Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial.

Importance: Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population. Objective: To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder. Design, Setting, and Participants: The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67 sites in North America and Europe from May 31, 2016, to January 30, 2018. Data analyses were conducted from January 31, 2018, to September 10, 2018. Participants were 55 years and older with insomnia disorder characterized by reported sleep maintenance difficulties and confirmed by sleep history, sleep diary, and polysomnography. Participants could have also had sleep onset difficulties. Interventions: Participants received placebo, zolpidem tartrate extended release (6.25 mg), or lemborexant (5 mg or 10 mg) for 1 month at bedtime. Main Outcomes and Measures: Paired polysomnograms were collected at baseline, the first 2 nights, and the last 2 nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant therapy vs placebo. Key secondary end points were changes from baseline in sleep efficiency and wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem therapy. Results: Among 1006 participants randomized (placebo, n = 208; zolpidem, n = 263; lemborexant 5 mg, n = 266; and lemborexant 10 mg, n = 269), 869 (86.4%) were women and the median age was 63 years (range, 55-88 years). Both doses of lemborexant therapy demonstrated statistically significant greater changes from baseline on objective sleep onset as assessed by latency to persistent sleep (log transformed) that was measured using polysomnography at the end of 1 month of treatment (nights 29 and 30) compared with placebo (primary end point for least squares geometric means treatment ratio vs placebo: for lemborexant 5 mg, 0.77; 95% CI, 0.67-0.89; P < .001; for lemborexant 10 mg, 0.72; 95% CI, 0.63-0.83; P < .001). For nights 29 and 30, as measured using polysomnography, the mean change from baseline in sleep efficiency (LSM treatment difference vs placebo for lemborexant 5 mg, 7.1%; 95% CI, 5.6%-8.5%; P < .001 and for lemborexant 10 mg, 8.0%; 95% CI, 6.6%-9.5%; P < .001) and wake-after-sleep onset (least squares mean treatment ratio vs placebo for lemborexant 5 mg, -24.0 min; 95% CI, -30.0 to -18.0 min; P < .001 and for lemborexant 10 mg, -25.4 min; 95% CI, -31.4 to -19.3 min; P < .001) were significantly greater for both doses of lemborexant therapy compared with placebo. Also, for nights 29 and 30, wake-after-sleep onset in the second half of the night (least squares mean treatment difference vs zolpidem for lemborexant 5 mg, -6.7 min; 95% CI, -11.2 to -2.2 min; P = .004 and for lemborexant 10 mg, -8.0 min; 95% CI, -12.5 to -3.5 min; P < .001) was significantly greater for both doses of lemborexant therapy compared with zolpidem therapy measured using polysomnography. Six participants (4 in the zolpidem group and 2 in the lemborexant 5 mg group) reported serious adverse events; none were treatment-related. Other adverse events were mostly mild or moderate in severity. Conclusions and Relevance: In this randomized clinical trial, lemborexant therapy significantly improved both sleep onset and sleep maintenance, including in the second half of the night, compared with both placebo and zolpidem measured objectively using polysomnography. Lemborexant therapy was well tolerated. Trial Registrations: ClinicalTrials.gov identifier: NCT02783729; EudraCT identifier: 2015-001463-39.

Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel.

OBJECTIVE: Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is indicated for adjunctive treatment of partial seizures in patients ≥12 years based on three phase III clinical studies. The perampanel U.S. Prescribing Information includes a boxed warning for serious psychiatric and behavioral adverse reactions. To provide context for this warning, detail on psychiatric and behavioral safety data from perampanel clinical studies is presented. METHODS: An analysis of pooled safety data from three phase III studies in patients with partial seizures is presented. Data from phase I and phase II studies in patients with and without epilepsy were also analyzed. Psychiatric and behavioral treatment-emergent adverse events (TEAEs) were evaluated according to Medical Dictionary for Regulatory Activities (MedDRA) terms, using "narrow" and "narrow-and-broad" standardized MedDRA queries (SMQs) for TEAEs suggestive of hostility/aggression. RESULTS: From the three phase III partial-seizure studies, the overall rate of psychiatric TEAEs was higher in the 8 mg (17.2%) and 12 mg (22.4%) perampanel groups versus placebo (12.4%). In the "narrow" SMQ, hostility/aggression TEAEs were observed in 2.8% for 8 mg and 6.3% for 12 mg perampanel groups, versus 0.7% of placebo patients. "Narrow-and-broad" SMQs for hostility/aggression TEAE rates were 12.3% for 8 mg and 20.4% for 12 mg perampanel groups, versus 5.7% for placebo; rates for events resulting in discontinuation were perampanel = 1.6% versus placebo = 0.7%. For events reported as serious AEs (SAEs), rates were perampanel = 0.7% versus placebo = 0.2%. In nonepilepsy patients, psychiatric TEAEs were similar between patients receiving perampanel and placebo. In phase I subjects/volunteers, all psychiatric TEAEs were mild or moderate. These analyses suggest that psychiatric adverse effects are associated with use of perampanel. SIGNIFICANCE: Patients and caregivers should be counseled regarding the potential risk of psychiatric and behavioral events with perampanel in patients with partial seizures; patients should be monitored for these events during treatment, especially during titration and at higher doses.

Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies.

Rufinamide is a novel antiepileptic agent recently approved in the United States for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. To help inform clinical decision making, the authors analyzed safety and tolerability data from the entire pediatric population in the rufinamide epilepsy clinical development program. The analysis population comprised 212 rufinamide-treated (age range 3-16 years) and 197 placebo patients (age range 4-17 years) in the double-blind studies, and 391 patients receiving rufinamide in the double-blind and/or open-label extensions. The most common adverse effects observed in rufinamide-treated patients in the double-blind studies were somnolence, vomiting, and headache. Changes in laboratory values, vital signs, and weight were generally clinically insignificant. This pooled analysis of data from pediatric patients in clinical studies of rufinamide for the treatment of seizures, mainly as adjunctive therapy, suggests a favorable safety and tolerability profile in this patient population.