Clinical trial NCT00700310: Evaluating 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: Partial onset seizures
E2007
perampanel
refractory partial seizures
adjunctive therapy
seizure frequency
reduction in seizure frequency
safety
concomitant AED(s)
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2008-06-18
Enrollment: 712
Sex: ALL
Minimum age (years): 12
Maximum age (years): 120
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 efficacy, safety and tolerability of perampanel when given as an adjunctive therapy in subjects with refractory partial seizures.


Eligibility criteria: Inclusion Criteria:

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 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), or greater than or equal to 18 years of age (depending on location) at the time of signing the informed consent.
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 methods 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:

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 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 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 patients 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: Responder Rate
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: Woodville South
country: Australia
state: South Australia
city: Woodville
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Clayton
country: Australia
state: Victoria
city: Fitzroy
country: Australia
state: Victoria
city: Heidelberg
country: Australia
state: Victoria
city: Parkville
country: Australia
state: Victoria
city: Clayton
country: Australia
city: Fitzroy
country: Australia
city: Parkville
country: Australia
city: West Heidelberg
country: Australia
city: Woodville
country: Australia
city: Pleven
country: Bulgaria
city: Plovdiv
country: Bulgaria
city: Sofia
country: Bulgaria
city: Sofia
country: Bulgaria
city: Brno
country: Czech Republic
city: Olomouc
country: Czech Republic
city: Praha 4
country: Czech Republic
city: Praha 5
country: Czech Republic
city: Tallinn
country: Estonia
city: Tallinn
country: Estonia
city: Tartu
country: Estonia
city: Dusseldorf
country: Germany
city: Kehl-Kork
country: Germany
city: Konigstein-Falkenstein
country: Germany
city: Mainz
country: Germany
city: Marburg
country: Germany
city: Munchen
country: Germany
city: Munchen
country: Germany
city: Ulm
country: Germany
city: Westerstede
country: Germany
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Hong Kong
country: Hong Kong
city: Kowloon
country: Hong Kong
facility: Queen Elizabeth Hospital
city: Kowloon
country: Hong Kong
facility: United Christian Hospital
city: Kowloon
country: Hong Kong
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
city: Budapest
country: Hungary
city: Budapest
country: Hungary
city: Budapest
country: Hungary
city: Budapest
country: Hungary
city: Kecskemet
country: Hungary
city: Hyderabad
country: India
state: Andhra Pradesh
city: Hyderabad
country: India
state: Andhra Pradesh
city: Vishakhapatnam
country: India
state: Andhra Pradesh
city: Mumbai
country: India
state: Maharashtra
city: Pune
country: India
state: Maharashtra
city: Pune
country: India
state: Maharashtra
city: Jaipur
country: India
state: Rajasthan
city: New Delhi
country: India
city: Milano
country: Italy
city: Napoli
country: Italy
city: Padova
country: Italy
city: Siena
country: Italy
city: Torino
country: Italy
city: Busan
country: Korea, Republic of
city: Busan
country: Korea, Republic of
city: Daegu
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Riga
country: Latvia
city: Riga
country: Latvia
city: Valmiera
country: Latvia
city: Kaunas
country: Lithuania
city: Klaipeda
country: Lithuania
city: Vilnius
country: Lithuania
city: Kuala Terengganu
country: Malaysia
state: Terengganu
city: Kuala Lumpur
country: Malaysia
state: Wilayah Persekutuan
city: Ermita
country: Philippines
city: Makati City
country: Philippines
city: Bialystok
country: Poland
city: Gdansk
country: Poland
city: Gdansk
country: Poland
city: Katowice
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 7 Slaskiego Uniwersytetu Medycznego w Katowicach
city: Katowice
country: Poland
city: Lodz
country: Poland
city: Lublin
country: Poland
city: Warszawa
country: Poland
city: Coimbra
country: Portugal
city: Lisboa
country: Portugal
city: Porto
country: Portugal
city: Porto
country: Portugal
city: Brasov
country: Romania
city: Bucharest
country: Romania
facility: Sapiens Medical Center
city: Bucharest
country: Romania
city: Bucharest
country: Romania
facility: Colentina Clinical Hospital
city: Bucharest
country: Romania
city: Cluj Napoca
country: Romania
facility: Emergency County Clinical Hospital
city: Cluj Napoca
country: Romania
facility: Pediatric Neurology Clinic of Emergency Children Hospital
city: Cluj Napoca
country: Romania
city: Ekaterinburg
country: Russian Federation
city: Moscow
country: Russian Federation
facility: Moscow State University of Medicine and Dentistry
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
facility: Moscow Research Institute of Psychiatry
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
facility: Moscow Research Institute of Pediatrics and Pediatric Surgery
city: Moscow
country: Russian Federation
city: Samara
country: Russian Federation
city: Tyumen
country: Russian Federation
city: Yaroslavl
country: Russian Federation
city: Belgrade
country: Serbia
city: Nis
country: Serbia
city: Novi Sad
country: Serbia
city: Granada
country: Spain
state: Andalucia
city: Badalona
country: Spain
state: Cataluna
city: Barcelona
country: Spain
state: Cataluna
city: Barcelona
country: Spain
state: Cataluna
city: Alcorcon
country: Spain
state: Comunidad de Madrid
city: Madrid
country: Spain
state: Comunidad de Madrid
city: Valencia
country: Spain
state: Comunidad Valenciana
city: Valencia
country: Spain
state: Comunidad Valenciana
city: Barcelona
country: Spain
city: Valencia
country: Spain
city: Kaohsiung
country: Taiwan
city: Taichung
country: Taiwan
city: Taichung
country: Taiwan
city: Tainan
country: Taiwan
city: Taoyuan
country: Taiwan
city: Bangkok
country: Thailand
city: Bangkok
country: Thailand
city: Bangkok
country: Thailand
city: Chiang Mai
country: Thailand
city: Khon Kaen
country: Thailand
city: Muang District
country: Thailand
city: Dnipropetrovsk
country: Ukraine
city: Dnipropetrovsk
country: Ukraine
city: Donetsk
country: Ukraine
city: Donetsk
country: Ukraine
city: Kharkiv
country: Ukraine
city: Kharkiv
country: Ukraine
city: Kyiv
country: Ukraine
city: Kyiv
country: Ukraine
city: Kyiv
country: Ukraine
city: Lviv
country: Ukraine
city: Uzhgorod
country: Ukraine
Study officials:
affiliation: Eisai Inc.
name: David Squillacote, M.D.
role: STUDY_DIRECTOR
References:
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.
citation: Krauss GL, Serratosa JM, Villanueva V, Endziniene M, Hong Z, French J, Yang H, Squillacote D, Edwards HB, Zhu J, Laurenza A. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012 May 1;78(18):1408-15. doi: 10.1212/WNL.0b013e318254473a. Epub 2012 Apr 18.