Pharmacokinetics, Efficacy, and Safety of Perampanel Oral Suspension on Seizure Frequency in Pediatric Subjects Maintained on One to Three Stable Antiepileptic Drugs

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT01527006
First received: November 10, 2011
Last updated: July 31, 2015
Last verified: June 2015
  Purpose

This study is designed to evaluate the pharmacokinetics, efficacy, and safety of perampanel oral suspension on seizure frequency in pediatric participants maintained on one to three stable antiepileptic drugs


Condition Intervention Phase
Central Nervous System
Drug: perampanel
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-label Pilot Study With an Extension Phase to Evaluate the Pharmacokinetics, and to Generate Preliminary Safety, Tolerability, and Efficacy of Perampanel (E2007) Oral Suspension When Given as an Adjunctive Therapy in Pediatric Subjects From 2 to Less Than 12 Years of Age With Epilepsy

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Apparent Clearance (CL/F) of Perampanel - for Core Study [ Time Frame: Blood samples were collected at day 8, Day 36, Day 64 , and Day 78. ] [ Designated as safety issue: No ]
    CL/F was defined as the volume of plasma cleared of the drug per unit time. The CL/F values were calculated for each visit and averaged to derive the total CL/F value per arm. Data was analyzed for 2 categories: CYP3A4/5 inducers (carbamazepine, oxcarbazepine and phenytoin) and non-inducers. Data is presented as mean Liter per hour +/-standard deviation.

  • Steady-state Average Concentration (C av,ss) of Perampanel (for Core Study) [ Time Frame: Blood samples were collected at day 8, Day 36, Day 64 , and Day 78. ] [ Designated as safety issue: No ]
    C av,ss was calculated as 'Dose (mg)/Dosing Interval (24 h)/(CL/F [L/h]) x 1000'. C av,ss during a dosing interval was dose-normalized to 0.12 mg/kg in participants aged ≥ 2 to less than 12 years (intended to correspond to 8 mg/70 kg in adults/adolescents). Data was analysed for 2 categories: CYP3A4/5 inducers (carbamazepine, oxcarbazepine and phenytoin) and non-inducers. Data is presented as mean Liter per hour +/- standard deviation.

  • The Effect of Demographics on Population PK Parameters: AUC [ Time Frame: 11 weeks ] [ Designated as safety issue: No ]
    This outcome was not assessed in the study.

  • The Effect of Demographics on Population PK Parameters: Cmax [ Time Frame: 11 weeks ] [ Designated as safety issue: No ]
    This outcome was not assessed in the study.

  • The Effect of Demographics on Population PK Parameters: Tmax [ Time Frame: 11 weeks ] [ Designated as safety issue: No ]
    This outcome was not assessed in the study.

  • The Effect of the Most Common Concomitant AEDs on Population PK Parameters: AUC [ Time Frame: 11 weeks ] [ Designated as safety issue: No ]
    This outcome was not assessed in the study.

  • The Effect of the Most Common Concomitant AEDs on Population PK Parameters: Cmax [ Time Frame: 11 weeks ] [ Designated as safety issue: No ]
    This outcome was not assessed in the study.

  • The Effect of the Most Common Concomitant AEDs on Population PK Parameters: Tmax [ Time Frame: 11 weeks ] [ Designated as safety issue: No ]
    This outcome was not assessed in the study.


Secondary Outcome Measures:
  • Percent Change From Baseline in Seizure Frequency Per 28 Days in Treatment Phase (for Core Study) [ Time Frame: Baseline [2 weeks Pretreatment Phase (Visit 1) plus 4 weeks Prior to Pretreatment Phase], Week 0 to Week 15 or up to 21 weeks ] [ Designated as safety issue: No ]
    Seizure frequency was derived from information (seizure count and type) recorded in participant diary. The seizure frequency per 28 days was calculated as the number of seizures divided by the number of days in the interval and multiplied by 28. The percent change in 28-day seizure frequency from baseline was assessed for overall seizures, overall partial seizures, overall generalized seizures, and unclassified seizures. The data is presented as mean percent change =/- standard deviation.

