Treatment Of Insomnia In Adults Research Articles

Clinical safety of daridorexant in insomnia treatment: Analysis of FDA adverse event reports

ObjectiveDaridorexant, a novel dual orexin receptor antagonist, was approved by the FDA in 2022 for the treatment of insomnia in adults. The aim of this study is to delve into the adverse events (AEs) of daridorexant by analyzing data from the FAERS database, to assess its safety and effectiveness in clinical applications. MethodsThis study selected data from the FAERS database from the first quarter of 2022 to the third quarter of 2023. Various data analysis methods were used, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM), to assess AEs related to daridorexant. ResultsThe study analyzed a total of 2,624,030 AE reports, of which 1318 were related to daridorexant. It identified 59 preferred terms (PTs) involving 23 system organ classes (SOCs). Signal mining identified new potential AEs related to daridorexant, including sleep-related psychiatric symptoms (nightmare, abnormal dreams, sleep terror, etc.), emotional and perceptual abnormalities (hallucination, depression, agitation), physiological and behavioral responses (palpitations, dry mouth, energy increased, etc.), suicide risk (suicidal ideation, intentional overdose), and other special concern AEs (tachyphrenia, sleep-related eating disorder, hypersensitivity). ConclusionAlthough some new potential AEs have been identified, these findings need further verification in broader datasets and long-term studies due to limitations in data sources and analysis methods. Future research should comprehensively assess the safety and effectiveness of daridorexant, providing more accurate guidance for medical professionals in the treatment of insomnia.

Effects of nurse-led brief behavioral treatment for insomnia in adults: a randomized controlled trial.

To examine the effects of nurse-led brief behavioral treatment for insomnia (BBTI) on insomnia severity, sleep status, daytime function, quality of life (QoL), psychological distress levels, treatment response, and insomnia remission in young and middle-aged Asian adults with insomnia symptoms. This two-parallel, randomized controlled trial recruited 42 participants with insomnia symptoms randomly allocated to the nurse-led BBTI group or sleep hygiene (SH) group. The outcome measurements included the Insomnia Severity Index, sleep diary, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Brief Fatigue Inventory, RAND-36 Health Status Inventory, and the Depression, Anxiety and Stress Scale-21. The measurement time points included baseline, the end of each week of the intervention period, and one-month follow-up. Compared with the SH group, participants in the BBTI group significantly improved insomnia severity, sleep onset latency, sleep efficiency, sleep quality, daytime sleepiness, and the mental components of QoL after completing nurse-led BBTI immediately and one month later (p < 0.05). In addition, 52.4% and 71.4% of the participants achieved remission after completing nurse-led BBTI immediately and one month later, which were significantly higher than the SH group (14.3%, p = 0.02; 14.3%, p < 0.001, respectively). We suggested the relative effects of BBTI on declined insomnia severity and improved sleep status among young and middle-aged Asian adults with insomnia symptoms and confirmed the benefits of nurse-led BBTI in alleviating insomnia. Nurses should incorporate BBTI into insomnia care further to enhance the daytime function and quality of life of the population with insomnia symptoms. Registry: ClinicalTrials.gov; Name: Effects of Nurse-led Brief Behavioral Treatment for Insomnia: A Feasibility Randomized Controlled Trial; URL: https://clinicaltrials.gov/study/NCT05310136; Identifier: NCT05310136.

2023 Guidelines on the Diagnosis and Treatment of Insomnia in Adults – Brazilian Sleep Association

AbstractChronic insomnia disorder (simplified in this document as insomnia) is an increasingly common clinical condition in society and a frequent complaint at the offices of different areas of health practice (particularly Medicine and Psychology). This scenario has been accompanied by a significant evolution in treatment, as well as challenges in approaching patients in an appropriately way. This clinical guideline, coordinated by the Brazilian Sleep Association and the Brazilian Association of Sleep Medicine and counting on the active participation of various specialists in the area, encompasses an update on the diagnosis and treatment of insomnia in adults. To this end, it followed a structured methodology. Topics of interest related to diagnosis were written based on theoretical framework, evidence in the literature, and professional experience. As for the topics related to the treatment of insomnia, a series of questions were developed based on the PICO acronym (P – Patient, problem, or population; I – Intervention; C – Comparison, control, or comparator; O – Outcome). The work groups defined the eligible options within each of these parameters. Regarding pharmacological interventions, only the ones currently available in Brazil or possibly becoming available in the upcoming years were considered eligible. Systematic reviews were conducted to help prepare the texts and define the level of evidence for each intervention. The final result is an objective and practical document providing recommendations with the best scientific support available to professionals involved in the management of insomnia.

Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease.

Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.

0340 AASM Insomnia Summit 2022

Abstract Introduction Significant challenges exist in access to high-quality care for insomnia disorder. After the recent publication of clinical practice guidelines on behavioral/psychological treatments for insomnia in adults, the American Academy of Sleep Medicine (AASM) hosted a virtual one-day summit in September 2022 to discuss improving care for patients with insomnia disorder. Methods Fifty attendees representing a variety of organizations (e.g., medical, psychological, and nursing associations; patient advocacy groups; and federal institutions) participated in the Summit. Videos highlighting patient perspectives and an overview of current insomnia disorder treatment guidelines were followed by thematic sessions: (1) barriers to care, (2) facilitators of high-quality care, and (3) future directions and innovations. After 3-4 brief topical presentations by content experts, summit participants divided into seven breakout groups to brainstorm and prioritize issues. Each breakout highlighted 3-5 priorities and reported back to the broader group following each thematic session. Results The top barriers to care for insomnia disorder identified by summit participants included (1) limited access to care, (2) limited awareness of insomnia treatment options, (3) limited treatment formats, (4) low perceived value of insomnia treatment, and (5) insufficient number of trained clinicians to provide care. The top facilitators of care included (1) increased education and awareness, (2) novel models to increase access to care, (3) developing and expanding the insomnia patient care workforce, (4) incorporating research into practice, and (5) increasing reimbursement. Top priorities for future directions included (1) increasing awareness among patients and healthcare providers, (2) increasing the number of skilled behavioral sleep medicine providers, (3) increasing advocacy efforts to address insurance issues (e.g., billing, reimbursement, and performance measures), and (4) working collaboratively with multidisciplinary organizations to achieve common goals for insomnia disorder care. Conclusion The AASM and participants from partnering organizations successfully engaged in a summit and identified prioritized strategies to improve access to high-quality care for insomnia disorder across diverse clinical settings (e.g., private practice, academic institutions, and rural areas). The priorities are to improve access to care for insomnia disorder, which require advocacy efforts to increase awareness of treatment options, improve reimbursement, and grow the skilled workforce for treating insomnia disorder. Support (if any) AASM

Reply to Hertenstein et al. ’s commentary on Yue et al.: Efficacy and tolerability of pharmacological treatments for insomnia in adults: A systematic review and network meta-analysis

Reply to Hertenstein et al. ’s commentary on Yue et al.: Efficacy and tolerability of pharmacological treatments for insomnia in adults: A systematic review and network meta-analysis

Insomnia in the context of affective disorders

The article analyzes the current literature on the relationship of insomnia with affective disorders, in particular with depression and anxiety. Research shows that there is a strong multi-channel relationship between insomnia, depression, and anxiety, with insomnia being considered a risk factor for mood disorders more often than vice versa. The so-called insomnia paradox of bipolar disorder is described, the essence of which is that in manic episodes the frequency of insomnia is higher than in depressive episodes. The data of a network meta-analysis, which found an evidence base for the use of a variety of drugs used for the pharmacological treatment of insomnia in adults, are presented. Efficiency and convenience in taking the drug Valocordin-Doxylamine are noted.

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.

Abuse Potential of Lemborexant, a Dual Orexin Receptor Antagonist, Compared With Zolpidem and Suvorexant in Recreational Sedative Users.

