorexant is efficacious in the older adults for improvements in sleep and daytime functioning. No significant safety concerns in this vulnerable population were identified at either dose.

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

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

An observational study investigating the CRY1\u039411 variant associated with delayed sleep\u2013wake patterns and circadian metabolic output

We conducted an observational research study to collect information on sleep–wake patterns from participants with a confirmed status of the cryptochrome circadian clock 1 (CRY1) splicing variant, CRY1Δ11 c.1657 + 3A > C, and their controls, defined as wild-type (WT) family members. Altogether, 67 participants were enrolled and completed this study in Turkey, recruited from a list of families with at least one CRY1-confirmed member. We measured sleep–wake patterns and metabolic output, specifically time and frequency of bowel movements, for all participants by daily post-sleep diaries over 28 days. The sleep diary measured self-reported bed time, wake time, midpoint of sleep, and latency to persistent sleep (LPS), and accounted for naps and awakenings for religious purposes. Wake time and midpoint of sleep were significantly later in the CRY1Δ11 variant group versus WT, and LPS was significantly greater in participants in the CRY1Δ11 variant group. The mean bed time on all nights of sleep was later in participants with a CRY1Δ11 variant versus WT. Additionally, participants with a CRY1Δ11 variant had significantly affected metabolic outputs, measured by later bowel movements than WT participants. These results demonstrate that, on average, individuals with the studied splicing variant experience pronounced delays in sleep period and circadian-related metabolic processes.

348 Absence of Withdrawal Symptoms and Rebound Insomnia Upon Discontinuation of Daridorexant in Patients with Insomnia

Abstract Introduction Abrupt discontinuation of sleep medications in patients with insomnia often causes withdrawal symptoms and rebound insomnia. In a Phase 3 program evaluating efficacy and safety of daridorexant on sleep and daytime functioning in patients with insomnia during 3 months of treatment, the risks of withdrawal symptoms and rebound insomnia were evaluated at treatment cessation. Methods In two randomized, double-blind, 3-month trials, adult (18–64 years) and elderly (≥65) patients with insomnia were assigned (1:1:1) to receive oral daridorexant 25mg, 50mg or placebo (Trial-1, NCT03545191) or 10mg, 25mg or placebo (Trial-2, NCT03575104) every evening. Each trial included a 7-day, single-blind, placebo run-out period following double-blind treatment to evaluate withdrawal symptoms and rebound insomnia. Withdrawal effects were assessed by the change in Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) total score, from last assessment on double-blind treatment to end of placebo run-out, and occurrence of relevant adverse events (AEs). Rebound insomnia was assessed objectively by change in wake-after-sleep-onset (WASO) and latency-to-persistent sleep (LPS), from baseline to first night of placebo run-out, and by subjective total-sleep-time (sTST), from baseline to end of run-out (mean of 7-days). Analyses included all patients who received ≥1 dose of placebo run-out treatment (Trial-1: N=852; Trial-2: N=851). Results No increase in mean BSWQ score from last assessment on double-blind treatment to end of placebo run-out was reported (Trial-1: 25mg, -0.6±2.3; 50mg, -0.6±2.3; placebo, -0.7±2.3; Trial-2: 10mg, -0.5±2.6; 25mg, -0.4±1.9; placebo, -0.4±1.4). No patients had a BWSQ score &amp;gt;20 at end of run-out. No AEs suggestive of withdrawal symptoms were reported. Mean WASO and LPS values (min) decreased from baseline to placebo run-out (WASO Trial-1: 25mg, -8.6±55.5; 50mg, -2.5±52.4; placebo, -20.4±45.8; Trial-2: 10mg, -11.6±58.3; 25mg, -5.1±57.9; placebo, -26.2±53.5; LPS Trial-1: 25mg, -17.2±56.7; 50mg, -15.0±55.8; placebo, -27.8±47.2; Trial-2: 10mg, -17.3±67.2; 25mg, -10.3±67.3; placebo, -18.3±63.8) while sTST values (min) increased (Trial-1: 25mg, 43.3±53.8; 50mg, 42.9±59.6; placebo, 42.3±52.7; Trial-2: 10mg, 43.3±52.9; 25mg, 46.8±55.4; placebo, 42.3±53.8) indicating absence of rebound effects. Conclusion Treatment with daridorexant for up to 3-months was not associated with any evidence of drug withdrawal or rebound insomnia upon abrupt discontinuation, indicating no safety concerns for patients should treatment be stopped. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

