Clinical trial NCT00699972: Evaluating the Efficacy and Safety of E2007 (Perampanel) Given as Adjunctive Therapy in Subjects With Refractory Partial Seizures
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Refractory Partial Seizures
Keywords: E2007
perampanel
refractory partial seizures
adjunctive therapy
seizure frequency
partial onset seizures
reduction in seizure frequency
safety
concomitant AED(s)
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2008-06-18
Enrollment: 390
Sex: ALL
Minimum age (years): 12
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percent Change in the 28-day Seizure Frequency From Baseline to the End of the Double-blind Phase (Titration and Maintenance Phases)
timeFrame: Baseline (Pre-randomization) through Week 19
Secondary outcomes:
measure: Percentage of Participants Who Were Responders
timeFrame: Baseline (Pre-randomization) through Week 19
measure: 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)
timeFrame: Baseline (Pre-randomization) through Week 19
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: St. Joseph's Hospital And Medical Center
state: Arizona
city: Little Rock
country: United States
facility: Clinical Trials, Inc.
state: Arkansas
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: San Francisco
country: United States
facility: Bright Minds Institute
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Denver
country: United States
facility: Mile High Research Center
state: Colorado
city: Washington
country: United States
facility: Children's Research Institute
state: District of Columbia
city: Jacksonville
country: United States
facility: University of Florida Health Sciences, Jacksonville
state: Florida
city: Loxahatchee Groves
country: United States
facility: Pediatric Neurology and Epilepsy Center
state: Florida
city: Loxahatchee Groves
country: United States
state: Florida
city: Orlando
country: United States
facility: Pediatric Neurology PA
state: Florida
city: Pensacola
country: United States
facility: North West Florida Clinical Research Group
state: Florida
city: Pensacola
country: United States
facility: Child Neurology Center Of Nw Florida
state: Florida
city: Sarasota
country: United States
facility: Lovelace Scientific Resources
state: Florida
city: Sarasota
country: United States
facility: Ronald Aung-Din, MD, PC
state: Florida
city: Tallahassee
country: United States
facility: Tallahassee Neurological Clinic
state: Florida
city: Tampa
country: United States
facility: Pediatric Epilepsy and Neurology Specialists
state: Florida
city: Atlanta
country: United States
facility: PANDA
state: Georgia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta at Scottish Rite
state: Georgia
city: Suwanee
country: United States
facility: Georgia Neurology and Sleep Medicine Associates
state: Georgia
city: Indianapolis
country: United States
facility: Josephson Wallack Munshower Neurology
state: Indiana
city: Ames
country: United States
facility: McFarland Clinic, PC
state: Iowa
city: Wichita
country: United States
facility: Via Christi Comprehensive Epilepsy Center
state: Kansas
city: Wichita
country: United States
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky Research Foundation
state: Kentucky
city: Louisville
country: United States
facility: Kentucky Neuroscience Research
state: Kentucky
city: Houma
country: United States
facility: Leonard J. Chabert Medical Center
state: Louisiana
city: Shreveport
country: United States
facility: Louisiana State University Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: Neurology/Johns Hopkins Hospital
state: Maryland
city: Bethesda
country: United States
facility: Mid-Atlantic Epilepsy and Sleep Center
state: Maryland
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Clinton Township
country: United States
facility: Michigan Neurology Associates, P.C.
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Cedarhurst
country: United States
facility: Five Towns Neurology, PC
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: Rochester
country: United States
facility: Univeristy of Rochester Strong Epilepsy Center
state: New York
city: Asheville
country: United States
facility: Asheville Neurology Specialists, PA
state: North Carolina
city: Akron
country: United States
facility: Children's Hospital Medical Center Of Akron D/B/A Akron Children's Hospital
state: Ohio
city: Cincinnati
country: United States
facility: University Neurology, Inc.
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
city: Toledo
country: United States
facility: University Of Toledo Medical Center
state: Ohio
city: Tulsa
country: United States
facility: Neurological Associates of Tulsa, Inc.
state: Oklahoma
city: Portland
country: United States
facility: Providence St. Vincent's Epilepsy Center
state: Oregon
city: Altoona
country: United States
facility: Blair Medical Assiciates, Inc.