BackgroundLemborexant (LEM) is a dual orexin receptor antagonist approved for the treatment of insomnia in adults in multiple countries including the the United States, Japan, Canada, Australia and several Asian countries.ProceduresThis was a randomized, single-dose, single-center, double-blind, active-control, 6-way crossover study to evaluate LEM abuse potential. The study assessed oral doses of LEM 10 mg (LEM10), 20 mg (LEM20), and 30 mg (LEM30) compared with placebo (PBO), zolpidem (ZOL) immediate release 30 mg, and suvorexant (SUV) 40 mg. Subjects were healthy, nondependent, recreational sedative users able to discriminate/like the effects of both SUV and ZOL from PBO during a qualification phase.ResultsAbuse potential endpoints were analyzed in qualified subjects who received and completed all treatments (n = 32). On the “at this moment” drug-liking visual analog scale (VAS), mean maximum (peak) effect (primary endpoint) values were 78.4, 80.5, and 83.6 for LEM10, LEM20, and LEM30, respectively, which were all significantly greater than PBO (57.8; all P > 0.05) but not different from SUV (76.1) or ZOL (78.3). Similarly, for secondary endpoints overall drug-liking VAS and take-drug-again VAS, mean maximum (peak) effect values for all LEM doses were significantly greater than PBO (P > 0.05) but not different compared with ZOL or SUV.ConclusionsFor all doses, LEM demonstrated abuse potential versus PBO and appeared to have a similar abuse potential profile to ZOL and SUV in this study population. Lemborexant was well tolerated. Lemborexant has been placed in Schedule IV, the same drug schedule as ZOL and SUV.

0453 Lemborexant Exposure Is Independent of Race

Abstract Introduction Some hypnotic treatments for insomnia require dosing consideration due to exposure differences based on patient characteristics. Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries for the treatment of adult insomnia. LEM is not associated with exposure differences based on sex, age, or BMI that impact dosing. The potential impact of race on exposure was determined in two stand-alone pharmacokinetic (PK) studies and by modeling data from studies comprising the LEM clinical development program, which included healthy subjects and insomnia patients. Methods Study 003 (NCT02039089) was a single-center, multiple-dose, randomized, double-blind, placebo-controlled, parallel-group study in healthy Japanese and White subjects. Study 014 (NCT04555733) was a phase 1, single center, open-label, single and multiple oral dose study in healthy Chinese subjects. Additionally, effect of race on LEM exposure was independently examined as part of a population PK analysis incorporating LEM data from 9 Phase 1 studies (n=407), and Studies 201 (NCT01995838; n=235), 303 (NCT02952820; n=726) and 304 (NCT02783729; n=524) (Lalovic et al., 2020). Plasma concentrations of LEM were quantified from plasma by validated liquid chromatography with tandem mass spectrometry. Adverse events (AE) were recorded. Results Exposure of LEM increased in an approximately dose-proportional manner across the dose range (2.5 mg to 25 mg) in studies 003 and 014. There were no significant exposure differences between Japanese and White subjects following single LEM10 administration on Day 1 in Study 003 (maximum concentration [Cmax] mean[SD], ng/mL: Japanese, 46.5[25.8]; White, 47.3[28.1]; area under the curve from time zero to 24h [AUC0-24] mean[SD], ng·h/mL: Japanese, 231[40.2]; White, 208[83.4]) or when comparing PK data from Chinese subjects in Study 014 following single dose administration on Day 1 (Cmax mean[SD], ng/mL: LEM5, 29.8[12.8]; LEM10, 56.2[16.9]; LEM25, 116[46.8]; AUC0-24 mean[SD], ng·h/mL: LEM5, 106[29.9]; LEM10, 205[35.6]; LEM25, 549[116]) to Japanese and White subjects in Study 003. These results are supported by the cross-study, population PK model-based analysis, indicating no significant clinical or statistical differences in LEM PK attributable to the intrinsic factor race. Conclusion LEM exposure is not significantly affected by race. Therefore, dosing of LEM can be consistent across patient populations from different racial groups. Support (If Any) Eisai Inc.

Long-term Perception of Medication Effectiveness in Elderly Subjects With Insomnia Receiving Lemborexant for up to 12 Months

