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Evaluate changes in insomnia severity in subjects with moderate to severe insomnia (Insomnia Severity Index [ISI] score ≥15) treated for 12 months nightly with lemborexant.This phase 3 randomized study comprised two 6-month treatment periods. In Period 1, 949 subjects were randomized to placebo, lemborexant 5 mg (LEM5) or 10 mg (LEM10). In Period 2, placebo subjects were rerandomized to LEM5 or LEM10; subjects initially randomized to lemborexant continued their assigned treatment. Insomnia severity was assessed using baseline ISI and 1-, 3-, 6-, 9-, and 12-month post-treatment scores.Mean ISI scores improved significantly across treatment groups and disease severities, with greater decreases from baseline in the LEM5 and LEM10 versus placebo groups at months 1 (-7.1, -7.2, -5.2, respectively), 3 (-8.6, -8.9, -6.1, respectively), and 6 (-9.9, -9.8, -7.2 respectively); ISI score improvements were maintained with LEM5 and LEM10 at months 9 (-11.1 and -11.2, respectively) and 12 (-11.5 and -11.2, respectively). At months 1, 3, and 6, significantly more treatment responders (≥7-point ISI score decrease from baseline) were observed with LEM5 (44%-57%) and LEM10 (44%-52%) versus placebo (30%-41%). At months 1, 3, and 6, more remitters (ISI total score10 and 8) were observed with LEM5 (30%-44% and 22%-34%, respectively) and LEM10 (31%-41% and 22%-31%, respectively) versus placebo (18%-28% and 11%-21%, respectively).Lemborexant significantly reduced insomnia severity for 12 months and increased clinically meaningful response and remission rates versus placebo.ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

Background The COVID-19 pandemic has caused an unprecedented global public health emergency. Vaccine uptake in low and middle income countries (LMICs) lags developing nations and immunity from vector-based vaccines commonly used in LMICs may be inferior to mRNA vaccines. Thus, defining clinical characteristics that can help identify and triage cases and allocate resources in LMICs of priority. Hyperglycemia has been associated with higher morbidity and mortality in numerous diseases and in critical illness. We seek to understand the relationship between COVID-19 and hyperglycemia. Methods This is a single center retrospective review of cases with COVID-19 between January 2021 and June 2021. Adult patients >18 years of age were reviewed and those with a molecular-based laboratory confirmed SARS-CoV-2 infection were included in our study. Patients with known diabetes, elevated A1C or prior steroid use within 2 weeks of admission were excluded. Clinical characteristics, demographics, glucose levels, C-reactive protein (CRP) and ferritin were reviewed. Results A total of 120 patients were reviewed, of which 60.8% were male. Hyperglycemia ( >140mg/dL) was present in 57.5%. Hyperglycemia was associated with elevation of inflammatory markers including CRP and Ferritin (p=0.12) (Table 1). Hyperglycemia was more common in patients requiring supplemental low flow oxygen (table 2) and was more common in patients who did not survive (Figure 1). The mortality rate was higher in the hyperglycemia group with 61.5%, a statistically significant finding. Association between hyperglycemia and inflammatory markers. Supplemental oxygen needs and hyperglycemia. Survival and hyperglycemia. Conclusion Hyperglycemia on admission was an independent risk factor for disease progression and death. Inflammatory markers were also higher in patients with hyperglycemia. These patients had no prior steroid use or diabetes. Thus, it is possible that it reflects inflammation, stress, or endocrine end-organ damage due to SARS-CoV-2. If validated in larger studies, this simple test can help clinicians identify patients at risk of decompensation and allocate resources and therapeutics accordingly. Disclosures All Authors: No reported disclosures.

The natural abundance technique is used to estimate the amount of N fixed by a legume, but the B value of this particular species has to be known first. This value, however, varies with the rhizobi...

STUDY OBJECTIVES: Changes to sleep architecture that occur as a result of the normal aging process may also exacerbate insomnia in older individuals. Therefore, this study assessed the impact of lemborexant compared with placebo and zolpidem tartrate extended release on objective sleep architecture parameters, as measured by polysomnography, in older adults (ages ≥ 55 years) with insomnia disorder from a phase 3 study. METHODS: Study E2006-G000-304 (SUNRISE 1; NCT02783729) was a global, multicenter, randomized, double-blind, placebo-controlled, active comparator (zolpidem)–controlled, parallel-group study comparing 2 dose levels of lemborexant (5 mg and 10 mg). Sleep architecture was measured using polysomnography. Assessments were collected at baseline during a single-blind placebo run-in and during the first 2 nights and last 2 nights of treatment. Mean values for each sleep stage were based on the 2 consecutive polysomnograms. RESULTS: Treatment with lemborexant resulted in significantly greater increases from baseline in total sleep time compared with both placebo and zolpidem. Significant increases from baseline in rapid eye movement sleep and significant decreases from baseline in latency to rapid eye movement sleep were also observed with lemborexant compared with placebo and zolpidem. CONCLUSIONS: These findings suggest that treatment with lemborexant may address some of the alterations in sleep architecture normally observed in older individuals with insomnia. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1); URL: https://clinicaltrials.gov/ct2/show/NCT02783729; Identifier: NCT02783729. CITATION: Moline M, Zammit G, Cheng J, Perdomo C, Kumar D, Mayleben D. Comparison of the effect of lemborexant with placebo and zolpidem tartrate extended release on sleep architecture in older adults with insomnia disorder. J Clin Sleep Med. 2021;17(6):1167–1174.

Objective/background Lemborexant 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/methods Study 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. Results For 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. Conclusions LEM5 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 registration ClinicalTrials.gov , NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

Fatigue is a common symptom in patients with insomnia. This analysis evaluated whether treatment of nighttime symptoms of insomnia with a dual orexin receptor antagonist, lemborexant, might also reduce fatigue.Analyses were conducted of two phase 3 studies of subjects with insomnia disorder. Subjects received placebo, lemborexant 5 mg, or lemborexant 10 mg in the 12-month (6 months placebo-controlled) Study E2006-G000-303 (Study 303: SUNRISE-2) of adults (N = 949; full analysis set [FAS]), and the 1-month, placebo- and active-controlled Study E2006-G000-304 (Study 304; SUNRISE-1) of older adults (females ≥55 years, males ≥65 years) (N = 1006; FAS). Fatigue was assessed using the Fatigue Severity Scale (FSS). Patient-reported sleep onset and maintenance endpoints were analyzed using data from electronic sleep diaries.Lemborexant significantly reduced subject-reported fatigue versus placebo over a 6-month treatment period (FSS total score least-squares mean treatment difference of -2.50 for 5 mg and -2.56 for 10 mg of lemborexant;In addition to improving sleep onset and sleep maintenance in subjects with insomnia disorder, lemborexant provides further benefit by reducing daytime fatigue.https://clinicaltrials.gov/ct2/show/NCT02952820 and https://clinicaltrials.gov/ct2/show/NCT02783729.

