Evaluation of Perampanel as Adjunctive Therapy in Pediatric Patients with Childhood Epilepsy: An Open-Label Study with Extension Phase
- Trial ID
- 2023-507794-17-00
- Protocol
- E2007-G000-236
- Sponsor
- Eisai Limited
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of perampanel, as measured by the 50% responder rate during the Maintenance Period of the Core Study for seizure frequency. This is defined as the percentage of subjects achieving at least a 50% reduction in seizure frequency per 28 days compared to baseline, across each cohort and epileptic syndrome. This objective is clinically relevant as it aims to determine the potential of perampanel to significantly reduce seizure frequency in pediatric patients with childhood epilepsy, thereby improving their quality of life.
Secondary objectives include:
- Evaluating the efficacy of perampanel by the proportion of subjects who are seizure-free during the Maintenance and Treatment Periods of the Core Study and Extension A.
- Assessing the efficacy of perampanel through absolute and percentage reduction in seizure frequency per 28 days during the Treatment Periods.
- Evaluating the effects of perampanel on the Clinical Global Impression (CGI) and Subject Global Impression (SGI) of Change at the end of the Treatment Periods.
- Assessing the effects of perampanel on growth and development, including cognition, behavior, visuomotor skills, and sexual maturation in the pediatric population.
- Evaluating the efficacy of perampanel by the proportion of responders (≥25% and ≥75%) during the Maintenance and Treatment Periods.
- Characterizing the pharmacokinetics of perampanel and exploring relationships between exposure and safety endpoints, including treatment-emergent adverse events, cognition, and behavior.
- Exploring the relationship between perampanel exposure and partial-onset seizures response graphically.
- Evaluating the safety and tolerability of perampanel.
Participants
The clinical trial involves a total of **35 participants** diagnosed with **Childhood Epilepsy**. The study population includes both male and female subjects, ranging in age from 1 month to less than 18 years for Cohort 1, and from 1 month to less than 2 years for Cohort 2. Participants must have a confirmed diagnosis of epilepsy with a pediatric epileptic syndrome or epilepsy with partial-onset seizures (POS), with or without secondary generalization, as per the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures. The selection criteria require subjects to have experienced at least 4 seizures in the 4 weeks prior to the second visit, and they must be on stable doses of 1 to 4 approved antiepileptic drugs (AEDs). The trial population was selected based on these criteria, ensuring the absence of any progressive cause of epilepsy confirmed clinically or through brain imaging. The study includes a vulnerable population, given the young age of the participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **perampanel** as an adjunctive therapy in pediatric subjects with childhood epilepsy. This study is structured as an open-label trial with an extension phase, focusing on the 50% responder rate during the maintenance period for seizure frequency reduction. The trial is categorized as a Phase 4 study, aiming to assess both the therapeutic efficacy and safety profile of perampanel, alongside its impact on growth and development parameters such as cognition, behavior, and sexual maturation.
The trial will involve a sequence of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific criteria, including age, diagnosis, and seizure frequency. Participants will be required to have a stable regimen of 1 to 4 approved antiepileptic drugs (AEDs) prior to enrollment. Following the screening, participants will enter the core study phase, which includes a treatment period and a maintenance period, with regular follow-up visits to monitor efficacy and safety outcomes. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment.
The expected duration of participant involvement is up to 52 weeks, with the trial estimated to conclude by December 2026. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial's primary endpoint is the proportion of 50% responders for all seizures during the maintenance period, while secondary endpoints include various measures of seizure frequency reduction, safety, and tolerability assessments.
Treatment
The clinical trial involves the administration of **Perampanel**, an experimental medication, in two pharmaceutical forms: film-coated tablets and oral suspension. The film-coated tablets, marketed under the name Fycompa, are available in a dosage of 2 mg per tablet. These tablets are intended for **oral use** and are administered once daily, with a maximum daily dose of 12 mg. The tablets are packaged in non-commercial, clinical packaging for the purpose of the trial. The treatment period for the film-coated tablets is up to 52 weeks. Participant compliance is monitored through regular assessments and adherence checks.