<h3>Introduction</h3> Amongelderly persons (age ≥65 years), insomnia is a prevalent sleep disorder. Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries, including the United States, Japan, Canada, Hong Kong, Australia, and India, for the treatment of insomnia in adults (age ≥18 years). Clinical trials for insomnia therapies include data from daily sleep diaries to assess the magnitude of change quantitatively in subjective sleep outcomes, including sleep onset and maintenance. Additionally, there are instruments that assess patient estimates of time to sleep onset and duration of nighttime awakenings. Assessment of symptom improvement provides critical information on treatment effectiveness. The demonstration of improvement in sleep from the patient's perspective is important in the assessment of the effectiveness of an insomnia therapy, as insomnia is a symptom-based disorder. The Patient Global Impression–Insomnia version (PGI-I) is a self-report instrument used to evaluate a patient's perception (qualitative) of the effects of their insomnia medication on their sleep relative to their sleep before starting their treatment. The PGI-I includes 3 items related to medication effects (helped/worsened sleep; decreased/increased time to fall asleep; and increased/decreased total sleep; choices for patient responses include: 1=positive, 2=neutral, 3=negative). The PGI-I also includes 1 item related to perceived appropriateness of study medication strength with a different set of possible responses (choices for patient responses include: 1=too strong, 2=just right, 3=too weak). In Study E2006-G000-303 (Study 303; SUNRISE-2; NCT02952820), significantly greater percentages of subjects in the age ≥65 years subgroup reported a positive impact of LEM versus placebo (PBO) at 1, 3 and 6 months for each of the PGI-I items related to medication effects. The majority of subjects also reported medication strength as "just right" at 1, 3 and 6 months. PGI-I results at 9 and 12 months for subjects age ≥65 years are presented here for subjects that received continuous treatment with LEM for up to 12 months in Study 303. <h3>Methods</h3> Study303 was a Phase 3, 12-month, double-blind, global study in adults age ≥18 years with insomnia disorder that included a 6-month PBO-controlled period (Treatment Period 1) followed by a 6-month active-only (Treatment Period 2) period. Subjects received PBO, LEM 5mg (LEM5) or LEM 10mg (LEM10) for the first 6 months. For Treatment Period 2, PBO-treated subjects were rerandomized to LEM (not reported here), while LEM-treated subjects continued their original dose. Titration to higher or lower doses was not permitted. The PGI-I was administered at Months 1, 3, 6, 9, and 12. Results for the PGI-I were analyzed by age (age ≥65 years). <h3>Results</h3> TheFull Analysis Set comprised 949 subjects, of which 262 (27.6%;[PBO, n=89; LEM5, n=87; LEM10, n=86]) were age ≥65y. At 9 and 12 months, the majority of elderly LEM5-treated (total treated up to 9 months, n=68; total treated up to 12 months, n=61) and LEM10-treated (total treated up to 9 months, n=61; total treated up to 12 months, n=56) subjects reported that their study medication "helped" sleep at night (9 months: LEM5=51 [75.0%], LEM10=45 [73.8%]; 12 months: LEM5=47 [77.0%], LEM10=42 [75.0%]), reduced time to fall asleep (9 months: LEM5=59 [86.8%], LEM10=47 [77.0%]; 12 months: LEM5=53 [86.9%], LEM10=44 [78.6%]), and increased total sleep time (9 months: LEM5=43 [63.2%], LEM10=45 [73.8%]; 12 months: LEM5=38 [62.3%], LEM10=33 [58.9%]). Also, at both 9 and 12 months, the majority of subjects in the LEM5 and LEM10 groups responded that their medication strength was "just right" (9 months: LEM5=46 [67.6%], LEM10=37 [60.7%]; 12 months: LEM5=43 [70.5%], LEM10=37 [66.1%]). LEM was well tolerated. Most adverse events were mild or moderate. <h3>Conclusions</h3> Themajority of elderly subjects receiving LEM5 or LEM10 for up to 12 months reported a positive medication effect and perceived their medication strength as "just right" at both 9 and 12 months. These results demonstrate that the similar positive perceptions of the effects of LEM achieved during Treatment Period 1 in the elderly subgroup were sustained through Treatment Period 2. <h3>This research was funded by</h3> Supported by Eisai Inc.

Impact of Hypnotic Drug Zolpidem Tartrate on the Development of Forensic Fly Sarcophaga ruficornis (Diptera: Sarcophagidae).