The legume species Crotalaria juncea and Crotalaria spectabilis, used as cover crops (CC) in tropical and temperate zones, are being evaluated in Uruguay where their productive potential may be limited by periods of summer water deficit. In this study, C. juncea and C. spectabilis were sown in pots with soil as a substrate. After substantial growth (20 days), two different treatments of water (80% or 50% of field capacity) were imposed on the plants during 30 days, and later water was restored during 40 days. Afterward, the dry matter produced and total evapotranspired water was determined in all plants. Also, water-use efficiency (WUE) was determined using a gravimetric technique and by carbon isotope analysis (Δ13C). Dry matter production of C. spectabilis was 1.7 times higher than that of C. juncea and both legumes species tolerated a moderate water deficit, which did not affect the redistribution of dry matter between the shoot and root. A negative linear relationship (r = 0.8; p

Si bien las causas y consecuencias de la eutrofización son múltiples, este artículo analiza aspectos fundamentales en el contexto actual en Uruguay, con especial énfasis en las floraciones cianobacterianas como una de las consecuencias más frecuentes y notorias. El agravamiento de la eutrofización y sus síntomas, que se predicen con el cambio climático; las claves para la reducción de las pérdidas difusas de fósforo hacia el agua superficial en suelos bajo uso agropecuario; y los cambios actuales y futuros en la gobernanza del agua y la gestión ambiental, son algunos de los temas más importantes considerados. En el análisis se identifican también múltiples desafíos, tanto en la generación de conocimiento como en la gestión ambiental asociada.

Summary Study objectives To evaluate weight loss with lorcaserin in persons with obstructive sleep apnea (OSA). Methods This retrospective analysis evaluated weight loss of lorcaserin (10 mg twice daily) versus placebo in persons with obesity or overweight persons with OSA from a pooled database of three randomized, controlled trials. Primary end points were reductions in the baseline body weight of ≥5% and ≥10% at year 1 and overall weight change at year 1. Changes in heart rate and blood pressure were also evaluated. Results A total of 336 persons with OSA were identified in the overall pooled population (N = 6,636). At year 1, more patients receiving lorcaserin lost ≥5% (47.2% lorcaserin vs. 25.6% placebo; p

Summary Objective Drug development for patients with Lennox‐Gastaut syndrome (LGS) is based on clinical trials that use drop seizure counts. However, such counts do not assess total seizure burden and affect a patient's quality of life (QoL). In this post hoc analysis, we evaluated two novel seizure efficacy parameters related to QoL in pediatric patients with LGS, using seizure diary data from rufinamide Study 303 (NCT01405053). Methods Study 303 was a phase III, multicenter, randomized, controlled, open‐label study involving patients aged ≥1 to

Summary Introduction The elderly population is projected to be the fastest growing group of individuals with obesity group in the United States. As such, there is merit in examining factors that contribute to healthy aging and weight management. The effects of newer weight loss medications approved after 2013 have been studied but are not often assessed specifically in older persons. Methods This post hoc analysis evaluated the magnitude of weight loss in adults across age quartiles with lorcaserin, a serotonin (5‐HT) 2C receptor agonist indicated as an adjunct to a reduced‐caloric diet and increased physical activity for chronic weight management. Data from three lorcaserin pivotal phase 3 studies were used in this analysis. Data for patients with overweight/obesity without type 2 diabetes (T2D; BLOOM/BLOSSOM; body mass index [BMI] 27.0–29.9 kg/m2 and ≥1 comorbidity or BMI 30.0–45.0 kg/m2) and patients with overweight/obesity with T2D (BLOOM‐DM; BMI 27.0–45.0 kg/m2) were used. Patients were randomized to receive lorcaserin 10 mg twice daily or placebo in addition to diet and exercise for 52 weeks. Age quartiles between the studies differed as the T2D population was on average, 9 years older. Results This analysis shows that lorcaserin was associated with improved weight loss relative to placebo regardless of age. Importantly, these results were consistent for patients with and without T2D. Interestingly, the magnitude of weight loss for lorcaserin appeared to increase with increasing age. In patients without T2D, odds of achieving ≥5% and ≥10% reduction in body weight at 52 weeks were significantly higher for patients >36 years. Lorcaserin was well tolerated in all patients across all quartiles including the oldest quartile. Conclusions In summary, this post hoc analysis demonstrates that lorcaserin treatment in patients with and without T2D was safe and effective at reducing weight across all age groups analysed. Weight loss appeared to be greater for older patients; additional analyses are warranted to confirm these findings and to better understand the factors for improved weight loss.

Background: Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61). Methods: CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death. Results: At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) −1 ·1.73 m −2 and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79–0.96; P =0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min −1 ·1.73 m −2 , those with an eGFR 60-90 and those −1 ·1.73 m–2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (P for trend Conclusions: Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.

Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with the first symptoms usually appearing during early childhood. Due to the highly variable underlying etiologies, LGS cannot be considered as one disease but as an electro-clinical entity, often challenging to diagnose early and treat accordingly. The anti-seizure medication, rufinamide, is indicated for the adjunctive treatment of patients with LGS aged ≥1 year. This post hoc analysis assessed the safety and efficacy of adjunctive rufinamide for total and tonic-atonic seizures during Study 022 in children (aged16 years) and adults (aged ≥16 years).Randomized, placebo-controlled, phase III Study 022 included patients with a diagnosis of LGS and a history of multiple seizure types (including tonic-atonic or astatic seizures and atypical absence seizures; ≥90 seizures in the month prior to baseline). Assessments included monitoring of treatment-emergent adverse events (TEAEs), percent change in tonic-atonic seizure frequency/28 days during the double-blind phase relative to study baseline (a primary endpoint), and percentage of patients with ≥25%, ≥50%, or ≥75% reduction in seizure frequency relative to baseline.Of 138 enrolled patients, 74 received rufinamide (16 years, n = 49 [66%]) and 64 received placebo (16 years, n = 43 [67%]). Incidence of TEAEs was generally similar between age groups. The frequency (per 28 days) of tonic-atonic seizures was reduced with rufinamide (vs. placebo) in both younger and older patients: age16 years (-41% vs. -6%), age ≥16 years (-55% vs. +16%) (p 0.025; both age groups). In patients aged16 years receiving rufinamide, 38% and 17% achieved ≥50% and ≥75% reductions in tonic-atonic seizure frequency vs. 18% and 3% with placebo, respectively. Corresponding responder rates for patients aged ≥16 years were 52% and 32% (rufinamide) vs. 15% and 5% (placebo), respectively.In this post hoc analysis, adjunctive rufinamide was well tolerated and improved seizure control in patients with LGS, irrespective of age.

