Search

Objectives. To investigate the effectiveness, safety, and tolerability of perampanel (PER) when used as monotherapy to treat focal or generalized epilepsy in everyday clinical practice, using data from the PERMIT study. Methods. PERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which people with focal and generalized epilepsy were treated with PER. This post hoc analysis included people with epilepsy (PWE) from PERMIT who were treated with PER monotherapy at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months. Effectiveness assessments included ≥50% responder rate and seizure freedom rate (no seizures since at least the prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. Results. Overall, 268 PWE were treated with PER monotherapy at baseline. Retention was assessed for 168 PWE, effectiveness for 183 PWE, and safety and tolerability for 197 PWE. Retention rates were 91.1%, 87.3%, and 73.3% at 3, 6, and 12 months, respectively. At 12 months, responder rates were 84.2% overall, 82.9% in PWE with only focal-onset seizures at baseline, and 88.0% in those with only generalized-onset seizures at baseline; corresponding freedom rates were 62.9%, 57.7%, and 80.0%, respectively. AEs were reported for 45.2% of PWE. The most frequently reported AEs (≥5% of PWE) were dizziness/vertigo (16.8%), irritability (11.2%), somnolence (9.1%), and depression (6.6%). Over 12 months, 13.7% discontinued due to AEs. Conclusions. PER was effective when used as monotherapy in clinical practice, particularly in those with generalized-onset seizures, and was generally well tolerated.

Background: Cardiovascular (CV) event risk, healthcare resource utilization (HCRU) and costs have not been elucidated among hypertension patients with treated insomnia (H + TI). Materials & methods: Adult patients with H + TI were identified in IBM MarketScan databases. H + TI patients were matched 1:1 on age and sex to controls with hypertension but without sleep disorders. Multivariable models were used to estimate associations between treated insomnia and CV event risk, HCRU and costs. Results: In total, 81,502 H + TI patients (mean age = 62 years, 53% female) were matched. Relative to controls, H + TI patients were 2.4 times as likely to have CV events. H + TI patients incurred higher costs per patient per month (US$2343 vs US$1013). Conclusion: Treated insomnia was associated with higher costs and HRCU in hypertension patients.

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.

Objective To assess the retention rate, efficacy, safety, and dosing of perampanel administered to patients with epilepsy during routine clinical care in the retrospective phase IV, PROVE Study (NCT03208660). Methods Exposure, efficacy, and safety data were obtained from the medical records of patients initiating perampanel after January 1, 2014, across 29 US study sites. The cutoff date for this interim analysis was October 10, 2018. The primary efficacy endpoint was retention rate. Secondary efficacy endpoints included median percent changes in seizure frequency, seizure‐freedom rate, and overall investigator impression of seizure effect. Results All enrolled patients (N = 1121) received perampanel. Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 16.6 (14.7) months; overall mean (SD) daily perampanel dose was 5.7 (2.7) mg. Perampanel uptitration occurred weekly (21.1%), biweekly (23.8%), every 3 weeks (1.5%), other (43.3%), and unknown (10.3%). Across the Safety Analysis Set (N = 1121), retention rate on perampanel at 24 months was 49.5% (n = 319/645). At 12 months, the median reduction in seizure frequency per 28 days from baseline in the small number of patients for whom data were available was 75.0% (n = 85), and 30/85 (35.3%) patients were seizure free. Based on investigator impression at the end of treatment, improvement, no change (ie, stable), or worsening of seizures was reported in 54.3%, 33.7%, and 12.0% of patients, respectively. Treatment‐emergent adverse events occurred in 500 (44.6%) patients; the most common were dizziness (9.2%), aggression (5.4%), and irritability (4.5%). Serious treatment‐emergent adverse events occurred in 32 (2.9%) patients. Significance Favorable retention and sustained efficacy were demonstrated for ≥12 months following initiation of perampanel during routine clinical care in patients with epilepsy.

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.

Aims This post hoc analysis assessed the efficacy and safety/tolerability of adjunctive perampanel in patients from China (aged ≥12 years) with focal seizures (FS), with/without focal to bilateral tonic‐clonic seizures (FBTCS), or generalized tonic‐clonic seizures (GTCS). Methods Study centers in China were identified using data from five double‐blind, randomized, phase III studies of adjunctive perampanel (2‐12 mg/day) and their open‐label extensions (OLEx). Efficacy assessments included median percent reduction in seizure frequency per 28 days, and 50% and 75% responder and seizure‐freedom rates. Safety/tolerability assessments included monitoring of treatment‐emergent adverse events (TEAEs). Results Overall, 277 patients (placebo, n = 79; perampanel, n = 198) were included in the double‐blind safety analysis set. The full analysis set comprised 274 patients (FS, n = 238 [placebo, n = 60; perampanel, n = 178]; FBTCS, n = 120 [placebo, n = 31; perampanel, n = 89]; GTCS, n = 36 [placebo, n = 18; perampanel, n = 18]). Median percent reductions in seizure frequency for placebo vs perampanel were as follows: 16.6% vs 32.4% (FS; P, Adjunctive perampanel was associated with greater median percent reductions in seizure frequency per 28 days vs placebo in Chinese patients with focal or generalized seizure types during double‐blind, randomized, phase III studies.During OLEx studies, adjunctive perampanel showed efficacy for up to 4 years for FS and FBTCS, and up to 2 years for GTCS.Perampanel was generally well tolerated during short‐ and long‐term treatment.

