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

Gregory L. Krauss, Emilio Perucca, Elinor Ben-Menachem, Patrick Kwan, Jerry J. Shih, David Squillacote, Haichen Yang, Michelle Gee, Jin Zhu, Antonio Laurenza

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)126-134
Number of pages9
JournalEpilepsia
Volume54
Issue number1
DOIs
StatePublished - Jan 2013

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Seizures
Acids
Therapeutics
perampanel
Safety
Maximum Tolerated Dose
Dizziness
Fatigue
Headache

Keywords

  • α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • Long-term
  • Open-label
  • Partial epilepsy
  • Perampanel
  • Safety

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

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. / Krauss, Gregory L.; Perucca, Emilio; Ben-Menachem, Elinor; Kwan, Patrick; Shih, Jerry J.; Squillacote, David; Yang, Haichen; Gee, Michelle; Zhu, Jin; Laurenza, Antonio.

In: Epilepsia, Vol. 54, No. 1, 01.2013, p. 126-134.

Research output: Contribution to journalArticle

Krauss, Gregory L. ; Perucca, Emilio ; Ben-Menachem, Elinor ; Kwan, Patrick ; Shih, Jerry J. ; Squillacote, David ; Yang, Haichen ; Gee, Michelle ; Zhu, Jin ; Laurenza, Antonio. / 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. In: Epilepsia. 2013 ; Vol. 54, No. 1. pp. 126-134.
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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.",
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T1 - Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures

T2 - Interim results from phase III, extension study 307

AU - Krauss, Gregory L.

AU - Perucca, Emilio

AU - Ben-Menachem, Elinor

AU - Kwan, Patrick

AU - Shih, Jerry J.

AU - Squillacote, David

AU - Yang, Haichen

AU - Gee, Michelle

AU - Zhu, Jin

AU - Laurenza, Antonio

PY - 2013/1

Y1 - 2013/1

N2 - 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.

AB - 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.

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