Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate

ObjectiveThe objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures.MethodsThe Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms.ResultsOut of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200 mg/day was significantly lower than that for placebo (2.68 vs 3.20, p < 0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200 mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800 mg/day than for placebo; only SB was significant (p = 0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p = 0.006), DS (p = 0.031), and SB (p = 0.001).ConclusionsTherapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores.Classification of evidenceThis study presents Class I evidence that adjunctive ESL (800 and 1200 mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ.     

Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: A randomized, double-blind, placebo-controlled, parallel-group phase III study

Purpose: To study the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in adults with ≥4 partial‐onset seizures (simple or complex, with or without secondary generalization) per 4 weeks despite treatment with 1–2 antiepileptic drugs (AEDs). Methods: This multicenter, parallel‐group study had an 8‐week, single‐blind, placebo baseline phase, after which patients were randomized to placebo (n = 102) or once‐daily ESL 400 mg (n = 100), 800 mg (n = 98), or 1,200 mg (n = 102) in the double‐blind treatment phase. ESL starting dose was 400 mg; thereafter, ESL was titrated at weekly 400‐mg steps to the full maintenance dose (12 weeks). Results: Seizure frequency adjusted per 4 weeks over the maintenance period (primary endpoint) was significantly lower than placebo in the ESL 1,200‐mg (p = 0.0003) and 800‐mg (p = 0.0028) groups [analysis of covariance (ANCOVA) of log‐transformed seizure frequency]. Responder rate was 20% (placebo), 23% (400 mg), 34% (800 mg), and 43% (1,200 mg). Median relative reduction in seizure frequency was 16% (placebo), 26% (400 mg), 36% (800 mg), and 45% (1,200 mg). The most frequent concomitant AEDs were carbamazepine (56–62% of patients), lamotrigine (25–27%), and valproic acid (22–28%). Similar efficacy results were obtained in patients administered ESL with or without carbamazepine as concomitant AED. Discontinuation rates caused by adverse events (AEs) were 3.9% (placebo), 4% (400 mg), 8.2% (800 mg), and 19.6% (1,200 mg). AEs in >10% of any group were dizziness, headache, and diplopia. Most AEs were mild or moderate. Discussion: ESL, 800 and 1,200 mg once‐daily, was well tolerated and more effective than placebo in patients who were refractory to treatment with one or two concomitant AEDs.     

Efficacy and safety of eslicarbazepine acetate as add‐on treatment in patients with focal‐onset seizures: Integrated analysis of pooled data from double‐blind phase III clinical studies

Purpose:  To evaluate the efficacy and safety profile of eslicarbazepine acetate (ESL) added to stable antiepileptic therapy in adults with partial‐onset seizures. Methods:  Data from 1,049 patients enrolled from 125 centers, in 23 countries, in three phase III double‐blind, randomized, placebo‐controlled studies were pooled and analyzed. Following a 2‐week titration period, ESL was administered at 400 mg, 800 mg, and 1,200 mg once‐daily doses for 12 weeks. Key Findings:  Seizure frequency was significantly reduced with ESL 800 mg (p < 0.0001) and 1,200 mg (p < 0.0001) compared to placebo. Median relative reduction in seizure frequency was, respectively, 35% and 39% (placebo 15%) and responder rate was 36% and 44% (placebo 22%). ESL was more efficacious than placebo regardless of gender, geographic region, epilepsy duration, age at time of diagnosis, seizure type, and number and type of concomitant antiepileptic drugs (AEDs). Incidence of adverse events (AEs) and AEs leading to discontinuation were dose dependent. AEs occurred mainly during the first weeks of treatment, with no difference between groups after 6 weeks. Most common AEs (>10% patients) were dizziness, somnolence, and headache. The incidence of AEs in ESL groups compared to placebo was generally consistent among different subpopulations. Significance:  Once‐daily ESL 800 mg and 1,200 mg showed consistent results across all efficacy and safety end points. Results were independent of study population characteristics and type and number of concomitant AEDs.     