358 Daridorexant Improves Sleep in Patients with Mild/Moderate Obstructive Sleep Apnea

Abstract Introduction Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia. The effect of the highest phase-3 dose of 50 mg daridorexant on nighttime respiratory function was evaluated in patients with mild/moderate obstructive sleep apnea (OSA). This study showed that repeated doses of daridorexant had no clinically meaningful effect on the apnea-hypopnea index (AHI) or on peripheral oxygen saturation. In the same study, the effect on objective sleep parameters was also explored by polysomnography (PSG). Methods In this randomized, double-blind, placebo-controlled, two-period, crossover study, daridorexant or placebo was administered in each period once daily for 5 consecutive nights to 28 patients. Treatment difference (daridorexant – placebo) for total sleep time (TST), latency to persistent sleep (LPS), and wake after sleep onset (WASO) was analyzed for Night 5 using linear mixed-effects modeling. In addition, sleep was further explored based on sleep duration during each hour of PSG recording, duration of the different sleep phases (rapid eye movement [REM], non-REM [including N1 to N3 sleep stages]), as well as number and mean/longest duration of awakenings. Results Of 28 patients enrolled, 25 completed the study and were included in the analysis (n=15/10 with mild/moderate OSA; mean [standard deviation] AHI: 16.3 [8.2] events/h). One patient had mild insomnia symptoms at baseline. Compared to placebo, daridorexant prolonged mean TST by 38.8 min (90% confidence interval: 19.7–57.9), shortened mean LPS by 17.2 min (-35.5–1.02), and reduced mean WASO by 31.0 min (-47.3 to 14.7). Sleep architecture was maintained as no treatment differences in the duration of the evaluated sleep stages were observed when normalized to TST. Sleep duration was prolonged in the second part of the night. mean and longest duration of awakenings were decreased by a mean (90% CI) of 2.0 min (-3.1 to 0.9) and 16.3 min (-24.1 to -8.6), respectively, without treatment difference for the total number of awakenings. Conclusion Daridorexant improved objective sleep parameters in patients with mild to moderate OSA without modifying sleep architecture. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

347 Daridorexant is Safe and Improves Both Sleep and Daytime Functioning in Elderly Patients with Insomnia

Abstract Introduction Insomnia affects elderly more than younger adults, and comorbidities more prevalent in elderly populations can add to symptom burden and reduce therapeutic options. Drugs that improve insomnia symptoms with limited safety risks are needed to treat this patient group. We report elderly subgroup analyses from a Phase-3 registration trial with daridorexant. Methods In this multi-center, double-blind trial (NCT03545191), adult (18–64y) and elderly (≥65y) patients with insomnia were randomized (1:1:1) to receive oral daridorexant 25mg, 50mg or placebo every evening for 3 months. Month 3 endpoints were: change from baseline in polysomnography-measured wake-after-sleep-onset (WASO) and latency-to-persistent-sleep (LPS) (both primary endpoints), subjective total sleep time (sTST), and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire [IDSIQ] – sleepiness domain; with a lower score indicating improved daytime functioning). Safety endpoints included treatment emergent adverse events (TEAE), AEs of special interest (AESI; symptoms related to excessive daytime sleepiness or complex sleep behavior, and suicidal ideation/self-injury) and withdrawal effects upon treatment cessation (assessed by the Benzodiazepine Withdrawal Symptom Questionnaire total score and relevant AEs). Results Of the 930 patients randomized, 364 (39.1%) were ≥65y: daridorexant 25mg (n=121), 50mg (n=121) and placebo (n=122). In this subgroup, at Month 3, the placebo-corrected least-square mean of change from baseline [95%CL] for daridorexant 25mg and 50mg were: WASO -17.0[-27.0,-7.0] and -19.6[-29.5,-9.7] mins; LPS -7.8[-15.2,-0.4] and -14.9[-22.3,-7.5] mins; sTST 18.7[4.1,33.2] and 30.6[16.1,45.2] mins; IDSIQ sleepiness domain -0.6[-2.2,0.9] and -2.6[-4.1,-1.0], all respectively. TEAEs were reported in 32.2%, 35.3%, and 31.1% of patients ≥65y in the 25mg, 50mg and placebo groups, respectively. Falls (n=1,1,4 for 25mg, 50mg, placebo, respectively) and dizziness (n=4,1,1), both of particular interest in elderly, were least frequent in the 50mg group. Compared to placebo, somnolence was as frequent for 50mg daridorexant (n=6,1,1) while fatigue was more frequent in both daridorexant groups (n=4,3,1); incidence did not appear dose-related. AESI, of mild intensity, were reported in 2 patients ≥65y (one in each daridorexant group). There was no evidence of withdrawal symptoms. Conclusion Daridorexant is efficacious in the elderly population for improvements in sleep and daytime functioning. No safety concerns in this vulnerable population were identified at either dose. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

Effect of the new dual orexin receptor antagonist daridorexant on nighttime respiratory function and sleep in patients with mild and moderate obstructive sleep apnea.

