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Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate. Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients. In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).

Key words: sleepiness; excessive daytime sleepiness; fitness to drive; drowsy driving; maintenance of wakefulness test; sleep latency; driving simulation; ecological validity; accident prevention; Epworth Sleepiness Scale; Karolinska Sleepiness Scale

PurposeThe current meta-analysis aimed to obtain a more stable estimate of the effect size of Ramadan diurnal intermittent fasting (RDF) on sleep duration and daytime sleepiness.MethodsDatabases (Scopus, ScienceDirect, ProQuest Medical, PubMed/MEDLINE, Web of Science, EBSCOhost, Cochrane, CINAHL, and Google Scholar) were searched from database inception to the end of June 2019. The sleep quality measures analyzed were excessive daytime sleepiness (EDS) measured by the Epworth sleepiness scale (ESS) and total sleep time (TST). Subgroup analyses for age, sex, and levels of physical activity were conducted.ResultsWe identified 24 studies (involving 646 participants, median age 23.7 years, 73% men) conducted in 12 countries from 2001 to 2019. The results revealed that TST decreased from 7.2 h per night [95% confidence interval (CI) 6.7–7.8] before Ramadan to 6.4 h (95% CI 5.3–7.5) during Ramadan, while the ESS score increased slightly from 6.1 (95% CI 4.5–7.7) before Ramadan to 7.0 (95% CI 5.2–8.8) during Ramadan. Effect sizes on sleep quality measures during RDF demonstrated a moderate reduction in TST (number of studies, K = 22; number of subjects, N = 571, Hedges’ g value of −0.43, 95% CI − 0.64 to −0.22, Q = 90, τ2 = 0.15, I2 = 78%, P < 0.001), while ESS score showed negligible effect on EDS (K = 9, N = 362, Hedges’ g value of −0.06, 95% CI −0.43 to 0.28, Q = 21, τ2 = 0.13, I2 = 76%, P value = 0.001).ConclusionDuring the month of Ramadan, there is approximately a 1 hour reduction in TST and nearly a 1 point increase in the ESS score.

Sleepiness at the wheel is widely believed to be a cause of motor vehicle accidents. Nevertheless, a systematic review of studies investigating this relationship has not yet been published. The objective of this study was to quantify the relationship between sleepiness at the wheel and motor vehicle accidents. A systematic review was performed using Medline, Scopus, and ISI Web of Science. The outcome measure of interest was motor vehicle accident defined as involving four- or two-wheeled vehicles in road traffic, professional and nonprofessional drivers, with or without objective consequences. The exposure was sleepiness at the wheel defined as self-reported sleepiness at the wheel. Studies were included if they provided adjusted risk estimates of motor vehicle accidents related to sleepiness at the wheel. Risk estimates and 95% confidence intervals (95% CIs) were extracted and pooled as odds ratios (ORs) using a random-effect model. Heterogeneity was quantified using Q statistics and the I2 index. The potential causes of heterogeneity were investigated using meta-regressions. Ten cross-sectional studies (51,520 participants), six case-control studies (4904 participants), and one cohort study (13,674 participants) were included. Sleepiness at the wheel was associated with an increased risk of motor vehicle accidents (pooled OR 2.51 [95% CI 1.87; 3.39]). A significant heterogeneity was found between the individual risk estimates (Q = 93.21; I2 = 83%). Sleepiness at the wheel increases the risk of motor vehicle accidents and should be considered when investigating fitness to drive. Further studies are required to explore the nature of this relationship. PROSPERO 2015 CRD42015024805.