  • 50% Responder Rate During the Maintenance Period-LOCF (for Core Study) [ Time Frame: Baseline [2 weeks Pretreatment Phase (Visit 1) plus 4 weeks Prior to Pretreatment Phase], Week 9 to 11 ] [ Designated as safety issue: No ]
    Responder rate was defined as the proportion of participants with a 50% decrease in 28-day seizure frequency during the Maintenance Period compared to Baseline [2 weeks Pretreatment Phase (Visit 1) plus 4 Weeks Prior to Pretreatment Phase] for overall seizures, overall partial seizures, overall generalized seizures, and unclassified seizures. The data is presented as percent responders. LOCF = Last Observation Carried Forward.

  • Seizure-free Rate During the Maintenance Period - for Core Study [ Time Frame: Week 9 to Week 11 ] [ Designated as safety issue: No ]
    Seizure-free rate, defined as the percentage of participants who were seizure-free during the Maintenance Period. SG = Secondary Generalization.

  • The Clinical Global Impression of Change at the End of Treatment (EOT) - for Core Study [ Time Frame: Day 1 and Day 84 (end of Week 11) ] [ Designated as safety issue: No ]
    The Clinical Global Impression (CGI) evaluated perceived seizure frequency and severity, the occurrence of AEs, and overall functional status of the participant. The investigator performed the Clinical Global Impression of Severity for all participants at Baseline (Day 1). The evaluation used a 7-point scale where 1=normal, not at all ill and 7=extremely ill. The investigator performed the Clinical Global Impression of Change for all participants at the end of treatment (Day 78). The evaluation used a 7-point scale where 1=very much improved and 7=very much worse. This tool was used to assess the participant's status over the 4-week period prior to its completion compared to Baseline (Day 1).

  • Number of Participants With Treatment Emergent Non Serious Adverse Events (AEs) and Treatment Emergent Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Perampanel [ Time Frame: For each participant, from the first treatment dose till 30 days after the last dose or up to Week 15 for Core Study and 56 for the Extension Phase ] [ Designated as safety issue: Yes ]
    An AE was defined as any untoward medical occurrence in a clinical investigation participant administered an investigational product. A SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening (ie, the participant was at immediate risk of death from the 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, or was as a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). In this study, treatment emergent AEs (defined as an AE/SAE that started/increased in severity on/after the first dose of study medication up to 30 days after the final dose of study medication) were assessed. The data is presented in the safety section of the results.

  • Palatability Questionnaire Assessment - How Does This Medicine Taste [ Time Frame: Day 36 or at the time of early discontinuation ] [ Designated as safety issue: No ]
    The Palatability Questionnaire was answered directly by participants in Cohort ( ≥ 7 to ≤ 12 years) and indirectly by participants in Cohort ( ≥ 2 to ≤ 7 years) via their parents/caregivers. Participants selected their response from one of the five options (very good, good, not good-not bad, bad, very bad).

  • Palatability Questionnaire Assessment - How Does This Medicine Smell [ Time Frame: Day 36 or at the time of early discontinuation ] [ Designated as safety issue: No ]
    The Palatability Questionnaire was answered directly by participants in Cohort ( ≥ 7 to ≤ 12 years) and indirectly by participants in Cohort ( ≥ 2 to ≤ 7 years) via their parents/caregivers. Participants selected their response from one of the five options (very good, good, not good-not bad, bad, very bad).

  • Palatability Questionnaire Assessment - Based on Its Taste, Smell, and How it Felt in the Mouth, How Easy or Difficult Was it for You / Your Child to Take This Medicine Every Day [ Time Frame: Day 36 or at the time of early discontinuation ] [ Designated as safety issue: No ]
    The Palatability Questionnaire was answered directly by participants in Cohort ( ≥ 7 to ≤ 12 years) and indirectly by participants in Cohort ( ≥ 2 to ≤ 7 years) via their parents/caregivers. Participants selected their response from one of the five options (very easy, easy, neither easy or difficult, difficult and very difficult).

  • Palatability Questionnaire Assessment - Would You/Your Child Have Preferred This Medicine to Have Been Flavored, e.g. Fruity [ Time Frame: Day 36 or at the time of early discontinuation ] [ Designated as safety issue: No ]
    The Palatability Questionnaire was answered directly by participants in Cohort ( ≥ 7 to ≤ 12 years) and indirectly by participants in Cohort ( ≥ 2 to ≤ 7 years) via their parents/caregivers. Participants selected their response from one of the three options (yes, no and don't mind).