The flesh fly Sarcophaga ruficornis (Fabricius) is one of the fly species of significant medical and forensic importance since it is one of the most common flesh flies used in forensic investigations. Zolpidem tartrate is a sedative-hypnotic drug used for the short-term treatment of insomnia in adults and its use has been implicated in many suicide cases worldwide. Fresh chopped liver of buffalo Bubalus bubalis (Artiodactyla: Bovidae) containing different concentrations of Zolpidem tartrate was given to S. ruficornis larvae to evaluate the effect of Zolpidem tartrate on the developmental rate of the different stages, life cycle duration, and the morphological parameters. The findings have shown significant variation in the time required for the different developmental stages and total life cycle duration, which correlated positively with the Zolpidem tartrate concentration in different cultures. Compared to the control, the morphological parameters were negatively correlated with the concentration of Zolpidem tartrate in the treated cultures. The obtained results indicate that the Zolpidem tartrate retards larval development and alters the estimation of the total developmental duration. Thus, when Zolpidem tartrate may be the cause of death, the entomological evidence needs to be analyzed so it takes zolpidem-related changes to the mPMI into account.

Is cannabidiol an effective treatment of insomnia in adults?

Is cannabidiol an effective treatment of insomnia in adults?

Cognitive Behavioral Therapy for Insomnia in Geriatric Primary Care

Insomnia is common in older adults and may have adverse cognitive, emotional, and physical consequences. Some older people are prescribed sleep medications for insomnia despite longstanding concerns about their use with older people (i.e., BEERS criteria). Cognitive Behavioral Therapy for Insomnia (CBT-I) is highly effective in the treatment for insomnia in adults and older adults. However, most studies of CBT-I in late life have been conducted with individuals younger than 70. This paper discusses four years of experience of providing CBT-I to older people in geriatric primary care, two-thirds of whom were older than 75 years of age. Among the subgroup of 29 individuals who completed a full course of CBT-I, almost all of those who had been on sleep medications discontinued them. Treatment outcomes were large and clinically meaningful. This paper will also describe our experience in providing CBT-I via telehealth because of the COVID pandemic.

A Multicenter Open-label Pilot Study Evaluating Next-Dose Transition From Zolpidem to Lemborexant: Subgroup Analysis of Older Adults

<h3>Introduction</h3> Treatment for insomnia often includes prescription medication but some commonly prescribed insomnia drugs, such as the GABA-ergic agonist zolpidem (ZOL), are associated with safety concerns in older adults. Studies examining methods for transitioning patients between insomnia medications of different drug classes are needed. Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) that is approved in the US, Canada, and Japan for the treatment of insomnia in adults. Study E2006-A001-312 (Study 312; NCT04009577) was a pilot study designed to examine pre-planned dosing approaches for directly transitioning from ZOL (immediate [IR] or extended release [ER] formulations) to LEM (5mg [LEM5] or 10mg [LEM10]). Here we present a post hoc analysis of outcomes in subjects aged ≥60y from Study 312. <h3>Methods</h3> The design of Study 312 comprised a 3-week Screening Period (SCR; subjects continued ZOL), 2-week Titration Period (TITR), 12-week Extension Period (EXT), and 4-week Follow-up Period. Adults with insomnia who were intermittent (INT; 3-4 nights/week) or frequent (FREQ; ≥5 nights/week) users of ZOL-IR or ZOL-ER participated. Cohort 1 included INT ZOL users and subjects with one week each of INT and FREQ ZOL usage; subjects began TITR with LEM5. Cohort 2 included FREQ ZOL users who were randomized 1:1 to LEM5 (Cohort 2A) or LEM10 (Cohort 2B). Subjects who successfully transitioned to LEM could choose to enter EXT. Subjects could change LEM dose during TITR (one dose change allowed) and EXT. The primary endpoint was the proportion of subjects who transitioned to LEM at the end of TITR. Treatment-emergent adverse events (TEAEs) were assessed based on dose at time of TEAE. <h3>Results</h3> Of the 53 subjects in the Full Analysis Set (Cohort 1, n=10; Cohort 2, n=43), 30 subjects were age ≥60y (Cohort 1, n=6; Cohort 2, n=24); mean (SD) age was 67.5 (4.9) years and 76.7% were female. During SCR, 63.3% of these 30 subjects reported that waking too early was their main sleep complaint, followed by difficulty staying asleep (30.0%) and difficulty falling asleep (6.7%). Overall, 23/30 (76.7%) transitioned to LEM after TITR. In Cohort 1, 5/6 (83.3%) transitioned, with 3 ending TITR on LEM5, and 2 on LEM10. In Cohort 2A (LEM5), 7/8 (87.5%) transitioned; with 3 ending TITR on LEM5 and 4 on LEM10. In Cohort 2B (LEM10), 11/16 (68.8%) transitioned; 1 ending TITR on LEM5 and 10 on LEM10. For the 7 subjects who discontinued during TITR, 1 subject (on LEM5) opted to discontinue and 6 subjects discontinued due to treatment-emergent adverse events (TEAEs; 1 each of intentional overdose, hemiparalysis, nausea, over-sedation, paralysis, and diarrhea; 2 were on LEM5 and 4 were on LEM10 at the time of the TEAE). The hemiparalysis and paralysis were not adjudicated as cataplexy. All 23 subjects who transitioned to LEM chose to continue in EXT. One subject discontinued during EXT and 22/30 (73.3%) subjects completed the study. Based on modal dose (defined as most frequent dose taken during TITR and EXT combined) groups, median time to first dose change during EXT was 15 days and 55 days for LEM5 and LEM10, respectively. Across the study (TITR and EXT), TEAEs occurred more frequently with LEM10 than with LEM5; the most common TEAEs (in 2 or more subjects) for either LEM dose were abnormal dreams (n=4) and somnolence (n=2). All TEAEs were mild to moderate in severity. <h3>Conclusions</h3> The majority of older subjects from Study 312 successfully transitioned from INT or FREQ ZOL-IR or ZOL-ER use to LEM, and completed the study. LEM was generally well tolerated with a safety profile that was consistent with that observed in Phase 3 clinical development. <h3>Funding</h3> Eisai Inc.

