Evaluating the Efficacy and Safety of E2007 (Perampanel) Given as Adjunctive Therapy in Subjects With Refractory Partial Seizures

A Double-Blind, Placebo-Controlled, Dose-Escalation, Parallel-Group Study to Evaluate the Efficacy and Safety of E2007 (Perampanel) Given as Adjunctive Therapy in Subjects With Refractory Partial Seizures

The purpose of this study is to evaluate the safety, efficacy and tolerability of perampanel when given as an adjunctive therapy in subjects with refractory partial seizures.

Study Overview

• Status: Completed
• Conditions: Refractory Partial Seizures
• Intervention / Treatment: Drug: E2007 (perampanel); Drug: E2007 (perampanel); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 390
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Capital Federal- Provincia de Buenos Aires, Argentina
    • FLENI (Fundación para la Lucha Contra Las Enfermedades Neurológicas de La Infancia)
  • Capital Federal- Provincia de Buenos Aires, Argentina
    • Hospital Británico
  • Capital Federal- Provincia de Buenos Aires, Argentina
    • Hospital de Niños Ricardo Gutiérrez
  • Capital Federal- Provincia de Buenos Aires, Argentina
    • Hospital General de Agudos Jose Maria Ramos Mejía
  • Capital Federal- Provincia de Buenos Aires, Argentina
    • Hospital General de Agudos Teodoro Álvarez
  • Capital Federal- Provincia de Buenos Aires, Argentina
    • Hospital Italiano de Buenos Aires
  • Capital Federal- Provincia de Buenos Aires, Argentina
    • Policlínica Bancaria 9 de Julio
  • Córdoba, Argentina
    • Centro de Estudio y Tratamiento de la Epilepsia y Sueño- CETES S.A.
  • Rosario, Argentina
    • Sanatorio Parque
  • Córdoba- Provincia De Córdoba
    • Córdoba, Córdoba- Provincia De Córdoba, Argentina
      • Hospital San Roque
  • Provincia De Córdoba
    • Córdoba, Provincia De Córdoba, Argentina
      • Sanatorio Allende
  • Provincia De Salta
    • Salta, Provincia De Salta, Argentina
      • Hospital Santa Clara de Asis
• Brazil
  • Campinas, Brazil
    • Faculdade de Ciências Médicas - UNICAMP
  • Curitiba, Brazil
    • Hospital de Clinicas da UFPR
  • Porto Alegre, Brazil
    • Santa Casa de Porto Alegre
  • Ribeirão Preto, Brazil
    • HC Ribeirão Preto
  • Rio De Janeiro, Brazil
    • Hospital Pedro Ernesto - UERJ
  • Salvador, Brazil
    • Hospital Universitario Professor Edgar Santos
  • São José do Rio Preto, Brazil
    • Faculdade de Medicinade São José do Rio preto
  • São Paulo, Brazil
    • Hospital Santa Marcelina
  • São Paulo, Brazil
    • UNIFESP
  • São Paulo, Brazil
    • HC-FMUSP
  • São Paulo, Brazil
    • Hospital Brigadeiro
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Foothills Medical Center
  • Ontario
    • London, Ontario, Canada
      • London Health Sciences Center
    • Toronto, Ontario, Canada, M5B 1T9
      • Youthdale Treatment Centers
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2J2
      • Neuro Rive-Sud
    • Montreal, Quebec, Canada
      • CHU Sainte-Justine
• Chile
  • Santiago, Chile
    • Hospital Dr. Sótero del Río
  • Santiago, Chile
    • Hospital Barros Luco Trudeau
  • Santiago, Chile
    • Hospital Base Valdivia Servicio de Neurología
  • Santiago, Chile
    • Neuropsicología Ltda.
• Mexico
  • Aguascalientes, Mexico, 20127
    • Instituto Biomedico de Investigacion AC
  • Aguascalientes, Mexico, 20127
    • Sarug Reyes
  • Mexico City, Mexico, 14050
    • Medica Sur SIF-BIOTEC
  • San Luis Potosi, Mexico, 78240
    • Hospital Central "Dr. Ignacio Morones Prieto"
  • Nuevo Leon CP
    • Monterrey, Nuevo Leon CP, Mexico, 64000
      • MIRC
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
    • Birmingham, Alabama, United States
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital and Medical Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Clinical Trials, Inc.
  • California
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
    • San Francisco, California, United States, 94109
      • Bright Minds Institute
  • Colorado
    • Denver, Colorado, United States, 80218
      • Mile High Research Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's Research Institute
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health Sciences, Jacksonville
    • Loxahatchee Groves, Florida, United States, 33470
      • Pediatric Neurology and Epilepsy Center
    • Loxahatchee Groves, Florida, United States
    • Orlando, Florida, United States, 32819
      • Pediatric Neurology PA
    • Pensacola, Florida, United States, 32504
      • North West Florida Clinical Research Group
    • Pensacola, Florida, United States, 32561
      • Child Neurology Center of NW Florida
    • Sarasota, Florida, United States, 34233
      • Lovelace Scientific Resources
    • Sarasota, Florida, United States, 34233
      • Ronald Aung-Din, MD, PC
    • Tallahassee, Florida, United States, 32308
      • Tallahassee Neurological Clinic
    • Tampa, Florida, United States, 33609
      • Pediatric Epilepsy and Neurology Specialists
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Children's Healthcare of Atlanta at Scottish Rite
    • Atlanta, Georgia, United States, 30328
      • PANDA
    • Suwanee, Georgia, United States, 30024
      • Georgia Neurology and Sleep Medicine Associates
  • Indiana
    • Indianapolis, Indiana, United States, 46256
      • Josephson Wallack Munshower Neurology
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic, PC
  • Kansas
    • Wichita, Kansas, United States
    • Wichita, Kansas, United States, 67214
      • Via Christi Comprehensive Epilepsy Center
  • Kentucky
    • Lexington, Kentucky, United States, 40508
      • University of Kentucky Research Foundation
    • Louisville, Kentucky, United States, 40202
      • Kentucky Neuroscience Research
  • Louisiana
    • Houma, Louisiana, United States, 70363
      • Leonard J. Chabert Medical Center
    • Shreveport, Louisiana, United States, 71103
      • Louisiana State University Health Sciences Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Neurology/Johns Hopkins Hospital
    • Bethesda, Maryland, United States, 20817
      • Mid-Atlantic Epilepsy and Sleep Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University Medical Center
  • Michigan
    • Clinton Township, Michigan, United States, 48035
      • Michigan Neurology Associates, P.C.
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • Albany, New York, United States
      • Albany Medical College
    • Cedarhurst, New York, United States, 11516
      • Five Towns Neurology, PC
    • New Hyde Park, New York, United States, 11040
      • Long Island Jewish Medical Center
    • Rochester, New York, United States, 14642
      • Univeristy of Rochester Strong Epilepsy Center
  • North Carolina
    • Asheville, North Carolina, United States, 28806
      • Asheville Neurology Specialists, PA
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center Of Akron D/B/A Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45219
      • University Neurology, Inc.
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Medical Center
    • Toledo, Ohio, United States
      • University of Toledo Medical Center
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74137
      • Neurological Associates of Tulsa, Inc.
  • Oregon
    • Portland, Oregon, United States
      • Providence St. Vincent's Epilepsy Center
  • Pennsylvania
    • Altoona, Pennsylvania, United States, 16602
      • Blair Medical Assiciates, Inc.
    • Philadelphia, Pennsylvania, United States
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States
      • Children's Hospital of Philadelphia
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • UT Le Bonheur Pediatric Specialists
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75230
      • Dallas Pediatric Neurology Associates
    • Dallas, Texas, United States, 75230
      • Neurological Clinic of Texas, P.A.
    • El Paso, Texas, United States, 79905
      • Texas Tech University Health Sciences Center
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Medical Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Regional Epilepsy Center
    • Milwaukee, Wisconsin, United States, 53215
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 99 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