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital Of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: UT Le Bonheur Pediatric Specialists
state: Tennessee
city: Dallas
country: United States
facility: Dallas Pediatric Neurology Associates
state: Texas
city: Dallas
country: United States
facility: Neurological Clinic of Texas, P.A.
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: El Paso
country: United States
facility: Texas Tech University Health Sciences Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University Medical Center
state: Virginia
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Regional Epilepsy Center
state: Wisconsin
city: Córdoba
country: Argentina
facility: Hospital San Roque
state: Córdoba- Provincia De Córdoba
city: Córdoba
country: Argentina
facility: Sanatorio Allende
state: Provincia De Córdoba
city: Salta
country: Argentina
facility: Hospital Santa Clara de Asis
state: Provincia De Salta
city: Capital Federal- Provincia de Buenos Aires
country: Argentina
facility: FLENI (Fundación para la Lucha Contra Las Enfermedades Neurológicas de La Infancia)
city: Capital Federal- Provincia de Buenos Aires
country: Argentina
facility: Hospital Británico
city: Capital Federal- Provincia de Buenos Aires
country: Argentina
facility: Hospital de Niños Ricardo Gutiérrez
city: Capital Federal- Provincia de Buenos Aires
country: Argentina
facility: Hospital General de Agudos José María Ramos Mejia
city: Capital Federal- Provincia de Buenos Aires
country: Argentina
facility: Hospital General de Agudos Teodoro Álvarez
city: Capital Federal- Provincia de Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Capital Federal- Provincia de Buenos Aires
country: Argentina
facility: Policlínica Bancaria 9 de Julio
city: Córdoba
country: Argentina
facility: Centro de Estudio y Tratamiento de la Epilepsia y Sueño- CETES S.A.
city: Rosario
country: Argentina
facility: Sanatorio Parque
city: Campinas
country: Brazil
facility: Faculdade de Ciências Médicas - UNICAMP
city: Curitiba
country: Brazil
facility: Hospital de Clinicas da UFPR
city: Porto Alegre
country: Brazil
facility: Santa Casa de Porto Alegre
city: Ribeirão Preto
country: Brazil
facility: HC Ribeirão Preto
city: Rio De Janeiro
country: Brazil
facility: Hospital Pedro Ernesto - UERJ
city: Salvador
country: Brazil
facility: Hospital Universitário Professor Edgar Santos
city: São José do Rio Preto
country: Brazil
facility: Faculdade de Medicinade São José do Rio preto
city: São Paulo
country: Brazil
facility: HC-FMUSP
city: São Paulo
country: Brazil
facility: Hospital Brigadeiro
city: São Paulo
country: Brazil
facility: Hospital Santa Marcelina
city: São Paulo
country: Brazil
facility: UNIFESP
city: Calgary
country: Canada
facility: Foothills Medical Center
state: Alberta
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
city: Toronto
country: Canada
facility: Youthdale Treatment Centers
state: Ontario
city: Greenfield Park
country: Canada
facility: Neuro Rive-Sud
state: Quebec
city: Montreal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Santiago
country: Chile
facility: Hospital Barros Luco Trudeau
city: Santiago
country: Chile
facility: Hospital Base Valdivia Servicio de Neurología
city: Santiago
country: Chile
facility: Hospital Dr. Sótero del Río
city: Santiago
country: Chile
facility: Neuropsicología Ltda.
city: Monterrey
country: Mexico
facility: MIRC
state: Nuevo Leon CP
city: Aguascalientes
country: Mexico
facility: Instituto Biomedico de Investigacion AC
city: Aguascalientes
country: Mexico
facility: Sarug Reyes
city: Mexico City
country: Mexico
facility: Medica Sur SIF-BIOTEC
city: San Luis Potosi
country: Mexico
facility: Hospital Central "Dr. Ignacio Morones Prieto"
Study officials:
affiliation: Eisai Inc.
name: David Squillacote, M.D.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.