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

Refractory Partial Seizures Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00699972
• Other study ID #: E2007-G000-304
• Status: Completed
• Phase: Phase 3
• Start date: April 30, 2008
• Est. completion date: October 19, 2010

Study information

• Verified date: October 2015
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 390
• Est. completion date: October 19, 2010
• Est. primary completion date: October 19, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 99 Years

Eligibility

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.

Related Conditions & MeSH terms

• Refractory Partial Seizures
• Seizures

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
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 José María Ramos Mejia	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	Capital Federal- Provincia de Buenos Aires
Argentina	Centro de Estudio y Tratamiento de la Epilepsia y Sueño- CETES S.A.	Córdoba
Argentina	Hospital San Roque	Córdoba	Córdoba- Provincia De Córdoba
Argentina	Sanatorio Allende	Córdoba	Provincia De Córdoba
Argentina	Sanatorio Parque	Rosario
Argentina	Hospital Santa Clara de Asis	Salta	Provincia De Salta
Brazil	Faculdade de Ciências Médicas - UNICAMP	Campinas
Brazil	Hospital de Clinicas da UFPR	Curitiba
Brazil	Santa Casa de Porto Alegre	Porto Alegre
Brazil	HC Ribeirão Preto	Ribeirão Preto
Brazil	Hospital Pedro Ernesto - UERJ	Rio De Janeiro
Brazil	Hospital Universitário Professor Edgar Santos	Salvador
Brazil	Faculdade de Medicinade São José do Rio preto	São José do Rio Preto
Brazil	HC-FMUSP	São Paulo
Brazil	Hospital Brigadeiro	São Paulo
Brazil	Hospital Santa Marcelina	São Paulo
Brazil	UNIFESP	São Paulo
Canada	Foothills Medical Center	Calgary	Alberta
Canada	Neuro Rive-Sud	Greenfield Park	Quebec
Canada	London Health Sciences Center	London	Ontario
Canada	CHU Sainte-Justine	Montreal	Quebec
Canada	Youthdale Treatment Centers	Toronto	Ontario
Chile	Hospital Barros Luco Trudeau	Santiago
Chile	Hospital Base Valdivia Servicio de Neurología	Santiago
Chile	Hospital Dr. Sótero del Río	Santiago
Chile	Neuropsicología Ltda.	Santiago
Mexico	Instituto Biomedico de Investigacion AC	Aguascalientes
Mexico	Sarug Reyes	Aguascalientes
Mexico	Medica Sur SIF-BIOTEC	Mexico City
Mexico	MIRC	Monterrey	Nuevo Leon CP
Mexico	Hospital Central "Dr. Ignacio Morones Prieto"	San Luis Potosi
United States	Children's Hospital Medical Center Of Akron D/B/A Akron Children's Hospital	Akron	Ohio
United States	Albany Medical College	Albany	New York
United States	Blair Medical Assiciates, Inc.	Altoona	Pennsylvania
United States	McFarland Clinic, PC	Ames	Iowa
United States	Asheville Neurology Specialists, PA	Asheville	North Carolina
United States	Children's Healthcare of Atlanta at Scottish Rite	Atlanta	Georgia
United States	PANDA	Atlanta	Georgia
United States	Neurology/Johns Hopkins Hospital	Baltimore	Maryland
United States	Mid-Atlantic Epilepsy and Sleep Center	Bethesda	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston University Medical Center	Boston	Massachusetts
United States	Five Towns Neurology, PC	Cedarhurst	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University Neurology, Inc.	Cincinnati	Ohio
United States	Michigan Neurology Associates, P.C.	Clinton Township	Michigan
United States	The Ohio State University Medical Center	Columbus	Ohio
United States	Dallas Pediatric Neurology Associates	Dallas	Texas
United States	Neurological Clinic of Texas, P.A.	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Mile High Research Center	Denver	Colorado
United States	Texas Tech University Health Sciences Center	El Paso	Texas
United States	Leonard J. Chabert Medical Center	Houma	Louisiana
United States	Texas Children's Hospital	Houston	Texas
United States	Josephson Wallack Munshower Neurology	Indianapolis	Indiana
United States	University of Florida Health Sciences, Jacksonville	Jacksonville	Florida
United States	University of Kentucky Research Foundation	Lexington	Kentucky
United States	Clinical Trials, Inc.	Little Rock	Arkansas
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	Kentucky Neuroscience Research	Louisville	Kentucky
United States	Pediatric Neurology and Epilepsy Center	Loxahatchee Groves	Florida
United States	UT Le Bonheur Pediatric Specialists	Memphis	Tennessee
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Regional Epilepsy Center	Milwaukee	Wisconsin
United States	Long Island Jewish Medical Center	New Hyde Park	New York
United States	Pediatric Neurology PA	Orlando	Florida
United States	Child Neurology Center Of Nw Florida	Pensacola	Florida
United States	North West Florida Clinical Research Group	Pensacola	Florida
United States	Children's Hospital Of Philadelphia	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	St. Joseph's Hospital And Medical Center	Phoenix	Arizona
United States	Providence St. Vincent's Epilepsy Center	Portland	Oregon
United States	Virginia Commonwealth University Medical Center	Richmond	Virginia
United States	Univeristy of Rochester Strong Epilepsy Center	Rochester	New York
United States	Washington University	Saint Louis	Missouri
United States	Bright Minds Institute	San Francisco	California
United States	California Pacific Medical Center	San Francisco	California
United States	Lovelace Scientific Resources	Sarasota	Florida
United States	Ronald Aung-Din, MD, PC	Sarasota	Florida
United States	Harborview Medical Center	Seattle	Washington
United States	Louisiana State University Health Sciences Center	Shreveport	Louisiana
United States	Georgia Neurology and Sleep Medicine Associates	Suwanee	Georgia
United States	Tallahassee Neurological Clinic	Tallahassee	Florida
United States	Pediatric Epilepsy and Neurology Specialists	Tampa	Florida
United States	University Of Toledo Medical Center	Toledo	Ohio
United States	Neurological Associates of Tulsa, Inc.	Tulsa	Oklahoma
United States	Children's Research Institute	Washington	District of Columbia
United States	Via Christi Comprehensive Epilepsy Center	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  Chile,  Mexico, 

References & Publications (1)

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. Epu — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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