In this randomized, double-blind, placebo-controlled, two-period crossover study, the effect of the dual orexin receptor antagonist daridorexant was evaluated on nighttime respiratory function and sleep in 28 patients with mild and moderate obstructive sleep apnea (OSA). In each period, 50 mg daridorexant or placebo was administered every evening for 5 days. The primary endpoint was apnea/hypopnea index (AHI) during total sleep time (TST) after the last dosing. Other endpoints included peripheral oxygen saturation (SpO2), sleep duration, latency to persistent sleep (LPS), wake after sleep onset (WASO), and sleep efficiency index (SEI). Pharmacokinetics, safety, and tolerability were also assessed. The mean treatment difference for AHI during TST (i.e. daridorexant - placebo) after the last dosing was 0.74 events/hour (90% confidence interval [CI]: -1.43, 2.92). The corresponding treatment difference for SpO2 during TST was 0.16% [90% CI: -0.21, 0.53]. Overall, there was no clinically relevant effect of daridorexant on AHI or SpO2-related data after single and repeated dosing irrespective of sleep phase (i.e. rapid eye movement [REM] vs non-REM). Moreover, after single and repeated dosing, daridorexant prolonged TST by 39.6 minutes (90% CI: 16.9, 62.3) and 38.8 minutes (19.7, 57.9), respectively, compared with placebo and favorably modulated other sleep-related endpoints (i.e. increased SEI, decreased WASO, and shortened LPS). It attained expected plasma concentrations and was well tolerated in patients with mild and moderate OSA. These results indicate that single and repeated doses of 50 mg daridorexant do not impair nighttime respiratory function and improve sleep in patients with mild and moderate OSA. Clinical Trial Registration: ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/ NCT03765294.

0504 Efficacy and Safety of Seltorexant in Insomnia Disorder

Abstract Introduction Insomnia disorder affects 3-6% of the population and includes functional impairing symptoms for ≥3 months. Current hypnotics have limitations (eg fall risk, dependency, parasomnia, cognitive impairment). In a previous proof-of-concept study, seltorexant, a selective orexin-2 receptor antagonist, dosed at 40mg nightly improved sleep efficiency, latency to persistent sleep (LPS), and wake after sleep onset (WASO) versus placebo. Methods A multicenter, double-blind, randomized, parallel-group, active- and placebo-controlled, 14-day, dose-finding study (NCT03375203) assessed the efficacy and safety of seltorexant in adult and elderly subjects meeting DSM-5 insomnia disorder criteria. Subjects were randomized (1:1:1:1:1 ratio) to: placebo, seltorexant 5mg, 10mg, 20mg, or zolpidem. Primary endpoint: Based on PSG, dose response in LPS change on Night 1 relative to baseline. Secondary endpoints included change from baseline in: WASO over the first 6 hours (WASO-6) on Night 1, and LPS and WASO-6 on Night 13. Multiple Comparison Procedure-Modeling, ANCOVA and MMRM were used for data analyses. Results 365 patients were randomized and 347 (95%) completed the double-blind phase with 68% women and median age of 59yr (22 to 84yr). Statistically significant dose-response relationship (p-value &amp;lt;0.001) was observed for LPS at Night 1 (5mg=12%, 10mg=36%, 20mg=49% improvement compared with placebo). Similar findings were observed for WASO-6 and benefits sustained from Night 1 to 13. The 20 mg dose showed greater improvement than zolpidem on LPS at Nights 1 and 13 and on WASO-6 at Night 13. Overall treatment-emergent adverse events rates were comparable in the seltorexant, placebo, and zolpidem treatment groups. Conclusion Statistically significant and clinically meaningful improvements on LPS &amp; WASO-6 were observed for seltorexant 10 and 20mg dose groups versus placebo. No safety concerns were observed. Seltorexant with its novel mechanism holds potential as a new treatment for insomnia disorder. Support