Primary Generalized Tonic-clonic Research Articles

Sudden unexpected death in epilepsy during cenobamate clinical development.

We assessed mortality, sudden unexpected death in epilepsy (SUDEP), and standardized mortality ratio (SMR) among adults treated with cenobamate during the cenobamate clinical development program. We retrospectively analyzed deaths among all adults with uncontrolled focal (focal to bilateral tonic-clonic [FBTC], focal impaired awareness, focal aware) or primary generalized tonic-clonic (PGTC) seizures who received ≥1 dose of adjunctive cenobamate in completed and ongoing phase 2 and 3 clinical studies. In patients with focal seizures from completed studies, median baseline seizure frequencies ranged from 2.8 to 11 seizures per 28 days and median epilepsy duration ranged from 20 to 24 years. Total person-years included all days a patient received cenobamate during completed studies or up to June 1, 2022 for ongoing studies. All deaths were evaluated by two epileptologists. All-cause mortality and SUDEP rates were expressed per 1000 person-years. A total of 2132 patients (n=2018 focal epilepsy; n=114 idiopathic generalized epilepsy) were exposed to cenobamate for 5693 person-years. Approximately 60% of patients with focal seizures and all patients in the PGTC study had tonic-clonic seizures. A total of 23 deaths occurred (all in patients with focal epilepsy), for an all-cause mortality rate of 4.0 per 1000 person-years. Five cases of definite or probable SUDEP were identified, for a rate of 0.88 per 1000 person-years. Of the 23 overall deaths, 22 patients (96%) had FBTC seizures, and all 5 of the SUDEP patients had a history of FBTC seizures. The duration of exposure to cenobamate for patients with SUDEP ranged from 130-620 days. The SMR among cenobamate-treated patients in completed studies (5515 person-years of follow-up) was 1.32 (95% CI 0.84-2.0), which was not significantly different from the general population. These data suggest that effective long-term medical treatment with cenobamate may reduce excess mortality associated with epilepsy.

Efficacy and safety of adjunctive perampanel in adolescent patients with epilepsy: Post hoc analysis of six randomized studies

ObjectiveThis post hoc analysis of six randomized, double-blind, Phase II and III studies evaluated efficacy and safety of adjunctive perampanel (2–12 mg/day) in adolescent patients (aged ≥12 to ≤17 years) with uncontrolled partial-onset seizures, with or without secondarily generalized (SG) seizures, or primary generalized tonic–clonic (PGTC) seizures. MethodsAdolescent patients from Studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), 335 (NCT01618695), 235 (NCT01161524), and 332 (NCT01393743) were included. Efficacy assessments (split by seizure type) included median percent change in seizure frequency per 28 days from baseline and seizure-freedom rates. Safety assessments (all seizure types combined) included monitoring of treatment-emergent adverse events (TEAEs). ResultsThe Safety Analysis Set included 372 adolescent patients (placebo, n = 114; perampanel, n = 258); the Full Analysis Set included 346 patients with partial-onset seizures (placebo, n = 103; perampanel, n = 243), of whom 125 experienced SG seizures during baseline (placebo, n = 37; perampanel, n = 88), and 22 with PGTC seizures (placebo, n = 9; perampanel, n = 13). Compared with placebo, perampanel 8 and 12 mg/day conferred greater median percent reductions in seizure frequency per 28 days for partial-onset seizures (18.0% vs 35.9% and 53.8% [both P < 0.01]) and SG seizures (24.4% vs 72.8% [P < 0.001] and 57.8% [P < 0.01]), and greater seizure-freedom rates (partial-onset: 7.8% vs 13.2% and 11.8% [not statistically significant]; SG: 8.1% vs 40.7% [P < 0.001] and 41.7% [P < 0.01]). For PGTC seizures, and compared with placebo, perampanel 8 mg/day was also associated with greater median percent reductions in seizure frequency per 28 days (29.8% vs 88.0%) and greater seizure-freedom rates (11.1% vs 23.1%). Treatment-emergent adverse events were reported in 76 (66.7%) placebo- and 192 (74.4%) perampanel-treated patients (most common: dizziness, somnolence, headache, and nasopharyngitis). Serious TEAEs occurred in 5 (4.4%) placebo- and 11 (4.3%) perampanel-treated patients. ConclusionsAdjunctive perampanel was efficacious and generally well tolerated in adolescent patients with partial-onset, SG, or PGTC seizures and represents a potentially beneficial treatment option for adolescents with uncontrolled epilepsy.