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.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.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.Across 9 clinical studies, lemborexant did not substantially impair next-day functioning among healthy subjects and subjects with insomnia.

Crotalaria spectabilis and Crotalaria juncea are cover crops (CC) that are used in many different regions. Among the main attributes of these species are their high potential for biomass production and biological fixation of nitrogen (BNF). Attempting to maximize these attributes, while minimizing water consumption through high transpiration efficiency (TE), is a challenge in the design of sustainable agricultural rotations. In this study, the relationship between biomass productivity, BNF, and TE in C. spectabilis and C. juncea was evaluated. For this purpose, an experiment was carried out under controlled conditions without water limitations and using non-inoculated soil. BNF was determined by the natural abundance of 15N, while TE was estimated by several different methods, such as gravimetric or isotopic method (13C). C. juncea produced 42% less dry matter, fixed 28% less nitrogen from the air, and had 20% less TE than C. spectabilis. TE results in both species were consistent across methodologies. Under simulated environmental conditions of high temperature and non-limiting soil water content, C. spectabilis was a relatively more promising species than C. juncea to be used as CC.

Study Objectives To assess long-term efficacy and safety of lemborexant (LEM), a novel dual orexin receptor antagonist, versus placebo in adults with insomnia disorder. Methods This was a 12-month, global, multicenter, randomized, double-blind, parallel-group phase 3 study comprising a 6-month placebo-controlled period (reported here) followed by a 6-month active-treatment-only period (reported separately). A total of 949 participants with insomnia (age ≥18 years) were randomized, received treatment with an oral dose of placebo or LEM (5 mg [LEM5] or 10 mg [LEM10]) and were analyzed. Sleep onset and sleep maintenance endpoints were analyzed from daily electronic sleep diary data. Treatment-emergent adverse events (TEAEs) were monitored throughout the study. Results Decreases from baseline in patient-reported (subjective) sleep onset latency and subjective wake after sleep onset, and increases from baseline in subjective sleep efficiency, were significantly greater with LEM5 and LEM10 versus placebo. Significant benefits over placebo were observed at the end of month 6, and at most time points assessed over the 6-month period, indicating long-term sustained efficacy of LEM. A significantly greater percentage of sleep onset responders and sleep maintenance responders were observed with LEM treatment versus placebo. Participants treated with LEM reported a significant improvement in quality of sleep after 6 months versus placebo. The majority of TEAEs were mild or moderate. There was a low rate of serious TEAEs and no deaths. Conclusions LEM5 and LEM10 provided significant benefit on sleep onset and sleep maintenance in individuals with insomnia disorder versus placebo, and was well tolerated. Clinical trial registration ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39

Study Objectives To assess potential effects of lemborexant on next-morning driving performance in adult and elderly healthy volunteers. Methods Randomized, double-blind, double-dummy, placebo and active-controlled, four period incomplete crossover study in 48 healthy volunteers (22 females), 23–78 years old. Participants were treated at bedtime for eight consecutive nights with two of three dose levels of lemborexant (2.5, 5, or 10 mg), zopiclone 7.5 mg (on the first and last night with placebo on intervening nights), or placebo. Driving performance was assessed in the morning on days 2 and 9 using a standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug–placebo differences in SDLP >2.4 cm were considered to reflect clinically meaningful driving impairment. Results Mean drug–placebo differences in SDLP following lemborexant 2.5, 5, and 10 mg on days 2 and 9 were 0.74 cm or less. The upper bound of the 95% confidence intervals (CIs) for lemborexant treatment groups were all below 2.4 cm and the 95% CIs included zero, indicating that the effects were neither clinically meaningful nor statistically significant. Symmetry analysis further supported the lack of clinically meaningful impairment with lemborexant. Conclusions When assessed starting ~9 h after lemborexant administration at bedtime the previous night, there was no statistically significant or clinically meaningful effect on driving performance in healthy adults and elderly, as assessed by either mean differences in SDLP relative to placebo or symmetry analysis. In this study, lemborexant at doses up to 10 mg was well-tolerated. Clinical Trial Registration clinicaltrials.gov, NCT02583451. https://clinicaltrials.gov/ct2/show/NCT02583451.

Objectives Lorcaserin, a selective serotonin 2C receptor agonist, is an effective pharmacologic weight-loss therapy that improves several cardiovascular risk factors. The long-term clinical cardiovascular and metabolic safety and efficacy in patients with elevated cardiovascular risk are unknown. Research design and methods CAMELLIA-TIMI 61 ( NCT02019264 ) is a randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the safety and efficacy of lorcaserin with regard to major adverse cardiovascular events and progression to diabetes in overweight or obese patients at high cardiovascular risk. Overweight or obese patients either with established cardiovascular disease or with diabetes and at least 1 other cardiovascular risk factor were randomized in a 1:1 ratio to lorcaserin 10 mg twice daily or matching placebo. The primary safety objective is to assess for noninferiority of lorcaserin for the composite end point of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular event [MACE]) (with noninferiority defined as the upper bound of a 1-sided 97.5% CI excluding a hazard ratio of 1.4) compared with placebo assessed at an interim analysis with 460 adjudicated events. The efficacy objectives, assessed at study completion, will evaluate the superiority of lorcaserin for the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization (MACE+) and the key secondary end point of conversion to diabetes. Recruitment began in January 2014 and was completed in November 2015 resulting in a total population of 12,000 patients. The trial is planned to continue until at least 1,401 adjudicated MACE+ events are accrued and the median treatment duration exceeds 2.5 years. Conclusion CAMELLIA-TIMI 61 is investigating the safety and efficacy of lorcaserin for MACEs and conversion to diabetes in overweight or obese patients with established cardiovascular disease or multiple cardiovascular risk factors.

