Health authorities and medical communities in many countries are discouraging the use of benzodiazepines and non-benzodiazepine hypnotics for patients with insomnia [...]

Objective:Using data from a clinical study of lemborexant, evaluate responses to the Patient Global Impression-Insomnia (PGI-I) questionnaire, a simple 4-item questionnaire that assesses patients' perceptions of the effects of medication on sleep, which may help evaluate clinically meaningful changes from the patient's perspective. Methods:Study E2006-G001-303, a 12-month, placebo (PBO)-controlled (first 6 months) Phase 3 study in adults with insomnia disorder, randomized subjects (1:1:1) to lemborexant 5 mg (LEM5; n=316), 10 mg (LEM10; n=315), or PBO (n=318). The second 6 months are not presented here. PGI-I results were analyzed post hoc in relation to patient-reported (subjective) sleep-onset latency (sSOL) and total-sleep-time (sTST). Results:At 6 months: 67.3% (LEM5) and 68.8% (LEM10) of subjects reported positive effects of medication helping them sleep versus 45.0% (both p<0.0001) with PBO. Positive effects on "time to fall asleep" were reported by 72.8% (LEM5) and 73.1% (LEM10) versus 46.1% with PBO (p<0.0001), and 58.0% (LEM5) and 62.0% (LEM10) reported positive effects on sleep duration versus 39.9% with PBO (p<0.0001). Subjects reporting positive effects on "time to fall asleep" had greater change from baseline (CFB; improvement) at 6 months in median sSOL (in minutes; LEM5= -26.8; LEM10= -32.1; PBO= -17.5; p<0.01) versus those reporting negative effects (LEM5= -9.1; LEM10= -10.4; PBO= -8.6; LEM5 vs PBO, p=0.52; LEM10 vs PBO, p=0.69). For sTST (in minutes) at 6 months, mean CFB tended to be greater for subjects reporting positive (LEM5=81.2, LEM10=93.2, PBO=74.8; LEM5 vs PBO, p=0.28; LEM10 vs PBO, p=0.18) versus negative (LEM5=46.4, LEM10=35.0, PBO=38.6; LEM5 vs PBO, p=0.44; LEM10 vs PBO, p=0.52) effects, although this was not statistically significant. Conclusion:Patient impressions of the effects of lemborexant were positive based on the PGI-I and reflected improvements in subjective sleep outcome measures, indicating that the brief PGI-I tool may be useful in clinical practice.

Objective: Insomnia and some insomnia treatments can impact an individual's daytime functioning. Here, we performed post hoc analyses of patient-reported outcomes from a phase 3 clinical trial to assess the impact of lemborexant (LEM), a dual orexin receptor antagonist, on daytime functioning. Methods: Adults with insomnia were randomized 1:1:1 to receive placebo, LEM 5 mg (LEM5) or LEM 10 mg (LEM10) for 6 months. Treatment impact on subjects' perceptions of their insomnia symptoms and daytime functioning was assessed by the Insomnia Severity Index (ISI) and Fatigue Severity Scale (FSS) questionnaires. Safety assessments included monitoring of treatment emergent adverse events. Results: Compared with placebo, LEM5 and LEM10 treatment significantly improved ISI Total Score (ISI-TS) (LEM5, P < .01; LEM10, P < .0001) and ISI Daytime Functioning Score (ISI-DFS) (LEM5, P < .05; LEM10, P < .01) at 1 month; these improvements were maintained at the end of 6 months (P < .0001 for LEM5 and LEM10, both scores). In separate analyses, baseline ISI-TS or ISI-DFS was used to classify subjects' symptom severity into 1 of 4 categories. At 1 and 6 months, greater proportions of subjects treated with LEM5 and LEM10 shifted to a category associated with less severe symptoms (P < .01 for all comparisons vs placebo). FSS score also improved with LEM treatment vs placebo as assessed at month 3; improvements were maintained at month 6 (P < .05). LEM5 and LEM10 treatment was well tolerated. Conclusion: Improved insomnia symptoms with LEM treatment may translate into improved daytime functioning, suggesting LEM may be appropriate for adults experiencing daytime impairment with their nighttime symptoms. Trial Registration: ClinicalTrials.gov identifier: NCT02952820. Prim Care Companion CNS Disord 2025;27(1):24m03810. Author affiliations are listed at the end of this article.