Each subject must meet all of the following criteria to be enrolled in this study:

1. Provide written informed consent signed by the subject or legal guardian prior to entering the study or undergoing any study procedures (If the written informed consent is provided by the legal guardian because the subject is unable to do so, a written or verbal assent from the subject must also be obtained).
2. Be considered reliable and willing to be available for the study period and able to record seizures and report Adverse Events (AEs) them self or have a caregiver who can record seizures and report AEs for them.
3. Male or female and greater than or equal to 12 years of age (within the course of the study).
4. Females should be either of non-childbearing potential (defined as having undergone surgical sterilization, or postmenopausal [age 50 and amenorrheic for 12 months]) or of childbearing potential. Females of childbearing potential must have a negative serum Beta Human Chorionic Gonadotropin (ß-hCG) at Visit 1 and a negative urine pregnancy test prior to randomization at Visit 2. Female subjects of childbearing potential must agree to be abstinent or to use at least 1 medically acceptable method of contraception (eg, a double-barrier method [eg, condom + spermicide, condom + diaphragm with spermicide], IUD, or have a vasectomised partner) starting at Visit 1 and throughout the entire study period and for 2 months after the last dose of study drug. Those women using hormonal contraceptives must also be using an additional approved method of contraception (as described previously) starting at Visit 1 and continuing throughout the entire study period and for 2 months after the last dose of study drug. (It is not required for male subjects to use contraceptive measures based on preclinical toxicology data).
5. Have a diagnosis of epilepsy with partial seizures with or without secondarily generalized seizures according to the International League Against Epilepsy's Classification of Epileptic Seizures (1981). Diagnosis should have been established by clinical history and an electroencephalogram (EEG) that is consistent with localization-related epilepsy; normal interictal EEGs will be allowed provided that the subject meets the other diagnosis criterion (ie, clinical history).
6. Have had a computed tomography (CT) or magnetic resonance imaging (MRI) within the last 10 years that ruled out a progressive cause of epilepsy.
7. Have uncontrolled partial seizures despite having been treated with at least 2 different anti-epileptic drugs (AEDs) within approximately the last 2 years.
8. During the 6-week Pre-randomization Phase subjects must have had ≥5 partial seizures per 6-week (with ≥2 partial seizures per each of 3-week period) and with no 25-day seizure-free period in the 6-week period, as documented via a valid seizure diary. Only simple partial seizures with motor signs, complex partial seizures, and complex partial seizures with secondary generalization are counted toward this inclusion.
9. Are currently being treated with stable doses of 1, 2 or a maximum of 3 approved AEDs. Only 1 inducer AED (defined as; carbamazepine, phenytoin, phenobarbital, or primidone only) out of the maximum of 3 AEDs is allowed.
10. Are on a stable dose of the same concomitant AED(s) for 1 month (or no less than 21 days) prior to Visit 1; in the case where a new AED regime has been initiated for a subject, the dose must be stable for 2 months (or no less than 49 days) prior to Visit 1.
11. If on a stable dose (other than intermittent rescue use) of benzodiazepines for epilepsy (or for anxiety or sleep disorders) the prescribed dose must be stable for 1 month (or no less than 21 days) prior to Visit 1. (Note: the use of intermittent rescue benzodiazepines is defined in the exclusion criterion #22 below.) When used in these cases (epilepsy, anxiety or sleep disorders), benzodiazepines will be counted as 1 AED; therefore, only 1 or a maximum of 2 additional approved AEDs will be allowed.
12. A vagal nerve stimulator (VNS) is allowed but it must have been implanted ≥5 months prior to Visit 1. Stimulator parameters can not be changed for 1 month (or no less than 21 days) prior to Visit 1 or thereafter during the study.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from the study:

1. Participated in a study involving administration of an investigational compound or device within 1 month (or no less than 21 days) prior to Visit 1, or within approximately 5 half-lives of the previous investigational compound, whichever is longer.
2. Pregnant and/or lactating.
