Perampanel for the treatment of epilepsy with genetic aetiology: Real-world evidence from the PERMIT Extension study.

Genetic factors contribute to the aetiology of epilepsy in >50% of cases, and information on the use of antiseizure medications in people with specific aetiologies will help guide treatment decisions. The PERMIT Extension study pooled data from two real-world studies (PERMIT and PROVE) to investigate the effectiveness and safety/tolerability of perampanel (PER) when used to treat people with focal and generalised epilepsy in everyday clinical practice. This post-hoc analysis of PERMIT Extension explored the use of PER when used to treat individuals presumed to have epilepsy with a genetic aetiology. Assessments included retention rate (evaluated at 3, 6 and 12 months), effectiveness (responder and seizure freedom rates; evaluated at 3, 6, 12 months and the last visit [last observation carried forward) and tolerability (adverse events [AEs]). Of the 6822 people with epilepsy included in PERMIT Extension, 1012 were presumed to have a genetic aetiology. The most common genetic aetiologies were idiopathic generalised epilepsy (IGE; 58.2%), tuberous sclerosis (1.1%), Dravet syndrome (0.8%) and genetic epilepsy with febrile seizures plus (GEFS+; 0.5%). Retention rates at 3, 6 and 12 months in the total genetic aetiology population were 89.3%, 79.7% and 65.9%, respectively. In the total genetic aetiology population, responder rates at 12 months and the last visit were 74.8% and 68.3%, respectively, and corresponding seizure freedom rates were 48.9% and 46.5%, respectively. For the specific aetiology subgroups, responder rates at 12 months and the last visit were, respectively: 90.4% and 84.4% (IGE), 100% and 57.1% (tuberous sclerosis), 100% and 71.4% (Dravet syndrome), and 33.3% and 20.0% (GEFS+). Corresponding seizure freedom rates were, respectively: 73.1% and 64.6% (IGE), 33.3% and 22.2% (tuberous sclerosis), 20.0% and 28.6% (Dravet syndrome), and 0% and 0% (GEFS+). The incidence of AEs was 46.5% for the total genetic aetiology population, 48.8% for IGE, 27.3% for tuberous sclerosis, 62.5% for Dravet syndrome, and 20% for GEFS+. Tolerability findings were consistent with PER's known safety profile. PER was effective and generally well tolerated when used in individuals with a presumed genetic epilepsy aetiology in clinical practice. PER was effective across a wide range of genetic aetiologies.

Perampanel outcomes at different stages of treatment in people with focal and generalized epilepsy treated in clinical practice: Evidence from the PERMIT study.

Introduction: The PERMIT study is the largest pooled analysis of perampanel (PER) clinical practice data conducted to date. Methods: This post-hoc analysis of PERMIT investigated the effectiveness, safety and tolerability of PER when used as early add-on therapy (after failure of one or two previous antiseizure medications) in comparison with late add-on therapy (after failure of three or more previous antiseizure medications). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness was assessed by seizure type (total seizures, focal seizures, generalized tonic-clonic seizures [GTCS]) and assessments included seizure freedom rate and responder rate. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. Results: The Full Analysis Set included 1184 and 2861 PWE treated with PER as early and late add-on therapy, respectively. Compared to the late add-on subgroup, the early add-on subgroup was characterized by later mean age at epilepsy onset, shorter mean duration of epilepsy, lower rates of intellectual disability and psychiatric comorbidity, and lower frequency of seizures per month, suggesting a less severe form of epilepsy in this subgroup. After 12 months, retention was significantly higher in the early versus late add-on subgroup (67.7% vs. 62.4%; p = 0.004). At the last visit, responder rates in the early versus late add-on subgroup were significantly higher for total seizures (68.2% vs. 39.3%; p < 0.001), focal seizures (65.0% vs. 36.8%; p < 0.001) and GTCS (83.7% vs. 67.2%; p < 0.001), as were seizure freedom rates (total seizures, 35.9% vs. 11.9% [p < 0.001]; focal seizures, 29.4% vs. 8.7% [p < 0.001]; GTCS, 69.0% vs. 48.1% [p < 0.001]). Incidence of AEs was significantly lower in the early versus late add-on subgroup (42.1% vs. 54.7%; p < 0.001), as was the rate of discontinuation due to AEs over 12 months (15.0% vs. 18.1%; p = 0.031). Discussion: This study demonstrated that PER was effective and generally well tolerated when initiated as early or late add-on therapy, but it was significantly more effective and better tolerated when initiated early. These findings support PER's use as a broad-spectrum, early add-on therapy for use in PWE with focal and generalized seizures.

