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October 13, 2010

Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy

November 16, 2010 issue
75 (20) 1817-1824

Abstract

Objective:

This study assessed the efficacy and safety of the neuronal potassium channel opener ezogabine (US adopted name; EZG)/retigabine (international nonproprietary name; RTG) as adjunctive therapy for refractory partial-onset seizures.

Methods:

This was a multicenter, randomized, double-blind, placebo-controlled trial in adults with ≥4 partial-onset seizures per month receiving 1 to 3 antiepileptic drugs. EZG (RTG) or placebo, 3 times daily, was titrated to 600 or 900 mg/d over 4 weeks, and continued during a 12-week maintenance phase. Median percentage seizure reductions from baseline and responder rates (≥50% reduction in baseline seizure frequency) were assessed.

Results:

The intention-to-treat population comprised 538 patients (placebo, n = 179; 600 mg, n = 181; 900 mg, n = 178), 471 of whom (placebo, n = 164; 600 mg, n = 158; 900 mg, n = 149) entered the maintenance phase. Median percentage seizure reductions were greater in EZG (RTG)–treated patients (600 mg, 27.9%, p = 0.007; 900 mg, 39.9%, p < 0.001) compared with placebo (15.9%). Responder rates were higher in EZG (RTG)–treated patients (600 mg, 38.6%, p < 0.001; 900 mg, 47.0%, p < 0.001) than with placebo (18.9%). Treatment discontinuations due to adverse events (AEs) were more likely with EZG (RTG) than with placebo (placebo, 8%; 600 mg, 17%, 900 mg, 26%). The most commonly reported (>10%) AEs in the placebo, EZG (RTG) 600 mg/d, and EZG (RTG) 900 mg/d groups were dizziness (7%, 17%, 26%), somnolence (10%, 14%, 26%), headache (15%, 11%, 17%), and fatigue (3%, 15%, 17%).

Conclusions:

In this dose-ranging, placebo-controlled trial, adjunctive EZG (RTG) was effective and generally well tolerated in adults with refractory partial-onset seizures.

Classification of evidence:

This study provides Class II evidence that adjunctive EZG/RTG reduces the occurrence of partial-onset seizures.

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Supplementary Material

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Information & Authors

Information

Published In

Neurology®
Volume 75Number 20November 16, 2010
Pages: 1817-1824
PubMed: 20944074

Publication History

Received: April 3, 2010
Accepted: July 28, 2010
Published online: October 13, 2010
Published in print: November 16, 2010

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Disclosure

Prof. Brodie serves on scientific advisory boards for Pfizer Inc, UCB, Eisai Inc., Johnson & Johnson, GlaxoSmithKline, Valeant Pharmaceuticals International, Sierra Neuropharmaceuticals, Inc., and Medtronic, Inc.; has received funding for travel from UCB; serves as a consultant for Eisai Inc.; serves on speakers' bureaus for UCB, GlaxoSmithKline, and Eisai Inc.; and has received research support from Pfizer Inc, UCB, and Eisai Inc. Prof. Lerche serves on scientific advisory boards for Pfizer Inc, UCB, Valeant Pharmaceuticals International, GlaxoSmithKline, and Eisai Inc.; has received funding for travel from GlaxoSmithKline and UCB; has received speaker honoraria from Pfizer Inc, Desitin Pharmaceuticals, GmbH, Eisai Inc., UCB, GlaxoSmithKline, and Valeant Pharmaceuticals International; and has received research support from sanofi-aventis, UCB, DFG, BMBF, and the European Union. Dr. Gil-Nagel serves on scientific advisory boards for UCB, Eisai Inc., GlaxoSmithKline, and BIAL; serves on speakers' bureaus for and has received speaker honoraria from BIAL, Eisai Inc., GlaxoSmithKline, Janssen, Sepracor Inc., and UCB; serves on the editorial boards of Seizure and Revista de Neurología; serves as a consultant to BIAL, Eisai Inc., GlaxoSmithKline, Medtronic, Inc., UCB, and Valeant Pharmaceuticals International; and has received research support from UCB. Dr. Elger serves on scientific advisory boards for UCB and Desitin Pharmaceuticals, GmbH; has received speaker honoraria from Pfizer Inc, Eisai Inc., Desitin Pharmaceuticals, GmbH, and UCB; serves as an Associate Editor for Epilepsy and Behaviour; and receives research support from the DFG. Dr. Hall is an employee of and holds stock and stock options in Valeant Pharmaceuticals International. Mr. Shin was an employee of Valeant Pharmaceuticals International at the time of the study. Dr. Nohria served as a consultant to Valeant Pharmaceuticals International during the course of the study and the preparation of this manuscript; has served on scientific advisory boards or as a consultant for UCB, Archimedes Pharma, Shire plc, Marinus Pharmaceuticals, Inc., Upsher-Smith Laboratories, Inc., and Antisense Pharma; is a nonexecutive director of Allergy Therapeutics plc and an officer of Alaven Pharmaceutical LLC; and holds stock/stock options in Allergy Therapeutics PLC. Dr. Mansbach was employed by Valeant Pharmaceuticals International at the time of the study and holds stock in the company; and served as a paid contractor for and received funding for travel from GlaxoSmithKline during the development of the first draft of this manuscript.