3. Participated in previous perampanel studies.
4. Presence of nonmotor simple partial seizures only.
5. Presence of primary generalized epilepsies or seizures, such as absences and or myoclonic epilepsies.
6. Presence or previous history of Lennox-Gastaut syndrome.
7. A history of status epilepticus within approximately 12 months prior to Visit 1.
8. Seizure clusters where individual seizures cannot be counted.
9. A history of psychogenic seizures.
10. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the Investigator(s) could affect the subject's safety or the study conduct.
11. Scheduled and/or confirmed to have epilepsy surgery within 6 months after Visit 1; however those who have previously documented "failed" epilepsy surgery will be allowed.
12. Evidence of significant active hepatic disease. Stable elevations of liver enzymes, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) due to concomitant medication(s) will be allowed if they are less than 3 times the upper limit of normal (ULN).
13. Evidence of significant active hematological disease; white blood cell (WBC) count <= 2500/µL (2.50 1E+09/L) or an absolute neutrophil count <= 1000/µL (1.00 1E+09/L).
14. A clinically significant electrocardiogram (ECG) abnormality, including prolonged QTc defined as >450 msec.
15. Suffering from psychotic disorder(s) and/or unstable recurrent affective disorder(s) evident by use of antipsychotics or have had a suicide attempt(s) within approximately the last 2 years.
16. Presence of a progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors.
17. History of drug or alcohol dependency or abuse within approximately the last 2 years.
18. Have had multiple drug allergies or a severe drug reaction to an AED(s), including dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
19. If felbamate is used as a concomitant AED, subjects must be on felbamate for at least 2 years, with a stable dose for 2 months (or no less than 49 days) prior to Visit 1. They must not have a history of white blood cell (WBC) count below 2500/µL (2.50 1E+09/L), platelets below 100,000, liver function tests (LFTs) above 3 times the upper limit of normal (ULN), or other indication of hepatic or bone marrow dysfunction while receiving felbamate. If subjects received felbamate in the past, it must have been discontinued 2 months (or no less than 49 days) prior to Visit 1.
20. Concomitant use of vigabatrin. Subjects who took vigabatrin in the past must be off vigabatrin for approximately 5 months prior to Visit 1 and must have documentation showing no evidence of a vigabatrin associated clinically significant abnormality in a visual perimetry test.
21. Concomitant use of barbiturates (except for seizure control indication) within 1 month (or no less than 21 days) prior to Visit 1.
22. Use of intermittent rescue benzodiazepines (ie, 1-2 doses over a 24-hr period considered one-time rescue) 2 or more times in a 1-month period prior to Visit 1; or
23. Any condition(s) that will make the subject, in the opinion of the Investigator, unsuitable for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: E2007 (perampanel); 8 mg perampanel in a 1:1:1 ratio, 125 subjects/arm. All subjects will take a maximum of 6 tablets daily for the duration of the study and will be up-titrated weekly in 2-mg increments to their randomized dose.; Other Names: Perampanel; Drug: E2007 (perampanel); 12 mg perampanel in a 1:1:1 ratio, 125 subjects/arm. All subjects will take a maximum of 6 tablets daily for the duration of the study and will be up-titrated weekly in 2-mg increments to their randomized dose.; Other Names: Perampanel
Experimental: 2	Drug: E2007 (perampanel); 8 mg perampanel in a 1:1:1 ratio, 125 subjects/arm. All subjects will take a maximum of 6 tablets daily for the duration of the study and will be up-titrated weekly in 2-mg increments to their randomized dose.; Other Names: Perampanel; Drug: E2007 (perampanel); 12 mg perampanel in a 1:1:1 ratio, 125 subjects/arm. All subjects will take a maximum of 6 tablets daily for the duration of the study and will be up-titrated weekly in 2-mg increments to their randomized dose.; Other Names: Perampanel
Placebo Comparator: 3	Drug: Placebo; Placebo in a 1:1:1 ratio, 125 subjects/arm. All subjects will take a maximum of 6 tablets daily for the duration of the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in the 28-day Seizure Frequency From Baseline to the End of the Double-blind Phase (Titration and Maintenance Phases)	Seizure frequency per 28 days was derived from the information recorded in the subject diaries.	Baseline (Pre-randomization) through Week 19