Objective: Insomnia and some insomnia treatments can impact an individual's daytime functioning. Here, we performed post hoc analyses of patient-reported outcomes from a phase 3 clinical trial to assess the impact of lemborexant (LEM), a dual orexin receptor antagonist, on daytime functioning. Methods: Adults with insomnia were randomized 1:1:1 to receive placebo, LEM 5 mg (LEM5) or LEM 10 mg (LEM10) for 6 months. Treatment impact on subjects' perceptions of their insomnia symptoms and daytime functioning was assessed by the Insomnia Severity Index (ISI) and Fatigue Severity Scale (FSS) questionnaires. Safety assessments included monitoring of treatment emergent adverse events. Results: Compared with placebo, LEM5 and LEM10 treatment significantly improved ISI Total Score (ISI-TS) (LEM5, P < .01; LEM10, P < .0001) and ISI Daytime Functioning Score (ISI-DFS) (LEM5, P < .05; LEM10, P < .01) at 1 month; these improvements were maintained at the end of 6 months (P < .0001 for LEM5 and LEM10, both scores). In separate analyses, baseline ISI-TS or ISI-DFS was used to classify subjects' symptom severity into 1 of 4 categories. At 1 and 6 months, greater proportions of subjects treated with LEM5 and LEM10 shifted to a category associated with less severe symptoms (P < .01 for all comparisons vs placebo). FSS score also improved with LEM treatment vs placebo as assessed at month 3; improvements were maintained at month 6 (P < .05). LEM5 and LEM10 treatment was well tolerated. Conclusion: Improved insomnia symptoms with LEM treatment may translate into improved daytime functioning, suggesting LEM may be appropriate for adults experiencing daytime impairment with their nighttime symptoms. Trial Registration: ClinicalTrials.gov identifier: NCT02952820. Prim Care Companion CNS Disord 2025;27(1):24m03810. Author affiliations are listed at the end of this article.

Background: Improvements in daytime functioning ideally accompany improvements in insomnia. Scores on the Insomnia Severity Index (ISI) daytime-related items were analyzed following treatment with lemborexant (LEM), a dual orexin receptor antagonist, or placebo (PBO), based on baseline severity. Methods: Participants (≥18 y) with insomnia disorder in E2006-G000-303, a 12-month, randomized, double-blind, PBO-controlled study (first 6 months: Treatment Period 1 [TP1]), were randomized to PBO or LEM 5 mg (LEM5) or 10 mg (LEM10) for 6 months. ISI items are rated 0 (no problem) to 4 (very severe problem); daytime-related ISI items have a maximum score of 16. Results: Of 949 participants, 749 (78.9%) completed the ISI at baseline and end of TP1. Baseline daytime ISI total score distributions were similar between groups. More participants with baseline scores of 9-12 and 13-16 shifted to 0-4 with LEM5 (49.7% and 39.1%, respectively) and LEM10 (46.2% and 46.3%) versus PBO (26.6% and 29.6%). Overall shift distributions were significantly different, favoring both LEM groups ( P <0.01). LEM was well tolerated. Conclusions: More LEM-treated participants had improved daytime functioning, evidenced by the significantly larger number of participants whose scores moved into lower categories (ie, better sleep) versus PBO-treated participants, demonstrating additional value beyond improved sleep parameters.

Abstract Aim Individuals with insomnia frequently have comorbid depression or anxiety. This study sought to provide a preliminary indication of the effects of lemborexant (LEM) in subjects treated for mild depression/anxiety symptoms. Methods E2006‐G000‐303 (NCT02952820; EudraCT 2015‐001463‐39; SUNRISE‐2) was a 12‐month, phase 3, randomized, placebo‐controlled, double‐blind study where subjects with insomnia disorder were randomized (1:1:1) to placebo, LEM 5 mg (LEM5), or LEM 10 mg (LEM10) for 6 months. During the second 6 months (not reported), placebo‐treated subjects were re‐randomized to LEM5 or LEM10. In this post hoc analysis, changes from baseline (CFB) in subject‐reported (subjective) sleep onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), total sleep time (sTST), Fatigue Severity Scale, and Insomnia Severity Index were evaluated in subjects treated with medications for symptoms of depression/anxiety (subpopulation). Results Of 949 randomized subjects, 61 treated with medications for symptoms of depression/anxiety were included. In the subpopulation, CFB comparing LEM with placebo were generally smaller than the overall population due to a larger placebo response in the subpopulation. However, the magnitudes of CFB within the active treatment groups for sSOL, sWASO, sTST, and sSE were similar between the subpopulation and the overall population. No new safety signals were observed in the subpopulation. Conclusion LEM treatment benefited subjects with insomnia treated with medications for depression/anxiety symptoms, with no new safety signals. A greater placebo response in the subpopulation than in the overall population decreased the drug versus placebo effect size for LEM, as has been reported for other insomnia medications.