Objective This post hoc analysis evaluated the efficacy and safety of adjunctive perampanel 4 mg/d received as modal dose, which may have differed from randomized dose, for treatment of focal seizures. Methods Data were pooled from four randomized, double‐blind, placebo‐controlled, phase III studies of adjunctive perampanel in patients (aged ≥12 years) with focal seizures, with/without focal to bilateral tonic‐clonic (FBTC) seizures: studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), and 335 (NCT01618695). Efficacy assessments included median percentage reductions in seizure frequency per 28 days and seizure‐freedom rates for patients receiving placebo and perampanel 4 mg/d (modal dose). Treatment‐emergent adverse events (TEAEs) were assessed in patients receiving perampanel 4 mg/d at their TEAE onset. Outcomes were also assessed with/without enzyme‐inducing antiseizure medications (EIASMs). Results The full analysis set included 979 patients with focal seizures (placebo: n = 616 [235 with FBTC seizures]; perampanel 4 mg/d: n = 363 [134 with FBTC seizures]). Compared with placebo, perampanel 4 mg/d conferred significantly greater median percentage reductions in seizure frequency per 28 days for focal (12.6% vs 21.1%; P = .0004) and FBTC seizures (17.4% vs 49.8%; P

PROVE is a retrospective, phase IV study assessing retention, dosing, efficacy, and safety of perampanel when administered to patients during routine clinical care. We report an interim analysis of preadolescent (1 to

This post hoc analysis of four open-label extension (OLEx) studies evaluated the long-term efficacy and safety of adjunctive perampanel in adolescent patients (aged 12 to ≤17 years) with focal-onset seizures (FOS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS).Patients who completed one of six double-blind, placebo-controlled studies could enter one of four OLEx studies comprising a blinded Conversion Period (6-16 weeks) followed by a Maintenance Phase (27 to ≤256 weeks; perampanel dose: ≤12 mg/day). Exposure, retention, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed. Efficacy outcomes were analyzed using observed case and last observation carried forward (LOCF) approaches; the latter was used to account for early dropouts.The Full Analysis Set comprised 309 adolescents with FOS (FBTCS, n = 109) and 19 with GTCS, and the Safety Analysis Set comprised 311 with FOS (FBTCS, n = 110) and 19 with GTCS. Mean (standard deviation) cumulative duration of perampanel exposure (weeks) was: FOS, 77.7 (58.7); FBTCS, 88.7 (63.8); and GTCS, 97.0 (35.5). Retention rates were maintained for ≤2 years (FOS, 50.0 %; FBTCS, 57.1 %; GTCS, 41.7 %). Seizure control (median percent reduction in seizure frequency/28 days) was sustained for up to 2 years; FOS (59.4 %, n = 113), FBTCS (64.6 %, n = 53), and GTCS (86.5 %, n = 17). At Year 2, 50 % responder rates were: FOS, 58.4 % (n = 66); FBTCS, 54.7 % (n = 29); and GTCS, 82.4 % (n = 14); seizure-freedom rates were: FOS, 5.3 % (n = 6); FBTCS, 24.5 % (n = 13); and GTCS, 35.3 % (n = 6). Long-term seizure control was observed even in LOCF analyses. The incidence of TEAEs was highest during Year 1 (FOS, n = 269 [86.5 %]; FBTCS, n = 95 [86.4 %]; GTCS, n = 15 [78.9 %]), compared with Years 2-4; the most common (≥10 % of patients) were dizziness, somnolence, and nasopharyngitis. No new safety signals emerged with long-term treatment.This post hoc analysis suggests that long-term (≤2 years) adjunctive perampanel (≤12 mg/day) is efficacious and generally well tolerated in adolescent patients with FOS, with or without FBTCS, or GTCS.

Report final data from adolescent (12-18 years) and adult (≥18 years) patients from PROVE (NCT03208660), a multicenter, retrospective, non-interventional, Phase IV study to assess retention, efficacy, safety, and dosing of perampanel in patients with epilepsy during routine clinical care.Data were retrospectively collected from medical/pharmacy records of patients in the US initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary endpoints included median percent changes in seizure frequency, seizure-freedom rates, investigator's impression of seizure effect, and treatment-emergent adverse events (TEAEs).The Safety Analysis Set (SAS) included 294 adolescents and 1157 adults (median maximum perampanel dose, 6.0 mg/day). In patients eligible for inclusion in the retention rate analysis, 24-month retention rates were 53.5% (n=91/170) in adolescents and 47.8% (n=354/741) in adults. In patients with available efficacy data during Months 10-12, median percent seizure frequency reductions were 79.3% (n=20) in adolescents and 70.8% (n=92) in adults. Most patients in the SAS with seizure-effect data experienced an improvement in seizures at the last follow-up time point (adolescents, 51.4% [n=128/249]; adults, 52.3% [n=506/967]). TEAEs occurred in 113 adolescents (38.4%; most common, aggression [6.5%]) and 512 adults (44.3%; most common, dizziness [9.2%]).Perampanel demonstrated favorable retention rates and sustained efficacy (up to 2 years) in adolescent and adult patients during routine clinical care; no new safety signals were observed.NCT03208660 (https://clinicaltrials.gov/ct2/show/NCT03208660).