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in the 28-day Complex Partial Plus Secondarily Generalized Seizure Frequency From Baseline to the End of the Double-blind Phase (Titration and Maintenance Phases)	Percent Change in the Seizure frequency per 28 days was derived from the information recorded in the subject diaries.	Baseline (Pre-randomization) through Week 19
Percentage of Participants Who Were Responders	A responder was a participant who had a 50 percent or greater reduction in seizure frequency per 28 days from the Pre-randomization phase.	Baseline (Pre-randomization) through Week 19

Collaborators and Investigators

• Sponsor: Eisai Inc.
• Investigators: Study Director: David Squillacote, M.D., Eisai Inc.

Publications and helpful links

General Publications

• Maguire M. Response to "Perampanel and pregnancy: Could experience be a gloomy lantern that does not even illuminate its bearer?". Epilepsy Behav. 2022 Apr;129:108654. doi: 10.1016/j.yebeh.2022.108654. Epub 2022 Mar 16. No abstract available.
• French JA, Gil-Nagel A, Malerba S, Kramer L, Kumar D, Bagiella E. Time to prerandomization monthly seizure count in perampanel trials: A novel epilepsy endpoint. Neurology. 2015 May 19;84(20):2014-20. doi: 10.1212/WNL.0000000000001585. Epub 2015 Apr 15.
• Rosenfeld W, Conry J, Lagae L, Rozentals G, Yang H, Fain R, Williams B, Kumar D, Zhu J, Laurenza A. Efficacy and safety of perampanel in adolescent patients with drug-resistant partial seizures in three double-blind, placebo-controlled, phase III randomized clinical studies and a combined extension study. Eur J Paediatr Neurol. 2015 Jul;19(4):435-45. doi: 10.1016/j.ejpn.2015.02.008. Epub 2015 Mar 5.
• Steinhoff BJ, Ben-Menachem E, Ryvlin P, Shorvon S, Kramer L, Satlin A, Squillacote D, Yang H, Zhu J, Laurenza A. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia. 2013 Aug;54(8):1481-9. doi: 10.1111/epi.12212. Epub 2013 May 10.
• French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, Kumar D, Rogawski MA. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012 Aug 7;79(6):589-96. doi: 10.1212/WNL.0b013e3182635735. Epub 2012 Jul 25.

Study record dates

Study Major Dates

• Study Start: April 30, 2008
• Primary Completion (Actual): October 19, 2010
• Study Completion (Actual): October 19, 2010

Study Registration Dates

• First Submitted: June 17, 2008
• First Submitted That Met QC Criteria: June 17, 2008
• First Posted (Estimate): June 18, 2008

Study Record Updates

• Last Update Posted (Actual): January 10, 2020
• Last Update Submitted That Met QC Criteria: January 6, 2020
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: safety; adjunctive therapy; partial onset seizures; seizure frequency; refractory partial seizures; reduction in seizure frequency; concomitant AED(s); E2007; perampanel
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures
• Other Study ID Numbers: E2007-G000-304