Pharmacokinetic and pharmacodynamic considerations for the clinical efficacy of perampanel in focal onset seizures

ABSTRACTIntroduction: Medical therapy is the mainstay of management of epilepsy. Despite the increasing number of available antiepileptic drugs (AEDs), approximately one-third of epileptic patients do not have adequate control of seizures. There is still a need for the development of new AEDs with enhanced effectiveness and tolerability.Areas covered: The present manuscript is based on an Internet and PubMed search (January 2005 to August 2018). It is focused on pharmacokinetic and clinical data of perampanel (PER) for the treatment of epilepsy.Expert opinion: PER has a novel mechanism of action, which opens up new options for a rational combination therapy. Phase III trials have demonstrated the efficacy and safety of PER as adjunctive therapy for the treatment of partial-onset seizures (POS) and primary generalized tonic–clonic seizures in patients aged ≥12 years. PER is also approved by FDA as monotherapy for the treatment of POS. A clinical trial is ongoing to verify the efficacy and safety of PER monotherapy in untreated patients with POS. In the future, head-to-head comparisons are needed to determine the exact position of PER relative to other AEDs. Moreover, further studies are needed to evaluate the efficacy and safety of PER in patients aged <12 years.Abbreviations: 4βOHC: 4β-hydroxycholesterol; AUC: area under the curve; CBZ: Carbamazepine; CLCr: creatinine clearance; Cmax: maximum plasma concentration; CYP: cytochrome P; EIAED: enzyme-inducing antiepileptic drug; EMA: European Medicines Agency; FDA: Food and Drug Administration; GI: gastrointestinal; OXC: oxcarbazepine; PER: perampanel; PGTC: primary generalized tonic-clonic; PHT: phenytoin; POS: partial-onset seizures; QD: once-daily; TEAE: treatment-emergent adverse event; Tmax: median time to reach peak concentration; UGT: uridine diphosphoglucose-glucuronosyltransferase; VPA: valproic acid

Cost-effectiveness of perampanel for the treatment of primary generalized tonic-clonic seizures (PGTCS) in epilepsy: A Spanish perspective

BackgroundPersistent seizures are associated with physical injury, reduced quality of life, and psychosocial impairment. Perampanel is approved for the adjunctive treatment of primary generalized tonic–clonic seizures (PGTCS). ObjectiveThis study aimed to determine the cost-effectiveness of perampanel as adjunctive therapy to other antiepileptic drugs (AED) compared with AED maintenance therapy alone for the treatment of PGTCS. MethodsWe developed a Markov model for PGTCS where transitions were based on treatment response rates. The analysis was conducted over a 33-year time horizon from the Spanish National Health Service (NHS) and societal perspectives. Efficacy data were derived from clinical studies. Resource use, market shares, costs, and utilities were obtained from Kantar Health's National Health and Wellness Survey. Drug costs were obtained from the Consejo General de Colegios Oficiales de Farmacéuticos. One-way and probabilistic sensitivity analyses were performed. ResultsIn the base case analysis from the NHS perspective, perampanel was associated with an incremental cost-effectiveness ratio (ICER) of €16,557/quality-adjusted life year (QALY) relative to AED maintenance therapy for the treatment of PGTCS. Incremental costs were €5475 and incremental QALYs were 0.33. In one-way sensitivity analyses, the ICERs were strongly influenced by discounting rate for costs and health effects, with little influence of other parameters, including perampanel cost and utilities. In probabilistic sensitivity analyses, the probability of perampanel being cost-effective at a willingness-to-pay threshold of €30,000/QALY was 89.3%. From the societal perspective, perampanel provided a cost-savings of €5288 per patient compared with AED maintenance therapy alone. ConclusionOur study demonstrates that perampanel is likely to be a cost-effective option.

Time to Pre-randomization Monthly Seizure Count for Perampanel in Patients with Primary Generalized Tonic-Clonic (PGTC) Seizures: A Potential New Clinical Endpoint (P1.270)

Time to Pre-randomization Monthly Seizure Count for Perampanel in Patients with Primary Generalized Tonic-Clonic (PGTC) Seizures: A Potential New Clinical Endpoint (P1.270)

Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings.

Epileptic seizures are refractory to treatment in approximately one-third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore remains a high priority. Perampanel is a first-in-class non-competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic-clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long-term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add-on perampanel resulted in median percent reduction in seizure frequency 23.3%-34.5% and ≥50% responder rate 28.5%-37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%-35.6%; ≥50% responder rate 40.9%-45.0%) and elderly people (reduction in seizure frequency 12.5%-16.9%; ≥50% responder rate 22.2%-42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%-38.0%) and global populations. Perampanel has been extensively studied in real-world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%-75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real-world observational studies suggest that perampanel tolerability can be improved by slow titration (2mg every 2-4weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.