Introduction Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries for the treatment of adults with insomnia. In Study E2006-G000-304 (Study 304; NCT02783729), LEM improved sleep onset and sleep maintenance. This analysis evaluated treatment with LEM in subjects reporting “problems waking up too early” on the Insomnia Severity Index (ISI) Item-3 as assessed by wake after sleep onset in the second half of the night (WASO2H). Methods Study 304 was a 1-month, randomized, double-blind, placebo(PBO)-controlled and active-comparator (zolpidem extended-release 6.25mg [ZOL]) study of LEM 5mg (LEM5) and LEM 10mg (LEM10). Subjects whose baseline scores were ≥3 (severe/very severe) for ISI Item-3 were included in this analysis. WASO2H was defined as minutes of wake during the interval from 240 minutes after lights off until lights on (based on 8hr time in bed). WASO2H was measured at Days 1/2 and 29/30 using polysomnography and averaged across consecutive nights; change from baseline was analyzed using mixed effect model repeated measurement analysis. Results Treatment groups were (number of subjects: treated/had ISI Item-3 scores ≥3) LEM5 (220/140), LEM10 (219/140), ZOL (216/158) and PBO (180/122). Baseline mean (standard deviation) WASO2H (minutes) ranged from 77.8-82.25 (30.3-35.5) across treatment groups. By Day 1/2, WASO2H improved significantly with LEM versus ZOL and PBO. Least-squares mean (LSM; standard error [SE]) WASO2H change from baseline at Day 1/2 was -15.56(2.3) (PBO), -34.19(2.2) (LEM5), -42.54(2.2) (LEM10), and -27.82(2.1) (ZOL); all P Conclusion LEM provided significant benefit in WASO2H versus PBO (LEM5 and LEM10) and versus ZOL (only LEM10 at Day 29/30) among subjects with severe/very severe problems with waking too early. Improvements reported for ISI Item-3 for LEM subjects supports this benefit. Support (If Any) Eisai Inc.

Introduction Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries for the treatment of adults with insomnia. In Study 303 (NCT02952820), LEM provided significant benefit on sleep outcomes including patient-reported (subjective) sleep onset latency (sSOL) and wake after sleep onset (sWASO) versus placebo (PBO). This post-hoc analysis assessed these measures in Insomnia Severity Index (ISI) responders, defined as subjects with clinically meaningful reductions (≥7 points) in ISI total scores (ISI-TS). Methods Study 303 was a 12-month, PBO-controlled (first 6mo), randomized, double-blind, phase 3 study in subjects with ISI-TS ≥15 (moderate to severe insomnia). Subjects (n=949; Full Analysis Set [FAS]) received LEM (5mg [LEM5]; 10mg [LEM10]) or PBO for 6mo. Changes from baseline (CFB) in sSOL (min) and sWASO (min) at 6mo were analyzed in ISI responders from the FAS and in subjects with severe insomnia (baseline ISI-TS ≥22), using mixed-effect model repeated measurement analysis. Results At 6mo, 175 (LEM5), 151 (LEM10), and 124 (PBO) subjects were ISI responders; of these, 46 (LEM5), 48 (LEM10) and 29 (PBO) had severe insomnia. CFB in the FAS in median sSOL was significantly greater with LEM5 (−21.8) and LEM10 (−28.2) versus PBO (−11.4; both P0.05), but not with LEM5 (−32.9, P>0.05).Least-squares mean (standard error) CFB in sWASO in the FAS was −46.8(3.7) with LEM5 (P0.05) and significantly greater with LEM5 (−58.9[3.8], P0.05); CFB with LEM10 (−71.4[9.0]) was similar to PBO. Conclusion ISI responders including those from the severe insomnia subgroup reported greater CFB in sSOL and sWASO than the FAS that was somewhat dose dependent. LEM generally showed benefit versus PBO. Support (If Any) Eisai Inc.

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.

BackgroundWe report data from three Phase IV, observational studies (Studies 506 [US;NCT03208660], 508 [India;NCT03836924] and 501 [Italy;NCT04257604]), which assessed real-world safety and efficacy of adjunctive perampanel across different regions.MethodsStudy 506 included patients with any seizure type. Studies 508/501 included patients with focal- onset seizures.Endpoints included: retention rate (Studies 506/501), median percent reduction in seizure frequency/28 days, seizure-freedom rates and safety.ResultsIn Study 506, the 12-month retention rate was 58.5% (n=876/1498). At Months 10–12, the median percent reduction in seizure frequency/28 days was 75.0% (n=123) and the seizure-freedom rate was 30.9% (n=38/123). In Study 508, the 6-month median percent reduction in seizure frequency/28 days was 100.0% (n=174) and seizure-freedom rate was 49.4% (n=86/174). In Study 501, the 6-month median percent reduction in seizure frequency/28 days, retention rate and seizure-freedom rate were 55.4% (n=198), 72.6% (n=170/234) and 18.0% (n=36/200), respectively. Treatment-emergent adverse events occurred in 704/1703 (41.3%; Study 506), 36/199 (18.1%; Study 508) and 132/234 (56.4%; Study 501) patients; the most common was dizziness/vertigo.ConclusionsPerampanel is efficacious and well tolerated during real-world use regardless of geographi- cal region; no unexpected safety signals emerged.FundingEisai Inc., Eisai Pharmaceuticals India Pvt., Ltd., and Eisai s.r.l.