In addition to the film-coated tablets, the study also utilizes Fycompa oral suspension, which contains **Perampanel** at a concentration of 0.5 mg/ml. This formulation is also administered orally, with a maximum daily dose of 12 mg, equivalent to 24 ml of the suspension. The oral suspension is provided with oral syringes and a Press-In Bottle Adapter (PIBA) to ensure accurate dosing. The suspension is similarly packaged in non-commercial, clinical packaging, and the treatment duration is up to 52 weeks. Compliance with the dosing regimen is monitored through scheduled visits and participant diaries.
Both formulations of **Perampanel** are of chemical origin and are not classified as orphan drugs. The trial does not include any non-experimental treatments such as placebo or comparator treatments. The primary objective of the study is to evaluate the efficacy of **Perampanel** as an adjunctive therapy in pediatric subjects with childhood epilepsy, focusing on the reduction of seizure frequency. The study is conducted under the sponsorship of Eisai GmbH, with the medication being authorized for use in the European Union.
Efficacy
The efficacy of **perampanel** in the clinical trial will be assessed primarily by measuring the proportion of 50% responders for all seizures during the Maintenance Period of the Core Study. This primary endpoint evaluates the percentage of subjects who achieve at least a 50% reduction in seizure frequency per 28 days compared to baseline. Secondary endpoints include the proportion of 50% responders during the Treatment Period of the Core Study and Extension A, as well as the proportion of 25% and 75% responders during these periods. Additionally, the trial will assess the proportion of subjects who are seizure-free, the absolute and percent change from baseline in seizure frequency, and changes in various clinical parameters such as growth and development, cognition, behavior, and sexual maturation.
Data collection will involve both investigator-based and subject-based assessments, including the Clinical Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) at the end of the Treatment Period and Extension A. Changes from baseline in parameters such as the Child Behavior Checklist (CBCL), the Leiter International Performance Scale (LGPT), and growth and development metrics will also be evaluated. Safety and tolerability will be monitored through the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), as well as laboratory parameters, vital signs, and ECG parameters throughout the Treatment Period, Extension A, and Extension B.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female subject, from age 1 month to less than 18 years for Cohort 1, or age 1 month to less than 2 years for Cohort 2 at the time of informed consent/assent. Subjects below the age of 1 year must have been at least 36 weeks of gestational age at birth. (revised per Amendments 01 and 02)
- Have a diagnosis of epilepsy with a pediatric epileptic syndrome (Cohort 1) or epilepsy with POS with or without secondary generalization (Cohort 2) according to the International League against Epilepsy (ILAE) Classification of Epileptic Seizures (1981). The eligibility criteria for the 2 cohorts are not mutually exclusive as a subject may experience POS as part of an epilepsy syndrome; these subjects are eligible for Cohort 1 if: (1) they are 2 to less than 18 years of age; or (2) they are 1 month to less than 2 years of age AND Cohort 2 is filled. Diagnosis must have been established 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).
- Subjects must have had equal or greater than 4 seizures over the 4-week interval prior to Visit 2. For Cohort 1, all seizures except simple POS without motor signs are counted toward this inclusion. For Cohort 2, only simple POS with motor signs, complex POS, and complex POS with secondary generalization are counted toward this inclusion for POS.
- Absence of any progressive cause of epilepsy that has been confirmed clinically or based on brain imaging (eg, magnetic resonance imaging [MRI] scan, computed tomography [CT], or ultrasound [only for subjects <1 year old]). (revised per Amendment 02).
- Are currently being treated with stable doses of 1 to a maximum of 4 approved AEDs. A prescription medical marijuana (including products containing cannabidiol) is counted as 1 of the maximum of 4 allowed AEDs; however, it cannot be the only concomitant AED if this product is not an approved AED in the country where the study site is located. Doses must be stable for at least 4 weeks (at least 2 weeks for subjects <6 months old) before Visit 1; only 1 enzyme-inducing AED (EIAED) (defined as carbamazepine, phenytoin, oxcarbazepine, or eslicarbazepine) out of the maximum of 4 AEDs is allowed. (revised per Amendment 01).
Exclusion Criteria
- Females who are breastfeeding or pregnant at Screening/Baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the 1st dose of study drug.
