Evaluating Efficacy and Safety of E2007 (Perampanel) Given as Adjunctive Therapy in Subjects With Refractory Partial Seizures
Condition: Refractory Partial Seizures
MeSH terms: Seizures
Intervention: perampanel; perampanel; perampanel; Placebo
Intervention description: 2 mg perampanel or placebo in a 1:1:1:1 ratio, 170 subjects/arm, a total of 680 subjects. All subjects will take a maximum of 6 tablets daily and will be up-titrated weekly in 2-mg increments to their randomized dose.; 4 mg perampanel or placebo in a 1:1:1:1 ratio, 170 subjects/arm, a total of 680 subjects. All subjects will take a maximum of 6 tablets daily and will be up-titrated weekly in 2-mg increments to their randomized dose.; 8 mg perampanel or placebo in a 1:1:1:1 ratio, 170 subjects/arm, a total of 680 subjects. All subjects will take a maximum of 6 tablets daily and will be up-titrated weekly in 2-mg increments to their randomized dose.; Placebo in a 1:1:1:1 ratio, 170 subjects/arm, a total of 680 subjects. All subjects will take a maximum of 6 tablets daily.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 712.0
Sex: All
Minimum age: 12 Years
Maximum age: 120 Years
Healthy volunteers: No
Keywords: Partial onset seizures; E2007; perampanel; refractory partial seizures; adjunctive therapy; seizure frequency; reduction in seizure frequency; safety; concomitant AED(s)

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.