Long-term safety and efficacy outcomes of adjunctive perampanel: an open-label extension (OLEx) of a Phase III study in patients with drug-resistant primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE) (P5.233)

Long-term safety and efficacy outcomes of adjunctive perampanel: an open-label extension (OLEx) of a Phase III study in patients with drug-resistant primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE) (P5.233)

Budget impact of perampanel as adjunctive treatment of uncontrolled partial-onset and primary generalized tonic-clonic seizures in the United States.

To evaluate the budget impact (BI) of adopting perampanel for adjunctive treatment of partial-onset seizures (POS), with or without secondarily generalized seizures, and the adjunctive treatment of primary generalized tonic-clonic seizures (PGTCS) in patients 12years or older in the United States. A BI model was developed to estimate the potential BI of adopting adjunctive perampanel from a US payer (direct costs only) and societal (direct and indirect costs) perspective over a 5-year period. Efficacy data for perampanel and antiepileptic drug (AED) maintenance therapy were obtained from perampanel phase III clinical trials. Drug, direct medical (healthcare provider, emergency room, and hospitalizations), and indirect (productivity loss) costs were obtained from appropriate sources (e.g., AnalySource® Online [wholesale acquisition costs], 2013 Optum Insight Clinformatics Database [market share percentages, direct medical costs per unit], and 2011-2013 National Health and Wellness Survey [NHWS; healthcare resource utilization, overall work impairment, and baseline distribution of patients across the 4 health states]). Mapping of seizure frequency to medical resource utilization and work impairment was obtained from Kantar Health's NHWS. In a hypothetical health plan of 1 million members, 660 (0.066%) members ≥12years old had uncontrolled POS (395 [59.8%]) or PGTCS (265 [40.2%]). During the first 5years of adoption of perampanel, absolute BI (including drug, direct medical, and indirect costs) was $852, $2124, $3855, $5318, and $6397, respectively, for a cumulative absolute BI of $18,545. Drug cost was estimated to increase by $13,888, $34,646, $62,863, $86,728, and $104,326, respectively; however, this cost would be mostly offset by decreases in direct medical ($5041, $12,576, $22,818, $31,481, and $37,869, respectively) and indirect ($7995, $19,946, $36,190, $49,929, and $60,060, respectively) costs. Total per-member-per-month cost (drug and direct medical costs) was estimated to increase by $0.0007, $0.0018, $0.0033, $0.0046, and $0.0055 from years 1 to 5. Based on results of this BI model, increased cost of adopting perampanel in a health plan of 1 million members would be minimal for payers, and societal costs would be close to neutral.

Perampanel in the treatment of patients with epilepsy

Development of new antiepileptic drugs (AED) does not stop due to the fact that the number of patients with pharmacoresistant epilepsy remains at about 30%. One of the newest AEDs is perampanel (PER), a selective, non-competitive AMPA receptor antagonist to target post-synaptic glutamate transmission. PER is approved in the Russian Federation as adjunctive treatment for focal seizures with or without secondarily generalized seizures and for primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE) in patients with epilepsy aged ≥12 years. The drug is effective and well-tolerated in the dose of 4-8 mg/day, and most side effects are dose-dependent. The high efficacy of PER combined with the good tolerability, absence of life-threatening adverse reactions and convenient intake allow us to recommend PER as the first choice additional drug in treatment of patients with epilepsy.

Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy A randomized trial.

Objective:To assess efficacy and safety of adjunctive perampanel in patients with drug-resistant, primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE).Methods:In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743; funded by Eisai Inc.), patients 12 years or older with PGTC seizures and IGE were randomized to placebo or perampanel during a 4-week titration period (perampanel uptitrated from 2 to 8 mg/d, or highest tolerated dose) and 13-week maintenance period. The primary endpoint was percent change in PGTC seizure frequency per 28 days (titration plus maintenance vs baseline). The key secondary endpoint (primary endpoint for European Union registration) was 50% PGTC seizure responder rate (patients achieving ≥50% reduction in PGTC seizure frequency; maintenance vs baseline). Treatment-emergent adverse events were monitored.Results:Of 164 randomized patients, 162 comprised the full analysis set (placebo, 81; perampanel, 81). Compared with placebo, perampanel conferred a greater median percent change in PGTC seizure frequency per 28 days (−38.4% vs −76.5%; p < 0.0001) and greater 50% PGTC seizure responder rate (39.5% vs 64.2%; p = 0.0019). During maintenance, 12.3% of placebo-treated patients and 30.9% of perampanel-treated patients achieved PGTC seizure freedom. For the safety analysis (placebo, 82; perampanel, 81), the most frequent treatment-emergent adverse events with perampanel were dizziness (32.1%) and fatigue (14.8%).Conclusions:Adjunctive perampanel was well tolerated and improved control of drug-resistant PGTC seizures in patients with IGE.Classification of evidence:This study provides Class I evidence that adjunctive perampanel reduces PGTC seizure frequency, compared with placebo, in patients with drug-resistant PGTC seizures in IGE.