e18816 Background: Almost half of all cancer patients have trouble sleeping, usually insomnia or other sleep-wake disorders. Cancer treatment can exacerbate sleep problems. This study evaluated all-cause healthcare resource utilization (HCRU) and costs in cancer patients undergoing treatment who also have insomnia relative to a matched cohort of cancer patients undergoing treatment who do not have insomnia. Methods: This retrospective study used the IBM MarketScan Commercial and Medicare Supplemental Databases (Jan 2014-Dec 2019) to identify patients: (1) age ≥18 years; (2) with ≥1 ICD-9/ICD-10 codes for insomnia OR with ≥2 prescriptions for zolpidem immediate release (IR) OR trazodone ≤150mg OR benzodiazepine; (3) with ≥12 months of continuous enrollment pre-/post-index date (earliest diagnosis or medication fill date); (4) with ≥2 ICD-9/ICD-10 codes for any cancer; and (5) ≥1 claim for oncology treatment. Patients with sleep disorders other than insomnia were excluded. The resulting patients (“insomnia cohort”) were 1:1 matched on age, sex and Elixhauser Comorbidity Index (ECI) score to patients with cancer undergoing treatment without insomnia or other sleep disorders (“control cohort”). HCRU and costs were reported per patient per month (PPPM). Generalized linear models were used to compare adjusted outcomes between cohorts. Results: For each cohort, 7,132 patients (mean age 60.8 years, 69.5% female, 13.6 ECI score) were identified. In adjusted analyses, significantly more patients in the insomnia cohort had at least one inpatient visit per month, inpatient stays were significantly longer, and mean outpatient visits were significantly higher (all p < 0.001) relative to the control cohort. The insomnia cohort had higher mean number of emergency department (ED) visits (p < 0.05); however, mean number of inpatient visits was not significantly different between cohorts. Adjusted analyses also showed significantly higher mean total PPPM costs for the insomnia cohort than the control cohort ($4,864 and $3,302, respectively; mean ratio = 1.47; p < 0.0001). Mean PPPM costs for inpatient visits, ED visits, and outpatient costs were also higher for the insomnia cohort (p < 0.001). Conclusions: Cancer patients undergoing treatment who have insomnia had more intensive HCRU and higher costs relative to those without insomnia. These results suggest that better managing insomnia in this population may have a beneficial impact on both patients and payers.

Summary Objective Weight management pharmacotherapies can improve metabolic diseases through weight‐dependent and weight‐independent effects. Lorcaserin is a selective 5‐hydroxytryptamine 2C receptor agonist. The objective of this analysis is to quantify the relative contribution of weight loss to the treatment effects of lorcaserin 10 mg twice a day on key metabolic parameters. Methods This retrospective analysis evaluated 6,897 patients with overweight or obesity (with or without diabetes mellitus) across three randomized, placebo‐controlled, double‐blind, 52‐week clinical trials that evaluated lorcaserin 10 mg twice daily (BID; NCT00395135, NCT00603902, and NCT00603291); 509 patients from only one of the studies had type 2 diabetes mellitus. A mediation analysis was applied to help rank the relative contribution of weight loss to metabolic study outcomes. Results According to this mediation analysis, lorcaserin 10 mg BID improved a spectrum of adiposopathic metabolic abnormalities with varying contributions attributable to weight loss. Improvements in waist circumference and blood pressure were almost exclusively attributable to weight loss. Less than 50% of the improvement in glucose parameters (fasting blood glucose and haemoglobin A1c) were attributable to weight loss. Conclusions Across Phase III clinical trials, lorcaserin 10 mg BID improved multiple cardiometabolic parameters through both weight‐loss dependent and independent mechanisms.

Objectives (1) To evaluate risk of hospitalization following initiation of perampanel (pre‐ and post‐analysis) and (2) to compare hospitalization rates following initiation of perampanel vs lacosamide. Methods Patients were identified from Symphony Health's Patient Integrated Database if they had a prescription for perampanel (July 1, 2014‐June 30, 2016). Patients 4‐11 years of age with any partial‐onset seizure (POS) or ≥12 years of age with any POS or primary generalized tonic‐clonic seizure (GTCS) (pre‐post); or ≥12 years of age (perampanel vs lacosamide). The first fill of perampanel (“index date”) marked the start of the analysis period. Patients had ≥1 additional fill for perampanel and ≥2 diagnoses for epilepsy or nonfebrile convulsion diagnosis during pre‐index (based on ICD‐9/ICD‐10 codes). Patients were matched using a 1:1 propensity scoring method for the perampanel vs lacosamide analysis. Primary outcome was hospitalization during the one year following medication initiation. Results Pre‐ and post‐perampanel: N = 1771 (mean age 34 years, 55% female). One‐year all‐cause hospitalization risk ratio was 0.76 (P

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.

BackgroundThis post hoc analysis assessed the efficacy and safety of adjunctive perampanel in adult/adolescent/paediatric patients with myoclonic and absence seizures during Phase II/III clinical studies.MethodsDuring Study 332 (NCT01393743), patients aged ≥12 years with generalised tonic-clonic seizures (GTCS) received placebo/adjunctive perampanel 8-mg/day. In Study 311 (NCT02849626), patients aged 4–NCT01527006), patients aged 2–ResultsOverall, 66/393 patients had myoclonic seizures (placebo, n=23; perampanel, n=43) and 72/393 had absence seizures (placebo, n=33; perampanel, n=39); patients with both seizure types are counted twice. Reductions in seizure frequency/28 days were observed with placebo and perampanel: myoclonic, 52.5% and 24.6%; absence, 7.6% and 25.1%, respectively. TEAEs with placebo and perampanel occurred in 18 (78.3%) and 36 (83.7%) patients with myoclonic seizures, and 25 (75.8%) and 34 (87.2%) patients with absence seizures, respectively; most common TEAEs with perampanel were dizziness and fatigue.ConclusionThese data suggest adjunctive perampanel does not worsen myoclonic/absence seizures in adult/adolescent/paediatric patients.FundingEisai Inc. stella_ngo@eisai.com32

