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Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304.

ABSTRACT: 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.

SUBMITTER: French JA

PROVIDER: S-EPMC3413761 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304.

French Jacqueline A JA Krauss Gregory L GL Biton Victor V Squillacote David D Yang Haichen H Laurenza Antonio A Kumar Dinesh D Rogawski Michael A MA

Neurology 20120725 6

<h4>Objective</h4>To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive α-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.<h4>Methods</h4>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: ...[more]

PMID: 22843280

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Project description:To evaluate safety, tolerability, seizure frequency, and regional variations in treatment responses with the AMPA antagonist, perampanel, in a large extension study during up to 3 years of treatment.Patients ? 12 years old with partial-onset seizures despite treatment with 1-3 antiepileptic drugs at baseline completed a perampanel phase III trial and entered extension study 307 (NCT00735397). Patients were titrated to 12 mg/day (or their individual maximum tolerated dose) during the blinded conversion period, followed by open-label maintenance. Exposure, safety (adverse events [AEs], vital signs, weight, electrocardiography [ECG], laboratory values) and seizure outcomes were analyzed; key measures were assessed by geographic regions.Among 1,216 patients, median exposure was 1.5 years (range 1 week to 3.3 years), with >300 patients treated for >2 years. Treatment retention was 58.5% at cutoff. AEs reported in ? 10% of patients were dizziness, somnolence, headache, fatigue, irritability, and weight increase. Only dizziness and irritability caused discontinuation in >1% of patients (3.9% and 1.3%, respectively). The only serious AEs reported in >1% of patients were epilepsy-related (convulsion, 3.0%; status epilepticus, 1.1%). No clinically relevant changes in vital signs, ECG or laboratory parameters were seen. After titration/conversion, responder rate and median percentage change from baseline in seizure frequency were stable: 46% for both measures at 9 months (in 980 patients with ? 9 months' exposure) and 58% and 60%, respectively, at 2 years (in the 337 patients with 2 years' exposure). Median percentage reduction in frequency of secondarily generalized (SG) seizures ranged from 77% at 9 months (N = 422) to 90% at 2 years (N = 141). Among the 694 patients with maintenance data ? 1 year, 5.3% were seizure-free for the entire year.No new safety signals emerged during up to 3 years of perampanel exposure in 39 countries. Seizure responses remained stable, with marked reductions, particularly in SG seizures.

Project description:Introduction: China has ~6 million patients with active epilepsy every year, around 60% of whom suffer from partial-onset seizures. Perampanel (PER) is a novel anti-epileptic drug for partial-onset seizures. PER has been included in the latest Chinese National Reimbursement Drug List (NRDL) in 2020. However, there is still a lack of evaluation evidence on the value of PER in China. Methods: This study selected a health system perspective. A Markov model was established to simulate the lifelong transition of different response levels and calculate the number of seizures in Chinese patients. Based on the utility value and mortality risk, the life years and quality-adjusted life years (QALYs) of patients using PER vs. lacosamide (LCM) were estimated. Efficacy data were derived from clinical trials and the literature. Cost data (in US dollars) included drug costs and medical service costs. A lifetime horizon was adopted. Health outcomes and costs were discounted at an annual discount rate of 5%. Deterministic sensitivity analysis, probability sensitivity analysis, and scenario analysis were performed. The impact of the inclusion of PER in the NRDL on the medical insurance budget over 3 years (2021-2023) was also estimated. Results: Cost-effectiveness analysis indicates that 8 mg/day of PER increases QALYs by 0.054 and saves costs by $2,390 compared with 400 mg/day of LCM. 4 mg/day of PER increases QALYs by 0.010 and saves costs by $860 compared with 200 mg/day of LCM. Deterministic sensitivity analysis reveals that utility value and the extreme discount rate are the factors with the greatest impact on the incremental cost-effectiveness ratio. Probabilistic sensitivity analysis and scenario analysis show that the results are robust. Budget impact analysis indicates that after inclusion of PER in the NRDL, the incremental budget would be $1.28, $2.83, and $4.56 million from 2021 to 2023, respectively, but covering more eligible epileptic patients in the same time (1,918, 4,287, and 8,983, respectively). Conclusion: PER (8 or 4 mg/day) is of relatively high value as an add-on therapeutic regimen for partial-onset seizures in China because of its dominate advantage of cost-effectiveness over LCM and acceptable budget impact.

