E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Epilepsy: refractory partial seizures with or without secondary generalisation |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to evaluate the efficacy of 2 doses of perampanel (8 and 12 mg) in comparison to placebo given as an adjunctive therapy in subjects with refractory partial seizures. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to evaluate the safety and tolerability of perampanel vs. placebo in subjects with refractory partial seizures. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.); • In Germany: Provide written informed consent signed prior to entering the study or undergoing any study procedures (revised per Amendment B) 2. Be considered reliable and willing to be available for the study period and is 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); • In Germany, the Netherlands, France, and India, subjects must be greater than or equal to 18 years of age (at the time of signing the informed consent). (revised per Amendments B, C, E, and F) • In Denmark and Sweden subjects must be greater than or equal to 18 years of age (within the course of the study). (revised per Amendment A) 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 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 AEDs within approximately the last 2 years; • For Germany: Have uncontrolled partial seizures despite having been treated with at least 2 different AEDs for a minimum of 2 years (revised per Amendment B) 8. During the 6-week Pre-randomization Phase subjects must have had ≥5 partial seizures (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; and 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.
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E.4 | Principal 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 QT 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 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. 24. The following criteria apply to only those countries specified: In Germany: Those committed to an institution by official or judicial order. (added per Amendment B) In France: Protected people in accordance with French regulation (persons under tutelage or guardianship). (added per Amendment D)
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the percent change in seizure frequency per 28 days in the Maintenance Period relative to the Pre-randomization Phase in the ITT Population. Last-observation-carried-forward (LOCF) method will be used to impute for missing data for subjects who withdraw from the study early. For subjects with less than 8 weeks of Maintenance Period, the seizure frequency during the last 8 weeks of the entire double-blind phase (or seizure frequency during the entire double-blind phase for subjects with less than 8 weeks of double-blind phase; see ITT definition) will be used to impute for the primary endpoint. Seizure frequency will be based on number of seizures per 28 days, calculated as the number of seizures over the entire time interval divided by the number of days in the interval and multiplied by 28. Analysis will be conducted using rank ANCOVA with treatment, study region (such as site or country) as factors, and the baseline seizure frequency as a covariate. In this analysis, all seizure frequency data will be rank transformed first for both baseline and endpoint seizure frequencies separately. The ANCOVA will be conducted based on the rank transformed data. Details will be specified in the SAP. Due to an expected irregular distribution of seizure frequency, median will be the primary statistics of interest for the primary endpoint, as well as for all other seizure frequency based continues endpoints. A sensitivity analysis of the change in seizure frequency will be conducted. This may include analyses of primary endpoint based on trimmed mean, response ratio (RRatio), and log-transformation (under log-normal assumption), and analysis of percent change in seizure frequency per 28 days in the Double-blind Phase (Titration Period + Maintenance Period) relative to the Pre-randomization Phase.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of trial is database lock - see protocol |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |