A Randomized, Double-blind, Placebo-controlled, Parallel-group Study With an Open-label Extension Phase to Evaluate the Effect of Perampanel (E2007) on Cognition, Growth, Safety, Tolerability, and Pharmacokinetics When Administered as an Adjunctive Therapy in Adolescents (12 to less than 18 years of age) With Inadequately Controlled Partial-onset Seizures
This will be a multi-center, randomized, double-blind, placebo-controlled, dose-escalation (to a maximum of 4 mg/day), parallel-group study of perampanel given as adjunctive therapy in subjects with refractory partial seizures (e2007-a001-206) demonstrated: 1) a trend in therapeutic effect (31% in perampanel vs. 22% in placebo, p[?]0.19 for the primary analysis of responder rate), 2) perampanel at a 4 mg dose was well-tolerated. a second completed double-blind, placebo-controlled, parallel-group, escalating dose trial of perampanel up to 12 mg/day given as adjunctive therapy in subjects with refractory partial seizures (e2007-G000-208) demonstrated greater treatment effects with acceptable tolerability at doses up to and including 12 mg/day. The effect size of responder rate in both studies is within the range of other anti-epileptic drugs (aeD's).
Currently, efficacy and safety of perampanel doses up to 12 mg/day are being studied in subjects (12 years and above) with refractory partial-onset seizures in 3 ongoing randomized, doubleblind, placebo-controlled, parallel-group Phase 3 studies: e2007-G000-304 and e2007-G000- 305 (8 and 12 mg/day perampanel) and e2007-G000-306 (2, 4, and 8 mg/day perampanel). The currently available safety information from these ongoing studies does not suggest any significant safety concerns for use up to 12 mg/day of perampanel in subjects aged 12 to 17 years, which is the target patient population in this study.
This study will use a similar study design and dose range as ongoing Phase 3 studies. The same titration increment (weekly 2-mg/day increments) and duration will be employed. The age group is a subset of Phase 3 studies. However, in this study, the primary endpoint will be the CDR System Global Cognition Score. it was chosen to compare the short-term effect of perampanel on cognition to placebo when administered as an adjunctive therapy in adolescents (12 to less than 18 years of age) with inadequately controlled partial-onset seizures with or without secondary generalized seizures. The key secondary endpoints include the 5 core CDR System domains of Power of attention, Continuity of attention, Quality of episodic Memory, Quality of Working Memory, and Speed of Memory. Long-term effects of perampanel on cognition and growth and development will also be evaluated as secondary endpoints. The primary and secondary endpoints are chosen in order to fulfill the european Regulatory requirements for the development of aeDs in adolescents. Based on the CHMP guidance, short- and long-term data on cognition, growth, and development are required for pediatric indications.
Randomization will be used in this trial to avoid bias in the assignment of subjects to treatment, to increase the likelihood that known and unknown subject attributes (eg, demographics and baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity of statistical comparisons across treatment groups. Blinding to treatment will be employed to reduce potential bias during data collection and evaluation of endpoints.
1. Considered reliable and willing to be available for the study duration and is able to record seizures and report adverse events (AEs) themselves or have a legal guardian or a caregiver who can record seizures and report AEs for them
2. Understand the requirements of the CDR System tests and able to perform the tests appropriately at Visit 1
3. Male or female, 12 to less than 18 years of age at the time of consent/assent
4. Have a diagnosis of epilepsy with partial-onset seizures with or without secondarily generalized seizures according to the International League Against Epilepsy[Single Quote]s (ILAE) Classification of Epileptic Seizures (1981). Diagnosis should have been established at least 6 months prior to Visit 1, by clinical history and an 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)
5. Have had a brain imaging (eg, magnetic resonance imaging [MRI] scan or computed tomography[CT]) within the 5 years prior to Visit 1 that ruled out a progressive cause of epilepsy
6. Must have had at least 1 partial-onset seizure during the 4 weeks prior to Visit 1 despite a stable regimen of 1 to 3 concomitant AEDs
7. Are currently being treated with stable doses of 1-3 AEDs. Only 1 inducer AED (either carbamazepine or phenytoin) out of the maximum of 3 AEDs is allowed
8. Are on a stable dose of the same concomitant AED(s) for at least 4 weeks prior to Visit 1; in the case where a new AED regimen has been initiated for a subject, the dose must be stable for at least 8 weeks prior to Visit 1
9. Female subjects of childbearing potential must have a negative serum human chorionic gonadotropin ([BETA]-hCG) at Visit 1 and a negative urine pregnancy test prior to randomization at Visit 2. Female subjects of childbearing potential must agree for the duration of the study and for a period of at least 60 days following administration of the last dose of study medication to commit to the consistent and correct use of a medically acceptable method of birth control (eg, a double-barrier method [condom + spermicide, condom + diaphragm with spermicide]).
10. Abstinence will be considered an acceptable method of contraception on a case by case basis upon prior approval by the Medical Monitor
11. Have an intelligence quotient (IQ) of >=70, using the Kaufman Brief Intelligence Test, second edition (KBIT-2)
* Have completed all scheduled visits up to and including Visit 8 in the Core Study Randomization Phase