Pharmacokinetic Study With an Oral Suspension of Perampanel as Adjunctive Therapy in Pediatric Subjects With Epilepsy

Eisai Inc.26 enrolled

Overview

The purpose of this study is to evaluate the pharmacokinetics (PK) of perampanel during the Maintenance Period of the Core Study following oral suspension administration given as an adjunctive therapy in pediatric participants from 1 month to less than 4 years of age with epilepsy.

This is a multicenter, open-label study comprised of pretreatment, treatment (core study), and extension phases that is designed to evaluate the PK of an oral suspension of perampanel (maximum dose must not exceed 12 milligrams per day \[mg /day\] for participants taking non-enzyme-inducing antiepileptic drug \[non-EIAED\] or 16 mg/day for participants taking EIAED) when given as an adjunctive therapy in participants ranging from 1 month to less than 4 years of age with epilepsy. The Pretreatment Phase will last up to 2 weeks, during which participants will be assessed for their eligibility to participate in the study. The Treatment Phase will consist of 3 periods: Titration (12 \[for participants taking non-EIAED\] to 16 weeks \[for participants taking EIAED\]), Maintenance (4 weeks), and Follow-Up (4 weeks; only for those participants who complete the Maintenance Period but do not continue into the Extension Phase and those participants who discontinue study participation). Extension Phase: The Extension Phase will consist of 2 periods: Maintenance (32 weeks \[for participants taking EIAED\]; 36 weeks \[for participants taking non-EIAED\]) and Follow-Up (4 weeks). The maximum total duration of treatment for each participant will be 52 weeks and the maximum total duration of the study for each participant will be 58 weeks (2 weeks Pretreatment+52 weeks of treatment+4 weeks Follow-up).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Epilepsy

Interventions

perampanelDRUG

oral suspension.

Eligibility

Sex: ALLMin age: 1 MonthMax age: 4 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Male or female, from 1 month to less than 4 years of age (and of at least 36 weeks gestational age) at the time of consent * Have a minimum weight of 4 kilograms (kg) (8.8 pounds \[lb\]) * Have a diagnosis of epilepsy with any type of seizure according to the International League Against Epilepsy's (ILAE) Classification of Epileptic Seizures (1981). Diagnosis should have been established at least 2 weeks (≤6 months of age) or 4 weeks (\>6 months of age) before Visit 1, by clinical history and an electroencephalogram (EEG) that is consistent with epilepsy; normal interictal EEGs will be allowed provided that the participant meets the other diagnosis criterion (i.e., clinical history) * Have had brain imaging (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) before Visit 1 that ruled out a progressive cause of epilepsy * Have had 1 or more seizure(s) before Visit 1 * Currently being treated with a stable dose (i.e., unchanged for at least 5 half-lives) of 1 to a maximum of 4 antiepileptic drugs (AEDs) (at least 6, but not more than 8, in the age group of 1 to less than 24 months, and up to 13 subjects in the age group of 2 to less than 4 years, will be taking 1 EIAEDs \[that is, carbamazepine (CBZ), oxcarbazepine (OXC), phenytoin (PHT), or eslicarbazepine (ESL)\] out of the maximum of 4 AEDs. The remaining participants cannot be taking any EIAEDs). * Have been on their current concomitant AED(s) with a stable dose for at least 2 weeks or 5 half-lives, whichever is longer, before Visit 1 * Must have discontinued all restricted medications (example, medications known to be inducers of cytochrome P450 3A) at least 2 weeks or 5 half-lives (whichever is longer) before Visit 1 * If entering the Extension Phase, must have completed the last visit of the Maintenance Period of the Core Study Exclusion Criteria: * Have a history of status epilepticus that required hospitalization during the 3 months before Visit 1 * Have seizures due to treatable medical conditions, such as those arising due to metabolic disturbances, toxic exposure, or an active infection * Have epilepsy secondary to progressive central nervous system (CNS) disease or any other progressive neurodegenerative disease, including tumors * Have had epilepsy surgery within 1 year of Visit 1 * Are scheduled and/or confirmed to have epilepsy surgery within 6 months after Visit 1 * Used intermittent rescue benzodiazepines (i.e., 1 to 2 doses over a 24-hour period considered one-time rescue) 2 or more times in the 2 weeks before Visit 1 * Current use of felbamate, or any evidence of ongoing hepatic or bone marrow dysfunction associated with prior felbamate treatment. (Prior use of felbamate must be discontinued at least 8 weeks before Visit 1.) * Current use of vigabatrin or any evidence of clinically significant vision abnormality associated with prior vigabatrin treatment. (Prior use of vigabatrin must be discontinued at least 2 weeks before Visit 1.) * Are on ketogenic diet regimen that has not been stable for at least 4 weeks before Visit 1 * Concomitant use of other drugs known to influence the CNS, (other than AEDs for epilepsy), where the dose has not been stabilized for at least 5 half-lives or 2 weeks, whichever is longer, before Visit 1 * Have any concomitant illnesses/co-morbidities that could severely affect the participant's safety or study conduct * Have evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the participant's safety or study conduct * Have clinically significant laboratory abnormalities or any clinically acute or chronic disease * Have evidence of significant active hepatic disease. Stable elevation 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) * Have clinical evidence of significant active hematological disease; white blood cell (WBC) count ≤2500/ microliter (μL) (2.50 x 10\^9/Liter \[L\]) or an absolute neutrophil count ≤1000/μL (1.00 x 10\^9/L) * Have conditions that may interfere with their participation in the study and/or with the PK of study drug * 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 * Have recently (within 30 days before Visit 1) been exposed to perampanel in a clinical study or by prescription, and/or previous discontinuation from perampanel treatment due to adverse events related to perampanel * Have a clinically significant ECG abnormality, including prolonged corrected QT interval (QTc) defined as \>450 milliseconds (msec) * Have had multiple drug allergies or a severe drug reaction to an AED(s), including dermatological (e.g., Stevens-Johnson syndrome), hematological, or organ toxicity reactions