Introduction Dosing paradigms for transitioning patients to lemborexant (LEM) from zolpidem (ZOL: immediate [IR] or extended-release [ER]) were examined in E2006-A001-312 (Study 312; NCT04009577), an open-label pilot study. Given insomnia prevalence in women, post hoc analyses in female subjects were conducted. Methods Study 312 included: 3-week Screening Period (subjects continued ZOL); 2-week Titration Period (TITR); 12-week Extension Period (EXT); 4-week Follow-up. Adults with insomnia taking ZOL-IR or ZOL-ER intermittently (3–4 nights/week) or frequently (≥5 nights/week) were enrolled. Subjects with intermittent, or one week each of intermittent and frequent ZOL use, were assigned to Cohort-1 and started TITR with LEM 5mg (LEM5). Frequent ZOL users (Cohort-2) were randomized 1:1 to LEM5 (Cohort-2A) or LEM 10mg (LEM10; Cohort-2B). Subjects who transitioned to LEM could opt into EXT. Subjects could change LEM dose during TITR (only once) and during EXT. The primary endpoint was the proportion of subjects who transitioned to LEM at end of TITR. Treatment-emergent adverse events (TEAEs) were assessed by dose at time of TEAE. Results Overall, 35 subjects were female and 29/35 (82.9%) transitioned to LEM. In Cohort-1, 7 subjects began TITR; all transitioned to LEM (5 subjects ended TITR on LEM5; 2 ended on LEM10). In Cohort-2A, 14 subjects began TITR with LEM5; 12/14 (85.7%) transitioned (6 subjects each ended TITR on LEM5 or LEM10). In Cohort-2B, 14 subjects began TITR with LEM10; 10/14 (71.4%) transitioned to LEM (3 subjects ended TITR on LEM5 and 7 on LEM10). All 29 transitioned subjects opted into EXT, and 27/29 (93.1%) completed the study. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change during EXT was 14.5 and 17.0 days for LEM5 and LEM10, respectively. Overall, most TEAEs were mild/moderate in severity. Across TITR and EXT, more TEAEs occurred with LEM10 than with LEM5; the most common TEAEs were somnolence (n=3) and abnormal dreams (n=3). Conclusion Most female subjects successfully transitioned from intermittent or frequent ZOL-IR/ZOL-ER use to LEM and completed the study. LEM was generally well tolerated. The safety profile was consistent with that observed in Phase 3 studies. Support (if any) Eisai Inc.

Introduction The Patient Global Impression–Insomnia version (PGI-I) is a self-report instrument used to evaluate a patient’s perception of the effects of their insomnia medication on their sleep relative to starting 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; responses include: 1=positive, 2=neutral, 3=negative) and 1 item related to perceived appropriateness of study medication strength (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 reported a positive impact of the dual orexin receptor antagonist lemborexant (LEM) versus placebo (PBO) at 1, 3, and 6mo for each of the PGI-I items related to medication effects. PGI-I results at 9 and 12mo are presented here for subjects that received continuous treatment with LEM for up to 12mo. Methods Study 303 was a 12-mo, randomized, double-blind, PBO-controlled (first 6mo [Period 1]), phase 3 study. Subjects were aged ≥18y with insomnia disorder. During Period 1, subjects received PBO (n=318) or LEM (5mg, [LEM5], n=316; 10mg, [LEM10], n=315). During Period 2 (second 6mo), LEM subjects continued their assigned dose while PBO subjects were rerandomized to LEM5 or LEM10 (reported separately). Subjects were also administered the PGI-I at months 9 and 12. Results At 9 and 12mo, the majority of LEM5 (9mo, n=241; 12mo, n=205) and LEM10 (9mo, n=211; 12mo, n=192) subjects reported that their study medication “helped” sleep at night (9mo: LEM5=73.4%; LEM10=76.3%; 12mo: LEM5=74.6%; LEM10=77.6%), reduced time to fall asleep (9mo: LEM5=79.3%, LEM10=78.2%; 12mo: LEM5=76.6%, LEM10=80.2%), and increased total sleep time (9mo: LEM5=62.2%, LEM10=73.0%; 12mo: LEM5=62.4%; LEM10=65.1%). Also, at both 9 and 12mo, the majority of subjects in the LEM5 and LEM10 groups, responded that treatment strength was “just right” (9mo: LEM5=60.6%, LEM10=62.1%; 12mo: LEM5=63.4%; LEM10=60.4%). LEM was well tolerated. Most adverse events were mild or moderate. Conclusion The majority of subjects receiving LEM5 or LEM10 reported a positive medication effect at both 9 and 12mo, sustaining similar positive effects for LEM achieved earlier, during the first 6mo of treatment in Study 303. Support (if any) Eisai Inc.

Livestock for beef and milk production are important economic activities worldwide. These require intensive cultures of pastures and forages, with the consequent impacts on water quality in downstream rivers and reservoirs. Monthly temporal variation of nutrients and water quality were assessed along one year at basin scale (basin area

Purpose Lennox–Gastaut syndrome (LGS), a rare, severe form of childhood-onset epilepsy, is difficult to control. Rufinamide is indicated for adjunctive treatment of seizures associated with LGS in adults and pediatric patients aged ≥1 year. In clinical practice, rufinamide dosing and titration may differ from the trial setting. Here, rufinamide clinical trial data are compared with real-world experience to provide insight into optimal dosing and titration strategies. Methods Rufinamide Phase III and open-label extension (OLE) studies were reviewed; effect of titration and dose on adverse events (AEs) and concomitant AED use were analyzed. Real-world studies of rufinamide in LGS were identified via PubMed search. Clinical data were extracted and compared. Results Results demonstrated that a rapid titration schedule (7 or 14 days) of rufinamide was tolerable for most patients and resulted in highly significant reductions in total and tonic–atonic seizures, with efficacy and tolerability sustained over 3 years. The most common AEs during the Phase III study – somnolence, vomiting, and pyrexia – occurred during the first 3 weeks of treatment, and a small subset of patients were unable to reach target dose in that time. Use of concomitant AEDs had no clinically significant effect on plasma concentrations of rufinamide. Data from real-world clinical studies are consistent with the Phase III and OLE study results. However, relative to those used in clinical trials, lower doses and slower titration schedules were commonly employed in real-world settings. Conclusions A lower dose and slower titration schedule ("low and slow") may reduce incidence of AEs without compromising efficacy of rufinamide in LGS.