AIM:Managing blood glucose (BG) levels during intense physical activity is challenging for elite athletes with type 1 diabetes (T1D), as it can lead to unpredictable hyper- or hypoglycemia, which can affect performance. This case study presents an 18-year-old male hockey goalie with hyperglycemia-related anxiety during competition and its impact on his T1D management.METHODS:Mixed-methods approach, incorporating qualitative data from an unstructured interview and responses from the Hyperglycemia Avoidance Scale along with quantitative data retrieved from Diasend and laboratory results.RESULTS:The athlete experiences physical and cognitive symptoms during hyperglycemia, affecting his performance. Hyperglycemia-related anxiety influences insulin dosage adjustments and eating habits on game days. Glycemic variability analysis reveals lower BG levels during game time.CONCLUSION:Hyperglycemia-related anxiety leads to modified therapeutic and lifestyle regimens on competition day. Tailored treatment programs are needed for elite athletes with T1D and hyperglycemia-related anxiety.

What is this summary about? This is a summary of an article originally published in the journal Postgraduate Medicine. Lemborexant is a type of medication called a dual orexin receptor antagonist (often abbreviated to DORA) that is approved for treating people with insomnia, a sleep disorder in which people have trouble falling asleep, staying asleep or both. Two studies, one called SUNRISE-1 (Study 304), which lasted one month, and SUNRISE-2 (Study 303), which lasted 12 months, looked at the effects of lemborexant on sleep compared to placebo in people with insomnia. People with insomnia often experience fatigue (or tiredness) during the daytime, which affects their daily lives and health, and often have other conditions which can also cause fatigue. This summary reports an analysis that looked at whether lemborexant improves fatigue during the daytime as well as nighttime symptoms of insomnia in all participants and in participants with clinically significant fatigue before treatment. What were the results? In both studies, participants completed a questionnaire, called the Fatigue Severity Scale, that measured how significant their fatigue was. The researchers looked at the change in fatigue over time in participants treated with lemborexant compared with those given placebo. They also looked at the change in a group of participants who reported clinically important levels of fatigue at the beginning of the study. People in these studies also completed diaries about how long it took them to fall asleep and how long they slept. The researchers compared improvements in fatigue with changes in how participants slept over time. Overall, lemborexant reduced daytime fatigue compared with placebo in all study participants. It also reduced daytime fatigue in the smaller group of participants who had clinically significant fatigue at the beginning of the study. The reductions in fatigue seen with lemborexant remained during 1 year of treatment. There was also a relationship between reduced fatigue, falling asleep faster and not waking up as much. What do the results mean? Researchers concluded that in addition to improving sleep in people with insomnia, lemborexant can reduce daytime fatigue.

ObjectiveInsomnia is common in midlife women. The efficacy and safety of lemborexant (LEM), a competitive dual orexin receptor antagonist, was assessed for 12 months in a subgroup of midlife women (age, 40-58 y) from Study E2006-G000-303 (Study 303; SUNRISE-2).MethodsThis was a randomized, double-blind, placebo (PBO)-controlled (first 6 mo) study of adults with insomnia disorder (N = 949). During treatment period 1 (TP1), participants received PBO or LEM 5 mg (LEM5) or 10 mg (LEM10). During TP2 (second 6 mo), LEM participants continued their assigned dose; PBO participants were rerandomized to LEM5 or LEM10. Assessments included patient-reported sleep- and fatigue-related measures and treatment-emergent adverse events.ResultsThe midlife female subgroup comprised 280 of 949 participants (TP1: PBO, n = 90 of 318 [28.3%]; LEM5, n = 82 of 316 [25.9%]; LEM10, n = 108 of 315 [34.3%]). At 6 months, median changes from baseline in subjective sleep-onset latency (in minutes) were -17.9, -20.7, and - 30.4 for PBO, LEM5, and LEM10 (vs PBO: LEM5, P = not significant; LEM10, P = 0.0310). At 6 months, mean changes from baseline in subjective wake after sleep onset (in minutes) were -37.0 (59.6), -50.1 (74.5), and -54.5 (65.4) for PBO, LEM5, and LEM10 (vs PBO: LEM5 and LEM10, P = not significant), with benefits sustained through 12 months. Greater decreases from baseline (improvement) in Insomnia Severity Index total score and Fatigue Severity Scale total score were seen with LEM versus PBO at 6 months; benefits continued through 12 months. Most treatment-emergent adverse events were mild to moderate in severity.ConclusionsConsistent with the total population, subjective sleep parameters improved, and improvement was sustained over time in midlife women. LEM was well tolerated, suggesting that LEM may be a potential treatment option for midlife women with insomnia.