Study Objectives: Children with craniopharyngioma are at risk for excessive daytime sleepiness (EDS). Multiple Sleep Latency Testing (MSLT) is the gold standard for objective evaluation of EDS; however, it is time and resource intensive. We compared the reliability, sensitivity, and specificity of the modified Epworth Sleepiness Scale (M-ESS) and MSLT in monitoring EDS in children with craniopharyngioma. Methods: Seventy patients (ages 6 to 20 years) with craniopharyngioma completed the M-ESS and were evaluated by polysomnography and MSLT. Evaluations were made after surgery, if performed, and before proton therapy. Results: MSLT revealed that 66 participants (81.8%) had EDS, as defined by a mean sleep latency (MSL) < 10 minutes, with only 28.8% reporting EDS on the M-ESS by using a cutoff score of 10. The M-ESS demonstrated adequate internal consistency and specificity (91.7%) but poor sensitivity (33.3%) with the established cutoff score of 10. A cutoff score of 6 improved the sensitivity to 64.8% but decreased the specificity to 66.7%. Conclusions: Patients with craniopharyngioma are at high risk for EDS, as documented objectively on the MSLT, but they frequently do not recognize or accurately report their sleepiness. Future sleep studies should investigate whether specific items or alternative self- and parent-reported measures of sleepiness may have greater clinical utility in monitoring sleepiness in this population. Citation: Crabtree VM, Klages KL, Sykes A, Wise MS, Lu Z, Indelicato D, Merchant TE, Avent Y, Mandrell BN. Sensitivity and specificity of the modified Epworth Sleepiness Scale in children with craniopharyngioma. J Clin Sleep Med. 2019;15(10):1487–1493.

Randomized controlled trials (RCTs) that compared the safety and efficacy of medical treatments for narcolepsy were analyzed using network meta-analysis. The RCTs in narcolepsy were searched. Network meta-analysis compared efficacy and safety of multiple treatments, multi-arm studies, and multi-criteria treatment decisions, based on a random model that assumed heterogeneity between studies, with corrections for multi-arm studies. Fourteen RCTs, three drug treatments, and six doses were identified: sodium oxybate (6 and 9 g/d), modafinil (between 200 and 400 mg/d), and pitolisant (up to 20 and up to 40 mg/d). Significant heterogeneity (>50%) between studies was found in 12/14 studies for almost all endpoints, but between-design consistency was present. For ESS and MWT, sodium oxybate 9 g/d, modafinil, and pitolisant up to 40 mg/d had similar efficacy. Pitolisant 40 mg/d and sodium oxybate 9 g/d in two nightly doses had similar efficacy in reducing cataplexy. A good safety profile characterized by a TEAE incidence risk ratio (IRR) <1.5 was found for all the compared treatments, except for sodium oxybate 9 g/d. Although no significant difference was found, Pitolisant 40 mg was shown with the best P scores for the benefit/risk (BR) ratio. Modafinil (200-400 mg/d), sodium oxybate 9 g/d, and pitolisant up to 40 mg/d had similar efficacy in reducing excessive day time sleepiness. Only sodium oxybate 9 g/d and pitolisant up to 40 mg/d were shown with a comparable beneficial effect on cataplexy. Overall, Pitolisant was found with the best P score on the BR ratio. PROSPERO 2017 CRD42017054686. Efficacy, safety, and benefit-risk comparison of alternative treatments in narcolepsy: a network multiple comparisons of treatment meta-analysis. http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017054686.

Sleep is one of the basic physiological processes for human survival. Both sleep quantity and sleep quality are fundamental components of sleep. This review looks at both sleep quantity and sleep quality, considering how to manage the complex but probably unavoidable physiological phenomenon of sleep. The need for sleep has marked variations between individuals, in addition to the effects of variable conditions. Studies on sleep quality started later than those on sleep quantity, beginning in 1989 when Ford and Kamerow revealed that insomnia increases the risk of psychiatric disorders. According to the nationwide research team on the quality of sleep (19FA0901), sleep quality is superior to sleep quantity as an index for assessing sleep, and that restfulness obtained through sleep is a useful index for assessing sleep quality. We should pay more attention to obtaining sleep of good quality (restfulness, no sleepiness, no need for more sleep, sufficient objective sleep depth, etc.), although there have not been enough studies on the associations between sleep quality and health or disorders in children and adolescents. Further studies using the deviation from an individual’s optimal sleep quantity may show us another aspect of the effects of sleep quantity on various life issues.