Health-related quality of life in double-blind Phase III studies of brivaracetam as adjunctive therapy of focal seizures: A pooled,post-hoc analysis

PurposeThe effect of adjunctive brivaracetam on health-related quality of life (HRQoL) was assessed in a post-hoc analysis using pooled data from three randomized, double-blind, placebo-controlled Phase III studies in patients with refractory focal seizures (NCT00490035, NCT00464269, and NCT01261325).MethodsThe Patient-Weighted Quality of Life in Epilepsy Questionnaire (QOLIE-31-P) was completed at randomization, and weeks 4, 8 (in two of three studies), and 12 (end of the treatment period). Mean change from baseline to week 12 or early discontinuation, and percentage of patients with clinically meaningful improvement were reported for the placebo and brivaracetam 50, 100, and 200 mg/day groups.ResultsAt baseline, mean QOLIE-31-P scores were similar between treatment groups. At week 12 or early discontinuation, mean (standard deviation) changes from baseline in QOLIE-31-P total score were 2.8 (12.7), 3.0 (14.0), 2.4 (14.0), and 3.0 (12.1) points for the placebo and brivaracetam 50, 100, and 200 mg/day groups, respectively, indicating HRQoL improved slightly over time during the treatment period, but was similar for placebo and brivaracetam groups. All subscale score changes were positive, indicating stable or improved HRQoL over time. The brivaracetam 100 and 200 mg/day groups showed the largest differences compared with placebo in Seizure Worry subscale scores (7.3 and 8.8 vs. 5.0 points). Approximately 40% of patients had improvements in QOLIE-31-P scores beyond the Minimal Important Change (MIC) thresholds. The subgroup of ≥ 50% focal seizure frequency responders had higher improvements for all treatment arms and all subscales than for those in the overall pooled population.ConclusionIn this post-hoc analysis, adjunctive brivaracetam treatment was shown to be associated with stable or improving overall HRQoL over time, similar to placebo, with modest improvements in subscales sensitive to efficacy, and no deterioration in subscales sensitive to tolerability. These results reflect the known efficacy and tolerability profile of brivaracetam.     

Retigabine as adjunctive therapy in adults with partial-onset seizures: Integrated analysis of three pivotal controlled trials

We assessed the efficacy and tolerability of retigabine (RTG; international non-proprietary name)/ezogabine (EZG; US adopted name) as adjunctive therapy in adults with partial-onset seizures in an integrated analysis of three trials. Studies 205, 301 (NCT00232596), and 302 (NCT00235755) were randomized, double-blind, placebo-controlled studies in adults having ≥4 partial-onset seizures per 28 days and receiving 1-3 antiepileptic drugs with/without vagus nerve stimulator. Patients underwent titration to RTG/EZG 600, 900, or 1200mg/day or to placebo followed by 8 or 12 weeks maintenance. For efficacy analyses, placebo was compared with RTG/EZG 600 and 900mg/day in Studies 205 and 302, and RTG/EZG 1200mg/day in Studies 205 and 301. Responder rates (≥50% reduction in baseline seizure frequency) were 35% and 45% for RTG/EZG 600 and 900mg/day, respectively (placebo=21%; p<0.001), and 50% for RTG/EZG 1200mg/day (placebo=24%, p<0.001). Reductions in 28-day total partial-seizure frequency (medians: placebo=14%; 600mg/day=26%, p=0.003; 900mg/day=37%, p<0.001; placebo=15%; 1200mg/day=39%, p<0.001) were significantly greater with all RTG/EZG doses vs. placebo from baseline to the double-blind phase, and similarly during the maintenance phase. The most commonly reported (>10%) treatment-emergent adverse events were dizziness, somnolence, headache, and fatigue. RTG/EZG demonstrated efficacy and was generally tolerated as adjunctive therapy in adults with partial-onset seizures in this integrated analysis.     

Impact of comorbid anxiety disorders on health-related quality of life among patients with major depressive disorder

OBJECTIVE: This study examined the impact of comorbid anxiety disorders-posttraumatic stress disorder (PTSD), generalized anxiety disorder, and panic disorder-on health-related quality of life among primary care patients enrolled in a collaborative care depression intervention study for the Department of Veterans Affairs (VA). METHODS: Baseline data were used from 324 participants in the Telemedicine Enhanced Antidepressant Management (TEAM) Study, a multisite randomized effectiveness trial targeting VA primary care patients with depression. Health-related quality of life was measured by using the Quality of Well-Being Scale, self-administered version (QWB-SA) and the mental component summary (MCS-12V) and physical component summary (PCS-12V) of the 12-item Short Form Health Survey for Veterans (SF-12V). RESULTS: A majority of participants (69 percent) had at least one anxiety disorder. Generalized anxiety disorder and PTSD predicted scores on the QWB-SA. PTSD predicted scores on the PCS-12V, but none of the comorbid anxiety disorders predicted scores on the MCS-12V. In addition, social support, depression severity, and the number of chronic medical conditions significantly predicted QWB-SA scores; the number of self-reported chronic physical health conditions and the number of depression episodes significantly predicted PCS-12V scores; and social support and depression severity significantly predicted MCS-12V scores. CONCLUSIONS: According to scores on the QWB-SA, generalized anxiety disorder and PTSD comorbid with major depressive disorder impair health-related quality of life above and beyond major depressive disorder alone.     

Perampanel efficacy and safety by gender: Subanalysis of phase III randomized clinical studies in subjects with partial seizures

The antiepileptic drug (AED) perampanel is approved in ≥40 countries as adjunctive therapy for drug‐resistant partial seizures in patients with epilepsy. This post hoc analysis of pooled data from three phase III, double‐blind, randomized studies of perampanel examines between‐gender differences in perampanel efficacy and safety. Of the 1,478 subjects in the pooled analysis (719 male, 759 female), 1,109 were included in the pharmacokinetic/pharmacodynamic analysis. Perampanel oral clearance was 17% lower in female than in male patients not receiving enzyme‐inducing AEDs. Pooled efficacy analysis revealed that seizure frequency was reduced with perampanel treatment regardless of gender; a greater numerical reduction in seizure frequency and increased responder rates occurred in female participants at perampanel doses of 4, 8, and 12 mg. Tolerability was similar between groups, although common adverse events such as dizziness and headache occurred more frequently in female subjects. Modest elevations in perampanel exposure in female patients may result in meaningful between‐gender differences in efficacy and safety; therefore, dosing should be individualized and clinical response monitored.     

The effects of adjunctive topiramate therapy on seizure severity and health-related quality of life in patients with refractory epilepsy---a Canadian study.

Although reduction in seizure frequency is the most common endpoint used to assess the antiepileptic efficacy, seizure frequency alone does not provide a complete picture of effectiveness, particularly in patients with refractory epilepsy. The aim of our study was to assess the effects of topiramate on seizure severity and health-related quality of life (HRQL), in addition to standard efficacy measures, in an open, multicentre, 6-month trial of patients with epilepsy uncontrolled on antiepileptic drugs other than topiramate. Two hundred and nine patients were enrolled and received topiramate for up to 6 months (initiated at 50 mg/day and titrated to a recommended dose of 200-400 mg/day) in addition to existing medication. The median reduction in seizure frequency from baseline to the post-titration period was 40.9% ( P< 0.0001). Patients also demonstrated a mean reduction in the Liverpool Seizure Severity Scale (LSSS) of 5.3 ( P< 0.0001), which was considered clinically significant. Statistically significant changes in HRQL were not observed with the SF-36, a generic measure. Tolerability of antiepileptic medication was good, with a low incidence of cognitive adverse events. The results indicate that topiramate significantly reduces seizure severity---an important aspect of HRQL---when administered as adjunctive therapy to anticonvulsant therapy.     

Vagal nerve stimulation in patients with refractory epilepsy. Effect on seizure frequency, severity and quality of life.

Vagal nerve stimulation using an NCP (Cyberonics) device has been suggested as a potential treatment for patients with epilepsy that has previously proven refractory. Ten patients in Northern Ireland have had this device implanted and been fully audited pre- and post-operatively. Twelve months post-implantation, five patients have demonstrated a greater than 50% reduction in seizure frequency. A statistical reduction in seizure severity of the ictal phase of the major seizures has also been shown. Improvement in the patients' overall quality of life has, however, not been demonstrated in parallel to seizure reduction.     

Oxcarbazepine reduces seizure frequency in a high proportion of patients with both newly diagnosed and refractory partial seizures in clinical practice.