Abstract Introduction The Insomnia Severity Index (ISI) is a 7-item self-reported questionnaire evaluating perception of symptom severity included in Phase 3 studies of lemborexant (LEM), a competitive dual orexin receptor antagonist approved in several countries to treat adults with insomnia. The ISI total score, and items 4-7 for daytime function (DF), improved significantly with LEM treatment compared to placebo (PBO) as assessed at 1, 3 and 6 months. Here we report shifts in DF scores at 6 months depending on baseline severity. Methods Study 303 was a 12-month, randomized, double-blind PBO-controlled (first 6months; Treatment Period 1 [TP1]) phase 3 study in subjects (age ≥18y) with insomnia disorder. Subjects were randomized to PBO, LEM 5mg (LEM5) or 10mg (LEM10) for 6 months. ISI items are rated on a 5-point Likert scale from 0 (no problem) to 4 (very severe problem). Daytime-related items include ratings on sleep satisfaction, extent symptoms are noticeable to others, cause worry/distress, or interferes with daily function. Data were analyzed by Cochran-Mantel-Haenszel test of general association vs placebo. Results Of the 949 subjects, 749 (78.9%) completed the ISI at baseline and end of TP1: PBO (258/318 [81.1%]; LEM5, 257/316 [81.3%]; LEM10, 234/315 [74.3%]). Baseline daytime ISI-total-score distribution was similar between groups; most had scores of 9-12 (66.7-68.6%). At the end of TP1, more subjects with baseline scores of 9-12 shifted to 0-4 with LEM5 (49.7%) and LEM10 (46.2%) than with PBO (26.6%). Similarly, more subjects with baseline scores of 13-16 shifted to 0-4 with LEM5 (39.1%) and LEM10 (46.3%) than with PBO (29.6%). An additional 28.1% and 25.9% of subjects with LEM5 or LEM10, respectively, with baseline scores of 13-16 shifted to scores of 9-12, compared with 31.5% of PBO. The overall shift distributions were significantly different, favoring both LEM groups (p< 0.01). Conclusion More LEM-treated subjects improved in daytime functioning as evidenced by the significantly large number of subjects whose scores moved into the lower categories (i.e., better sleep) compared with PBO subjects. These data support important improvements in daytime function that are evident even after 6 months of continuous LEM treatment. Support (if any) Eisai Inc.

Abstract Introduction Items 4-7 (daytime function [DF]) of the 7-item Insomnia Severity Index (ISI) can assess daytime impairment. In Study E2006-G000-303 (Study 303; NCT02952820), lemborexant (LEM), a dual-orexin receptor antagonist, was associated at 6 months (6mo) with both significant improvement in ISI-DF items and significantly more subjects reporting positive effects on sleep, as assessed by the Patient Global Impression–Insomnia version (PGI-I), versus placebo (PBO). This analysis looked at the correlation between ISI-DF improvement and patient ratings on the PGI-I. Methods Study 303 was a 12-month, randomized, double-blind PBO-controlled (first 6mo) phase-3 study in adults with insomnia disorder. Subjects were randomized to PBO, LEM 5mg or 10mg for 6mo (2nd 6mo not reported here). ISI items are rated from 0 (no problem) to 4 (very severe problem). ISI-DF includes sleep satisfaction, extent symptoms are noticeable to others, cause worry/distress, and interfere with daily function. On the PGI-I, subjects assess positive, neutral or negative treatment impact on falling asleep, overall benefit on sleep, and total sleep time. Results A total of 739 subjects completed the ISI and PGI-I and were included in these analyses. At 6mo in all treatment groups, there were significant correlations (all P<0.001) between improvement in both ISI-DF items and PGI-I ratings regarding falling asleep, overall benefit on sleep, and total sleep time. Discussion These data suggest that the PGI-I may be a useful, quick tool to use in clinical practice, since an improvement in its score reflects improvements in daytime function. Sponsor Funded by Eisai Inc.

