Dataset Information

First add-on perampanel for focal-onset seizures: An open-label, prospective study.

ABSTRACT:

Objectives

This study aimed to determine the efficacy and safety of perampanel added to monotherapy in patients with focal-onset seizures, with or without secondarily generalized tonic-clonic seizures.

Materials & methods

In this multicentre, open-label trial, enrolled patients were treated with perampanel monotherapy. During a 12-week titration period, perampanel was incrementally increased by 2 mg/d over ≥2-week intervals. Patients then entered a 24-week maintenance period. The primary objective was to investigate the 50% responder rate in total seizure frequency, with 75% and 100% responder rates as secondary objectives. Treatment-emergent adverse events (TEAEs) and adverse drug reactions were recorded. A post hoc analysis was performed to investigate the effect of titration speed and different concomitant AEDs on the efficacy and safety of perampanel.

Results

Of the 85 patients analysed, seizure reductions of 50%, 75% and 100% were observed in 80.0% (95% confidence interval [CI]: 69.9-87.9), 71.8% (95% CI: 61.0-81.0) and 47.1% (95% CI: 36.1-58.2) during the maintenance period, respectively. The 50%, 75% and 100% response rates in patients with secondarily generalized tonic-clonic seizures were 87.5% (95% CI: 61.7-98.5), 87.5% (95% CI: 61.7-98.5) and 75.0% (95% CI: 47.6-92.7), respectively. The most common TEAEs were dizziness (50.0%), somnolence (9.8%) and headache (8.8%). The efficacy outcomes and safety profile of perampanel were more favourable with slow titration and relatively consistent when stratified by concomitant AEDs.

Conclusions

Perampanel was effective and well tolerated as a first add-on to monotherapy in patients with focal-onset seizures, with or without secondarily generalized seizures.

SUBMITTER: Kim JH

PROVIDER: S-EPMC6973118 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ObjectiveOur study assessed perampanel monotherapy in patients (aged ≥12 years) with focal-onset seizures (FOS) with or without focal to bilateral tonic-clonic seizures (FBTCS) in Japan and South Korea.MethodsStudy 342 (NCT03201900; FREEDOM) is a single-arm, open-label, Phase III study. Patients initially received perampanel in a 32-week 4-mg/d Treatment Phase (6-week Titration; 26-week Maintenance Periods). If they experienced a seizure during the 4-mg/d Maintenance Period, they could be up-titrated to 8 mg/d across an additional 30-week Treatment Phase (4-week Titration; 26-week Maintenance Periods). Primary endpoint was the seizure-freedom rate during the Maintenance Period (4 mg/d and last evaluated dose [4 or 8 mg/d]). Secondary endpoints included time to first seizure onset and to withdrawal during Maintenance. Treatment-emergent adverse events (TEAEs) were monitored.ResultsAt data cutoff (February 28, 2019), 89 patients with FOS (84 [94.4%] with newly diagnosed epilepsy and 5 [5.6%] with recurrence of epilepsy after a period of remission) had received ≥1 perampanel dose; 16 patients discontinued during the 4-mg/d Titration Period, meaning 73 patients entered the 4-mg/d Maintenance Period and were included in the primary analysis set for efficacy. Seizure-freedom rate in the 26-week Maintenance Period was 46/73 (63.0%; 95% confidence interval [CI]: 50.9-74.0) at 4 mg/d and 54/73 (74.0%; 95% CI: 62.4-83.5) at 4 or 8 mg/d. Cumulative probability of seizure-onset and withdrawal rates during Maintenance was 30.8% (95% CI: 21.5-43.0) and 23.7% (95% CI: 15.4-35.3) at 4 mg/d, and 18.2% (95% CI: 11.0-29.3) and 23.3% (95% CI: 15.2-34.8) at 4 or 8 mg/d. Perampanel was generally well tolerated, and the most common TEAE was dizziness.SignificancePerampanel monotherapy (4 to 8 mg/d) was efficacious and consistent with the known safety profile up to 26 weeks in patients (≥12 years) with primarily newly diagnosed FOS with or without FBTCS.