Sleep disorders, such as insomnia with objective short sleep duration, are associated with increased risk of hypertension. The objective of the study was to evaluate the effects of insomnia and daytime sleepiness on the quality of life (QOL) among elderly hypertensive patients. This cross-sectional study covered 100 patients with hypertension. All participants completed standardized questionnaires, such as the Epworth Sleepiness Scale (ESS), the Athens Insomnia Scale (AIS), and the World Health Organization Quality of Life-Brief (WHOQOL-BREF), and clinical data were obtained from patients' medical records. We showed that more than half of the patients experienced insomnia (AIS score ≥6) and 39% experienced daytime sleepiness. Daytime sleepiness was negatively associated with perceived QOL ( =-0.478, <0.001). It was also shown that insomnia might be influenced by older age ( <0.001), occupational activity ( =0.011), overweight (body mass index [BMI] 25-30) ( =0.042), and longer duration of illness ( =0.049) among hypertensive patients. Sleep problems have a significant negative impact on the QOL in patients with hypertension, especially in the physical domain of the QOL questionnaire. The occurrence of sleep problems in patients with hypertension is influenced by older age, primary education, overweight, occupational activity, and longer duration of illness.

Study Objectives: Sleep fragmentation and daytime sleepiness often persist in patients with sleep apnea despite correctly administered continuous positive airway pressure (CPAP). Our proof-of-concept study tested the acceptability and efficacy of morning bright light therapy (BLT) to improve sleep, circadian rhythms, and CPAP-resistant daytime symptoms in patients with sleep apnea. Methods: In this within-subject crossover study, 14 individuals completed 4 weeks of BLT and sham BLT in randomized order. Outcomes included actigraphy-based objective sleep measures, sleepiness, depressive symptoms, and sleep-related functional impairment, analyzed with multilevel models. Results: Patients experienced greater reductions in wake after sleep onset and increased amplitude of rest-activity rhythms in a shorter photoperiod with BLT compared with sham. Patients also reported reductions in self-reported sleepiness and depressive symptoms with BLT compared with sham only during the early stages of treatment and shorter photoperiod. Conclusions: These results suggest the potential for novel applications for existing chronotherapeutic interventions for improving symptoms and quality of life for those patients who experience residual symptoms with current available treatments. Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Bright Light Therapy for Residual Daytime Symptoms Associated With Obstructive Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/NCT04299009 ; Identifier: NCT04299009. Citation: Soreca I, Arnold N, Dombrovski AY. Bright light therapy for CPAP-resistant OSA symptoms. J Clin Sleep Med . 2024;20(2):211–219.

Abstract Study Objectives To evaluate long-term safety and maintenance of efficacy of solriamfetol treatment for excessive daytime sleepiness in narcolepsy and obstructive sleep apnea (OSA). Methods Participants with narcolepsy or OSA who completed a prior solriamfetol study were eligible. A 2-week titration period was followed by a maintenance phase (up to 50 weeks). Efficacy was assessed by Epworth Sleepiness Scale (ESS) and Patient and Clinical Global Impression of Change (PGI-C and CGI-C, respectively). After approximately 6 months of treatment, a subgroup entered a 2-week placebo-controlled randomized withdrawal (RW) phase. Change in ESS from beginning to end of the RW phase was the primary endpoint; PGI-C and CGI-C were secondary endpoints. Safety was assessed throughout the study. Results In the maintenance phase, solriamfetol-treated participants demonstrated clinically meaningful improvements on ESS, PGI-C, and CGI-C. In the RW phase, least squares mean change on ESS was 1.6 in participants continuing solriamfetol versus 5.3 in participants switched to placebo (p < .0001). For both secondary endpoints, higher percentages of participants receiving placebo were reported as worse at the end of the RW phase versus solriamfetol (p < .0001). Common treatment-emergent adverse events (TEAEs) with solriamfetol were headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection; 27 (4.2%) participants experienced at least one serious TEAE, and 61 (9.5%) withdrew because of TEAEs. Conclusions This study demonstrated long-term maintenance of efficacy of solriamfetol under open-label and double-blind, placebo-controlled conditions. Safety profile of solriamfetol was consistent with previous 12-week studies; no new safety concerns were identified. Trial Registration NCT02348632