Study Objective(s):The dual orexin receptor antagonist, lemborexant (LEM), is being investigated for the treatment of insomnia disorder. Drugs targeting the orexin system, like LEM, may decrease wakefulness and promote sleep with fewer potential adverse effects (AEs) than some currently available pharmacological insomnia therapies. LEM has been studied in 2 pivotal phase 3 trials for insomnia disorder, SUNRISE-1 (NCT02783729; E2006-G000-304) and SUNRISE-2 (NCT02952820; E2006-G000-303). Analyses presented here are derived from patient-reported (subjective) efficacy data pooled from SUNRISE-1 and SUNRISE-2 during 1-month of treatment in adult and elderly (age ≥65y) subjects with DSM-5 insomnia disorder.Method:SUNRISE-1 was a 1-month, double-blind, randomized, placebo (PBO)- and active-controlled (zolpidem tartrate extended-release 6.25mg [ZOL; not reported), parallel-group study in 1006 subjects (age ≥55y). SUNRISE-2 was a 12-month (6-month PBO-controlled, 6-month active treatment), double-blind study in 949 subjects (age ≥18y). In both studies, subjects were randomized to PBO, LEM5, or LEM10 (SUNRISE-1 subjects could also be randomized to ZOL; not included in pooled analysis) following a 2-week PBO run-in. Changes from baseline (BL) in subjective sleep onset latency (sSOL), subjective sleep efficiency (sSE), and subjective wake after sleep onset (sWASO) were analyzed using mixed effect model repeated measurement analysis. Sleep onset and sleep maintenance responders were analyzed via Cochran–Mantel–Haenszel test stratified by study, region and age group.Results:The pooled analysis set comprised 1693 subjects (PBO, n=527; LEM5, n=582; LEM10, n=584). Reductions from BL in sSOL were significantly greater for LEM5 and LEM10 vs PBO during the first 7 days of treatment and at the end of Month 1 (all comparisons P30 min) was statistically significantly larger for LEM5 and LEM10 vs PBO (first 7 days: both P10 min, if BL >60 min) was statistically significantly larger for LEM5 and LEM10 vs PBO (first 7 days: both PConclusions:LEM improved sleep onset and sleep maintenance in adult and elderly subjects with insomnia disorder, and was well tolerated. Average values on sleep maintenance endpoints showed that subjects treated with LEM obtained >1 hour of additional sleep per night vs subjects who received PBO.Funding Acknowledgements:Supported by Eisai Inc.

Introduction Demonstrating improvement from the patient's perspective is an important objective for an insomnia treatment regimen to be regarded as successful. Clinical trials for insomnia therapies generally include outpatient data using daily sleep diaries to assess the magnitude of change in sleep onset and, in some cases, sleep maintenance outcomes. Instruments that assess patient perception of disease severity and symptom improvement can provide additional information on treatment effectiveness. Change in severity of insomnia symptoms is often assessed using the Insomnia Severity Index. The Patient Global Impression – Insomnia version (PGI‑I) is another self‑report questionnaire that evaluates subjects’ perception of the effects of a study medication on their sleep. The PGI-I does not have a baseline; therefore, the outcome is the global impression of the study medication's effects during or at the end of treatment relative to their sleep prior to study enrollment. The PGI‑I contains 3 items related to study medication effects (helped/worsened sleep; decreased/increased time to fall asleep; and increased/decreased total sleep), rated on a 3‑point scale (1=positive, 2=neutral, 3=negative), and 1 item related to perceived appropriateness of study medication strength, rated on a different 3-point scale (1=too strong, 2=just right, 3=too weak). SUNRISE-2 (NCT02952820; E2006-G000-303) examined the efficacy and safety of lemborexant (LEM), a dual orexin receptor antagonist under development for the treatment of insomnia, vs placebo (PBO) in adult subjects with insomnia disorder. Here we present the results of the PGI-I at the end of 6 months of treatment based on age of subjects ( Methods SUNRISE-2 was a Phase 3, 12-month, double-blind, global study in female and male adults aged ≥18y with insomnia disorder that included a 6-month PBO-controlled treatment period (after a PBO run-in) followed by a 6-month active-only treatment period. Subjects received PBO, LEM 5mg (LEM5) or LEM 10mg (LEM10) for the first 6 months. Titration to higher or lower doses was not possible. The PGI-I was administered at Months 1, 3, 6, 9, and 12; results from the end of PBO-controlled treatment are reported. Chi-square tests were used to compare the percentage of “positive” (or “just right”) responses with the combined “neutral” and “negative” (or combined “too strong” and “too weak”) response categories for LEM vs PBO subjects. Results The full analysis set of SUNRISE-2 included 949 subjects. The subgroup of subjects Conclusions Overall, in both the This research was funded by: Eisai, Inc.

Introduction In SUNRISE-2 (NCT02952820; E2006-G000-303), while lemborexant (LEM) provided significant benefit versus placebo (PBO) on sleep-diary measurements over 6mo, some improvement was noted in PBO subjects. We report outcomes from PBO subjects rerandomized to LEM during the last 6mo of SUNRISE-2. Methods SUNRISE-2 was a randomized, double-blind, global phase 3 study in adults (≥18y) with insomnia disorder. Subjects received PBO or LEM (5mg [LEM5]; 10mg [LEM10]) for 6mo. PBO subjects were rerandomized to LEM for another 6mo; LEM subjects continued assigned treatment. Changes from 6mo baseline (calculated after PBO completion) in subjective sleep onset latency (sSOL), subjective sleep efficiency (sSE), and subjective wake after sleep onset (sWASO) are reported for rerandomized subjects. Results At study baseline for PBO subjects (n=318), median sSOL (min) was 55.9, mean (SD) sSE (%) and sWASO (min) were 61.3 (17.8) and 132.5 (80.2), respectively. The 6mo baseline values for rerandomized PBO-LEM5 (n=133) and PBO-LEM10 (n=125) subjects, respectively, were: median sSOL, 31.2, 34.3; mean (SD) sSE, 70.5 (20.2), 71.1 (18.0); mean (SD) sWASO, 105.1 (80.6), 100.1 (84.6). Median sSOL decreased from the 6mo baseline after 1mo (PBO-LEM5, −3.2; PBO-LEM10, −2.9) and 6mo (PBO-LEM5, −2.7; PBO-LEM10, −5.0). Mean (SD) sSE increased from the 6mo baseline after 1mo (PBO-LEM5, 3.9 [12.1]; PBO-LEM10, 3.5 [8.1]) and 6mo (PBO-LEM5, 3.9 [13.6]; PBO-LEM10, 4.5 [13.0]). Mean (SD) sWASO decreased after 1mo (PBO-LEM5, −8.5 [49.4]; PBO-LEM10, −5.7 [36.1]) and 6mo (PBO-LEM5, −8.2 [49.0]; PBO-LEM10, −10.0 [58.8]). Treatment-emergent adverse events incidence was similar during PBO (62.7%) and LEM treatment (PBO-LEM5, 54.9%; PBO-LEM10, 57.7%). Adverse events were consistent with those seen in the initial 6mo of treatment for patients originally randomized to LEM. Conclusion Rerandomization to LEM was associated with additional improvement in sleep outcomes following the PBO-related response. LEM benefit was evident after 1mo and was sustained throughout treatment. LEM was well tolerated. Support Eisai Inc.

