| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Epilepsy :
1) Partial-Onset Seizures (POS)
2) Primary Generalized Tonic-Clonic Seizures (PGTC) |
|
| E.1.1.1 | Medical condition in easily understood language |
1) Fits that affect one part of your brain called a “partial seizure”
2) Certain fits that affect all of your brain from the start called “generalised seizures and cause convulsions or staring spells |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10018101 |
| E.1.2 | Term | Generalised tonic-clonic seizures |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061334 |
| E.1.2 | Term | Partial seizures |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 |
| To evaluate the safety and tolerability of perampanel oral suspension when administered as an adjunctive therapy in children (ages 4 to <12 years) with inadequately controlled partial-onset seizures (POS) or primary generalized tonic-clonic seizures (PGTC) |
|
| E.2.2 | Secondary objectives of the trial |
1. Characterize PK of perampanel & the relationship between perampanel plasma concentrations, efficacy & safety using population PK/PD modeling
2. Evaluate effects of perampanel on cognition, behavior, visuomotor skills & growth & development in children during short-term (23 wks) & long-term (up to 52 wks) treatment
3. Evaluate frequency of EEG abnormalities during awake & sleep state during 52 wks of treatment
4. Evaluate suicidal ideation & suicidal behavior in children 6 yrs to less than 12 yrs as measured by the C-SSRS during 52 wks of treatment
5. Evaluate efficacy of perampanel as measured by the median percent change per 28 days in seizure frequency by the proportion of responders (≥25%, ≥50% & ≥75%) & by the proportion of subjects who are seizure-free for POS, PGTC, & GTC seizures
6. Evaluate, in Japanese subjects, efficacy of perampanel on POS in this study compared to Pbo in Study
E2007-J000-335
7. Assess effects of perampanel on the CGI, CGIS & CGIC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have a diagnosis of epilepsy with POS with or without secondarily generalized seizures or PGTC according to the International League Against Epilepsy’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 the diagnosis; normal interictal EEGs will be allowed provided that the subject meets the other diagnosis criterion (ie, clinical history)
2. Male or female subject, from age 4 to less than 12 years at the time of informed consent/assent
3. Have a minimum weight of 16 kg (35 lb)
4. Have had a brain imaging (eg, magnetic resonance imaging [MRI] scan or computed tomography[CT]) before Visit 1 that ruled out a progressive cause of epilepsy
5. During the 4 weeks ± 3 days before Visit 2, subjects must have had equal or greater than 1 POS or 1 PGTC seizure. Only simple POS with motor signs, complex POS, and complex POS with secondary generalization are counted toward this inclusion for POS.
6. Are currently being treated with stable doses of 1 to a maximum of 2 approved AEDs. Doses must be stable for at least 4 weeks before 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. Only 1 EIAED (defined as carbamazepine, phenytoin, oxcarbazepine, or eslicarbazepine) out of the maximum of 2 AEDs is allowed (A vagal nerve stimulator [VNS] will be counted as one of the 2 allowed AEDs). |
|
| E.4 | Principal exclusion criteria |
1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive [ß-hCG] or [hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained >72 hours before the 1st dose of study drug.
2. Females of childbearing potential who:
• Had unprotected sexual intercourse within 30 days before study entry & who do not agree to use a highly effective method of contraception ( total abstinence, an intrauterine device, a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period or for 28 days after study drug discontinuation. If a highly effective method is not appropriate or acceptable for the subject, then the subject may use a medically effective method (a double barrier method such as condom plus diaphragm with spermicide).
• Are currently abstinent & do not agree to use a double-barrier method (as above) or refrain from sexually active during the study period or for 28 days after study drug discontinuation.
• Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing & who do not agree to use the same contraceptive during the study or for 28 days after study drug discontinuation.
3. Current or history of pseudo-seizures (psychogenic nonepileptic seizures) within approximately 5 years before Visit 1.
4. Have a history of status epilepticus that required hospitalization during the 6 months before to Visit 1.
5. Have an unstable psychiatric diagnosis that may confound subjects’ ability to participate the study or that may prevent completion of the protocol specified tests (significant suicide risk, including suicidal behavior & ideation within 6 months before Visit 1, current psychotic disorder, acute mania).
6. Any suicidal ideation with intent with or without a plan within 6 months before Visit 2 (ie answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS) in subjects aged > 6 years.