Impact of Lemborexant on Fatigue Severity and Sleep Outcomes in Older Adults With Clinically Significant Fatigue at Baseline

<h3>Introduction</h3> In addition to sleep onset and/or maintenance difficulties, sleep-related daytime impairments must be acknowledged by patients to meet DSM-5 insomnia disorder diagnostic criteria. Daytime functioning impairments of insomnia disorder may include mood disturbances, decreased energy and fatigue. Given higher insomnia disorder prevalence and negative fatigue health and function impacts in older adults, treatment may require monitoring and managing sleep-related fatigue. Lemborexant (LEM) is a dual orexin receptor antagonist, approved in the US, Canada and Japan for the treatment of insomnia in adults. In the pivotal Phase 3 Study E2006-G000-303 (Study 303; SUNRISE-2; NCT02952820), LEM provided significant benefit on subjective sleep and fatigue severity outcomes vs placebo (PBO). In this post-hoc analysis, these outcomes were analyzed in subjects aged ≥65y with baseline Fatigue Severity Scale (FSS) total score ≥36 indicating clinically significant fatigue (analysis subgroup). <h3>Methods</h3> Study 303 was a 12-month, randomized, double-blind study in subjects aged ≥18y (n=949). For the first 6 months (Treatment Period 1), subjects received PBO or LEM (5mg [LEM5]; 10mg [LEM10]). During the second 6 months (Treatment Period 2), PBO subjects were rerandomized to LEM5 or LEM10 (reported separately) while LEM subjects remained on their original doses. The FSS is a self-report questionnaire that evaluates the impact of fatigue on quality of life and daily functioning. FSS total score (TS) ≥36 indicates clinically significant fatigue, and baseline FSS-TS ≥36 was used to select the analysis subgroup in subjects aged ≥65y. Changes from baseline in FSS-TS, subjective sleep onset latency (sSOL), subjective sleep efficiency (sSE) and subjective wake after sleep onset (sWASO) for LEM vs PBO, assessed during Treatment Period 1 are presented. <h3>Results</h3> For the analysis subgroup (Total, n=134; PBO, n=41; LEM5, n=44; LEM10, n=49), mean FSS-TS (SD) at baseline was 44.1 (6.8), 46.2 (7.6), and 44.9 (6.3) in PBO, LEM5, and LEM10, respectively. At 6 months, mean (SD) decreases from baseline (improvement) in FSS-TS were significantly greater with LEM vs PBO (PBO: −8.7 [10.0]; LEM5: −18.3 [12.9], <i>P</i>=0.006 vs PBO; LEM10: −17.4 [11.6], <i>P</i>=0.003 vs PBO).Median decreases from baseline in sSOL (min) were significantly greater with LEM5 and numerically greater with LEM10 vs PBO (PBO: −9.0; LEM5: −20.1, <i>P</i>=0.0008 vs PBO); LEM10: −19.8) at 6 months. At baseline, mean (SD) sSE was 61.8% (18.1%), 65.2% (14.3%) and 61.0% (14.6%) for PBO, LEM5 and LEM10, respectively. Mean (SD) increases (improvement) from baseline in sSE were significantly greater with LEM5 and numerically greater with LEM10 vs PBO at 6 months (PBO: 5.8% [10.3%]; LEM5: 17.1% [14.3%], <i>P</i>=0.0012 vs PBO; LEM10, 13.1% [14.0%]). Lastly, mean sWASO (min) at baseline was 134.9 (82.3), 126.8 (65.1) and 166.4 (91.0) for PBO, LEM5 and LEM10, respectively. At 6 months, mean (SD) decreases (improvement) from baseline in sWASO (min) were significantly greater with LEM for both doses vs PBO (PBO: −9.9 [47.2]; LEM5: −58.3 [79.9], <i>P</i>=0.004 vs PBO; LEM10, −50.6 [56.6], <i>P</i>=0.03 vs PBO). Overall, treatment –emergent adverse events (AE) rates were similar across treatment groups (58.5%, 65.9%, 53.1% for PBO, LEM5 and LEM10, respectively). The most common AEs (≥5% in any LEM group and >PBO) were somnolence (0%, 11.4%, 22.4%), nasopharyngitis (4.9%, 6.8%, 8.2%), gastroenteritis (0%, 2.3%, 8.2%), upper abdominal pain (0%, 2.3%, 6.1%), diarrhea (0%, 0%, 6.1%), and vomiting (0%, 0%, 6.1%) in PBO, LEM5, LEM10, respectively. <h3>Conclusions</h3> In this post hoc analysis from Study 303, subjects aged ≥65y with clinically significant fatigue at baseline had greater improvements in FSS-TS and all sleep parameters with LEM vs PBO at 6 months. Reductions in fatigue severity generally paralleled the time course of sleep parameter improvements. <h3>Funding</h3> Eisai Inc.

Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a phase 3 randomized clinical trial

Objective/backgroundLemborexant is a dual orexin receptor antagonist approved in the United States, Japan, and Canada for the treatment of insomnia in adults. We report effectiveness and safety outcomes in subjects with insomnia who received up to twelve months of continuous lemborexant treatment in Study E2006-G000-303 (Study 303; SUNRISE-2). Patients/methodsStudy 303 was a twelve-month, global, multicenter, randomized, double-blind, parallel-group, Phase 3 study divided into two treatment periods. In Treatment Period 1 (first six months), subjects (n = 949, Full Analysis Set) were randomized to daily placebo, lemborexant 5 mg (LEM5) or lemborexant 10 mg (LEM10). In Treatment Period 2 (second six months), placebo subjects were rerandomized to LEM5 or LEM10, and subjects randomized to lemborexant continued their assigned treatment (LEM5, n = 251; LEM10, n = 226). Sleep onset and sleep maintenance endpoints were analyzed from daily electronic sleep diary data. Treatment-emergent adverse events (TEAEs) were monitored. ResultsFor all sleep parameters, the significant benefits observed with LEM5 and LEM10 versus placebo over six months were maintained at twelve months in subjects who received twelve continuous months of treatment. There was no evidence of rebound insomnia or withdrawal in either lemborexant group following treatment discontinuation. Over twelve months of lemborexant treatment, most TEAEs were mild/moderate; the most common TEAEs were nasopharyngitis, somnolence and headache. ConclusionsLEM5 and LEM10 had significant benefit on sleep onset and sleep maintenance compared with placebo, and importantly, lemborexant effectiveness persisted at twelve months, suggesting that lemborexant may provide long-term benefits for subjects with insomnia. Clinical trial registrationClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

One-Week Self-Guided Internet Cognitive Behavioral Treatments for Insomnia in Adults With Situational Insomnia During the COVID-19 Outbreak.