Enrollment: 63
Study Start Date: February 2012
Study Completion Date: April 2015
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: perampanel
Age Cohort 1 ( greater than or equal to 7 to less than 12 years of age at time of consent/assent) and age Cohort 2 ( greater than or equal to 2 to less than 7 years of age).
Drug: perampanel
During the titration period, participants started at a set daily dose of 0.015 mg/kg and had doses up-titrated at 1-week intervals (6 titration steps) to a maximum daily dose of 0.18 mg/kg. During the Maintenance Period, participants continued taking perampanel oral suspension once daily at the dose level they achieved at the end of the Titration Period.

Detailed Description:

This is a multicenter, multiple ascending dose, open-label study (Core Study) with an Extension Phase. The Core Study consisted of 2 phases, the Pretreatment Phase and the Treatment Phase. The Pretreatment Phase lasted up to 2 weeks in duration, during which participants were assessed for their eligibility to participate in the study. The Treatment Phase consisted of 3 periods: Titration (7 weeks), Maintenance (4 weeks), and Follow-up (4 weeks; only for those participants not rolling over into the Extension Phase after completing the Treatment Phase and for those participants who discontinued from the study). The extension phase consists of 41 weeks.

  Eligibility

Ages Eligible for Study:   2 Years to 11 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion:

  1. Have a minimum weight of 10 kg (22 lb)
  2. Have had brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) prior to Visit 1 that ruled out a progressive cause of epilepsy
  3. 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 6 months prior to 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)
  4. Have had one or more seizure(s) during the 4 weeks prior to Visit 1
  5. Are currently being treated with stable doses of one to a maximum of three AEDs for at least 4 weeks prior to Visit 1 and throughout the study duration (Only one perampanel inducing AED [i.e. carbamazepine, oxcarbazepine, phenytoin] out of the maximum of 3 AEDs is allowed in at least one third of the participants in each age cohort and not to exceed one half of the population of each age cohort. The remaining participants should not be taking any inducer)
  6. Have been on their current concomitant AED regimen for 2 months or more with a stable dose for at least 4 weeks prior to Visit 1
  7. Must have discontinued all restricted medications at least 2 weeks or five half-lives (whichever is longer) prior to Visit 1
  8. Females aged at least 8 years or of child-bearing potential must have a negative serum beta-hCG at Visit 1 and a negative urine pregnancy test prior to titration at Visit 2. Female participants 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 drug to be abstinent or commit to the consistent and correct use of a medically acceptable method of birth control (e.g., a double-barrier method [condom + spermicide, condom + diaphragm with spermicide])

Exclusion:

  1. Have a history of status epilepticus that required hospitalization during the 6 months prior to Visit 1
  2. Have current or a history of pseudo-seizures (psychogenic non-epileptic seizures [PNES]) from birth or within approximately 5 years prior to Visit 1
  3. Have seizures due to treatable medical conditions, such as those arising due to metabolic disturbances, toxic exposure, or an active infection
  4. Have epilepsy secondary to progressive cerebral disease or any other progressive neurodegenerative disease
  5. Have had epilepsy surgery within 1 year prior to Visit 1
  6. 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
  7. Use of intermittent rescue benzodiazepines (i.e. 1-2 doses over a 24-hour period considered one-time rescue) two or more times in a 30-day period prior to Visit 1
  8. If felbamate is used as a concomitant AED, participants must be on felbamate for at least 2 years, with a stable dose for 8 weeks prior to Visit 1. They must not have a history of white blood cell (WBC) count below 2500/L (2.50 x 10^9/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 participants received felbamate in the past, it must have been discontinued 8 weeks prior to Visit 1
  9. Have concomitant use of vigabatrin: participants 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 the visual perimetry test
  10. If ketogenic diet is used, participants must be on a stable regimen for at least 4 weeks prior to Visit 1
  11. Have previously participated in a clinical trial involving perampanel
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01527006

  Show 23 Study Locations
Sponsors and Collaborators
Eisai Inc.
Investigators
Study Director: Michelle Gee Eisai Limited
  More Information

No publications provided

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT01527006     History of Changes
Other Study ID Numbers: E2007-G000-232
Study First Received: November 10, 2011
Results First Received: July 31, 2015
Last Updated: July 31, 2015
Health Authority: United States: Food and Drug Administration

ClinicalTrials.gov processed this record on September 01, 2015