The antiepileptic efficacy and tolerability of oxcarbazepine, used both as monotherapy and adjunctive therapy, were observed for 1 year in 202 adult patients, aged 17-83 years, with newly diagnosed or refractory partial epilepsy in clinical practice in Italy. At first observation, the seizure free rate was 72.2% in newly diagnosed patients given monotherapy, 40% in patients in whom oxcarbazepine replaced another monotherapy and 10.3% in patients given oxcarbazepine as adjunctive therapy. At least 50% reduction in seizure frequency was achieved in 90.7, 72 and 57%, respectively. Efficacy increased with the duration of treatment (p < 0.0001). In the 160 completers the seizure free rate was 61.3% with monotherapy and 28% with adjunctive therapy. 16.3% of patients reported adverse effects, mainly sedation and sleepiness; 5% discontinued oxcarbazepine because of adverse events. OXC is an effective and well-tolerated antiepileptic agent for the long-term treatment of partial epilepsy in adults.     

Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials

Journal of Neurology - Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, hereditary neuromuscular disease characterized by muscle atrophy, weakness, contraction fasciculation, and bulbar...     

Neurocognitive effects of adjunctive levetiracetam in children with partial-onset seizures: A randomized, double-blind, placebo-controlled, noninferiority trial

Purpose : Evaluate potential neurocognitive effects of adjunctive levetiracetam in children with inadequately controlled partial‐onset seizures (POS). Methods : Randomized, double‐blind, placebo‐controlled, noninferiority safety study. Children (4–16 years; IQ ≥65) with ≥1 POS during 4 weeks before screening despite taking 1–2 antiepileptic drugs (AEDs) were randomized (2:1) to levetiracetam (20–60 mg/kg/day) or placebo for 12 weeks. Results : Ninety‐nine patients were randomized with 98 (levetiracetam 64, placebo 34) in intent‐to‐treat (ITT) and 73 (levetiracetam 46, placebo 27) in per protocol (PP) populations. Primary cognitive assessment was the Leiter International Performance Scale–Revised Attention and Memory Battery with the memory screen composite score change from baseline as the primary endpoint. PP Least Square Mean [LSM (standard error)] were 5.36 (1.78) for levetiracetam; 5.17 (2.33) for placebo; difference [two‐sided 90% confidence interval (CI)] 0.19 (?4.69, 5.08). Levetiracetam was noninferior to placebo because the 90% CI lower bound was greater than the defined noninferiority margin (?9.0). There were no statistically significant differences between groups in Wide Range Assessment of Memory and Learning‐2 indexes and Leiter‐R Examiner’s Rating Scale scores. Median reductions from baseline in weekly POS frequency were 91.5% versus 26.5% for levetiracetam versus placebo; ≥50% responder rates: 62.5% versus 41.2%; seizure freedom rates: 46.9% versus 8.8% (ITT). Adverse events were reported by 89.1% levetiracetam‐treated and 85.3% placebo‐treated patients; those reported by ≥10% levetiracetam patients and more often with levetiracetam were headache, nasopharyngitis, fatigue, vomiting, somnolence, and aggression. Discussion : Neurocognitive effects were no different in pediatric patients with POS treated with adjunctive levetiracetam or placebo. Levetiracetam was effective and well tolerated.     

Psychogenic nonepileptic seizures and health-related quality of life: the relationship with psychological distress and other physical symptoms

This study explores the relationship between the frequency of psychogenic nonepileptic seizures (PNES) and health-related quality of life (HRQoL), as well as the effect of psychological distress and other physical symptoms on this relationship. Data were collected on 96 patients with PNES. Correlations of seizure frequency with HRQoL, psychological distress, and physical symptoms were computed. Partial correlations of seizure frequency with HRQoL while controlling for psychological distress and physical symptoms were also computed. Seizure frequency was found to be significantly related to subjective HRQoL, although the relationship with HRQoL was rendered nonsignificant when the effects of psychological distress and the number of other physical symptoms were taken into account. The results of this study suggest that summary scores of HRQoL are not independently related to frequency of PNES and that there is a close association between PNES frequency, levels of psychological distress, and number of other physical symptoms experienced.