Objective/Background: To examine the effects of lemborexant (LEM) 5 mg (LEM5) or LEM 10 mg (LEM10) following extended placebo treatment. This post-hoc analysis used subject-reported sleep outcomes data from a phase 3 trial. Patients/Methods: The subjects in these post-hoc analyses were randomized to placebo for 6 months (Time Period [TP]1) in Study E2006-G000-303 (SUNRISE-2; NCT02952820). Following placebo exposure, subjects were re-randomized to LEM5 or LEM10 for another 6 months (TP2). Subject-reported sleep outcomes derived from sleep diaries included sleep onset latency (sSOL), wake after sleep onset (sWASO), sleep efficiency (sSE), and total sleep time (sTST). Magnitude and change rate in parameters were assessed for 7 days before/after initial randomization to placebo and 7 days before/after re-randomization to LEM (6 months later). Month 6 placebo non-responders were assessed for LEM response in TP2 using predetermined responder definitions. Safety was monitored throughout the study. Results: Overall, 321 subjects received placebo; 258 re-randomized subjects received LEM5 (n = 133) and LEM10 (n = 125). Subjective sleep outcomes improved during TP1 with approximately 62 subjects (similar to 20%) exhibiting a sustained placebo response. Upon re-randomization to LEM, all measures showed an additional incremental benefit, most prominently in sSOL and sTST. Among Month 6 placebo non-responders, 11%-15% subsequently responded to LEM as assessed at Month 12. The safety profile was similar between treatment periods and treatment groups. Conclusions: These data suggest that even when insomnia symptoms have improved over time with placebo treatment, additional and sustained clinical gains in sleep outcomes are possible with active treatment using lemborexant.

Objective: Investigate the impact of lemborexant (LEM), a competitive dual orexin receptor antagonist approved in multiple countries for the treatment of adults with insomnia, on the Insomnia Severity Index (ISI) and Fatigue Severity Scale (FSS), and on correlation between the 2 measures. Background: An effective insomnia treatment should both improve sleep and reduce daytime impairments and fatigue in patients reporting these symptoms. Study E2006-G000–303 (Study 303; NCT02952820) showed LEM provided significant benefit versus placebo (PBO) on patient-reported sleep outcomes based on the ISI and on fatigue assessed by FSS. Design/Methods: Study 303 was a 12mo, randomized, double-blind PBO-controlled (first 6mo) phase 3 study in subjects (age ≥18y) with insomnia disorder and baseline (BL) ISI Total Score (TS) ≥15. There was no fatigue criterion for study eligibility. Subjects were randomized to PBO or LEM 5mg (LEM5) or 10mg (LEM10) for 6mo. ISI and FSS were administered at BL and Months 1, 3, and 6. Mean changes from BL in ISI daytime functioning score (ISI-DFS; items 4–7) and FSS-TS were assessed. Results: Mean (SD) ISI-DFS and FSS-TS at BL were similar between groups (PBO, n=318; LEM5, n=316; LEM10, n=315). At 6mo, mean (SD) ISI-DFS decreased (improved) from BL (PBO, −4.3 [3.66]; LEM5, −6.0 [3.76] and LEM10, −5.7 [4.00], both P<0.0001 versus PBO) and mean FSS-TS decreased (improved) (PBO, −6.3 [12.07]; LEM5, −10.1 [13.56], P=0.0134 versus PBO; LEM10, −8.9 [14.91], P=0.0128 versus PBO) for both LEM groups. Pearson analysis showed a positive correlation over time between reductions in ISI-DFS and FSS-TS (correlation: PBO, 0.513; LEM5, 0.553; LEM10, 0.539; all P<0.0001). Most adverse events were mild/moderate in severity. Conclusions: Compared with PBO, in these post-hoc analyses, LEM significantly improved daytime functioning and fatigue in subjects with insomnia, and improvements in both measures were correlated. Disclosure: Craig Chepke has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Janssen. Craig Chepke has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Otsuka. Craig Chepke has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine. Craig Chepke has received personal compensation in the range of $100,000-$499,999 for serving on a Speakers Bureau for Neurocrine. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for AbbVie. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Acadia. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Otsuka. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Takeda. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Janssen. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Ironshore. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Teva. Craig Chepke has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sunovion. Craig Chepke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Intracellular. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Eisai. Craig Chepke has received research support from Acadia. Craig Chepke has received research support from Harmony. Craig Chepke has received research support from Neurocrine. Jane Yardley has received personal compensation for serving as an employee of Eisai Ltd. Kate Pinner has received personal compensation for serving as an employee of Eisai Ltd. Dr. Lundwall has received personal compensation for serving as an employee of Eisai. Margaret Moline has received personal compensation for serving as an employee of EISAI, INC.. Margaret Moline has received intellectual property interests from a discovery or technology relating to health care. Margaret Moline has received personal compensation in the range of $0-$499 for serving as a review, loan repayment program with NIH.