Perampanel for the treatment of people with idiopathic generalized epilepsy in clinical practice.

OBJECTIVE: This study was undertaken to evaluate perampanel (PER) when used under real-world conditions to treat people with idiopathic generalized epilepsy (IGE) included in the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study. METHODS: The multinational, retrospective, pooled analysis PERMIT explored the use of PER in people with focal and generalized epilepsy treated in clinical practice across 17 countries. This subgroup analysis included PERMIT participants with IGE. Time points for retention and effectiveness measurements were 3, 6, and 12 months (last observation carried forward, defined as "last visit," was also applied to effectiveness). Effectiveness was evaluated by seizure type (total seizures, generalized tonic-clonic seizures [GTCS], myoclonic seizures, absence seizures) and included ≥50% responder rate and seizure freedom rate (defined as no seizures since at least the previous visit). Safety/tolerability was monitored throughout PER treatment and evaluated by documenting the incidence of adverse events (AEs), including psychiatric AEs and those leading to treatment discontinuation. RESULTS: The Full Analysis Set included 544 people with IGE (51.9% women, mean age = 33.3 years, mean epilepsy duration = 18.1 years). At 3, 6, and 12 months, 92.4%, 85.5%, and 77.3% of participants were retained on PER treatment, respectively (Retention Population, n = 497). At the last visit, responder and seizure freedom rates were, respectively, 74.2% and 54.6% (total seizures), 81.2% and 61.5% (GTCS), 85.7% and 66.0% (myoclonic seizures), and 90.5% and 81.0% (absence seizures) (Effectiveness Population, n = 467). AEs occurred in 42.9% of patients and included irritability (9.6%), dizziness/vertigo (9.2%), and somnolence (6.3%) (Tolerability Population, n = 520). Treatment discontinuation due to AEs was 12.4% over 12 months. SIGNIFICANCE: This subgroup analysis of the PERMIT study demonstrated the effectiveness and good tolerability of PER in people with IGE when administered under everyday clinical practice conditions. These findings are in line with clinical trial evidence, supporting PER's use as broad-spectrum antiseizure medication for the treatment of IGE.

Perampanel for the treatment of patients with myoclonic seizures in clinical practice: Evidence from the PERMIT study.

PURPOSE: To investigate the effectiveness, safety and tolerability of perampanel (PER) in treating myoclonic seizures in clinical practice, using data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study. METHODS: PERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which patients with focal and generalised epilepsy were treated with PER. This post-hoc analysis included patients with myoclonic seizures at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months; effectiveness was additionally assessed at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥50% seizure frequency reduction from baseline) 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: 156 patients had myoclonic seizures (59.0% female; mean age, 32.1 years; idiopathic generalised epilepsy, 89.1%; Juvenile Myoclonic Epilepsy, 63.1%; monthly median myoclonic seizure frequency [interquartile range], 1.7 [1.0-10.0]; mean [standard deviation] prior antiseizure medications, 2.9 [2.6]). Retention was assessed for 133 patients (mean time, 12.1 months), effectiveness for 142, and safety/tolerability for 156. Responder and seizure freedom rates were, respectively, 89.5% and 68.8% at 12 months, and 85.9% and 63.4% at the last visit. Incidence of AEs was 46.8%, the most frequent being dizziness/vertigo (19.2%), irritability (18.6%) and somnolence (9.6%). AEs led to discontinuation of 14.0% of patients over 12 months. CONCLUSION: PER was associated with reduction in myoclonic seizure frequency in patients with myoclonic seizures treated in everyday clinical practice.

