Objective: To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive ␣-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures.Methods: This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (Ն12 years, with ongoing seizures despite 1-3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo. Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6-week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period. Percent change in seizure frequency was the primary endpoint; 50% responder rate was the primary endpoint for EU registration. Results:Of 388 patients randomized and treated, 387 provided seizure frequency data. Using this intent-to-treat population over the double-blind phase, the median percent change in seizure frequency was Ϫ21.0%, Ϫ26.3%, and Ϫ34.5% for placebo and perampanel 8 and 12 mg, respectively (p ϭ 0.0261 and p ϭ 0.0158 for 8 and 12 mg vs placebo, respectively). Fifty percent responder rates during the maintenance period were 26.4%, 37.6%, and 36.1%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg; these differences were not statistically significant for 8 mg (p ϭ 0.0760) or 12 mg (p ϭ 0.0914). Sixty-eight (17.5%) patients discontinued, including 40 (10.3%) for adverse events. Most frequent treatment-emergent adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia. Conclusions:This trial demonstrated that once-daily, adjunctive perampanel at doses of 8 or 12 mg improved seizure control in patients with uncontrolled partial-onset seizures. Doses of perampanel 8 and 12 mg were safe, and tolerability was acceptable. Classification of evidence:This study provides Class I evidence that once-daily 8 and 12 mg doses of adjunctive perampanel are effective in patients with uncontrolled partial-onset seizures. Neurology ® 2012;79:589-596 GLOSSARY AE ϭ adverse event; AED ϭ antiepileptic drug; AMPA ϭ ␣-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; ANCOVA ϭ analysis of covariance; CGIC ϭ Clinical Global Impression of Change; CI ϭ confidence interval; EU ϭ European Union; ITT ϭ intent-to-treat; PGIC ϭ Patient Global Impression of Change; QOLIE-31-P ϭ Quality of Life in Epilepsy questionnaire; SAE ϭ serious adverse event; TEAE ϭ treatment-emergent adverse event.Perampanel is an orally active, noncompetitive ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist under development for the treatment of epilepsy. AMPA receptors, a class of ionotropic glutamate receptors, are localized at excitatory synapses in the CNS where they serve as the principal mediators of fast excitatory postsynaptic neurotransmission and are critical to the generation and spread of epileptic activity.

SUMMARYPurpose: To assess the efficacy and safety of once-daily doses of perampanel 8 and 12 mg when added to 1-3 concomitantly administered, approved antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. Methods: Study 305 was a multicenter, double-blind, placebo-controlled trial in patients aged 12 years and older with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving 1-3 AEDs. Equal randomization to once-daily oral perampanel 8 or 12 mg, or placebo was performed. Patients entered a 19-week double-blind treatment phase comprising a 6-week titration period, with weekly 2-mg dose increments, followed by a 13-week maintenance period. Primary efficacy end points were the responder rate (proportion of patients who had a ‡50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre-perampanel baseline. A secondary end point was percent change in the frequency of complex partial plus secondarily generalized seizures. Adverse events (AEs) were monitored throughout the study. Key Findings: Three hundred eighty-six patients were randomized and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent-to-treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001). The median percent change from baseline in seizure frequency per 28 days (intent-to-treat analysis) was )9.7%, )30.5%, and )17.6% for placebo, 8 mg, and 12 mg, respectively, with significant reductions compared with placebo for both 8 mg (p < 0.001) and 12 mg (p = 0.011). For complex partial seizures plus partial seizures that secondarily generalized, the median percent change in frequency was )32.7% (8 mg), )21.9 (12 mg), and )8.1% (placebo), with significant reductions for both 8 mg (p < 0.001) and 12 mg (p = 0.005). The most frequent (occurring in ‡10% of patients in any treatment group) treatment-emergent AEs were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache. Significance: This phase III trial demonstrated that adjunctive treatment with once-daily perampanel at 8 mg and 12 mg was effective in improving seizure control in patients 12 years and older with refractory partial-onset seizures. These study results also demonstrated that once-daily doses of 8 mg and 12 mg were safe and acceptably tolerated in this study. Perampanel demonstrated a favorable risk/benefit ratio in this population.

On the basis of cross-sectional studies, it has been proposed that hepatic steatosis is a cytopathic effect of hepatitis C virus (HCV) genotype 3 but not genotype 1 infections. We tested this hypothesis by examining whether antiviral treatment altered hepatic steatosis in chronic hepatitis C. In 28 patients with genotype 1 and 34 with genotype 3 HCV, we determined the severity of steatosis in pre-and posttreatment liver biopsies using computerassisted morphometric image analysis as well as conventional semiquantitative scoring. Before treatment, hepatic steatosis was present in 16 (57%) patients infected with HCV genotype 1 and 21 (62%) of those with genotype 3. Sustained viral response (SVR) was achieved in 9 (32%) patients with genotype 1 and 22 (65%) with genotype 3. In neither group were there significant changes in body weight or alcohol consumption between preand posttreatment biopsies. In patients with HCV genotype 1, there was no change in hepatic steatosis after treatment, irrespective of the treatment response. Among those infected with genotype 3, SVR significantly reduced steatosis (P < .001), but there was no change in steatosis among those without a SVR. By logistic regression analysis, SVR was the only variable predictive of improvement in hepatic steatosis (OR ‫؍‬ 36, 95% CI ‫؍‬ 2.7-481, P ‫؍‬ .007). In conclusion, these data provide strong support for a direct causal association between HCV genotype 3 infection and hepatic steatosis. H epatic steatosis is a common feature on liver biopsy specimens from patients with chronic hepatitis C, and its presence is associated with fibrotic progression. 1,2 The pathogenesis is complex; host factors including alcohol consumption, exposure to other hepatotoxins, obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia have been identified as determinants. 3 We and others have recently found that viral factors, particularly hepatitis C virus (HCV) genotype, may be a critical determinant of steatosis in chronic hepatitis C. 2,4,5 Thus, patients with HCV genotype 3 infection and chronic hepatitis C are more likely to have steatosis and more likely to have extensive hepatic steatosis than those infected with HCV genotype 1. Furthermore, hepatic steatosis in genotype 3 chronic hepatitis C correlates directly with serum and intrahepatic titers of HCV RNA and inversely with apolipoprotein B levels. 2,5,6 In contrast, steatosis in HCV genotype 1 infection appears independent of virus levels but correlates with measures of obesity, including body mass index and visceral fat distribution. 2,4 We hypothesized that, if the genotype-specific associations between HCV and hepatic steatosis are real, then a sustained response to antiviral therapy should be accompanied by improvement in steatosis in those infected with genotype 3 but not in those with genotype 1 HCV infection.The effect of viral eradication on hepatic steatosis in relation to HCV genotype has not been evaluated. Published data on steatosis after antiviral treatment of hepatitis C are limited b...

Although significant treatment effects were not seen in the primary efficacy measures, outcomes on secondary measures suggest promising directions for further evaluation of donepezil treatment in patients with MCI.

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