7. Are 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.
8. Evidence of clinically significant disease (cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigators could affect the subject’s safety or interfere with the study assessments.
9. Severe renal insufficiency
10. Evidence of significant active hepatic disease. Stable elevation of liver enzymes, ALT & AST due to concomitant medication(s), will be allowed if they are less than 3 times the ULN.
11. Evidence of significant active hematological disease;WBC count ≤ 2500/μL (2.50 1E+09/L) or an absolute neutrophil count ≤ 1000/μL (1.00 1E+09/L).
12. Clinically significant ECG abnormality, including prolonged corrected QT interval defined as > 450 msec.
13. Have a progressive central nervous system disease, including degenerative CNS diseases & progressive tumors.
14. Multiple drug allergies or a severe drug reaction to an AEDs, including dermatological (Stevens-Johnson syndrome) haematological or organ toxicity.
15. Concomitant use of felbamate as an AED for < 2 years or where the dose has not been stable for at least 8 weeks before Visit 1. They must not have a history of WBC count below ≤ 2500/μL (2.50 1E+09/L), platelets < 100,000, liver function tests > 3 times the 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 8 weeks before Visit 1 to be eligible for study participation.
16. Concomitant use of vigabatrin: Subjects who took vigabatrin in the past must be off vigabatrin for at least 5 months before Visit 1 & with documentation showing no evidence of a vigabatrin associated clinically significant abnormality in a visual perimetry test.
17. Used barbiturates (except for seizure control indication) within 4 weeks before to Visit 1.
18. Used benzodiazepines (other than intermittent rescue use) for epilepsy (or for anxiety or sleep disorders) & for which the dose has not been stable for ≥ 4 weeks before to Visit 1.
19. A VNS implanted < 5 months before Visit 1 or changes in parameter < 4 weeks before Visit 1 (or thereafter during the study)
20. On a ketogenic diet for which the diet is not stable regimen for at least 4 weeks before to Visit 1.
21. History of or a concomitant medical condition that in the opinion of the investigator(s) would preclude the subject's participation in a clinical study or compromise the subject’s ability to safely complete the study.
22. Have previously been exposed to perampanel in a clinical trial or by prescription for > 2 months or discontinued for AEs.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety and tolerability, which include incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), laboratory parameters, vital signs, and ECG parameters, of perampanel oral suspension in children (ages 4 to <7 years and ≥7 years to <12 years) with POS or PGTC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the end of the core phase and the extension phase |
|
| E.5.2 | Secondary end point(s) |
1. The relationship between plasma levels of perampanel and efficacy endpoints (ie, change in average seizure frequency over 28 days, responder probability, and the proportion of subjects who are seizure-free in the Maintenance Period of the Core Study) separately for each seizure type
2. The relationship between plasma levels of perampanel and cognition endpoints including change from baselines in ABNAS, CBCL, and LGPT. In addition, depending on the AE data, the relationship between plasma levels of perampanel and select AEs will be assessed.
3. Change from baseline at Week 23 and Week 52 in ABNAS, CBCL, and LGPT
4. Changes from baseline at Week 23 and Week 52 in growth and development parameters (height, weight, thyroid, and IGF-1)
5. Change from baseline in EEG and the frequency of EEG abnormalities during awake and sleep state
6. Proportion of subjects (aged 6 or older at time of consent/assent) with any treatment-emergent reports of suicidal ideation and behavior on the C-SSRS and intensity of these behaviors assessed using C-SSRS scores
7. The median percent change in seizure frequency per 28 days during Treatment Phase (Titration Period and Maintenance Period) of the Core Study, and during the long-term treatment (up to 52 weeks) relative to the Pretreatment Phase. Seizure frequency will be based on the 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.
8. Proportion of responders (25% responders defined as a decrease in 28-day seizure frequency of equal or greater than 25% compared to baseline seizure frequency; 50% responders defined as a decrease in 28-day seizure frequency of equal or greater than 50% compared to baseline seizure frequency; 75% responders defined as a decrease in 28-day seizure frequency of equal or greater than 75% compared to baseline seizure frequency) during Maintenance Period of Core Study, and during the long term treatment (up to 52 weeks)
9. Proportion of subjects who are seizure-free during Maintenance Period of Core Study, and during the long term treatment (up to 52 weeks)
10. CGI of Change |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of the core phase and the extension phase |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Exposure-Efficacy relationship |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 | No |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Latvia |
| Poland |
| Spain |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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