Introduction Lemborexant (LEM), a dual orexin receptor antagonist, demonstrated significant benefits vs placebo on patient-reported sleep outcomes in adults age ≥18y in SUNRISE-2 (NCT02952820; E2006-G000-303). The impact of intrinsic factors (sex, race, and region) on LEM efficacy outcomes was assessed. Methods SUNRISE-2 was a randomized, double-blind, global phase 3 study in adults age ≥18y with insomnia disorder (Full Analysis Set, n=949). Subjects received placebo (n=318) or LEM (5mg [LEM5], n=316; 10mg [LEM10]; n=315) for 6 months. At 6 months, placebo subjects were rerandomized to LEM for another 6 months (not reported here); LEM subjects remained on their assigned dose. Sleep diary-based (subjective) sleep onset latency (sSOL) and wake after sleep onset (sWASO) were assessed for prespecified patient subgroups including: sex (male [n=302], female [n=647]), race (white [n=679], black [n=76], Asian [n=178]), and region (North America [n=302], Europe/New Zealand [n=483], Asia [n=164]). Analyses were not controlled for multiplicity. Results LEM5 and LEM10 provided numerically greater median reductions (improvement) from baseline in sSOL vs placebo at 6 months in across all subgroups examined. Also, LEM5 and LEM10 led to mean reductions (improvement) from baseline at 6 months in sWASO for all subgroups. While several subgroups had small numbers of subjects, changes from baseline in sSOL and sWASO were in the direction of improvement in the majority of subgroups. Pharmacokinetic analyses showed no important differences in exposure by these factors. Conclusion LEM treatment demonstrated efficacy in improving sSOL and sWASO across patient subgroups, supporting common dosing instructions for both sexes and all races. Support Eisai Inc.

Introduction How much improvement would be considered meaningful from the patient perspective is not well defined. In SUNRISE-2 (NCT02952820; E2006-G000-303), using the Patient Global Impression-Insomnia version (PGI-I), subjects rated how treatment impacted subjective (sleep diary-based) sleep onset latency (sSOL; Question2; positive, neutral, and negative) relative to before starting treatment. Meaningful change can thus be determined based on the change from baseline (CFB) in subjects with a positive score. Methods SUNRISE-2 (n=949, full analysis set) was a Phase 3, 12-month, double-blind, global study in subjects age ≥18y with insomnia disorder. Subjects received PBO (N=318), LEM 5mg (LEM5, N=316) or LEM 10mg (LEM10, N=315) for 6 months. At the end of Month 6, PBO subjects were rerandomized to LEM5 or LEM10; LEM5 and LEM10 subjects continued at the same dose for 6 more months. The ranges of median CFB in sSOL (minutes) at 6 months were examined in response to PGI-I Item 2. Results At 6 months, subjects reporting positive medication effect (PBO, n=110; LEM5, n=178; LEM10, n=159) showed median CFB in sSOL from -17.5 to -32.1 minutes across treatment groups. In subjects reporting neutral effect (PBO, n=49; LEM5, n=28; LEM10, n=27), median CFB in sSOL ranged from -10.4 to -25.6 minutes across treatment groups. In subjects reporting negative medication effect (PBO, n=82; LEM5, n=34; LEM10, n=32), median CFB in sSOL ranged from -8.6 to -10.4 minutes across treatment groups. The PBO group provided the smallest numbers for each response category range. Conclusion Subjects reporting positive medication effect on PGI-I Item 2, i.e. decreased time to fall asleep, had corresponding changes from baseline in sSOL ranging from -17.5 to -32.1 minutes. Thus, this range may represent a clinically meaningful improvement as perceived by patient-subjects, and may be useful to clinicians in determining whether a treatment regimen is working for their patients. Support Eisai Inc.