Adjunctive Perampanel for the Treatment of Drug-Resistant Primary Generalized Tonic-Clonic (PGTC) Seizures in Patients with Idiopathic Generalized Epilepsy (IGE): A Double-Blind, Randomized, Placebo-Controlled Phase III Trial (S31.007)

Adjunctive Perampanel for the Treatment of Drug-Resistant Primary Generalized Tonic-Clonic (PGTC) Seizures in Patients with Idiopathic Generalized Epilepsy (IGE): A Double-Blind, Randomized, Placebo-Controlled Phase III Trial (S31.007)

Adjunctive lamotrigine XR for primary generalized tonic–clonic seizures in a randomized, placebo-controlled study

Efficacy and tolerability of once-daily adjunctive lamotrigine extended-release (XR) for primary generalized tonic–clonic (PGTC) seizures in epilepsy were evaluated. Patients ( n = 153) ≥ 13 years old diagnosed with epilepsy with PGTC seizures were randomized to once-daily adjunctive lamotrigine XR or placebo in a double-blind, parallel-group trial comprising a baseline phase, a 7-week double-blind escalation phase, and a 12-week double-blind maintenance phase. Lamotrigine XR was more effective than placebo with respect to median percentage reduction from baseline in weekly PGTC seizure frequency (primary endpoint—19-week treatment phase: 75.4% vs 32.1%, P < 0.0001; escalation phase: 61.9% vs 30.6%, P = 0.0016; maintenance phase: 89.7% vs 33.3%, P < 0.0001). Lamotrigine XR was more effective than placebo with respect to the percentage of patients with ≥ 50% reduction in PGTC seizure frequency. Significant separation from placebo for ≥ 50% reduction in PGTC seizures was observed beginning on treatment day 8. The most common adverse event was headache (lamotrigine XR 14%, placebo 16%).

Effect of lamotrigine on depressive symptoms in adult patients with epilepsy

In this investigation, the effects of lamotrigine versus placebo on depressive symptoms in patients with epilepsy were prospectively assessed. This investigation was a secondary analysis of a randomized, double-blind, placebo-controlled, parallel-group study in which adult patients received adjunctive lamotrigine ( n = 32) or placebo ( n = 38) for a 7-week dose escalation phase, followed by a 12-week maintenance phase, for primary generalized tonic–clonic (PGTC) seizures. Mood symptoms were assessed with the Beck Depression Inventory, second edition (BDI-II), the Profile of Mood States (POMS), and the Cornell Dysthymia Rating Scale—Self-Report (CDRS). Mean (SD) BDI-II scores at screening reflected mild depressive symptoms and were similar between groups (lamotrigine 18.3 (12.1), placebo 16.8 (12.0)). At the end of the maintenance phase, mean (SD) improvement from baseline was greater with lamotrigine than placebo with respect to BDI-II score (lamotrigine 8.9 (7.6), placebo 1.7 (8.5), P = 0.01) and POMS total score (lamotrigine 32.0 (30.4), placebo 6.5 (32.3), P = 0.03) and numerically greater with lamotrigine than placebo for CDRS score (lamotrigine 7.3 (7.8), placebo 4.1 (13.9), P = 0.50). Among the subset of patients with at least mild depression (BDI-II score ⩾ 10), mean improvement from baseline was numerically, but not statistically significantly, greater with lamotrigine (11.5, n = 13) than placebo (3.1, n = 18) ( P = 0.054). Median percentage reductions in seizure frequency were significantly greater with lamotrigine than placebo during the escalation phase, the maintenance phase, and the escalation and maintenance phases combined for PGTC seizures and all generalized seizures. However, improvement in seizure frequency was not correlated with improvement in mood ( r = 0.1, P = ns). Compared with placebo, lamotrigine improved mood symptoms independently of seizure reduction in patients with generalized seizures. Lamotrigine may be useful in treating patients with epilepsy and comorbid depressive symptoms.

Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures

To evaluate the efficacy and tolerability of adjunctive lamotrigine in primary generalized tonic-clonic (PGTC) seizures in a randomized, double-blind, placebo-controlled trial. Patients with a diagnosis of epilepsy with PGTC seizures who were receiving one or two antiepileptic drugs at study entry were eligible. Patients with partial seizures were excluded on the basis of seizure history and screening EEGs. The study comprised a baseline phase, an escalation phase during which study medication was titrated to a target dose, and a 12-week maintenance phase during which doses of lamotrigine/placebo and concomitant antiepileptic drugs were maintained. Of the 121 randomized patients ages 2 to 55 years, 117 (58 lamotrigine, 59 placebo) entered the escalation phase and received study medication. During the escalation and maintenance phases combined, median percent reduction in PGTC seizure frequency was 66.5% with lamotrigine compared with 34.2% with placebo (p = 0.006). The corresponding numbers for lamotrigine and placebo were 60.6% and 32.8% (p = 0.038) during the escalation phase and 81.9% and 43.0% (p = 0.006) during the maintenance phase. During the maintenance phase, 72% of lamotrigine-treated patients compared with 49% of placebo-treated patients experienced a > or = 50% reduction in frequency of PGTC seizures (p = 0.014). A similar pattern of results was observed for all generalized seizures. The most common drug-related adverse events were dizziness (5% lamotrigine, 2% placebo), somnolence (5% lamotrigine, 2% placebo), and nausea (5% lamotrigine, 3% placebo). Adjunctive lamotrigine is effective in the treatment of primary generalized tonic-clonic seizures and has a favorable tolerability profile.

Antiepileptic Drugs: All Ages

Antiepileptic Drugs: All Ages

Primary generalized epilepsy: a risk factor for seizures in labor and delivery?

Purpose: Women in the United States who have epilepsy give birth to about 20 000 newborns every year. Because seizures during late gestation and delivery may seriously affect the fetus, and because primary generalized tonic–clonic (GTC) seizures may occur during labor and delivery in 1–2% of women with epilepsy, we attempted to define the rate, risks, and causes of seizures during labor and delivery. Methods: To characterize seizures during labor and delivery, we retrospectively analyzed 89 consecutive pregnancies of women with epilepsy on antiepileptic drugs (AEDs). Six epileptologists in our group had treated these patients. We confirmed data and acquired new information by telephone for 83.1% of the pregnancies, and categorized the women as having primary generalized or partial epilepsy. Most of the patients (78%) were on monotherapy during pregnancy; 20% took two AEDs, and 3% took three AEDs during that period. Results: Seizures during labor and delivery occurred in 4/32 (12.5%) patients with primary generalized epilepsy, but in none of the 57 women with partial epilepsy ( P<0.05). None of the 38 patients with therapeutic AED levels before labor and delivery had seizures, compared to 3/37 (8.1%) of the subtherapeutic group. However, drug levels were taken at variable times in relation to delivery, limiting their value. Also, the levels sampled were both total and free levels; the latter would be more helpful to determine the adequacy of AED drug coverage. Conclusions: Maintaining therapeutic AED levels during the last trimester may help prevent seizures during labor and delivery, especially in women with generalized epilepsy. Women with epilepsy who had subtherapeutic AED levels and had been seizure-free may be at-risk for seizures during labor and delivery. Our sample was small, and a random sampling bias may have affected the results.

A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures

Topiramate is effective as adjunctive treatment of partial-onset seizures in adults. The efficacy and safety of topiramate as adjunctive therapy for the treatment of primary generalized tonic-clonic (PGTC) seizures were investigated in a randomized, double-blind, placebo-controlled study. Eighty patients, 3 to 59 years old, who experienced three or more PGTC seizures during an 8-week baseline phase were randomly assigned to treatment with either topiramate (n = 39) or placebo (n = 41). Topiramate was titrated to target doses of approximately 6 mg/kg/day over 8 weeks and maintained for another 12 weeks. The median percentage reduction from baseline in PGTC seizure rate was 56.7% for topiramate patients and 9.0% for placebo patients (p = 0.019). The proportion of patients with 50% or higher reduction in PGTC seizure rate was 22/39 (56%) and 8/40 (20%) for the topiramate and placebo groups, respectively (p = 0.001). The median percentage reduction in the rate of all generalized seizures was 42.1% for topiramate patients and 0.9% for placebo patients (p = 0.003). The proportions of patients with 50% or higher reductions in generalized seizure rate were 18/39 (46%) and 7/41 (17%) for the topiramate and placebo groups, respectively (p = 0.003). The most common adverse events were somnolence, fatigue, weight loss, difficulty with memory, and nervousness. Treatment-limiting adverse events occurred in one patient in the topiramate group (anorexia and weight loss) and one in the placebo group (granulocytopenia and thrombocytopenia). Topiramate is well-tolerated and effective for the adjunctive treatment of PGTC seizures.