Authors

Affiliations & Disclosures

M.J. Brodie, MD
From the Epilepsy Unit (M.J.B.), Western Infirmary, Glasgow, Scotland, UK; Department of Neurology (H.L.), University Hospital Ulm, Germany; Epilepsy Program (A.G.-N.), Department of Neurology, Hospital Ruber International, Madrid, Spain; Department of Epileptology (C.E.), University of Bonn, Germany; Neurology R&D and Regulatory Compliance (S.H.), Valeant Pharmaceuticals North America, Durham, NC; Prometheus Therapeutics & Diagnostics (P.S.), San Diego, CA; Mercer University (V.N.), Atlanta, GA; and Medivation Inc. (H.M.), San Francisco, CA. Dr. Lerche is currently with the Department of Neurology and Epileptology (H.L.), Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Germany.
H. Lerche, MD
From the Epilepsy Unit (M.J.B.), Western Infirmary, Glasgow, Scotland, UK; Department of Neurology (H.L.), University Hospital Ulm, Germany; Epilepsy Program (A.G.-N.), Department of Neurology, Hospital Ruber International, Madrid, Spain; Department of Epileptology (C.E.), University of Bonn, Germany; Neurology R&D and Regulatory Compliance (S.H.), Valeant Pharmaceuticals North America, Durham, NC; Prometheus Therapeutics & Diagnostics (P.S.), San Diego, CA; Mercer University (V.N.), Atlanta, GA; and Medivation Inc. (H.M.), San Francisco, CA. Dr. Lerche is currently with the Department of Neurology and Epileptology (H.L.), Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Germany.
A. Gil-Nagel, MD
From the Epilepsy Unit (M.J.B.), Western Infirmary, Glasgow, Scotland, UK; Department of Neurology (H.L.), University Hospital Ulm, Germany; Epilepsy Program (A.G.-N.), Department of Neurology, Hospital Ruber International, Madrid, Spain; Department of Epileptology (C.E.), University of Bonn, Germany; Neurology R&D and Regulatory Compliance (S.H.), Valeant Pharmaceuticals North America, Durham, NC; Prometheus Therapeutics & Diagnostics (P.S.), San Diego, CA; Mercer University (V.N.), Atlanta, GA; and Medivation Inc. (H.M.), San Francisco, CA. Dr. Lerche is currently with the Department of Neurology and Epileptology (H.L.), Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Germany.
C. Elger, MD
From the Epilepsy Unit (M.J.B.), Western Infirmary, Glasgow, Scotland, UK; Department of Neurology (H.L.), University Hospital Ulm, Germany; Epilepsy Program (A.G.-N.), Department of Neurology, Hospital Ruber International, Madrid, Spain; Department of Epileptology (C.E.), University of Bonn, Germany; Neurology R&D and Regulatory Compliance (S.H.), Valeant Pharmaceuticals North America, Durham, NC; Prometheus Therapeutics & Diagnostics (P.S.), San Diego, CA; Mercer University (V.N.), Atlanta, GA; and Medivation Inc. (H.M.), San Francisco, CA. Dr. Lerche is currently with the Department of Neurology and Epileptology (H.L.), Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Germany.
S. Hall, PhD
From the Epilepsy Unit (M.J.B.), Western Infirmary, Glasgow, Scotland, UK; Department of Neurology (H.L.), University Hospital Ulm, Germany; Epilepsy Program (A.G.-N.), Department of Neurology, Hospital Ruber International, Madrid, Spain; Department of Epileptology (C.E.), University of Bonn, Germany; Neurology R&D and Regulatory Compliance (S.H.), Valeant Pharmaceuticals North America, Durham, NC; Prometheus Therapeutics & Diagnostics (P.S.), San Diego, CA; Mercer University (V.N.), Atlanta, GA; and Medivation Inc. (H.M.), San Francisco, CA. Dr. Lerche is currently with the Department of Neurology and Epileptology (H.L.), Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Germany.
P. Shin, MS