Objective: In the current global home confinement due to COVID-19, most individuals are facing unprecedented stress which can induce situational insomnia. We explored the efficacy of self-guided online cognitive behavioral treatment for insomnia (CBTI) on situational insomnia during the COVID-19 outbreak.Methods: Participants were recruited from March to April in 2020 in Guangzhou, China. A 1-week Internet CBTI intervention was performed for all individuals with situational insomnia. The Pre-sleep Arousal Scale (PSAS), Insomnia Severity Index (ISI), and Hospital Anxiety and Depression Scale (HADS) were measured before and after the intervention and compared between individuals who completed the intervention and those who did not.Results: One hundred and ninety-four individuals with situational insomnia were included. For PSAS score, significant group effects were found on total score (p = 0.003), somatic score (p = 0.014), and cognitive score (p = 0.009). Time effect was significant on total score (p = 0.004) and cognitive score (p < 0.001). There was a significant group × time effect of the somatic score (p = 0.025). For ISI total score, there were significant time effect (p < 0.001) and group × time effect (p = 0.024). For the HADS score, a significant group effect was found on the anxiety score (p = 0.045). The HADS had significant time effects for anxiety and depressive symptoms (all p < 0.001).Conclusion: Our study suggests good efficacy of CBTI on situational insomnia during COVID-19 for adults in the community, as well as on pre-sleep somatic hyperarousal symptom. The CBTI intervention is not applied to improve pre-sleep cognitive hyperarousal, depression, and anxiety symptoms.

Korean Clinical Practice Guideline for the Diagnosis and Treatment of Insomnia in Adults.

Objective We aim to present a clinical guideline for the diagnosis and treatment of insomnia in adults by reviewing and integrating existing clinical guidelines. The purpose of this guideline is to assist clinicians who perform evidence-based insomnia treatment. Methods We selected literature that may be appropriate for use in guideline development from evidence-based practice guidelines that have been issued by an academic or governmental institution within the last five years. The core question of this guideline was made in sentence form including Patient/Problem, Intervention, Comparison, Outcome (PICO) elements. After searching PubMed, EMBASE, and medical guideline issuing agencies, three guidelines were judged to be the most appropriately reviewed, up-to-date, and from trusted sources. Results The Appraisal of Guidelines for Research and Evaluation (AGREE) II tool was used to evaluate the quality of the three clinical guidelines. The final outcome of the guideline development process is a total of 15 recommendations that report the strength of the recommendation, the quality of evidence, a summary of content, and considerations in applying the recommendation. Conclusion It is vital for clinical guidelines for insomnia to be developed and continually updated in order to provide more accurate evidence-based treatments to patients.

Lack of residual morning effects of lemborexant treatment for insomnia: summary of findings across 9 clinical trials

ABSTRACT Objectives Residual next-day effects of sleep-promoting drugs are common and an important safety issue. Lemborexant is a dual orexin receptor antagonist approved in the United States and Japan for treatment of insomnia in adults. We evaluated the potential of lemborexant for residual morning and next-day effects, including somnolence, based on lemborexant clinical study findings. Methods This paper reports findings from 9 lemborexant clinical studies that incorporated next-day assessments of residual drug effects, based on published findings and data on file. Results are reported for healthy subjects or subjects with insomnia disorder treated with lemborexant 5 mg/day or 10 mg/day, placebo, or active comparator before bedtime. Outcomes assessed included next-morning postural stability (body sway measured by ataxiameter), cognitive performance (Cognitive Performance Assessment Battery), impact on driving (standard deviation of lateral position during highway driving test), subjective sleepiness (sleep diary entries), and adverse events of somnolence. Results Change from baseline in postural stability the morning after lemborexant administration did not differ from placebo. Among 4 Cognitive Performance Assessment Battery measures, only power of attention declined significantly more with lemborexant treatment compared with placebo in 1 of 2 studies, whereas zolpidem differed from placebo on multiple measures. On the highway-driving test, lemborexant did not significantly impair driving performance versus placebo, however, zopiclone did differ. In large phase 3 trials, next-morning sleep diary ratings showed significantly greater alertness with lemborexant compared with placebo after up to 6 months of treatment. As expected, somnolence was the most common adverse event reported with lemborexant treatment. Somnolence was typically mild to moderate in severity and rarely caused discontinuation of study drug. Conclusion Across 9 clinical studies, lemborexant did not substantially impair next-day functioning among healthy subjects and subjects with insomnia.