Introduction Insomnia is a prevalent sleep disorder among elderly persons, defined as persons aged ≥65?years. Lemborexant (LEM) is a dual orexin receptor antagonist in development for the treatment of insomnia and other sleep disorders. The Phase 3 SUNRISE-2 study demonstrated significant benefit of LEM versus placebo (PBO) on patient-reported (subjective) measures of sleep in adults aged ≥18?years over 6 months; these benefits were maintained at 9 and 12 months. Here, we examined the effects of lemborexant (LEM) on subject-reported insomnia disease severity, assessed by the Insomnia Severity Index (ISI), and fatigue, assessed by the Fatigue Severity Score (FSS), over 12 months in the subgroup of elderly (aged ≥65 years) subjects. Methods SUNRISE-2 (NCT02952820; E2006-G000-303) was a 12-month randomized, double-blind, PBO-controlled (first 6-months) Phase 3 study. Following a PBO run-in of ∼2 weeks, subjects were randomized to PBO, LEM 5mg (LEM5) or LEM 10mg (LEM10) for 6 months. At the end of Month 6, subjects from the PBO treatment group were rerandomized to LEM5 or LEM10, while subjects in the LEM5 and LEM10 groups continued at the same dose for another 6 months. The ISI and the FSS were administered at baseline (BL) and at the end of Months 1, 3, 6, 9, and 12. The ISI daytime functioning score (DFS), based on the ISI items that assess the impact of insomnia symptoms on daily functioning (items 4-7), was also evaluated. Mean changes from BL in ISI total score (ISI TS), ISI DFS, and FSS total score (FSS TS) were assessed. The least squares mean treatment difference for change from baseline for PBO versus LEM during the first 6 months of the study was analyzed using mixed-effect model repeated measurement analysis, adjusted for relevant factors and BL score as a covariate. Results Of 949 subjects in the SUNRISE-2 Full Analysis Set, 262 were aged ≥65y (PBO, n=89; LEM5, n=87; LEM10, n=86). Mean (SD) ISI TS at BL for PBO, LEM5, and LEM10 was 19.1 (3.0), 19.4 (3.2), and 19.2 (3.3), respectively. Mean [SD] ISI TS decreased (improved) from BL for all groups (PBO, −6.8 [5.6]; LEM5, −10.6 [6.2]; LEM10, −9.4 [6.3]) at Month 6; decreases were significantly larger for both LEM5 and LEM10 compared with PBO (LEM5, P Conclusions In the subgroup of elderly subjects from SUNRISE-2, LEM5 and LEM10 significantly reduced subject-reported disease severity and fatigue compared with PBO after 6 months of treatment. Reduced severity in insomnia symptoms with LEM5 and LEM10 also was associated with improved daytime functioning. The improvements in subject-reported disease severity and fatigue were maintained through 12 months of LEM treatment. This research was funded by: Eisai Inc.

Study Objective(s):This study examined the effects of lemborexant (LEM) compared with placebo (PBO) on subject-reported insomnia disease severity, assessed by the Insomnia Severity Index (ISI), and fatigue, assessed by the Fatigue Severity Score (FSS), from the 6-month PBO-controlled period of SUNRISE-2.Method:SUNRISE-2 (NCT02952820; E2006-G000-303) was a 12-month randomized, double-blind, PBO-controlled (first 6-months) Phase 3 study. After an ~2-week PBO run-in, subjects were randomized to PBO, LEM 5mg (LEM5) or LEM 10mg (LEM10) for 6 months. The ISI and the FSS were administered at baseline [BL] and at the end of Months 1, 3, and 6. The ISI daytime functioning score (DFS), based on the ISI items that assess the impact of insomnia symptoms specific to daily functioning (items 4-7), was also evaluated. Mean changes from BL in ISI total score (ISI TS), ISI DFS, and FSS total score (FSS TS) were analyzed using a mixed-effect model repeated measurement analysis, adjusted for relevant factors and BL score (ISI TS, ISI DFS, or FSS TS) as a covariate.Results:949 subjects (PBO, n=318; LEM5, n=316; LEM10, n=315) were included in the full analysis set. Median age was 55y (range 18-88y). Mean ISI TS at BL for PBO, LEM5, and LEM10 was 19.0, 19.6 and 19.1, respectively. While mean ISI TS decreased (improved) from BL for all groups, decreases were significantly larger for both LEM5 and LEM10 vs PBO at Month 1 (least squares mean treatment difference [LSM TD]: LEM5, −1.5 [P=0.001]; LEM10, −1.9 [PMean FSS TS at BL was 35.2, 37.4, and 36.0 for PBO, LEM5, and LEM10, respectively. Mean FSS TS decreased (improved) from BL in all groups at the end of Month 1 (decreases were larger and significant for LEM10 vs PBO [LSM TD: –2.0 (P=0.026)]), and Month 3 (decreases were larger and significant for LEM5 [LSM TD: –2.2 (P=0.021)] and LEM10 [LSM TD: –3.0; (P=0.001)] vs PBO). At Month 6, mean FSS TS remained improved from BL in all treatment groups (PBO, –6.3; LEM5, –10.1; and LEM10, –8.9). These decreases were larger and significant for LEM5 (LSM TD: –2.5 [P=0.013]) and LEM10 (LSM TD: –2.6 [P=0.013]) vs PBO. LEM was well tolerated with most adverse events mild to moderate in severity.Conclusions:In SUNRISE-2, LEM5 and LEM10 significantly reduced subject-reported disease severity and fatigue vs PBO after 6 months of treatment. Reduced severity in insomnia symptoms with LEM5 and LEM10 also translated to improved daytime functioning.Funding Acknowledgements:Supported by Eisai Inc.

Introduction In Phase 3 SUNRISE-1 (NCT02783729; E2006-G000-304) and SUNRISE-2 (NCT02952820; E2006-G000-303), lemborexant (LEM) provided significant benefit versus placebo on sleep diary-based sleep onset/maintenance outcomes over 1mo and 6mo, respectively, in subjects with insomnia disorder. The impact of LEM on patient-reported fatigue, assessed using the Fatigue Severity Scale (FSS), in subjects with clinically significant fatigue (CSF) at baseline was examined for each study. Methods SUNRISE-1 was a 1mo, randomized, double-blind, placebo- and active-controlled, parallel-group study in female (≥55y) and male (≥65y) subjects (n=1006); subjects received placebo, LEM 5mg (LEM5), LEM 10mg (LEM10) or zolpidem tartrate extended-release (not reported here). SUNRISE-2 was a 12mo, randomized, double-blind study in subjects age ≥18y (n=949). Subjects received placebo, LEM5, or LEM10 for 6mo. Placebo subjects were rerandomized to LEM5 or LEM10 for another 6mo; LEM subjects continued assigned treatment. CSF was defined as FSS total score (FSSts) ≥36. Results In subjects with baseline CSF, in SUNRISE-1, baseline FSSts was 46.8, 46.5, and 46.6 in placebo (n=117), LEM5 (n=157), and LEM10 (n=153) groups, respectively, and, in SUNRISE-2, was 45.7, 46.4, and 45.8 in placebo (n=169), LEM5 (n=181), and LEM10 (n=173) groups, respectively. At 1mo, mean changes from baseline in FSSts were not significantly different vs placebo for LEM5 in both studies, and for LEM10 in SUNRISE-1. In SUNRISE-2, LEM10 significantly decreased mean [SD] FSSts from baseline vs placebo at 1mo (LEM10, −11.2[13.9] vs placebo, −8.7[10.5]; P=0.03). By 6mo in SUNRISE-2, both LEM5 and LEM10 significantly decreased mean [SD] FSSts from baseline versus placebo (LEM5, −15.4[13.8]; LEM10, −15.0[14.2] vs placebo, −11.2[11.6]; both P Conclusion In subjects with CSF, longer treatments (>1mo) may be needed to observe significant FSSts improvements, which were evident at 6mo and sustained at 12mo with continuous LEM treatment. Support Eisai Inc.