PERMIT study: a global pooled analysis study of the effectiveness and tolerability of perampanel in routine clinical practice.

The PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study was a pooled analysis of data from 44 real-world studies from 17 countries, in which people with epilepsy (PWE; focal and generalized) were treated with perampanel (PER). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness assessments included 50% responder rate (≥ 50% reduction in seizure frequency from baseline) and seizure freedom rate (no seizures since at least the prior visit); in PWE with status epilepticus, response was defined as seizures under control. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. The Full Analysis Set included 5193 PWE. Retention, effectiveness and safety/tolerability were assessed in 4721, 4392 and 4617, respectively. Retention on PER treatment at 3, 6, and 12 months was 90.5%, 79.8%, and 64.2%, respectively. Mean retention time on PER treatment was 10.8 months. The 50% responder rate was 58.3% at 12 months and 50.0% at the last visit, and the corresponding seizure freedom rates were 23.2% and 20.5%, respectively; 52.7% of PWE with status epilepticus responded to PER treatment. Overall, 49.9% of PWE reported AEs and the most frequently reported AEs (≥ 5% of PWE) were dizziness/vertigo (15.2%), somnolence (10.6%), irritability (8.4%), and behavioral disorders (5.4%). At 12 months, 17.6% of PWEs had discontinued due to AEs. PERMIT demonstrated that PER is effective and generally well tolerated when used to treat people with focal and/or generalized epilepsy in everyday clinical practice.

Predictors of seizure freedom, response and retention after 12 months of treatment with eslicarbazepine acetate: A post-hoc analysis of the Euro-Esli study.

Eslicarbazepine acetate (ESL) is a once-daily antiseizure medication (ASM) that is approved in Europe and the USA for the treatment of focal-onset seizures. The Euro-Esli study, which included over 2000 patients, investigated the real-world effectiveness, safety and tolerability of ESL when used in everyday clinical practice in Europe. This post-hoc analysis of Euro-Esli employed univariate and multivariate binary logistic regression analyses to investigate the relationship between demographic and baseline characteristics (including epilepsy- and treatment-related factors) and the likelihood of seizure freedom, response and retention in adult patients with focal seizures after 12 months of ESL treatment in the real-world setting. Multivariate analysis revealed that the factors associated with seizure freedom and response at 12 months (N = 1054) were generally those characterising patients who were relatively early in their disease course and/or less refractory to treatment, such as older age at onset of epilepsy, absence of seizures at baseline and lower number of concomitant ASMs at baseline. Although it was not possible to construct a multivariate model to predict retention on ESL treatment at 12 months, when the univariate regression model was adjusted for age and epilepsy duration, the factors found to be significantly associated with retention at 12 months (N = 1559) comprised shorter duration of epilepsy, absence of any seizures at baseline, lower baseline seizure frequency (<5 vs. ≥ 5 seizures/month), lower number of previous ASMs, lower number of concomitant ASMs, and the absence of concomitant use of lamotrigine at baseline. These findings therefore identify baseline characteristics that are predictive of the effectiveness of ESL treatment in clinical practice, which may help clinicians choose appropriate ASM therapy for patients.

Eslicarbazepine acetate in post-stroke epilepsy: Clinical practice evidence from Euro-Esli.

OBJECTIVES: To assess the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) in patients included in the Euro-Esli study who had focal seizures associated with post-stroke epilepsy (PSE). MATERIALS AND METHODS: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Effectiveness assessments (evaluated after 3, 6 and 12 months of ESL treatment and at final follow-up ["last visit"]) included rates of response (≥50% seizure frequency reduction), seizure freedom (no seizures since at least the prior visit) and retention. Safety/tolerability was assessed throughout ESL treatment by evaluating adverse events (AEs) and discontinuation due to AEs. A post hoc analysis was conducted of patients with PSE versus patients without PSE ("non-PSE"). RESULTS: Of 1656 patients included in the analysis, 76 (4.6%) had PSE and 1580 (95.4%) had non-PSE. Compared with non-PSE patients, PSE patients were significantly older, had significantly shorter epilepsy duration, significantly lower total baseline seizure frequency, and were treated with significantly fewer prior and concomitant antiepileptic drugs (P < .001 for all). At the last visit, the responder rate was significantly higher in PSE versus non-PSE patients (72.9% vs 60.6%; P = .040), as was the seizure freedom rate (48.6% vs 31.7%; P = .003). After 12 months, retention was significantly higher in PSE versus non-PSE patients (87.8% vs 77.4%; P = .035). The incidence of AEs was similar for PSE versus non-PSE patients (36.0% vs 35.8%; P = .966). CONCLUSIONS: These findings suggest that ESL may be an effective and well-tolerated treatment option for patients with focal seizures due to PSE.

Safety, tolerability and effectiveness of transition to eslicarbazepine acetate from carbamazepine or oxcarbazepine in clinical practice.

PURPOSE: To assess the efficacy, safety and tolerability of eslicarbazepine acetate (ESL) in patients transitioning from carbamazepine or oxcarbazepine to ESL in clinical practice, by analysing data from the Euro-Esli study. METHODS: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Effectiveness assessments included responder rate (≥50 % seizure frequency reduction) and seizure freedom rate (seizure freedom at least since prior visit), assessed after 3, 6 and 12 months of ESL treatment, and at the last visit. Safety and tolerability were assessed throughout follow-up by evaluating adverse events (AEs) and ESL discontinuation due to AEs, respectively. Data were analysed for cohorts of patients who transitioned from carbamazepine and oxcarbazepine to ESL either due to lack of efficacy or poor tolerability. RESULTS: Euro-Esli included 2058 patients, of whom 233 (11.3 %) transitioned from carbamazepine to ESL and 134 (6.5 %) transitioned from oxcarbazepine to ESL. After 12 months of ESL treatment, responder and seizure freedom rates for patients transitioning from carbamazepine due to lack of efficacy (n = 163) were 70.0 % and 30.9 %, respectively. Corresponding values for patients transitioning from oxcarbazepine due to lack of efficacy (n = 90) were 57.1 % and 25.0 %, respectively. Among patients who transitioned from carbamazepine and oxcarbazepine to ESL due to poor tolerability (n = 64 and n = 61, respectively), 26.6 % and 39.5 % experienced AEs, and 8.3 % and 6.8 % discontinued ESL due to AEs, respectively. CONCLUSION: ESL was efficacious and generally well tolerated in patients transitioning from carbamazepine or oxcarbazepine in clinical practice due to inadequate seizure control or intolerable AEs with these agents.

Novel seizure outcomes in patients with Lennox-Gastaut syndrome: Post hoc analysis of seizure-free days in rufinamide Study 303.

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 <4 years with inadequately controlled LGS. Patients were randomized 2:1 to receive add-on therapy with rufinamide or any other approved antiseizure drug (ASD), in addition to their existing treatment of 1-3 ASDs, across a 106-week treatment phase. Seizure diaries, completed by parents or caregivers, recorded seizure occurrence, and were used in this post hoc analysis to evaluate two novel efficacy parameters comparing baseline vs postbaseline mean number of seizure-free days and assessing time to reach the number of prerandomization seizures for patients receiving rufinamide or any other ASD. RESULTS: Patients received rufinamide (n = 25) or any other ASD (n = 12). For rufinamide, mean number of seizure-free days was 42.2% greater postbaseline compared with baseline (P < 0.0001); only one rufinamide patient experienced a decrease in number of seizure-free days postbaseline. Median time to reach the baseline number of seizures increased by 10.5 days for rufinamide and 0.5 days for the any-other-ASD group during the treatment phase, to 46.0 and 54.0 days, respectively. SIGNIFICANCE: Both of these novel and contrasting endpoints demonstrated potential improvements in seizure outcomes in patients receiving rufinamide postbaseline vs baseline. Although these parameters should be investigated in larger patient populations, our initial findings suggest that they could be applied as predefined primary endpoints for seizure assessment in future clinical trials for LGS drug development.

Effectiveness and Safety/Tolerability of Eslicarbazepine Acetate in Epilepsy Patients Aged ≥ 60 Versus < 60 Years: A Subanalysis from the Euro-Esli Study.

INTRODUCTION: Clinical practice studies help guide antiepileptic drug (AED) therapy in patient groups routinely excluded from clinical trials, such as the elderly. The Euro-Esli study investigated the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) when used in everyday clinical practice in Europe. A subanalysis of data from elderly patients (≥ 60 years) included in the Euro-Esli study was conducted to assess these aspects of ESL use in this population. METHODS: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Effectiveness parameters included responder (≥ 50% seizure frequency reduction) and seizure freedom rates after 3, 6 and 12 months of treatment and at last visit. Safety and tolerability were assessed throughout the follow-up by evaluating adverse events (AEs) and ESL discontinuation due to AEs, respectively. Data were compared for patients aged ≥ 60 versus those aged < 60 years at study entry. RESULTS: Euro-Esli included 2058 patients (mean age 44.0 years). Age at study entry was known for 2057 patients, of whom 358 (17.4%) and 1699 (82.6%) were aged ≥ 60 and < 60 years, respectively. Mean maximum ESL dose was   882.0 and 1008.2 mg/day in patients aged ≥ 60 and < 60 years, respectively  (p < 0.001). At all timepoints, responder and seizure freedom rates were significantly higher in patients aged ≥ 60 versus < 60 years; for example, at 12 months, responder rates were 83.9 and 73.7%, respectively (p = 0.002), and seizure freedom rates were 58.5 and 37.1%, respectively (p < 0.001). The incidence of AEs was significantly higher in patients aged ≥ 60 versus < 60 years (41.4 vs. 32.5%; p = 0.001), but the rate of discontinuation due to AEs was comparable between age groups (16.2 vs 13.1%; p = not significant). The safety/tolerability of ESL in patients aged ≥ 60 years was consistent with its known    profile. CONCLUSION: Eslicarbazepine acetate was efficacious and generally well tolerated when used to treat elderly patients with focal epilepsy in clinical practice, with no new or unexpected safety signals emerging in this setting. FUNDING: Eisai Ltd.

Eslicarbazepine acetate in epilepsy patients with psychiatric comorbidities and intellectual disability: Clinical practice findings from the Euro-Esli study.

Psychiatric and intellectual comorbidities are common in patients with epilepsy. However, data on the use of antiepileptic drugs in these patients are still lacking. This study assessed the real-world effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) in patients with intellectual disability and psychiatric comorbidities, including a separate analysis specifically in those with depression, using data from the Euro-Esli study. Effectiveness measures included responder and seizure freedom rates. Safety and tolerability were assessed by evaluating adverse events (AEs) and ESL discontinuation due to AEs, respectively. Of the 2058 patients initially included in the Euro-Esli study, 952 patients had intellectual disability data available, 1138 had psychiatric comorbidity data available and 1134 had depression data available. Of those who had intellectual or psychiatric comorbidity data available, 11.3% (108/952) suffered from intellectual disability, 24.9% (283/1138) had a psychiatric disorder, including depression, and 12.4% (141/1134) specifically had depression. Responder and seizure freedom rates were generally comparable between patients with psychiatric comorbidity and those without, and patients with depression and those without. However, responder and seizure freedom rates were significantly lower in patients with intellectual disability compared with those without. Overall, patients with psychiatric and intellectual comorbidities experienced more AEs and AEs leading to ESL discontinuation than patients without these comorbidities. The incidence of psychiatric AEs was not significantly different for patients with psychiatric comorbidities or depression than those without, and the incidence of cognitive AEs was not significantly different for patients with intellectual disability than those without. These findings suggest that ESL is effective in patients with psychiatric and intellectual comorbidities and that its use in these patients is unlikely to exacerbate existing psychiatric or cognitive disturbances.

Eslicarbazepine acetate as monotherapy in clinical practice: Outcomes from Euro-Esli.

OBJECTIVES: To assess the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) monotherapy in clinical practice in Europe. MATERIALS AND METHODS: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Responder rate (≥50% seizure frequency reduction) and seizure freedom rate (seizure freedom at least since prior visit) were assessed after 3, 6 and 12 months of ESL treatment and at last visit. Adverse events (AEs) and AEs leading to ESL discontinuation were assessed throughout follow-up. A subanalysis was conducted to assess outcomes for patients treated initially with ESL monotherapy and for patients treated at the last visit with ESL monotherapy. RESULTS: ESL was used as monotherapy in 88/2045 (4.3%) patients initially and in 229/1340 (17.1%) patients at the last visit. At 12 months, responder and seizure freedom rates were 94.1% and 88.2%, respectively, in patients treated initially with ESL monotherapy, and 93.2% and 77.4%, respectively, in patients treated at the last visit with ESL monotherapy. Corresponding values for patients treated initially with ESL adjunctive therapy were 74.8% and 39.0%, respectively; and for patients treated at the last visit with ESL adjunctive therapy, corresponding values were 70.4% and 25.9%, respectively. Safety and tolerability were generally comparable in patients treated with ESL as monotherapy or adjunctive therapy. The most commonly reported AEs (≥5% of patients in any group) were dizziness, somnolence, instability/ataxia, and fatigue. CONCLUSIONS: These clinical practice data support the use of ESL as monotherapy, as well as adjunctive therapy, for focal-onset seizures, complementing evidence from clinical trials.

Dibenzazepine Agents in Epilepsy: How Does Eslicarbazepine Acetate Differ?

Carbamazepine (CBZ), oxcarbazepine (OXC), and eslicarbazepine acetate (ESL) belong to the dibenzazepine family of antiepileptic drugs and are all thought to primarily act as sodium channel blockers (SCBs). However, ESL is structurally distinct from CBZ and OXC, resulting in differences in metabolism, pharmacokinetics, and pharmacodynamics. Despite a lack of direct comparative data, evidence for potential differences in effectiveness and tolerability within the dibenzazepine family has emerged from studies in which patients being treated with one dibenzazepine agent have received adjunctive treatment with another (having achieved insufficient seizure control with the first) or have transitioned from one dibenzazepine agent to another because of lack of effectiveness or poor tolerability. Most of these studies have been conducted in the real-world clinical practice setting. ESL has been shown to be effective as adjunctive therapy in patients who have previously achieved inadequate seizure control with CBZ, indicating that the use of different dibenzazepine agents in combination can provide additive effectiveness benefits, which may reflect underlying differences in their mechanisms of action. Similarly, ESL monotherapy can be effective in patients who have switched from another dibenzazepine, such as CBZ or OXC, because of inadequate efficacy. There is also considerable evidence to demonstrate that patients transitioning from OXC or CBZ to ESL as a result of adverse events experience improvements in tolerability, which may also be associated with improvements in quality of life, alertness, and/or lipid profiles. Current evidence therefore demonstrates that ESL differs from other dibenzazepine agents in terms of effectiveness and tolerability.Funding: Eisai Ltd.

Rufinamide for the treatment of Lennox-Gastaut syndrome: evidence from clinical trials and clinical practice.

Rufinamide was granted orphan drug status in 2004 for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients aged ≥4 years, and was subsequently approved for this indication in several countries, including Europe and the United States. Structurally unrelated to other antiepileptic drugs, rufinamide is thought to act primarily by prolonging the inactivation phase of voltage-gated sodium channels. Rufinamide was approved on the basis of an international, randomised, placebo-controlled Phase III trial, conducted in 138 patients with Lennox-Gastaut syndrome, which demonstrated its favourable tolerability profile and efficacy in significantly reducing the frequency of drop attacks and total seizures, compared with placebo. The effectiveness and safety/tolerability of rufinamide in treating seizures associated with Lennox-Gastaut syndrome have subsequently been confirmed in several other clinical trials and long-term extension studies. These findings are supported by 'real-world' data from a series of clinical practice studies conducted in Europe, the United States, and Korea. Rufinamide has been shown to be effective and generally well tolerated in children as young as one year and in adults. It is particularly effective as treatment for drop attacks and generalised tonic-clonic seizures, and it has been suggested that it might be preferred over other antiepileptic drugs as a second-line treatment for Lennox-Gastaut syndrome when drop attacks are frequent. The most common side effects of rufinamide treatment include somnolence, headache, dizziness, nausea, vomiting, and fatigue. No new or unexpected safety signals have emerged following long-term treatment with rufinamide, either in clinical trials or in clinical practice.

Real-world data on rufinamide treatment in patients with Lennox-Gastaut syndrome: Results from a European noninterventional registry study.

INTRODUCTION: Rufinamide is approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥4years. The objective of this study was to provide real-world, long-term data on patients with LGS initiating rufinamide as add-on therapy and patients with LGS receiving other antiepileptic drugs (AEDs). METHODS: A Phase IV, noninterventional, multicenter registry study was conducted in patients with LGS aged ≥4years requiring modification to any AED treatment, including initiation of add-on rufinamide therapy. Safety/tolerability was assessed by evaluating treatment-emergent adverse events (TEAEs), and efficacy was assessed using a generic seizure frequency scale. RESULTS: A total of 111 patients from 64 sites in 8 European countries were included, of whom 64 initiated rufinamide ("rufinamide" group) and 21 did not receive rufinamide at any time during the study ("no-rufinamide" group). Mean ages were 16.1years (rufinamide) and 15.0years (no rufinamide). The median duration of follow-up was >2years (range: 1.3-46.4months). Antiepileptic drug-related TEAEs were reported for 40.6% (rufinamide) and 33.3% (no rufinamide) of patients and led to discontinuation of 7.8% and 4.8%, respectively. The most frequently reported rufinamide-related TEAEs (≥5% patients) were somnolence (7.8%) and decreased appetite (6.3%). There were no unexpected safety/tolerability findings. At month 12, the proportion of patients with improvement in all seizures ("much improved" or "very much improved") was 28.6% (12/42) for the rufinamide group and 14.3% (2/14) for the no-rufinamide group. CONCLUSION: The study provided valuable information on LGS and its management, and evidence that rufinamide has a consistent and generally favorable safety/tolerability profile when used in routine clinical practice. CLINICALTRIALS. GOV IDENTIFIER: NCT01991041.

Euro-Esli: a European audit of real-world use of eslicarbazepine acetate as a treatment for partial-onset seizures.

The Euro-Esli study was an exploratory pooled analysis of data from 14 European clinical practice studies, which was conducted to audit the real-world effectiveness, safety, and tolerability of eslicarbazepine acetate (ESL) as an adjunctive treatment for partial-onset seizures. Retention and effectiveness were assessed after 3, 6, and 12 months of ESL treatment, and at the final visit. Safety and tolerability were assessed throughout ESL treatment by evaluating adverse events (AEs) and ESL discontinuation due to AEs. Data from 2058 patients (52.1% male; mean age 44.0 years) were included. All 2058 patients were assessed for safety and 1975 (96.0%) patients were assessed for effectiveness. After 12 months, retention, responder (≥50% seizure frequency reduction), and seizure freedom rates were 73.4, 75.6, and 41.3%, respectively. AEs were reported for 34.0% of patients and led to discontinuation in 13.6% of patients. The most frequently reported AEs were dizziness (6.7% of patients), fatigue (5.4%), and somnolence (5.1%). No unexpected safety signals emerged over a median duration of follow-up of >5 years. Subgroup analyses revealed that ESL was significantly more effective in patients aged ≥65 versus <65 years, in patients who were not receiving treatment with other sodium channel blockers versus those who were receiving treatment with other sodium channel blockers, and in patients who were receiving <2 versus ≥2 concomitant antiepileptic drugs at baseline. Euro-Esli is the largest ESL clinical practice study conducted to date. This study provides strong and reassuring evidence of ESL's safety profile, and complements the data from clinical trials.