- Females of childbearing potential who: • Within 28 days before study entry, did not use a combination of a barrier method with a highly effective method of contraception, which includes any of the following: (revised per Amendment 01) o Total abstinence (if it is their preferred and usual lifestyle). o An intrauterine device or intrauterine hormone-releasing system (IUS). o A contraceptive implant. o An oral contraceptive (with additional barrier method). Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation. o Have a vasectomized partner with confirmed azoospermia. Do not agree to use a combination of a barrier method with a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation. (revised per Amendment 01). For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, ie, double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or cervical/vault cap with spermicide. NOTE: All postpuberty females should be considered to be of childbearing potential unless they have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
- Current or history of pseudo-seizures (psychogenic nonepileptic seizures) within approximately 5 years before Visit 1.
- Have a history of status epilepticus that required hospitalization during the 6 months before to Visit 1.
- Have an unstable psychiatric diagnosis that may confound subjects’ ability to participate in the study or that may prevent completion of the protocol specified tests (eg, significant suicide risk, including suicidal behavior and ideation within 6 months before Visit 1, current psychotic disorder, acute mania).
- 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 Columbia-Suicide Severity Rating Scale (C-SSRS) in subjects aged 6 and above or based on the opinion of the Investigator for subject less than 6 years.
- Are scheduled or confirmed or both to have epilepsy surgery within 6 months after Visit 1; however, those who have previously documented “failed” epilepsy surgery will be allowed.
- Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator could affect the subject’s safety or interfere with the study assessments.
- Evidence of moderate or severe renal insufficiency as defined by estimated glomerular filtration rates (eGFRs) based on Bedside Schwartz equation [eGFR=0.413×Height (cm)/Serum Creatinine (mg/dL)] of 31 to less than 60 mL/min/1.73m2 and less than 30 mL/min/1.73m2, respectively. (revised per Amendment 01)
- Evidence of significant active hepatic disease. Stable elevation of liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) due to concomitant medications, will be allowed if they are less than 3 times the upper limit of normal (ULN).
- Evidence of significant active hematological disease; white blood cell (WBC) count equal or less than 2500/μL (2.50 1E+09/L), or an absolute neutrophil count equal or less than 1000/μL (1.00 1E+09/L).
- Clinically significant ECG abnormality, including Fridericia prolonged corrected QT interval (QTcF) defined as greater than 450 msec.
- Have a progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors.
- Multiple drug allergies or a severe drug reaction to AEDs, including dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
- Concomitant use of felbamate as an AED for less than 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 equal or less than 2500/μL (2.50 1E+09/L), platelets below 100,000, liver function tests above 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.
- Concomitant or recent (within last 5 months before Visit 1) use of vigabatrin or any evidence of vigabatrin-associated clinically significant vision abnormality.
- Benzodiazepines for any indications other than epilepsy (eg, anxiety/sleep disorders) prohibited from 1 month before Visit 1 and during the study. Benzodiazepines for seizure control and as rescue medication are allowed. (revised per Amendments 01 and 02)
- A vagal nerve stimulator (VNS), responsive neurostimulator (RNS), or deep brain stimulator (DBS) implanted less than 5 months before Visit 1 or changes in parameter less than 4 weeks before Visit 1 (or thereafter during the study).
- On a ketogenic diet for which the diet is not stable regimen for at least 4 weeks before Visit 1.
- History of or a concomitant medical condition that in the opinion of the investigator would preclude the subject’s participation in a clinical study or compromise the subject’s ability to safely complete the study.
- Use of perampanel within 30 days before Visit 1, or perampanel was discontinued due to adverse reactions (perampanel-related) or lack of efficacy in case of previous exposure.
- Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
- Have participated in a study involving administration of an investigational drug or device within 4 weeks before Visit 1, or within approximately 5 half-lives of the previous investigational compound, whichever is longer.
- Hypersensitivity to the active substance or to any of the excipients of the study drug. (revised per Amendment 01)
- Weight less than 4.0 kg at Visit 1. (revised per Amendment 02).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 31 Jul 2019 | 9 |
 France | Not Recruiting | 31 Jul 2019 | 15 |
 Germany | Not Recruiting | 31 Jul 2019 | 10 |
 Spain | Not Recruiting | 31 Jul 2019 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Fycompa 2 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 12 | 52 | PRD754424 |
Fycompa 2 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 12 | 52 | PRD754447 |
Fycompa 2 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 12 | 52 | PRD754448 |
Fycompa 0.5 mg/ml oral suspension | Test | ORAL SUSPENSION | ORAL USE | 12 | 52 | PRD4442903 |