BackgroundThe long-term (≤1-year) effects of adjunctive perampanel on cognition, behaviour and growth/development were assessed in paediatric patients aged 4–NCT02849626).MethodsCore Study (4-week pretreatment/23-week treatment) completers could enter the Extension (29-week maintenance/4-week follow-up). Assessments included: change from baseline at Week 52 for cognition (Aldenkamp-Baker Neuropsychological Assessment Schedule [ABNAS]), behavioural/emotional problems (Child Behaviour Checklist [CBCL]), visuomotor skills (Lafayette Grooved Pegboard Test [LGPT]) and growth/development.ResultsMean standard deviation (SD) change from baseline to Week 52 in total ABNAS score was -3.3 (16.6) (n=112). Mean (SD) change from baseline at Week 52 in CBCL total problems was -6.0 (14.0) and-1.6 (14.7) for patients aged 1.5–5 (n=17) and 6–18 years (n=102), respectively; for time to complete the LGPT, this was 5.3 (48.0) seconds for patients aged ≤8 years (n=33) and 0.4 (23.2) for patients aged >8 years (n=51). No significant impact on growth/development observed.ConclusionNo clinically significant changes were observed in cognition, behaviour or growth/devel- opment parameters following long-term (≤1 year) adjunctive perampanel in paediatric patients (aged 4–manoj_malhotra@eisai.com

BackgroundPsychiatric safety data from perampanel randomised controlled trials (RCTs; Studies 304/305/306/335) and open-label extensions (OLEx; Studies 307/335 OLEx) in patients with focal epilepsy with/without psychiatric history were analysed.MethodsTreatment-emergent adverse events (TEAEs) were analysed for patients with/without psychi- atric history.ResultsIn RCTs, 352/2187 (16.1%) patients had psychiatric history; psychiatric TEAEs occurred in 73/244 (29.9%) and 21/108 (19.4%) patients with perampanel and placebo, respectively. Psychiatric TEAEs with perampanel 2 and 4 mg/day were 11.1% and 15.4%, respectively, vs placebo (19.4%). In patients without psychiatric history, psychiatric TEAEs were observed in 157/1325 (11.8%) and 47/510 (9.2%) patients with perampanel and placebo, respectively. Psychiatric TEAEs were more frequent in patients with psychiatric history for all combined doses and placebo (both PIn OLEx, 283/1895 (14.9%) patients had psychiatric history. Psychiatric TEAEs occurred in 151 (53.4%)/521 (32.3%) patients with/without psychiatric history (PConclusionPsychiatric TEAEs were reported by more patients with psychiatric history and were dependent on perampanel dose irrespective of previous psychiatric illness; 2 mg/day and 4 mg/day doses did not increase psychiatric TEAEs.FundingEisai Inc.manoj_malhotra@eisai.com

BackgroundLong-term (1-year) seizure-freedom rates with adjunctive perampanel were assessed in paediatric patients aged 4–NCT02849626).MethodsSeizure-freedom rates (FOS, FBTCS, GTCS) were assessed in patients who achieved seizure freedom during the Core Study Maintenance Period and then remained seizure free for up to 12 months (calculated from the start of their seizure-free period). Data were stratified by concomitant enzyme- inducing anti-seizure medications (EIASMs) (with and without) and age (4–ResultsFor FOS, 6/11 (54.5%) patients remained seizure free for 12 months (with EIASMs, n=2/5 [40.0%]; without EIASMs, n=4/6 [66.7%]; 4–ConclusionDespite small patient numbers, seizure-freedom rates are maintained during long-term (1-year) perampanel treatment in paediatric patients, consistent with analyses in adolescents/adults.Funding.Eisai Inc. stella_ngo@eisai.com

BackgroundThe long-term efficacy and safety of adjunctive perampanel was evaluated in patients aged≥60 years with focal-onset seizures (FOS) with/without focal to bilateral tonic-clonic seizures (FBTCS) who participated in open-label extension Studies 307 (NCT00735397) and 335 (NCT01618695).MethodsPatients received perampanel 2–12 mg/day during Studies 307 (16-week blinded Conversion; 256-week Maintenance) and 335 (4-week Pre-conversion; 6-week Conversion; ≥46-week Maintenance). Assessments included median per cent reduction in seizure frequency/28 days vs pre-perampanel baseline, 50% responder rates and treatment-emergent adverse events (TEAEs).ResultsThe Safety Analysis Set included 71 patients (mean age, 64.0 years). Seizure frequency reductions during Years 1 and 2 were 31.7% (n=71) and 44.5% (n=38) (total FOS), and 95.5% (n=19) and 100.0% (n=9) (FBTCS), respectively. Seizure frequency reductions were observed during Years 3/4 (low patient numbers); over one-third of patients achieved a ≥50% seizure reduction each year. During Years 1, 2, 3 and 4, TEAE incidence was 87.3% (n=62/71), 60.4% (n=29/48), 47.4% (n=9/19) and 57.1% (n=8/14), respectively; most common were dizziness and fall during Years 1/2 and 3/4, respectively.ConclusionPerampanel was associated with reductions in seizure frequency over 4 years in elderly patients. The safety profile was consistent with the overall populations.FundingEisai Inc. stella_ngo@eisai.com33