Treatment of Adults with Lennox-Gastaut Syndrome: Further Analysis of Efficacy and Safety/Tolerability of Rufinamide.

INTRODUCTION: Management of Lennox-Gastaut syndrome (LGS) in adulthood can be particularly challenging. Published reports describing the use of rufinamide specifically in adult patients with LGS are scarce. A post hoc subgroup analysis of data from a phase III trial was conducted to investigate the efficacy and safety/tolerability of rufinamide in adults with LGS. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in patients with LGS, aged 4 years and above. During an 84-day, double-blind treatment period, patients received either adjunctive rufinamide therapy or placebo. Efficacy and safety/tolerability were assessed in a post hoc subgroup analysis of adult patients (≥18 years). Efficacy was assessed as change from baseline in 28-day seizure frequency, 50% responder rate, and seizure freedom rate; each calculated for total seizures and drop attacks. Safety/tolerability assessments included the evaluation of adverse events (AEs). RESULTS: Thirty-one adults aged 18-37 years with LGS received treatment with either rufinamide (n = 21) or placebo (n = 10). Three patients in the rufinamide group did not complete the trial. The median change from baseline in seizure frequency was -31.5% for rufinamide versus +22.1% for placebo (P = 0.008) for all seizures and -54.9% versus +21.7% (P = 0.002) for drop attacks. Responder rates were 33.3% for rufinamide versus 0% for placebo (P = 0.066) for all seizures and 57.1% versus 10.0% (P = 0.020) for drop attacks. No patient achieved freedom from all seizures but two rufinamide-treated patients (9.5%) became free of drop attacks. Overall, 71.4% of patients treated with rufinamide and 60.0% of patients treated with placebo experienced AEs; most commonly, somnolence (33.3% vs. 20.0%) and vomiting (19.0% vs. 0%). Most AEs were of mild or moderate intensity. CONCLUSION: Rufinamide demonstrated favorable efficacy and was generally well tolerated when used as adjunctive treatment for adults with LGS. FUNDING: Eisai.

Retention, dosing, tolerability and patient reported seizure outcome of Zonisamide as only add-on treatment under real-life conditions in adult patients with partial onset seizures: Results of the observational study ZOOM.

PURPOSE: Zonisamide is licensed for adjunctive therapy for partial-onset seizures with or without secondary generalisation in patients 6 years and older and as monotherapy for the treatment of partial seizures in adult patients with newly diagnosed epilepsy, and shows a favourable pharmacokinetic profile with low interaction potential with other drugs. The aim of the present study was to gather real-life data on retention and modalities of zonisamide use when administered as only add-on treatment to a current AED monotherapy in adult patients with partial-onset seizures. METHODS: This multicenter observational study was performed in 4 European countries and comprised three visits: baseline, and after 3 and 6 months. Data on patients' retention, reported efficacy, tolerability and safety, and quality of life was collected. Of 100 included patients, 93 could be evaluated. RESULTS: After 6 months, the retention rate of zonisamide add-on therapy was 82.8%. At this time, a reduction of seizure frequency of at least 50% was observed in 79.7% of patients, with 43.6% reporting seizure freedom over the last 3 months of the study period. Adverse events were reported by 19.4% of patients, with fatigue, agitation, dizziness, and headache being most frequent. Approximately 25% of patients were older than 60 years, many of whom suffered from late-onset epilepsy. Compared to younger patients, these patients showed considerable differences with regard to their antiepileptic drug regimen at baseline, and slightly higher responder and retention rates at 6 months. CONCLUSIONS: Despite limitations due to the non-interventional open-label design and the low sample size, the results show that zonisamide as only add-on therapy is well retained, indicating effectiveness in the majority of patients under real-life conditions.