Locations (18)

Children's Hospital Los Angeles

Los Angeles, California, United States

David Geffen School of Medicine at UCLA

Los Angeles, California, United States

Outcomes

Primary Outcomes

Dose Normalized Area Under the Concentration-Time Curve for Dosing Interval at Steady State (AUCtau,ss) of Perampanel During the Maintenance Period of the Core Phase for Non-EIAED Participants

Dose normalized AUCtau,ss was calculated as AUCtau,ss/maintenance dose, where AUCtau,ss is the area under the curve during a dosing interval (tau, 24 hours) at steady state calculated using population pharmacokinetic (PK) model. PK sparse sampling was performed. One sample was collected at anytime between 1 to 5 hours post-dose on Days 99 and 113 (Cohort 1, Cohort 2, Cohort 3) and two samples were collected, one at pre-dose and other at anytime between 1 to 5 hours post-dose on Days 99 and 113 (Cohort 4). Plasma concentrations of perampanel were measured and concentration data were summarized. Plasma concentrations of perampanel were quantified using a validated liquid chromatography mass spectrometry (LC MS/MS) analytical method.

Time frame: Maintenance Period of the Core Phase- Days 99 and 113: 1-5 hours post-dose (Cohort 1, Cohort 2, Cohort 3); Days 99 and 113: Pre-dose, 1-5 hours post-dose (Cohort 4)

Dose Normalized Maximum (Peak) Steady-state Concentration (Cmax,ss) of Perampanel During the Maintenance Period of the Core Phase for Non-EIAED Participants

Dose normalized Cmax,ss was calculated as Cmax,ss/maintenance dose, where Cmax,ss is the maximum (peak) steady-state concentration calculated using population PK model. PK sparse sampling was performed. One sample was collected at anytime between 1 to 5 hours post-dose on Days 99 and 113 (Cohort 1, Cohort 2, Cohort 3) and two samples were collected, one at pre-dose and other at anytime between 1 to 5 hours post-dose on Days 99 and 113 (Cohort 4). Plasma concentrations of perampanel were measured and concentration data were summarized. Plasma concentrations of perampanel were quantified using a validated LC MS/MS analytical method.

Time frame: Maintenance Period of the Core Phase- Days 99 and 113: 1-5 hours post-dose (Cohort 1, Cohort 2, Cohort 3); Days 99 and 113: Pre-dose, 1-5 hours post-dose (Cohort 4)

Dose Normalized Average Steady-state Drug Concentration (Css,Av) of Perampanel During the Maintenance Period of the Core Phase for Non-EIAED Participants

Dose normalized Css,Av was calculated as Css,Av/maintenance dose. Css,Av of perampanel was calculated as the ratio of area under the curve (AUC)/tau, (tau = 24 hours for perampanel) using population PK model. PK sparse sampling was performed. One sample was collected at anytime between 1 to 5 hours post-dose on Days 99 and 113 (Cohort 1, Cohort 2, Cohort 3) and two samples were collected, one at pre-dose and other at anytime between 1 to 5 hours post-dose on Days 99 and 113 (Cohort 4). Plasma concentrations of perampanel were measured and concentration data were summarized. Plasma concentrations of perampanel were quantified using a validated LC MS/MS analytical method.

Data from ClinicalTrials.gov

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Secondary Outcomes

Core Phase and Extension Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

TEAE was an adverse event (AE) that emerged during treatment, having been absent at pretreatment (Baseline); or re-emerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment; or worsened in severity during treatment relative to the pretreatment state, when AE was continuous. SAE was any untoward medical occurrence that at any dose: Resulted in death; was life-threatening (meaning participant was at an immediate risk of death from AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect (in child of a participant who was exposed to the study drug).

Time frame: Core Phase: From the first dose of study drug up to 4 weeks of follow up after the last dose in Core Phase (up to Week 24); Extension Phase: From end of Core Phase treatment up to 4 weeks of follow up after the last dose in Extension Phase (up to Week 56)

Core Phase and Extension Phase: Mean Change From Baseline in Hematology Laboratory Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, and Platelets

Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils, and platelets were expressed as 10\^9 cells per liter (/L). Change from baseline was calculated as post-baseline absolute value minus baseline value. Baseline values of Core Phase was used to calculate the change from baseline data for Extension Phase. Mean change from baseline data at end of Core Phase and at end of Extension Phase treatment for specified parameters was reported.