BackgroundThe long-term (≤1-year) effects of adjunctive perampanel on cognition by responder status and modal dose were assessed in paediatric patients (aged 4–NCT02849626).MethodsCore Study (4-week pretreatment/23-week treatment) completers could enter the Extension (29-week maintenance/4-week follow-up). The Aldenkamp-Baker Neuropsychological Assessment Schedule [ABNAS] was used to assess cognition (change from baseline, Weeks 23/52) by total seizure response category (ResultsMean (standard deviation) change from baseline in total ABNAS for Weeks 23 and 52 by response category was: (14.8); 100%, -1.6 (18.3) and -0.6 (20.6), respectively; and by modal dose was: -2.0 (7.2); 4 mg/day, -4.8 (22.4) and -10.4 (25.6); >4–6 mg/day, 1.3 (8.3) and -1.3 (10.2); >6–8 mg/day, -0.5(10.7) and 1.9 (9.4); >8–12 mg/day, -0.1 (12.8) and -7.4 (20.2); >12–16 mg/day, 2.2 (12.4) and 1.1 (14.8), respectively.ConclusionAdjunctive perampanel had few long-term effects on cognition in paediatric patients, regard- less of responder status and modal dose.FundingEisai Inc.11m2anoj_malhotra@eisai.com

Introduction Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries for the treatment of adults with insomnia. In Study 303 (NCT02952820), LEM provided significant benefit on subject-reported sleep measures versus placebo (PBO). This post hoc analysis investigated whether changes from baseline in sleep parameters with LEM are correlated with insomnia disorder severity. Methods Study 303 was a randomized, double-blind, PBO-controlled (first 6mo [Period 1]), phase 3 study. During Period 1, subjects received LEM 5mg (LEM5), LEM 10mg (LEM10), or PBO. During Period 2 (second 6mo), LEM subjects continued their assigned dose and PBO subjects were rerandomized to LEM5 or LEM10 (rerandomized subjects not reported here). The correlation between changes in subject-reported sleep parameters (sleep onset latency [sSOL], wake after sleep onset [sWASO], sleep efficiency [sSE], total sleep time [sTST]) and insomnia disorder severity, as assessed by the Insomnia Severity Index total score (ISI-TS) were evaluated in the Full Analysis Set (FAS; ISI-TS ≥15) and in a subgroup of subjects with severe (ISI-TS ≥22 at baseline) insomnia over 12mo for LEM and over 6mo for PBO. Results Among 949 (PBO=318; LEM5=316; LEM10=315) subjects, 223 (PBO=65; LEM5=84; LEM10=74) had severe insomnia at baseline. Within each sleep parameter and severity group, baseline values were similar across treatments. Overall, strong to very strong correlations were observed between changes from baseline in sleep parameters and decrease in ISI-TS, regardless of treatment, as determined by correlation coefficients for sSOL (LEM5=0.973 [P=0.0053]; LEM10=0.997 [P=0.0002]; PBO=0.844 [P=0.361]), sSE (LEM5=–0.937 [P=0.0188]; LEM10=–0.992 [P=0.0008]; PBO=–0.950 [P=0.2018]), sWASO (LEM5=0.937 [P=0.0187]; LEM10=0.996 [P=0.0003]; PBO=0.979 [P=0.1299]), and sTST (LEM5=–0.876 [P=0.0515]; LEM10=–0.974 [P=0.0050]; PBO=–0.933 [P=0.2346]). Strong to very strong correlations were also observed in subjects with severe insomnia: sSOL (LEM5=0.818 [P=0.0904]; LEM10=0.823 [P=0.0868]; PBO=0.828 [P=0.3788]), sSE (LEM5=–0.860 [P=0.0616]; LEM10=–0.975 [P=0.0048]; PBO=–0.961 [P=0.1792]), sWASO (LEM5=0.871 [P=0.0544]; LEM10=0.936 [P=0.0194]; PBO=0.875 [P=0.3213]), and sTST (LEM5=–0.843 [P=0.0729]; LEM10=–0.969 [P=0.0095]; PBO=–0.974 [P=0.1449]). Conclusion Across the study period, changes from baseline in reported nocturnal sleep parameters correlated with reductions in severity of insomnia disorder regardless of insomnia severity at baseline. Support (If Any) Eisai Inc.

Introduction In Phase 3 Study 304 (NCT02783729), lemborexant (LEM) provided significant benefit versus placebo (PBO) on polysomnographic (PSG) and sleep diary-based sleep onset and maintenance outcomes over 1mo in subjects with insomnia disorder. Based on evidence that patients with insomnia and objective short sleep (ISS [total sleep time; TST] Methods Study 304 was a 1mo, randomized, double-blind, PBO- and active-controlled, parallel-group study in female (age ≥55y) and male (age ≥65y) subjects (n=1006). Subjects received PBO, LEM 5mg (LEM5), LEM 10mg (LEM10), or zolpidem tartrate extended-release 6.25mg (ZOL). Latency to persistent sleep (LPS) and wake after sleep onset (WASO) were assessed at Nights (NT) 1/2 and NT29/30 using PSG and averaged; change from baseline (paired PSGs during single-blind PBO run-in) were analyzed using mixed-effect model repeated measurement analysis. Results The ISS subgroup comprised 710/1006 (70.58%) subjects. Mean (SD) baseline LPS was similar across treatments: PBO=52.80(35.73); ZOL=54.77(40.93); LEM5=54.28(39.30); LEM10=53.31(34.45). On NT1/2, LEM5/10 led to statistically significantly greater (P Conclusion The data support LEM as an effective therapy for older adult patients with ISS and suggest LEM may be more beneficial than ZOL, particularly for patients with ISS and sleep onset difficulties. These findings suggest that LEM may be a reasonable therapy to consider for treating older patients with ISS where CBT-I may have relatively limited efficacy. Support (If Any) Eisai Inc.