Project description:OBJECTIVE:Study 311 (NCT02849626) was a global, multicenter, open-label, single-arm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics of once-daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with focal seizures (FS) (with/without focal to bilateral tonic-clonic seizures [FBTCS]) or generalized tonic-clonic seizures (GTCS). METHODS:In the 311 Core Study, a 4-week Pre-treatment Period (Screening/Baseline) preceded a 23-week Treatment Period (11-week Titration; 12-week Maintenance) and 4-week Follow-up. Endpoints included safety/tolerability (primary endpoint), median percent change in seizure frequency per 28 days from Baseline (Treatment Period), and 50% responder and seizure-freedom rates (Maintenance Period). Patients were stratified by age (4 to <7; 7 to <12 years) and concomitant enzyme-inducing anti-seizure drug (EIASD) use. RESULTS:One hundred eighty patients were enrolled (FS, n = 149; FBTCS, n = 54; GTCS, n = 31). The Core Study was completed by 146 patients (81%); the most common primary reason for discontinuation was adverse event (AE) (n = 14 [8%]). Mean (standard deviation) daily perampanel dose was 7.0 (2.6) mg/day and median (interquartile range) duration of exposure was 22.9 (2.0) weeks. The overall incidence of treatment-emergent AEs (TEAEs; 89%) was similar between patients with FS (with/without FBTCS) and GTCS. The most common TEAEs were somnolence (26%) and nasopharyngitis (19%). There were no clinically important changes observed for cognitive function, laboratory, or electrocardiogram (ECG) parameters or vital signs. Median percent reductions in seizure frequency per 28 days from Baseline were as follows: 40% (FS), 59% (FBTCS), and 69% (GTCS). Corresponding 50% responder and seizure-freedom rates were as follows: FS, 47% and 12%; FBTCS, 65% and 19%; and GTCS, 64% and 55%, respectively. Improvements in response/seizure frequency from Baseline were seen regardless of age or concomitant EIASD use. SIGNIFICANCE:Results from the 311 Core Study suggest that daily oral doses of adjunctive perampanel are generally safe, well tolerated, and efficacious in children age 4 to <12 years with FS (with/without FBTCS) or GTCS.

Project description: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.This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (?12 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.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 -21.0%, -26.3%, and -34.5% for placebo and perampanel 8 and 12 mg, respectively (p = 0.0261 and p = 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 = 0.0760) or 12 mg (p = 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.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.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.

Project description:AimsThis post hoc analysis assessed the efficacy and safety/tolerability of adjunctive perampanel in patients from China (aged ?12 years) with focal seizures (FS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS).MethodsStudy centers in China were identified using data from five double-blind, randomized, phase III studies of adjunctive perampanel (2-12 mg/day) and their open-label extensions (OLEx). Efficacy assessments included median percent reduction in seizure frequency per 28 days, and 50% and 75% responder and seizure-freedom rates. Safety/tolerability assessments included monitoring of treatment-emergent adverse events (TEAEs).ResultsOverall, 277 patients (placebo, n = 79; perampanel, n = 198) were included in the double-blind safety analysis set. The full analysis set comprised 274 patients (FS, n = 238 [placebo, n = 60; perampanel, n = 178]; FBTCS, n = 120 [placebo, n = 31; perampanel, n = 89]; GTCS, n = 36 [placebo, n = 18; perampanel, n = 18]). Median percent reductions in seizure frequency for placebo vs perampanel were as follows: 16.6% vs 32.4% (FS; P < 0.05) and 39.1% vs 48.2% (FBTCS; not significant [NS]) at 4-12 mg/day, and 37.9% vs 82.6% (GTCS; NS) at 8 mg/day; 50% responder rates were 31.7% vs 37.4% (FS; NS), 48.4% vs 51.9% (FBTCS; NS), and 33.3% vs 61.1% (GTCS; NS), respectively. Seizure-freedom rates were 1.7% vs 9.2%, 16.1% vs 25.3%, and 16.7% vs 44.4%, respectively (all NS). Overall, 262 patients entered the OLEx (FS, n = 228; GTCS, n = 34). Perampanel was efficacious for up to four years for FS and FBTCS and up to two years for GTCS. Across the double-blind and OLEx studies, TEAEs were reported in 65.7% and 81.3% of perampanel-treated patients, respectively; the most common was dizziness. Efficacy and safety/tolerability outcomes were generally similar between Chinese and non-Chinese patients.ConclusionAdjunctive perampanel (up to 12 mg/day) may be a suitable treatment for Chinese patients with FS, with/without FBTCS, or GTCS, with similar efficacy and safety/tolerability compared to non-Chinese patients.