Project description:Background. The relative efficacy and safety of lacosamide as adjunctive therapy compared to other antiepileptic drugs has not been well established. Objective. To determine if lacosamide provides improved efficacy and safety, reduced length of hospital stay and improved quality of life compared with other anti-epileptic therapies for adults with partial-onset seizures. Data Sources. A systematic review of the medical literature using Medline (1946-Week 4, 2012), EMBASE (1980-Week 3, 2012), Cochrane Central Register of Controlled Trials (Issue 1 of 12, January 2012). Additional studies were identified (through to February 7, 2012) by searching bibliographies, the FDA drug approval files, clinical trial registries and major national and international neurology meeting abstracts. No restrictions on publication status or language were applied. Study Selection. Randomized controlled trials of lacosamide in adults with partial-onset seizures were included. Data Extraction. Study selection, extraction and risk of bias assessment were performed independently by two authors. Authors of studies were contacted for missing data. Data Synthesis. All pooled analyses used the random effects model. Results. Three trials (1311 patients) met inclusion criteria. Lacosamide increased the 50% responder rate compared to placebo (RR 1.68 [95% CI 1.36 to 2.08]; I(2) = 0%). Discontinuation due to adverse events was statistically significantly higher in the lacosamide arm (RR3.13 [95% CI 1.94 to 5.06]; I(2) = 0%). Individual adverse events (ataxia, dizziness, fatigue, and nausea) were also significantly higher in the lacosamide group. Limitations. All dosage arms from the included studies were pooled to make a single pair-wise comparison to placebo. Selective reporting of outcomes was found in all of the included RCTs. Conclusions. Lacosamide as adjunctive therapy in patients with partial-onset seizures increases the 50% responder rate but with significantly more adverse events compared to the placebo.

Project description:ObjectiveTo evaluate the efficacy, tolerability, and safety of once-daily 1200 mg and 2400 mg SPN-804 (Oxtellar XR™, Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), added to 1-3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial-onset seizures, with or without secondary generalization.MethodsThe Prospective, Randomized Study of OXC XR in Subjects with Partial Epilepsy Refractory (PROSPER) study was a multinational, randomized, double-blind, parallel-group Phase 3 study. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week double-blind treatment period in the intent-to-treat (ITT) population with analyzable seizure data. Other efficacy analyses included proportion of patients with ≥ 50% seizure reduction, proportion of patients seizure free, and the relationship between clinical response and plasma concentration.ResultsMedian percent reduction was -28.7% for placebo, -38.2% (P = 0.08 vs placebo) for once-daily SPN-804 1200 mg, and -42.9% (P = 0.003) for SPN-804 2400 mg. Responder rates were 28.1%, 36.1% (P = 0.08), and 40.7% (P = 0.02); 16-week seizure-free rates in a pragmatic ITT analysis were 3.3%, 4.9% (P = 0.59), and 11.4% (P = 0.008), respectively. When data were analyzed separately for study site clusters, a post hoc analysis demonstrated that both SPN-804 dosages were significantly superior to placebo in median percent seizure reduction (placebo: -13.3%; 1200 mg: -34.5%, P = 0.02; 2400 mg: -52.7%, P = 0.006) in the North American study site cluster. A concentration-response analysis also supported a clinically meaningful effect for 1200 mg. Adverse event types reflected the drug's established profile. Adverse event frequency was consistent with a pharmacokinetic profile in which SPN-804 produces lower peak plasma concentrations vs immediate-release OXC. Once-daily dosing was not associated with any new safety signals.ConclusionsAdjunctive once-daily SPN-804 improved seizure control in patients with inadequately controlled partial-onset seizures. Adverse event occurrence and discontinuations due to adverse events suggest improved tolerability vs previously published data with immediate-release OXC.

Dataset Information

Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304.

Publications

Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304.

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