Introduction The reciprocal relationship between pain and poor sleep has been well established. Pain interferes with sleep, and insomnia increases pain sensitivity, thus reducing quality of life. Therefore, it is of clinical importance to evaluate whether a sleep-promoting drug such as the dual orexin receptor antagonist, lemborexant (LEM; approved in multiple countries to treat adults with insomnia) can improve sleep in older patients, in whom both sleep and ongoing pain are prevalent. Methods Study 304 (NCT02783729), was a 1-month, double-blind, PBO- and active-controlled study in subjects age ≥55y with insomnia (full analysis set [FAS]=1006). Those who also endorsed some/severe pain at baseline on the pain/discomfort dimension of the EuroQual-5 Dimension-3 Level scale (EQ-5D-3L; no problems/some problems/extreme problems) at baseline were eligible for these post-hoc analyses. Medical history of pain conditions and/or ongoing therapy were not required for eligibility and were not evaluated. Subjects were randomized to bedtime doses of placebo, LEM 5mg (LEM5),10mg (LEM10) or zolpidem tartrate extended release (not reported here). Changes from baseline (CFB) in objective sleep parameters assessed by polysomnography (latency to persistent sleep [LPS]; wake after sleep onset [WASO]) were analyzed by mixed-effect repeated measures analyses adjusted for relevant factors. Results Approximately 18% of the FAS reported some or extreme pain at baseline (PBO=55; LEM5=78; LEM10=50). For LPS, baseline median values (minutes) were 31.0, 29.4 and 42.1 for PBO, LEM5 and LEM10, respectively. Median CFB for LPS were larger and statistically significantly different for both LEM doses compared with PBO at the beginning of treatment (mean of Nights 1/2: +2.5; -8.4, -15.8; P Conclusion These data suggest that lemborexant can effectively treat insomnia in older adults with concomitant painful conditions. Support (If Any) Eisai Inc.

Although 50 % reduction in seizure frequency is a common efficacy endpoint in clinical trials of antiepileptic drugs (AEDs), 75 % or greater reductions may be required to improve patients' health-related quality of life. Identification of clinical factors that are associated with high responder rates may help to inform clinicians on which patients may optimally benefit from treatment. We evaluated potential predictive factors for achieving major treatment responses (≥75 % reduction in seizure frequency per 28 days from study baseline) in patients with drug-resistant focal-onset seizures, with/without focal to bilateral tonic-clonic (FBTC) seizures in perampanel trials designed for regulatory approval.Univariate analyses using logistic regression were performed using data from three double-blind, placebo-controlled Phase III studies of adjunctive perampanel (Studies 304 [NCT00699972], 305 [NCT00699582], 306 [NCT00700310]), and their open-label extension study (OLEx; Study 307 [NCT00735397]). For the double-blind studies, baseline seizure frequency, number of baseline AEDs, baseline seizure type, baseline concomitant enzyme-inducing AEDs (EIAEDs), baseline carbamazepine, lamotrigine, or valproic acid, age at diagnosis, time since diagnosis, etiology, and perampanel plasma concentration were included individually with study treatment. The same factors were included for the OLEx analysis except for plasma concentration and treatment. Variables found to be significant predictors for a major treatment response in univariate analyses were subsequently included in multivariable analyses using backwards and forwards selection.In the double-blind studies, 175/1374 patients had a major response to placebo (n = 25) or perampanel (n = 150). The best predictors of a major treatment response in multivariable models with forwards and backwards selection were: the presence of FBTC seizures during baseline (P = 0.0002), higher perampanel plasma concentration (P0.0001), older age at diagnosis (P = 0.0024 and 0.0045, respectively), and lower baseline seizure frequency (P = 0.0364 and 0.0127, respectively). In the OLEx, 217/1090 patients had a major treatment response. The best predictors of a major treatment response in the final multivariable model, regardless of backwards or forwards selection, were a lower baseline seizure frequency (P = 0.0022), the absence of focal impaired awareness seizures during baseline (P = 0.0011), the presence of FBTC seizures during baseline (P = 0.0164), lower number(s) of baseline AEDs (P = 0.0002), the absence of EIAEDs during baseline (P = 0.0059), an older age at diagnosis (P = 0.0054), and absence of structural etiologies (P = 0.0138).These analyses of placebo-controlled and long-term extension trial data identified a number of potential predictive factors for patients with focal-onset seizures achieving a major treatment response. These factors may help guide clinicians when predicting a patient's response to treatment and optimizing individual treatment regimens.

Purpose This post hoc analysis assessed the effects of adjunctive perampanel on myoclonic and absence seizure outcomes in patients (aged ≥12 years) with idiopathic generalized epilepsy (IGE) and generalized tonic-clonic seizures during the double-blind (up to 8 mg/day) and open-label extension (OLEx; up to 12 mg/day) phases of Study 332. Methods Patients experiencing myoclonic and/or absence seizures during study baseline were included. Assessments for myoclonic and absence seizures included: median percent change in seizure frequency, number of seizure days and seizure-free days (all per 28 days), 50 % and 75 % responder rates, seizure-freedom rates, seizure worsening, and monitoring of treatment-emergent adverse events (TEAEs). Results During the double-blind phase, myoclonic and/or absence seizures were reported in 47/163 and 60/163 patients, respectively. Median percent reductions in seizure frequency per 28 days from study baseline were 52.5% and 24.5% (myoclonic seizures) and 7.6 % and 41.2 % (absence seizures) for placebo and perampanel, respectively; seizure-freedom rates were 13.0 % and 16.7 % (myoclonic seizures) and 12.1 % and 22.2 % (absence seizures), respectively. During the OLEx phase, 46/138 and 52/138 patients experienced myoclonic and/or absence seizures, respectively. Responses during the double-blind phase were maintained during long-term (>104 weeks) adjunctive perampanel treatment. The frequency/type of TEAEs was consistent with the known safety profile of perampanel. Conclusion In this post hoc analysis, adjunctive perampanel was not associated with any overall worsening of absence seizures. Further research is needed to investigate the effect of adjunctive perampanel in IGE patients with myoclonic and/or absence seizures.