Project description:ObjectiveThis post hoc analysis assessed the efficacy and safety of adjunctive perampanel in patients (aged ? 12 years) with focal seizures (FS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS) in India.MethodsCenters in India were identified from six double-blind, randomized, Phase II and Phase III studies of adjunctive perampanel (2-12 mg/day) and their open-label extensions (OLEx). Efficacy assessments included median percent change in seizure frequency per 28 days, 50% and 75% responder and seizure-freedom rates. Treatment-emergent adverse events (TEAEs) were monitored.ResultsOverall, 128 patients (placebo, n = 39; perampanel, n = 89) were included in the double-blind Safety Analysis Set and 126 (FS, n = 113 [placebo, n = 32; perampanel, n = 81]; FBTCS, n = 35 [placebo, n = 14; perampanel, n = 21]; GTCS, n = 13 [placebo, n = 6; perampanel, n = 7]) comprised the Full Analysis Set. Median percent reductions in seizure frequency per 28 days for placebo vs perampanel for Indian patients were as follows: 34.8% vs 49.8% (FS; not significant [NS]) and 43.1% vs 60.5% (FBTCS; NS) at 4-12 mg/day, respectively, and -22.4% vs 8.2% (GTCS; NS) at 8 mg/day, respectively. Fifty-percent responder rates were 37.5% vs 55.1% (FS; NS), 42.9% vs 60.0% (FBTCS; NS), and 16.7% vs 42.9% (GTCS; NS), respectively; seizure-freedom rates were 0.0% vs 5.8%, 7.1% vs 10.0%, and 0.0% vs 14.3%, respectively (all NS). Overall, 110 patients entered OLEx studies (FS, n = 99; GTCS, n = 11). Perampanel was efficacious for up to four years for FS and FBTCS and two years for GTCS. Across double-blind and OLEx studies, TEAEs occurred in 58.4% and 83.6% of Indian perampanel-treated patients, respectively; dizziness was most common. Efficacy and safety outcomes were generally similar overall between Indian and non-Indian patients.SignificanceThese data suggest adjunctive perampanel (up to 12 mg/day) may be a suitable anti-seizure medication for patients (aged ? 12 years) with FS, with/without FBTCS, or GTCS in India.

Project description:ObjectiveTo report long-term post hoc efficacy and safety data from 10 US study sites from an open-label Phase 3 study of adjunctive cenobamate (NCT02535091).MethodsPatients with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications (ASMs) were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50-mg/day increments biweekly were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019.ResultsOf 255 patients, 240 with focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizure data while on treatment were evaluated (median [maximum] exposure = 30.2 [43.0] months across the entire study). Median baseline seizure frequency/28 days was 2.8 (mean = 18.1). Of the 240 patients, 177 (73.8%) were continuing cenobamate treatment at data cutoff. The ≥50% responder rate for the total treatment duration was 71.7% (172/240). During titration, the ≥50% responder rates were 48.1% during Weeks 1-4 (12.5-25 mg/day cenobamate) and 61.7% during Weeks 5-8 (50-100 mg/day cenobamate). Among all patients who received a dose of cenobamate in the maintenance phase (n = 214), 13.1% (28/214) and 40.2% (86/214) achieved 100% and ≥90% seizure reduction during their entire maintenance treatment duration (median = 29.5 months). Among all patients, 87 (36.3%) had any consecutive ≥12-month duration of 100% seizure reduction. Common treatment-emergent adverse events among all 240 patients included fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%).SignificanceThis post hoc analysis of a subset of patients from the long-term open-label study showed high rates of sustained 100% and ≥90% seizure reduction, with many achieving response early during titration. These findings suggest durable seizure frequency reduction with cenobamate in adults with uncontrolled focal seizures.

Project description:OBJECTIVE:During the development of cenobamate, an antiseizure medication (ASM) for focal seizures, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. To mitigate the rate of DRESS, a start-low, go-slow approach was studied in an ongoing, open-label, multicenter study. Also examined were long-term safety of cenobamate and a method for managing the pharmacokinetic interaction between cenobamate, a 2C19 inhibitor, and concomitant phenytoin or phenobarbital. METHODS:Patients 18-70 years old with uncontrolled focal seizures taking stable doses of one to three ASMs were enrolled. Cenobamate 12.5 mg/d was initiated and increased at 2-week intervals to 25, 50, 100, 150, and 200 mg/d. Additional biweekly 50 mg/d increases to 400 mg/d were allowed. During titration, patients taking phenytoin or phenobarbital could not have their cenobamate titration rate or other concomitant ASMs adjusted; phenytoin/phenobarbital doses could be decreased by 25%-33%. RESULTS:At data cutoff (median treatment duration = 9 months), 1347 patients were enrolled, of whom 269 (20.0%) discontinued, most commonly due to adverse events (n = 137) and consent withdrawn for reason other than adverse event (n = 74); 1339 patients received ?1 treatment dose (median modal dose = 200 mg). The most common treatment-emergent adverse events (TEAEs) were somnolence (28.1%), dizziness (23.6%), and fatigue (16.6%). Serious TEAEs occurred in 108 patients (8.1%), most commonly seizure (n = 14), epilepsy (n = 5), and pneumonia, fall, and dizziness (n = 4 each). No cases of DRESS were identified. In the phenytoin/phenobarbital groups, 43.4% (36/114) and 29.7% (11/51) of patients, respectively, had their doses decreased. At the end of titration, mean plasma phenytoin/phenobarbital levels were generally comparable to baseline. SIGNIFICANCE:No cases of DRESS were identified in 1339 patients exposed to cenobamate using a start-low (12.5 mg/d), go-slow titration approach. Cenobamate was generally well tolerated in the long term, with no new safety issues found. Phenytoin/phenobarbital dose reductions (25%-33%), when needed during cenobamate titration, maintained stable plasma levels.