| 1. |
- Kramer, L. D., et al.
(författare)
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Perampanel for adjunctive treatment of partial- onset seizures: A pooled dose- response analysis of phase III studies
- 2014
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Ingår i: Epilepsia. - : Wiley. - 0013-9580. ; 55:3, s. 423-431
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo better understand the relationship between efficacy and perampanel dose, integrated actual (last) dose data from three phase III trials and an extension study (blinded Conversion Period; open-label Maintenance Period) were analyzed. MethodsSeizure frequency data were analyzed in patients who were randomized to and completed the 13-week Maintenance Period of the phase III studies on perampanel 8mg, and who received an actual (last) dose of 12mg during (1) the extension 16-week blinded Conversion Period or (2) weeks 1-13 of the extension Maintenance Period. Due to a treatment-by-region interaction (p=0.042), analyses excluded patients from the Latin America region (n=162/1,480; 10.9% of the treated cohort). ResultsOf 372 patients randomized to 8mg in the phase III studies, 273 completed the Maintenance Period at 8mg and 267 entered the extension study. In patients who then had an actual (last) dose of 12mg during the extension blinded Conversion Period (n=217), median percent change in seizure frequency per 28days improved from -32.4% (8mg, phase III Maintenance Period) to -44.2% (12mg, extension blinded Conversion Period); 50% responder rates increased slightly from 37.3% to 42.9%. In patients who completed the phase III studies on 8mg and had an actual (last) dose of 12mg during weeks 1-13 of the extension Maintenance Period (n=181), median percent change in seizure frequency per 28days improved from -34.1% (phase III Maintenance Period) to -46.0% (weeks 1-13 extension Maintenance Period); 50% responder rates were 39.2% and 46.4%. Seizure control remained substantially unchanged in patients who completed the phase III studies at 12mg and continued on that dose during the extension. SignificanceIncreasing perampanel dose from 8 to 12mg can produce additional benefits in seizure control in at least some patients who tolerate the higher dose.
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| 2. |
- Krauss, G. L., et al.
(författare)
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Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: Results from phase III extension study 307
- 2014
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Ingår i: Epilepsia. - : Blackwell Publishing Inc.. - 0013-9580 .- 1528-1167. ; 55:7, s. 1058-1068
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Tidskriftsartikel (refereegranskat)abstract
- Objective 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. Methods 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. Results 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. Significance 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. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. © 2014 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.
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| 3. |
- Krauss, G. L., et al.
(författare)
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Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: Interim results from phase III, extension study 307
- 2013
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Ingår i: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 54:1, s. 126-134
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate safety, tolerability, and seizure outcome data during long-term treatment with once-daily adjunctive perampanel (up to 12 mg/day) in patients with refractory partial-onset seizures. Methods: Study 307 was an extension study for patients completing the double-blind phase of three pivotal phase III trials (studies 304, 305, and 306). The study consisted of two phases: an open-label treatment phase (including a 16-week blinded conversion period and a planned 256-week maintenance period) and a 4-week follow-up phase. Patients were blindly titrated during the conversion period to their individual maximum tolerated dose (maximum 12 mg/day). Adverse events (AEs) were monitored throughout the study and seizure frequency recorded. The interim data cutoff date for analyses was December 1, 2010. Key Findings: In total, 1,218 patients were enrolled in the study. At the interim cutoff date, 1,186 patients were in the safety analysis set; 1,089 (91.8%) patients had >16 weeks of exposure to perampanel, 580 (48.9%) patients had >1 year of exposure, and 19 (1.6%) patients had >2 years of exposure. At the interim analysis, 840 (70.8%) patients remained on perampanel treatment. The large majority of patients (n = 1,084 [91%]) were titrated to 10 mg or 12 mg/day. Median (range) duration of exposure was 51.4 (1.1-128.1) weeks. Treatment-emergent AEs were reported in 87.4% of patients. The most frequent were dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%). Serious AEs were reported in 13.2% of patients. In the intent-to-treat analysis set (n = 1,207), the frequency of all seizures decreased over the first 26 weeks of perampanel treatment in patients with at least 26 weeks of exposure to perampanel (n = 1,006 [83.3%]); this reduction was maintained in patients with at least 1 year of exposure (n = 588 [48.7%]). The overall median percent changes in seizure frequency in patients included in each 13-week interval of perampanel treatment were -39.2% for weeks 14-26 (n = 1,114), -46.5% for weeks 40-52 (n = 731), and -58.1% for weeks 92-104 (n = 59). Overall responder rates in patients included in each 13-week interval of perampanel treatment were 41.4% for weeks 14-26 (n = 1,114), 46.9% for weeks 40-52 (n = 731), and 62.7% for weeks 92-104 (n = 59). During the blinded conversion period, the reduction in seizure frequency in patients previously randomized to placebo (-42.4%, n = 369) was similar to that in patients previously randomized to perampanel (-41.5%, n = 817). Significance: Consistent with pivotal phase III trials, these interim results demonstrated that perampanel had a favorable tolerability profile in patients with refractory partial-onset seizures over the longer term. The decrease in seizure frequency was consistent and maintained in those patients over at least 1 year of perampanel exposure. © 2012 International League Against Epilepsy.
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| 4. |
- Steinhoff, B. J., et al.
(författare)
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Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: A pooled analysis of three phase III studies
- 2013
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Ingår i: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 54:8, s. 1481-1489
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Three phase III studies (304 [ClinicalTrials.gov identifier: NCT00699972], 305 [NCT00699582], 306 [NCT00700310]) evaluated perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as adjunctive therapy for refractory partial seizures. We report post hoc analyses of pooled study data by randomized dose. Methods Patients with partial seizures despite receiving 1-3 antiepileptic drugs were randomized to once-daily placebo, perampanel 8 or 12 mg (studies 304, 305), or placebo, perampanel 2, 4, or 8 mg (study 306). Studies included a 6-week baseline period and double-blind treatment phase (6-week titration; 13-week maintenance). Primary end points were median change in partial seizure frequency (baseline vs. double-blind phase) and percentage of patients achieving ≥50% reduction in seizure frequency (baseline vs. maintenance). Here, these end points, together with secondary, exploratory, and safety end points, were assessed using pooled study data. Key Findings The pooled intent-to-treat analysis set (randomized, treated patients with any seizure data) included 1,478 patients. Median changes in partial seizure frequency were greater with perampanel than placebo (perampanel 4 mg, -23.3%; 8 mg, -28.8%; 12 mg, -27.2%; placebo, -12.8%; p < 0.01, each dose vs. placebo), as were 50% responder rates (perampanel 4 mg, 28.5%; 8 mg, 35.3%; 12 mg, 35.0%; placebo, 19.3%; p < 0.05, each dose vs. placebo). In addition, median changes in complex partial plus secondary generalized seizure frequency were also greater with perampanel than placebo (perampanel 4 mg, -31.2%; 8 mg, -35.6%; 12 mg, -28.6%; placebo, -13.9%). Perampanel was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were dizziness, somnolence, and headache. Most TEAEs were mild/moderate; relatively few patients experienced severe TEAEs (placebo, 5.4%; perampanel, 8.9%) or serious TEAEs (placebo, 5.0%; perampanel, 5.5%). There were no deaths and no clinically important mean changes in laboratory values, electrocardiography (ECG) findings, or vital signs. Significance Perampanel reduced partial seizure frequency and improved responder rates compared with placebo, with an acceptable tolerability profile. © 2013 International League Against Epilepsy.
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