Objective This post hoc analysis evaluated long‐term efficacy and safety in patients with focal to bilateral tonic‐clonic seizures (FBTCS) or generalized tonic‐clonic seizures (GTCS) who entered open‐label extension (OLEx) studies to receive long‐term adjunctive perampanel. Methods Patients aged 12 years and older who completed phase II or III randomized, double‐blind, placebo‐controlled studies could enter an OLEx study, each comprising a blinded conversion period followed by an open‐label maintenance period (32‐424 weeks; maximum perampanel dose = 12 mg/d). Exposure, seizure outcomes, and treatment‐emergent adverse events (TEAEs) were analyzed. Results Baseline characteristics were generally balanced between patients with FBTCS (n = 720) and GTCS (n = 138). Mean (standard deviation) cumulative duration of perampanel exposure was 102.3 (70.3) weeks (FBTCS) and 83.9 (38.4) weeks (GTCS). Retention rates were 50.0% for up to 4 years (FBTCS) and 49.2% for up to 2 years (GTCS). Across OLEx treatment durations, median reductions in seizure frequency per 28 days were 66.7% (FBTCS) and 80.6% (GTCS). Fifty percent and 75% responder and seizure‐freedom rates were 59.5%, 45.3%, and 18.4%, respectively (FBTCS), and 72.5%, 51.5%, and 16.7%, respectively (GTCS). Efficacy was sustained for up to 4 years (FBTCS) and up to 3 years (GTCS), even when accounting for early dropouts. TEAE incidence was highest during Year 1 (FBTCS, 85.3%; GTCS, 86.2%); most common were dizziness and somnolence. During Year 1, serious TEAEs were reported in 81 (11.3%; FBTCS) and 10 (7.2%; GTCS) patients. TEAEs were consistent with the known safety profile of perampanel; no new safety signals were identified with long‐term treatment. Significance This post hoc analysis suggests long‐term (up to 4 years) adjunctive perampanel (up to 12 mg/d) is efficacious and well tolerated in patients (aged 12 years and older) with FBTCS or GTCS.

Objective Compared to other seizure types, generalized tonic-clonic (GTC) seizures may be disproportionately related to increased morbidity, and reducing seizure frequency could translate into improvements across measures of morbidity in medically treated patients with drug-resistant epilepsy (DRE). The primary objective of this analysis was to quantify the burden of patients with DRE who experience GTC seizures (GTC+) compared to patients with DRE who do not experience GTC seizures (GTC-). Methods Adult patients from the Cleveland Clinic Epilepsy Center-Neurological Institute from 2012-2016 with DRE with epilepsy for at least 1 year were eligible for inclusion and were divided into GTC ± groups based on whether the patient had experienced a GTC seizure in the year preceding the first visit. Epilepsy duration, comorbidities, antiepileptic drug use, patient-reported outcomes (PROs) and seizure type, frequency, and etiology were captured. Generalized linear models, negative binomial regression, logistic regression, and linear regression were used as appropriate for multivariate analyses. Results A total of 379 patients met inclusion criteria and had data at 1-year follow-up after their baseline visit (192 GTC+ and 187 GTC-). Although DRE patients experiencing GTC seizures had fewer seizures per day over the preceding 6 months than those not experiencing GTC seizures, seizure severity and levels of depression and anxiety were greater. GTC+ patients who reported five or more seizures in the preceding 4 weeks had 82% lower odds (1-0.18 = 0.82) of working than patients with no seizures. Significance Patients with DRE experience a significant burden and decreased quality of life. Multivariate analysis is necessary to understand the complex relationship between seizure type, frequency, and impact on health-related quality of life (HRQoL) and changes over time. Effective treatments to reduce the burden for DRE patients who experience GTC seizures continue to be needed.

The purpose of this study was to establish whether a past psychiatric history could play a role in the development of psychiatric treatment-emergent adverse events (PTEAEs) in patients randomized to perampanel (PER) or placebo.The development of PTEAEs was compared between patients with/without a psychiatric history in a post hoc analysis from four randomized placebo-controlled trials (RPCTs) of PER (304/305/306/335) in patients with treatment-resistant focal epilepsy.Among the 2,187 patients enrolled in the RPCTs, 352 (16.1%) had a psychiatric history (PER n = 244; placebo n = 108), while 1835 patients (83.9%) did not (PER n = 1325; placebo n = 510). Compared to patients without a psychiatric history, those with a positive history reported more PTEAEs for both patients randomized to PER (11.8% vs. 29.9%, p 0.01) or to placebo (9.2% vs. 19.4%, p 0.01). The prevalence of PTEAEs was not higher among patients randomized to 2 mg and 4 mg/day doses than placebo in both those with and without psychiatric history. Rather, the higher prevalence rates were among subjects randomized to 8 mg (29.8%) and 12 mg (36.4%) PER doses in patients with a past psychiatric history.A psychiatric history appears to increase the risk of PTEAEs in patients randomized to placebo and to PER at doses of 8 and 12 mg/day. It should be identified in all patients considered for treatment with PER, particularly when prescribed at doses above 4 mg/day.

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