To avoid false declarations of geographic and botanical honey origin, traceability should be based on analytical data, which could then be processed by multivariate statistical methods. Obtaining this data, however, is costly and time consuming. Thus, it would be more convenient to acquire this information from routine trials, for example from the analysis for determination of high fructose corn syrup (HFCS) concentration in honey. The availability of a procedure of this kind in Uruguay would be useful in discriminating between honeys from grasslands to that from eucalyptus, the two main floral sources for commercial production. To this effect, honey samples (47 from pastures and 42 from eucalypts) were analyzed for δ13C in both honey and its protein fraction. We identified a logistic regression model that allowed us to correctly assign 90% of the training samples, using δ13C data of honey, protein fraction, and the isotopic index as variables. This model was then validated, obtaining 100% correct allocation for honeys from pasture and 90% for honeys from eucalyptus. Moreover, we found that this information could also be used to establish adulteration with HFCS based on a local stricter cut-off limit than that of -1.0‰ of the international index.

In this work, we evaluated the possibility of predicting the geographic origin of Uruguayan honeys using discriminant analysis (DA) on mineral concentration. Although the DA results appeared to discriminate between honeys from the south, central and north, the subsequent cross-validation analysis did not confirm this result. We also compared honeys from Uruguay and the Buenos Aires province (Argentina) using DA on mineral composition data. In this case, a clear difference between these two origins was observed. It seems possible to differentiate between Uruguayan honeys and those produced in a neighbouring country based on multivariate statistical methods.

Study Objectives To assess potential effects of lemborexant on next-morning driving performance in adult and elderly healthy volunteers. Methods Randomized, double-blind, double-dummy, placebo and active-controlled, four period incomplete crossover study in 48 healthy volunteers (22 females), 23–78 years old. Participants were treated at bedtime for eight consecutive nights with two of three dose levels of lemborexant (2.5, 5, or 10 mg), zopiclone 7.5 mg (on the first and last night with placebo on intervening nights), or placebo. Driving performance was assessed in the morning on days 2 and 9 using a standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug–placebo differences in SDLP >2.4 cm were considered to reflect clinically meaningful driving impairment. Results Mean drug–placebo differences in SDLP following lemborexant 2.5, 5, and 10 mg on days 2 and 9 were 0.74 cm or less. The upper bound of the 95% confidence intervals (CIs) for lemborexant treatment groups were all below 2.4 cm and the 95% CIs included zero, indicating that the effects were neither clinically meaningful nor statistically significant. Symmetry analysis further supported the lack of clinically meaningful impairment with lemborexant. Conclusions When assessed starting ~9 h after lemborexant administration at bedtime the previous night, there was no statistically significant or clinically meaningful effect on driving performance in healthy adults and elderly, as assessed by either mean differences in SDLP relative to placebo or symmetry analysis. In this study, lemborexant at doses up to 10 mg was well-tolerated. Clinical Trial Registration clinicaltrials.gov, NCT02583451. https://clinicaltrials.gov/ct2/show/NCT02583451.

Introduction Effects of the dual orexin receptor antagonist lemborexant (LEM) on sleep architecture in adults ≥55y with insomnia disorder were assessed in Study E2006-G000-304 (Study 304; SUNRISE-1; NCT02783729). These post hoc analyses of Study 304 examined the acute effect of LEM on REM pressure (REM latency [REM-L] and REM by quarter of the night [QoN]). Methods This study was a 1mo, randomized, double-blind, placebo- and active-controlled (zolpidem tartrate extended-release 6.25mg [ZOL]) study of LEM (5mg, LEM5; 10mg, LEM10). Subjects received placebo (n=208), ZOL (n=263), LEM5 (n=266), or LEM10 (n=269). Two nights of PSGs were recorded at baseline, first 2 (N1/2), and last 2 (N29/30) treatment nights. Results Baseline REM-L (minutes) was similar across treatments (98.4–101.4). Significant decreases from baseline in REM-L were observed for LEM5 (−42.6 [53.9]) and LEM10 (−49.6[52.9]) vs placebo (−6.9[54.5]) and ZOL (0.2[54.2]) on N1/2 (all P Conclusion LEM, but not ZOL, acutely increases REM pressure as evidenced by REM latency and REM duration per quarter. Support (if any) Eisai Inc.

Introduction E2006-A001-312 (Study 312; NCT04009577) was an open-label pilot study that examined pre-specified dosing paradigms for transitioning patients from zolpidem (ZOL: immediate [IR] or extended-release [ER]) to the dual orexin receptor antagonist lemborexant (LEM; 5mg [LEM5] or 10mg [LEM10]). Methods Study 312 included a 3-week Screening Period (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 (3–4 nights/week) or frequent (≥5 nights/week) ZOL-IR or ZOL-ER users participated. Intermittent ZOL users and subjects with one week each of intermittent and frequent ZOL usage were assigned to Cohort-1 and began TITR with LEM5. Frequent ZOL users were assigned to Cohort-2 and randomized 1:1 to LEM5 or LEM10. Subjects who successfully transitioned to LEM had the option to enter EXT. During TITR and EXT, subjects could change LEM dose (only once during TITR). 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. Results Fifty-three subjects enrolled (Cohort-1, n=10; Cohort-2, n=43). Of these, 43/53 (81.1%) transitioned to LEM at the end of TITR; all 43 (100.0%) entered EXT wherein 41/43 subjects received treatment. Three of these subjects discontinued treatment during EXT, so that 38/41 (92.7%) subjects entered EXT, received treatment and completed EXT. At the end of EXT, 25/41 (61.0%) subjects were receiving LEM10 and 16/41 (39.0%) were receiving LEM5. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change was 14.5 days and 36.0 days for LEM5 and LEM10, respectively. The majority of TEAEs were mild/moderate in severity. Across the study (TITR and EXT), more TEAEs occurred with LEM10 than LEM5; the most common TEAEs were somnolence (n=4) and abnormal dreams (n=4). Conclusion Study results support the view that patients can successfully transition directly from ZOL to LEM. LEM was generally well tolerated; the safety profile was consistent with that observed in Phase 3 clinical development. Support (if any) Eisai Inc.