From the Epilepsy Unit (M.J.B.), Western Infirmary, Glasgow, Scotland, UK; Department of Neurology (H.L.), University Hospital Ulm, Germany; Epilepsy Program (A.G.-N.), Department of Neurology, Hospital Ruber International, Madrid, Spain; Department of Epileptology (C.E.), University of Bonn, Germany; Neurology R&D and Regulatory Compliance (S.H.), Valeant Pharmaceuticals North America, Durham, NC; Prometheus Therapeutics & Diagnostics (P.S.), San Diego, CA; Mercer University (V.N.), Atlanta, GA; and Medivation Inc. (H.M.), San Francisco, CA. Dr. Lerche is currently with the Department of Neurology and Epileptology (H.L.), Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Germany.
V. Nohria, MD
From the Epilepsy Unit (M.J.B.), Western Infirmary, Glasgow, Scotland, UK; Department of Neurology (H.L.), University Hospital Ulm, Germany; Epilepsy Program (A.G.-N.), Department of Neurology, Hospital Ruber International, Madrid, Spain; Department of Epileptology (C.E.), University of Bonn, Germany; Neurology R&D and Regulatory Compliance (S.H.), Valeant Pharmaceuticals North America, Durham, NC; Prometheus Therapeutics & Diagnostics (P.S.), San Diego, CA; Mercer University (V.N.), Atlanta, GA; and Medivation Inc. (H.M.), San Francisco, CA. Dr. Lerche is currently with the Department of Neurology and Epileptology (H.L.), Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Germany.
H. Mansbach, MD
From the Epilepsy Unit (M.J.B.), Western Infirmary, Glasgow, Scotland, UK; Department of Neurology (H.L.), University Hospital Ulm, Germany; Epilepsy Program (A.G.-N.), Department of Neurology, Hospital Ruber International, Madrid, Spain; Department of Epileptology (C.E.), University of Bonn, Germany; Neurology R&D and Regulatory Compliance (S.H.), Valeant Pharmaceuticals North America, Durham, NC; Prometheus Therapeutics & Diagnostics (P.S.), San Diego, CA; Mercer University (V.N.), Atlanta, GA; and Medivation Inc. (H.M.), San Francisco, CA. Dr. Lerche is currently with the Department of Neurology and Epileptology (H.L.), Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Germany.
On behalf of the RESTORE 2 Study Group
From the Epilepsy Unit (M.J.B.), Western Infirmary, Glasgow, Scotland, UK; Department of Neurology (H.L.), University Hospital Ulm, Germany; Epilepsy Program (A.G.-N.), Department of Neurology, Hospital Ruber International, Madrid, Spain; Department of Epileptology (C.E.), University of Bonn, Germany; Neurology R&D and Regulatory Compliance (S.H.), Valeant Pharmaceuticals North America, Durham, NC; Prometheus Therapeutics & Diagnostics (P.S.), San Diego, CA; Mercer University (V.N.), Atlanta, GA; and Medivation Inc. (H.M.), San Francisco, CA. Dr. Lerche is currently with the Department of Neurology and Epileptology (H.L.), Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Germany.

Notes

Address correspondence and reprint requests to Dr. Martin J. Brodie, Epilepsy Unit, Western Infirmary, Glasgow G11 6NT, Scotland, UK [email protected]
Study funding: Supported by Valeant Pharmaceuticals International (funded design and conduct of the study; collection, management, analysis, and interpretation of the data) and GlaxoSmithKline (funded preparation of the manuscript).

Author Contributions

M.J. Brodie was a study investigator, contributed to data analysis and interpretation, and oversaw the development of the manuscript. He takes responsibility for the data, the accuracy of the data analysis, and the conduct of the research. H. Lerche, A. Gil-Nagel, and C. Elger were study investigators and contributed to interpretation of the data and revision of the manuscript. S. Hall contributed to the data analyses and interpretations and to the revision of the manuscript. P. Shin contributed to the conception, design, oversight, and conduct of the study; to the data analysis and interpretation; and to the revision of the manuscript. V. Nohria contributed to the conception, design, and conduct of the study; to data analysis and interpretation; and to the first and subsequent drafts of the manuscript. H. Mansbach contributed to the conduct of the study, to data analysis and interpretation, and to the first and subsequent drafts of the manuscript.

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